Conditions: Focal Segmental Glomerulosclerosis
Keywords: calcineurin inhibitors Focal Segmental Glomerulosclerosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
Evaluating the Efficacy and Safety of Voclosporin in Achieving Complete or Partial Remission of Proteinuria in Subjects with Focal Segmental Glomerulosclerosis

Detailed description:
The aim of the current study to assess the efficacy of voclosporin in achieving complete or partial remission of proteinuria after 24 weeks of therapy in subjects with focal segmental glomerulosclerosis (FSGS). As well as to assess the safety and tolerability of voclosporin over 24 weeks in subjects with FSGS.

Arms:
arm 1: Cohort 1:

Maximum dose of 3 capsules (7.9mg) BID

Cohort 2

Dosing to be decided based on the safety from the first 5 or 6 subjects in Cohort 1.

Interventions: intervention 1: Voclosporin
Intervention descriptions: intervention 1: Voclosporin softgel capsules. Up to 10 subjects will be enrolled into Cohort 1 and take up to 3 capsules twice daily (BID).

The dose of voclosporin for Cohort 2 (at least 10 subjects) will be determined by analysis of efficacy and safety data at Week 12 from the first 5 or 6 subjects in Cohort 1.

Protocol document:
Prot_SAP_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. 
 
 
An Open-Label Dose-Exploration Cohort Study Evaluating the 
Efficacy and Safety of Voclosporin in Achieving Complete or 
Partial Remission of Proteinuria in Subjects with Focal 
Segmental Glomerulosclerosis  
 
Clinical Protocol Number: 
AUR-VCS-2017-03 
 
 
Study Name: 
AURONA 
 
 
Date: 
23 November 2018 
 
 
Version Number: 
Amendment 1 
 
 
Previous Protocol Versions 
Original Version, 27 April 2018 
 
 
 
 
IND Number: 
137,905 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Page 2 of 107 
 
NAMES AND ADDRESSES 
 
Sponsor 
Name: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Tel: 
 
 
24 Hour: 
 
 
 
Chief Medical Officer 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
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: 
 
 
 


AUR-VCS-2017-03 – Amendment 1 
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DECLARATION OF SPONSOR 
Title: An Open-Label Dose-Exploration Cohort Study Evaluating the Efficacy and Safety of 
Voclosporin in Achieving Complete or Partial Remission of Proteinuria in Subjects with Focal 
Segmental Glomerulosclerosis 
Version Number/Date: Amendment 1/23 November 2018 
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 
Chief Medical Officer 
Date (e.g., DD Month Year) 
Vice President, Quality and Regulatory 
Affairs 
Date (e.g., DD Month Year) 
23 Nov 2018
28NOV2018


 
 
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INVESTIGATOR AGREEMENT FORM 
I have read the attached protocol titled: An Open-Label Dose-Exploration Cohort Study 
Evaluating the Efficacy and Safety of Voclosporin in Achieving Complete or Partial Remission 
of Proteinuria in Subjects with Focal Segmental Glomerulosclerosis 
Version Number/Date: Amendment 1/23 November 2018 
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. 
 
 
 
<insert name> 
Principal Investigator 
 
Date (e.g., DD Month Year) 
 


 
 
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SYNOPSIS 
Title: 
An Open-Label, Dose-exploration, Cohort Study Evaluating the Efficacy and Safety 
of Voclosporin in Achieving Complete or Partial Remission of Proteinuria in 
Subjects with Focal Segmental Glomerulosclerosis 
Short Title: 
AURONA 
Study Product: 
Voclosporin  
Indication: 
Focal Segmental Glomerulosclerosis 
Phase: 
2 
Sponsor: 
Aurinia Pharmaceuticals Inc. 
Study Code: 
AUR-VCS-2017-03 
Objectives: 
Primary Objective: 
• 
To assess the efficacy of voclosporin (VCS) in achieving complete or partial 
remission of proteinuria after 24 weeks of therapy in subjects with focal 
segmental glomerulosclerosis (FSGS).  
Secondary Objective: 
• 
To assess the safety and tolerability of VCS over 24 weeks in subjects with 
FSGS. 
Design: 
Open-label, 24-week, multicenter, exploratory cohort study of VCS. 
Treatment: 
Investigational Treatment: 
Voclosporin softgel capsules containing 7.9 mg drug. Approximately 10 subjects will 
be enrolled into Cohort 1 and take VCS 23.7 mg orally (PO), twice daily (BID). 
The dose level of VCS for Cohort 2 (approximately 10 subjects) will be determined 
by analysis of efficacy and safety data at Week 12 from the first 6 subjects in 
Cohort 1. 
Inclusion Criteria: 
1. Written informed consent before any study-specific procedures are performed. 
2. Male or female subjects with a minimum age of 18 years (or legal age of consent 
if >18 years) to 75 years of age, inclusive, at the time of consent. 
3. Primary FSGS diagnosed by renal biopsy within 3 months prior to the screening 
visit. 
4. At initial screening assessment and at last qualifying assessment during 
screening period prior to baseline, FSGS subjects must have urine protein 
creatinine ratio (UPCR) ≥3.0 mg/mg, serum albumin <3.2 g/dL AND must be 
treatment-naïve, defined as subjects who have not received systemic steroids, 
cytotoxic or other systemic immunosuppressant treatment, and are not expected 
to require treatment with these medications during the study. 


 
 
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Inclusion Criteria 
(cont’d): 
5. All subjects should be treated with angiotensin converting enzyme inhibitors 
(ACEIs) and/or angiotensin receptor blockers (ARBs) unless they have 
documented intolerance or contraindication to these medications. Doses of these 
agents must be stable for at least 2 weeks prior to baseline, with blood pressure 
(BP) ≤150/90 mmHg at the baseline visit (Visit 2). 
a) Subjects with nephrotic edema may be treated with diuretics during the 
screening period. Volume status should be optimized based on the clinical 
judgment of the Investigator and the doses of diuretics must be stable for at 
least 2 weeks prior to baseline. 
b) At the discretion of the Investigator, subjects with hyperlipidemia may be 
treated with lipid-lowering agents (e.g., statins) in accordance with standard 
clinical practice. Doses must be stable for at least 2 weeks prior to baseline. 
6. Stable proteinuria, renal function, and BP for at least 2 weeks prior to baseline, 
as assessed by the Investigator. Substantial changes in UPCR, estimated 
glomerular filtration rate (eGFR), and/or BP during the screening period may be 
due to treatments administered (e.g., ACEIs and ARBs); and, therefore, may 
interfere with study assessments or outcomes, or may place the subject at 
increased risk. These subjects must be discussed with the medical monitor prior 
to initiation of study treatment. 
7. Women of childbearing potential must have a negative serum pregnancy test 
prior to dispensing study treatment. Two effective forms of contraception must 
be used simultaneously unless abstinence is the chosen method. Subjects must 
use effective contraception during the study. 
Exclusion Criteria: 
1. Subjects unable or unwilling to give written informed consent and/or to comply 
with study procedures. 
2. Clinical or histologic evidence of secondary FSGS. 
3. Histologic evidence of collapsing variant FSGS. 
4. eGFR as calculated by the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation of ≤30 mL/minute/1.73 m2 at initial screening assessment 
or ≤45 mL/minute/1.73 m2 at last qualifying assessment during screening period 
prior to baseline. 
5. Currently taking or expected to require any of the prohibited medications listed 
in the protocol at screening or during the study. This includes prohibited 
medications prior to screening as specified in the protocol. 
6. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or 
expected to require dialysis during the study period. 
7. A previous renal transplant or planned renal transplant during the study. 
8. Body mass index >40 kg/m2. 
9. Family history of nephrotic syndrome. 
10. Any known hypersensitivity or contraindication to cyclosporine, or components 
of any cyclosporine drug product. 


 
 
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Exclusion Criteria 
(cont’d): 
11. 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. 
• 
Current or past 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. 
12. Other clinically significant active medical conditions, such as: 
• 
Severe cardiovascular disease including congestive heart failure, history of 
cardiac dysrhythmia or congenital long QT syndrome. Subjects with 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 are excluded. 
• 
Liver dysfunction: aspartate aminotransferase, alanine aminotransferase, or 
bilirubin ≥2.5 times the upper limit of normal at last qualifying assessment 
during screening period prior to baseline. 
• 
Chronic obstructive pulmonary disease or asthma requiring oral steroids. 
• 
Bone marrow insufficiency: white blood cell count <2,500/mm3, absolute 
neutrophil count <1.3 × 103/μL, and/or thrombocytopenia (platelet count 
<50,000/mm3) at screening or at last qualifying assessment during screening 
period prior to baseline. 
• 
Current infection requiring intravenous antibiotics. 
13. Any overlapping autoimmune condition for which the condition or the treatment 
of the condition may affect the study assessments or outcomes (e.g., any 
condition for which additional immunosuppression, including systemic 
corticosteroids, and/or cytotoxic therapy is indicated). Overlapping conditions 
for which the condition or treatment is not expected to affect assessments or 
outcomes are not excluded. 
14. No vaccines using live organisms, virus or bacterial, are allowed during 
screening and while taking the study treatment. 


 
 
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Exclusion Criteria 
(cont’d): 
15. 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. 
16. 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. 
17. Subjects who are pregnant, breast feeding or, if of childbearing potential, not 
using adequate contraceptive precautions. 
18. 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. 
19. Subjects treated in a previous VCS clinical study. 
Primary Endpoint: 
Proportion of subjects with remission of proteinuria at Week 24, assessed overall and 
for each individual cohort, based on the following parameters: 
• 
Complete remission: UPCR of <0.3 mg/mg 
OR 
• 
Partial remission: UPCR ≥0.3 mg/mg and <3.0 mg/mg with >50% reduction in 
UPCR from baseline 
Secondary 
Endpoints: 
The following secondary endpoints will be assessed overall and for each individual 
cohort: 
• 
Proportion of subjects with complete remission or partial remission of 
proteinuria at Weeks 8 and 12 
• 
Proportion of subjects with complete remission of proteinuria at Weeks 8, 12, 
and 24 
• 
Proportion of subjects with UPCR <0.5 mg/mg at Weeks 8, 12, and 24 
• 
Proportion of subjects with partial remission of proteinuria at Weeks 8, 12, and 
24 
• 
Time to first occurrence of complete or partial remission of proteinuria 
• 
Time to first occurrence of complete remission of proteinuria 
• 
Time to first occurrence of partial remission of proteinuria 
• 
Time to first occurrence of 50% reduction in UPCR from baseline 
• 
Duration of UPCR <0.3 mg/mg 
• 
Change from baseline in UPCR at each time point 
• 
Proportion of subjects with a confirmed >30% decrease from baseline in eGFR 
(utilizing the CKD-EPI formula) at each time point  
• 
Proportion of subjects with a confirmed >30% increase in eGFR from the final 
visit (Week 24 or last on-treatment visit, for subjects who discontinue 
prematurely) to the second Safety Follow-up visit (Visit 10) 


 
 
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Secondary 
Endpoints (cont’d): 
• 
Change in UPCR from the final visit (Week 24 or last on-treatment visit, for 
subjects who discontinue prematurely) to the second Safety Follow-up visit 
(Visit 10)  
• 
Change in eGFR from the final visit (Week 24 or last on-treatment visit, for 
subjects who discontinue prematurely) to the second Safety Follow-up visit 
(Visit 10) 
• 
Change from baseline in serum creatinine, serum albumin, and eGFR at each 
time point 
• 
Quality of life assessments 
− 
Mean change in Patient Reported Outcome Measurement Information 
System (PROMIS) measures at Week 24 
− 
Change from baseline in Kidney Disease Quality of Life-Short Form 
(KDQOL-SFTM) score at Week 24 
• 
Safety and tolerability over 24 weeks 
• 
Renal biopsy: descriptive analyses of changes in histopathology will be 
evaluated in post-treatment (24 weeks) renal biopsies in a subset of patients 
• 
Change from baseline to Weeks 4 and 24 in the following biomarkers:  
− 
Urine nephrin 
− 
Urine synaptopodin 
− 
Serum transforming growth factor beta 
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. Subjects will be assigned a unique subject number which will 
be used to identify them throughout the study. If a subject has not had a renal 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 the end of screening. The duration of the screening period will be 
approximately 4 weeks to 10 weeks (allowing for visit windows) to ensure that 
subjects meet eligibility criteria, including renal disease stability assessments.  
The first 10 subjects meeting the required eligibility criteria will be assigned to 
Cohort 1 and will receive VCS according to the following dosing regimen: 
• 
Week 1: 1 capsule (7.9 mg) PO, BID 
• 
Week 2: 2 capsules (15.8 mg) PO, BID 
• 
Week 3 – Week 24: 3 capsules (23.7 mg) PO, BID 
Appropriate sponsor personnel (including the medical monitor) and the investigator 
will jointly decide whether to continue with the dose escalation for each subject.  


 
 
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When the first 6 subjects in Cohort 1 have completed 12 weeks of treatment with 
VCS, the top line efficacy and safety data will be analyzed to determine the dose level 
for Cohort 2. The selected dose may be higher or lower than 23.7 mg BID. The 
maximum dose possible for Cohort 2 will be 39.5 mg (5 capsules) BID.  Should this 
dose be selected the following dosing regimen will be followed: 
• 
Week 1: 1 capsule (7.9 mg) PO, BID 
• 
Week 2: 2 capsules (15.8 mg) PO, BID 
• 
Week 3: 3 capsules (23.7 mg) PO, BID 
• 
Week 4 – Week 24: 5 capsules (39.5 mg) PO, BID 
Evaluable safety and tolerability data at Week 12 from the first six subjects from 
Cohort 1 are required in order to make the decision to escalate to a higher dose level 
for Cohort 2.  
As a guidance, the dose will not be escalated if any of following criteria are met in 
the first 6 subjects from Cohort 1, unless it was obvious that the occurrence was not 
related to the administration of VCS: 
• 
Severe adverse events (SAEs) of same character in ≥2 subjects. 
• 
Clinically significant decrease in eGFR in ≥5 subjects. 
• 
Clinically significant laboratory abnormalities of same character in ≥
5 subjects. 
• 
Clinically significant abnormalities of electrolytes in ≥4 subjects. 
• 
Clinically significant changes in vital signs of same character in ≥4 
subjects. 
Doses and dose increments smaller than anticipated may be proposed for Cohort 2 
based on the safety and tolerability results from the Cohort 1.  
All subjects will complete dosing through 24 weeks of study treatment and will have 
2 Safety Follow-Up visits, 1 and 2 weeks after completion of treatment (i.e., at Week 
25 and Week 26). Subjects who permanently discontinue study treatment before the 
Week 24 visit will return for all remaining study visits and assessments, including 
the 2 Safety Follow-Up visits, unless they have withdrawn consent. 
Sample Size: 
As this is an exploratory study, sample size calculations are not required. It is 
estimated that approximately 20 subjects will be recruited, with approximately 10 
subjects in both of Cohorts 1 and 2. 


 
 
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Statistical Methods: 
Analysis: 
All statistical analyses relating to the primary and secondary objectives will be 
undertaken at study closure and will incorporate all available data. 
Given the small sample size, all analyses will be descriptive in nature. Confidence 
intervals (CIs) for proportions may be calculated but it is recognized that such 
intervals, being based on 20 patients, will be very wide. As an example, the 95% 
Clopper-Pearson CI for a proportion of 30% based on 20 patients is (11.9%, 54.3%). 
Populations:  
The efficacy analysis will be based on intent-to-treat (ITT) principles and will include 
all enrolled subjects (non-screening failures). 
The per-protocol data set will include the subset of subjects in the ITT population 
who do not have any major protocol violations (to be defined). 
The safety analysis set will consist of all subjects who receive at least 1 dose of study 
treatment. 
Methods: 
Top line efficacy (change from Baseline in UPCR) and safety data (AEs, eGFR, 
ECGs and vital signs) for the first 6 subjects in Cohort 1 completing 12 weeks of 
study treatment, will be reviewed and based on those data the commencement of 
enrolment and the target dose for Cohort 2 will be determined. 
The analysis of the primary endpoint, complete or partial remission of proteinuria at 
Week 24, will be conducted on the ITT population and confirmed with the per-
protocol population (if applicable). Remission of proteinuria will be summarized and 
an exact 2-sided 95% CI for the remission rate will be calculated.  
The analyses of the secondary endpoints will incorporate the use of 2-sided 95% CIs 
and are described below:  
• 
Binary endpoints will be summarized using exact 2-sided 95% CIs.  
• 
Endpoints measured as a time-to-event will be displayed using Kaplan-Meier 
methodology. Median time-to-event along with 2-sided 95% CIs will be 
displayed.  
• 
Other endpoints will be summarized by visit. Absolute values and differences 
between baseline and each time point up to and including Week 24 will be 
summarized using means and 2-sided 95% CIs. Changes between last on 
treatment value and post treatment follow-up will also be summarized. 
Safety Endpoints:  
Adverse events will be aggregated by System Organ Class and preferred term and 
presented as summary tables.  
Laboratory values, 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. 
Exploratory analyses will be undertaken should the data suggest areas worthy of 
further investigation. 


 
 
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STUDY SCHEMA 
 
 
 
Notes: 
BID=Twice daily; VCS=Voclosporin. 


 
 
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AUR-VCS-2017-03 SCHEDULE OF EVENTS 
Visit 
Visit 1 
Screening Period 
Visit 2 
Baseline 
Visit 3 
Visits 4-5 
Visit 6 
Visit 7 
Visit 8 
End of 
Treatment/ 
Early 
Termination 
Visit 9 
Safety 
Follow-up 
Visit 10 
Safety 
Follow-up 
Day/Week 
Screening  to Day -1 
Day 1 
(Within 1 
Wk Post 
Qualifying 
Assessment) 
Wk 2 
(±3 Days) 
Wks 4, 8 
(±3 Days) 
Wk 12 
(±3 Days) 
Wk 18 
(±5 Days) 
Wk 24 
(±7 Days) 
Wk 25 
(±3 Days) or 
Premature 
Disc. +7 Days 
Wk 26 
(±3 Days) or 
Premature 
Disc. +14 Days  
Screening 
Visit(1) 
Stability 
Assessments 1 & 
2, Optional 3 & 
4(1) 
Informed consent 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
 
 
 
 
 
 
 
 
 
 
Renal biopsy(2) 
 
 
 
 
 
 
 
(2) 
 
 
Medical history and 
demography 
 
 
 
 
 
 
 
 
 
 
Physical exam(3) 
 
 
 
 
 
 
 
 
 
 
Vital signs(4) 
 
 
 
 
 
 
 
 
 
 
ECG(5) 
 
 
 
 
 
 
 
 
 
 
Laboratory 
assessments(6)  
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics(7) 
 
 
 
 
 
 
 
 
 
 
Urinalysis and urine 
microscopy 
 
 
 
 
 
 
 
 
 
 
FMV urine collection(8) 
 
 
 
 
 
 
 
 
 
 
24-hour urine(9) 
 
 
 
 
 
 
 
 
 
 
QoL(10) 
 
 
 
 
 
 
 
 
 
 
Pregnancy test(11) 
 
 
 
 
 
 
 
 
 
 
Adverse events 
(12) 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
Dispense study 
medication/ 
compliance(13) 
 
 
 
 
 
 
 
(14) 
 
 
First dose of study 
medication 
 
 
(15) 
 
 
 
 
 
 
 


 
 
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1 
Stability assessments to occur at 14-day intervals (± 3 days) with first assessment approximately 2 weeks after the screening visit. Stability assessments 1 and 2 are mandatory; assessments 3 and 4 
are optional if additional time is required for the subject’s clinical status to stabilize. Note that the laboratory assessments and FMV results of the last stability assessment will be used as the 
qualifying values for eligibility. Enrolment of eligibile subjects must occur within 1 week of the final stability assessment.  
2 
If a subject has not had a recent renal biopsy, one may be performed to assess eligibility for the study provided informed consent has been given. The biopsy must have been performed 3 months 
prior to the screening visit. Repeat renal biopsies may be done at Week 24 in a subset of subjects at selected sites.  
3 
Complete physical exam at screening; abbreviated exam at all other visits. 
4 
BP, pulse, temperature, weight, and height. Height included at initial screening assessment only. At stability assessments, BP only will be included. 
5 
In the event that a subject is noted to have a QTcF value exceeding 500 msec, or an increase of >60 msec from baseline, the ECG should be repeated within 24 hours. Further details provided in the 
study protocol. 
6 
Laboratory assessments will be performed according to the schedule in the study protocol. Subjects must be fasting for at least 8-12 hours at Baseline and at end of study/early termination visit.  
7 
Pharmacokinetic assessments will be done at Weeks 4 and 24. PK samples will be drawn prior to study treatment dosing (trough sample), and at 1, 2 and 4 hours post-dose. In the event a subject 
experiences an SAE or requires a dose modification or is withdrawn from treatment, a VCS sample should be taken, with a trough sample preferred. 
8 
The UPCR will be calculated both from the FMV and from standard urinalysis results. If the FMV 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. 
9 
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. 
10 Patient Reported Outcome Measurement Information system (PROMIS) and Kidney Disease Quality of Life-Short Form (KDQOL-SFTM). 
11 Serum pregnancy test to be evaluated at central laboratory at Screening and Week 24; urine pregnancy test will be performed locally at all other visits as applicable. 
12 If screening visit occurs on the same day as informed consent, any findings are to be recorded as Medical History. Any change since the date of signed consent and/or during the screening period 
would be considered an AE. 
13 Subjects in Cohort 1, will be contacted by telephone at the end of Week 1 as a reminder to increase their dose to 2 capsules (15.8 mg) BID for 1 week, starting at Week 2. Subjects will be contacted 
again by telephone at the end of Week 2 as a reminder to increase their dose to 3 capsules (23.7 mg) BID, starting at Week 3, for the remainder of the treatment period.  Subjects in Cohort 2, will 
also be contacted at the end of each week (as required) up to Week 4, as a reminder to increase their dose to the maximum selected for Cohort 2. 
14 Compliance only. 
15 First dose of study medication should occur in the morning the day after dispensing. 
Notes: Subjects who discontinue therapy will be requested to attend their regularly scheduled study visits to the end of the study. 
 
AE=Adverse event; BID=Twice dialy; BP=Blood pressure; Disc.=Discontinuation; ECG=Electrocardiogram; FMV=First morning void; Min=Minimum; QoL=Quality of life; QTcF=QT 
interval duration corrected for heart rate using method of Fridericia; SAE=Serious adverse event; VCS=Voclosporin; Wk=Week. 
 
 
 


 
 
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TABLE OF CONTENTS 
Page 
NAMES AND ADDRESSES ...................................................................................................2 
DECLARATION OF SPONSOR ...........................................................................................3 
INVESTIGATOR AGREEMENT FORM ............................................................................4 
SYNOPSIS ................................................................................................................................5 
STUDY SCHEMA .................................................................................................................12 
AUR-VCS-2018-01 SCHEDULE OF EVENTS ..................................................................13 
TABLE OF CONTENTS ......................................................................................................15 
LIST OF TABLES .................................................................................................................19 
LIST OF APPENDICES .......................................................................................................19 
LIST OF ABBREVIATIONS ...............................................................................................20 
1. 
INTRODUCTION AND BACKGROUND ..................................................................23 
1.1 
Background of the Disease and Treatment Options ....................................................23 
1.1.1 
Limitations of Current Treatment .............................................................................24 
1.2 
Rationale for the Use of Calcineurin Inhibitors in FSGS ............................................25 
1.2.1 
Mechanism of Action of CNIs and Potential for Treatment Benefit in FSGS .........25 
1.2.2 
Clinical Studies of CNIs in FSGS ............................................................................26 
1.2.3 
Voclosporin ...............................................................................................................28 
1.2.3.1 
Pharmacokinetic Considerations ............................................................................29 
1.2.4 
Potential Toxicities of CNIs .....................................................................................29 
2. 
RATIONALE .................................................................................................................31 
2.1 
Dose Rationale .............................................................................................................31 
3. 
STUDY OBJECTIVES ..................................................................................................33 
3.1 
Primary Objective ........................................................................................................33 
3.2 
Secondary Objective ....................................................................................................33 
3.3 
Endpoints .....................................................................................................................33 
3.3.1 
Primary Endpoint ......................................................................................................33 
3.3.2 
Secondary Endpoints ................................................................................................33 
4. 
INVESTIGATIONAL PLAN .......................................................................................35 
4.1 
Overall Study Design ...................................................................................................35 
4.2 
Duration of Subject Participation and Study ...............................................................36 
5. 
SELECTION, 
WITHDRAWAL 
OF 
SUBJECTS 
AND 
PERMANENT 
DISCONTINUATION OF DRUG ................................................................................37 


 
 
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5.1 
Number of Subjects......................................................................................................37 
5.2 
Inclusion Criteria .........................................................................................................37 
5.3 
Exclusion Criteria ........................................................................................................38 
5.4 
Adequate/Effective Contraception ...............................................................................40 
5.5 
Withdrawal of Subjects ................................................................................................41 
5.6 
Discontinuation of Study Treatment ............................................................................41 
5.6.1 
Discontinuation of Study Treatment Due to an Adverse Event................................41 
6. 
RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES ..............42 
7. 
STUDY TREATMENTS ...............................................................................................43 
7.1 
Dosage Forms/Formulation .........................................................................................43 
7.1.1 
Voclosporin – Study Treatment ................................................................................43 
7.1.2 
Dosing Guidelines.....................................................................................................43 
7.1.2.1 
Voclosporin Study Treatment ................................................................................43 
7.2 
Package and Labeling ..................................................................................................44 
7.3 
Site Supply, Storage, Accountability ...........................................................................44 
7.3.1 
Site Supply ................................................................................................................44 
7.3.2 
Storage ......................................................................................................................45 
7.3.3 
Accountability ...........................................................................................................45 
7.4 
Voclosporin Dose Modification ...................................................................................45 
7.4.1 
Discontinuation of Study Therapy Due to Non-response .........................................45 
7.4.2 
Deterioration in Renal Function ...............................................................................46 
7.4.2.1 
Decrease in eGFR >30% and eGFR <90 mL/min/1.73 m2 ....................................46 
7.4.2.2 
Decrease in eGFR ≤30% and eGFR <90 mL/min/1.73 m2 ....................................46 
7.4.2.3 
Recovery of eGFR .................................................................................................46 
7.5 
Procedures for Overdose ..............................................................................................47 
7.6 
Prohibited Therapy and Concomitant Treatment .........................................................47 
7.6.1 
Prohibited Medications .............................................................................................47 
7.6.2 
Allowed Concomitant Medications ..........................................................................47 
7.7 
Increased Blood Pressure .............................................................................................48 
8. 
RISKS/PRECAUTIONS ...............................................................................................49 
9. 
STUDY PROCEDURES ...............................................................................................50 
9.1 
Description of Study Assessments ...............................................................................50 
9.1.1 
Laboratory Assessments ...........................................................................................50 
9.1.1.1 
Evaluation of Biomarkers ......................................................................................52 
9.1.2 
Physical Examinations ..............................................................................................52 
9.1.3 
Vital Signs.................................................................................................................53 
9.1.3.1 
Blood Pressure Management .................................................................................53 
9.1.4 
Standard 12-lead Electrocardiogram ........................................................................53 
9.1.4.1 
Procedures to Manage a Treatment-Emergent Increase in QTcF ..........................54 
9.1.5 
QoL Assessments ......................................................................................................54 


 
 
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9.1.6 
Voclosporin Pharmacokinetic and Biomarker Assessment ......................................54 
9.2 
Schedule of Assessments .............................................................................................54 
9.2.1 
Screening Visit and Stability Assessment Procedures ..............................................55 
9.2.2 
Treatment Procedures ...............................................................................................56 
9.2.3 
End of Study (or Early Discontinuation) Procedures ...............................................57 
9.2.4 
Follow-up Procedures ...............................................................................................58 
9.2.5 
Unscheduled Visit .....................................................................................................58 
10. EVALUATION, RECORDING AND REPORTING OF AES AND SAES .............59 
10.1 
Definitions....................................................................................................................59 
10.1.1 
Adverse Event ...........................................................................................................59 
10.1.2 
Adverse Drug Reaction .............................................................................................59 
10.1.3 
Serious Adverse Event ..............................................................................................59 
10.1.4 
Suspected Unexpected Serious Adverse Reaction....................................................60 
10.2 
Adverse Event Descriptors ..........................................................................................60 
10.2.1 
Intensity/Severity Categorization .............................................................................60 
10.2.2 
Causal Relationship Categorization ..........................................................................60 
10.2.3 
Outcome Categorization ...........................................................................................61 
10.2.4 
Clinical Laboratory Evaluations ...............................................................................61 
10.2.5 
Abuse, Misuse, Overdose and Medication Error ......................................................62 
10.3 
Reporting Procedure for AEs, SAEs, and Pregnancy ..................................................62 
10.3.1 
Adverse Events .........................................................................................................62 
10.3.2 
Serious Adverse Events ............................................................................................63 
10.3.3 
Pregnancy..................................................................................................................64 
11. CLINICAL ENDPOINTS COMMITTEE ..................................................................66 
12. DATA AND SAFETY MONITORING BOARD PROCEDURES ...........................67 
13. STATISTICAL ANALYSIS .........................................................................................68 
13.1 
Statistical Methods .......................................................................................................68 
13.2 
Sample Size and Power Calculations ...........................................................................68 
13.3 
Populations ...................................................................................................................68 
13.3.1 
Intent-to-Treat Population.........................................................................................68 
13.3.2 
Safety Set ..................................................................................................................68 
13.3.3 
Per-protocol Set ........................................................................................................68 
13.4 
Datasets ........................................................................................................................68 
13.5 
Background and Demographic Characteristics ............................................................68 
13.6 
Study Treatment ...........................................................................................................69 
13.7 
Concomitant Therapy...................................................................................................69 
13.8 
Efficacy Evaluations ....................................................................................................69 
13.8.1 
Primary Endpoint ......................................................................................................69 
13.8.2 
Secondary Endpoints ................................................................................................69 
13.9 
Statistical and Analytical Methods ..............................................................................71 


 
 
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13.10 Safety Evaluations .......................................................................................................71 
13.11 Interim Analyses ..........................................................................................................72 
13.12 Other Evaluations.........................................................................................................72 
13.12.1 Pharmacokinetics ......................................................................................................72 
14. ETHICAL CONDUCT OF THE STUDY ...................................................................73 
14.1 
Informed Consent.........................................................................................................73 
14.2 
Institutional Review Board or EC/IEC ........................................................................73 
15. QUALITY CONTROL AND QUALITY ASSURANCE ...........................................74 
16. ADMINISTRATIVE PROCEDURES .........................................................................75 
16.1 
Sponsor’s Responsibilities ...........................................................................................75 
16.1.1 
Study Supplies ..........................................................................................................75 
16.1.2 
Insurance ...................................................................................................................75 
16.1.3 
Study Monitoring ......................................................................................................75 
16.2 
Investigator’s Responsibilities .....................................................................................76 
16.2.1 
Reporting and Recording of Data .............................................................................76 
16.2.2 
Investigator Training.................................................................................................76 
16.2.3 
Source Documentation ..............................................................................................76 
17. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE 
TERMINATION OF THE STUDY .............................................................................77 
17.1 
Protocol Waivers, Deviations and Violations ..............................................................77 
17.2 
Study Termination .......................................................................................................77 
18. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ......................78 
19. REFERENCES ...............................................................................................................79 
 


 
 
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LIST OF TABLES 
Page 
Table 1 
Review of Laboratory Assessments .................................................................50 
 
LIST OF APPENDICES 
Appendix 1 
Drug Therapy for the Treatment of Hypertension ...........................................82 
Appendix 2 
Measurement of Blood Pressure ......................................................................83 
Appendix 3 
Classification of FSGS .....................................................................................84 
Appendix 4 
Expanded List of Allowed Concomitant Medications .....................................86 
Appendix 5 
Summary of Treatment and Food Restrictions ................................................88 
Appendix 6 
PROMIS QoL Assessment ..............................................................................89 
Appendix 7 
KDQOL-SFTM QoL Assessment Version 1.3 ..................................................90 
  
 
 
 


 
 
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LIST OF ABBREVIATIONS 
ACEI 
Angiotensin converting enzyme inhibitor 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ARB 
Angiotensin receptor blocker 
ATC 
Anatomical Therapeutic Chemical 
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 
Aurinia 
Aurinia Pharmaceuticals Inc. 
BID 
Twice daily 
BP 
Blood pressure 
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 
DEX 
Dexamethasone 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End-stage renal disease 
FMV 
First morning void 
FSGS 
Focal Segmental Glomerulosclerosis 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 


 
 
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GMP 
Good Manufacturing Practice 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISA247 
Voclosporin 
ITT 
Intent-to-treat 
IV 
Intravenous 
KDIGO 
Kidney Disease: Improving Global Outcomes 
KDQOL-SFTM 
Kidney Disease Quality of Life-Short Form 
LN 
Lupus nephritis 
MMF 
Mycophenolate mofetil 
NSAID 
Non-steroidal anti-inflammatory drug 
OR 
Odds ratio 
PD 
Pharmacodynamic 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PO 
Orally 
PPS 
Per-protocol set 
PROMIS 
Patient Reported Outcome Measurement Information System  
QoL 
Quality of life 
QTcF 
QT interval duration corrected for heart rate using method of 
Fridericia 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
t1/2 
Terminal elimination half-life 


 
 
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TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TGF-β 
Transforming growth factor beta 
UPCR 
Urine protein creatinine ratio 


 
 
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1. INTRODUCTION AND BACKGROUND 
1.1 
Background of the Disease and Treatment Options  
Focal segmental glomerulosclerosis (FSGS) is diagnosed by characteristic glomerular findings 
of podocyte injury evidenced by findings from immunofluorescence and electron microscopy 
following renal biopsy. The disease is categorized as primary (i.e., idiopathic FSGS) or 
secondary (e.g., adaptive changes resulting from glomerular hyperfiltration in conditions such 
as reflux nephropathy, obesity, and reduced nephron mass; drug-induced FSGS; and FSGS 
associated with viral diseases) [1].  
The predominate clinical feature of primary FSGS is proteinuria, typically with signs and 
laboratory abnormalities associated with nephrotic syndrome (i.e., total urine protein >3.5 
g/day, edema, hypoalbuminemia, and hypercholesterolemia) [1]. Patients may experience 
renal dysfunction which can progress to end-stage renal disease (ESRD). Reportedly 50-60% 
of patients have nephrotic syndrome at presentation, and approximately 50% of adult patients 
with idiopathic nephrotic syndrome are diagnosed with FSGS [1]. The amount of proteinuria 
at presentation and lack of response to treatment are correlated with progression to ESRD. 
FSGS is more common in males than in females and, in racially diverse populations, more 
common in black patients than in white patients [1]. 
Several published reviews have summarized the histopathologic features of FSGS and 
mechanisms of podocyte injury, disruption of the glomerular filtration barrier, and progression 
of renal dysfunction, e.g., D’Agati [1] and Kikuchi et al [2].  
The glomerular filtration barrier consists of glomerular endothelial cells, the glomerular 
basement membrane, and epithelial cells (podocytes). There is a complex interaction between 
these elements; the podocyte is not only a critical part of the structure, providing structural 
support to glomerular capillary, but also plays a role in maintaining the glomerular basement 
membrane and slit diaphragm proteins that permit filtration of water and small molecules and 
retention of large molecules and cells. Light microscopy findings include a segmental pattern 
of mesangial sclerosis occurring in some (i.e., focal), but not all glomeruli, without typical 
features of other proteinuric glomerulopathies. Immunofluorescence microscopy does not 
reveal immune deposits. The primary pathophysiologic mechanism of FSGS is reflected in 
electron microscopy findings, which include typical abnormalities of podocyte morphology, 
i.e., diffuse podocyte foot process effacement. In FSGS, as in other podocytopathies, these 
abnormalities disrupt the glomerular filtration barrier, resulting in protein leakage. 
The etiology of primary (idiopathic) FSGS is not known and is likely multifactorial. Based on 
indirect evidence, development of FSGS has been attributed to circulating factors (e.g., 
cytokines such as cardiotrophin-like cytokine 1, anti-CD40 (podocyte-B7-1 antigen) antibody, 
apolipoprotein A-Ib (ApoA-Ib) and serum soluble urokinase-type plasminogen activator 
receptor (suPAR)) which may mediate glomerular permeability. FSGS recurs in transplanted 


 
 
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kidneys, and proteinuria can be reduced by plasmapheresis in these patients; plasma and sera 
from FSGS patients have induced proteinuria in rats and in isolated rat glomeruli [3]. Several 
immune mechanisms have also been postulated to contribute to progressive glomerular damage 
subsequent to the initial podocyte injury, including cellular immunity and autoimmune 
reactivity [4].  
Elevated levels of transforming growth factor-beta (TGF-β) have been implicated in the 
pathogenesis of FSGS and have been reported in numerous tissues of patients with FSGS 
including the tubule-interstitium and the glomerular epithelial cells [5,6]. Calcineurin α, one 
of the calcineurin isoforms, is involved in broad cellular tasks including protein folding and 
regulation of TGF-β expression. The use of an immunosuppressive agent that increases TGF-
β levels may have a negative long-term impact on renal fibrosis, whereas the use of an 
immunosuppressive agent that either decreases or has no impact on TGF-β levels may stabilize 
presently existing renal fibrosis. Concerning the podocyte, Liao et al [7] showed that in a 
murine (MRL/lpr) model, the calcineurin inhibitor (CNI) tacrolimus may decrease TGF-β-
induced podocyte apoptosis, suggesting that calcineurin may play a role in the progression of 
renal disease, thereby suggesting a potential mechanism of CNI benefit.   
1.1.1 
Limitations of Current Treatment 
The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for 
Glomerulonephritis [8] provides Level 2C (low) and 2D (very low) suggestions for the 
treatment of primary FSGS: Corticosteroids are suggested as initial treatment at a daily single 
dose of 1 mg/kg (maximum 80 mg) or 2 mg/kg (maximum 120 mg) (Level 2C), to be 
administered for a minimum of 4 weeks and maximum of 16 weeks, as tolerated, or until 
complete remission has been achieved, whichever is earlier (Level 2D). Calcineurin inhibitors 
are suggested for use in FSGS as second-line treatment after failure of remission with steroid 
treatment and as first-line treatment in patients with relative contraindications to steroids. 
(Level 2D) (see Section 1.2.1, Mechanism of Action of CNIs and Potential for Treatment 
Benefit in FSGS). Up to 50% of patients fail to respond to corticosteroids [1]. Earlier use of 
CNIs in primary FSGS, as initial treatment at the time of diagnosis, would avoid the risks of 
corticosteroid use, and may result in proteinuria remission, as well as potentially decrease the 
risk of progression to ESRD. 
The potential benefit of voclosporin (VCS) in treatment-naïve FSGS patients is supported by 
the mechanism of action of CNIs (see Section 1.2.1, Mechanism of Action of CNIs and 
Potential for Treatment Benefit in FSGS) and clinical data suggesting benefit in steroid-
resistant patients (see Section 1.2.2, Clinical Studies of CNIs in FSGS), as well as potential 
advantages of VCS over cyclosporine (i.e., increased potency demonstrated in nonclinical 
studies with VCS, more predictable pharmacokinetic (PK)/pharmacodynamic (PD) profile 
(obviating the need for therapeutic drug monitoring), and a potentially improved safety profile 
compared to cyclosporine A (CsA)) (see FSGS Investigator’s Brochure (IB) [9]). These data, 
with the demonstrated efficacy in renal response (including reduction in proteinuria), suggest 


 
 
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that VCS may benefit patients with FSGS. Although treatment guidelines suggest 
corticosteroids as first line therapy in these patients [8], there are no data to support the use of 
corticosteroids instead of CNIs in this setting. Corticosteroids are associated with significant 
toxicities, and if VCS demonstrates treatment benefit and an acceptable safety profile, it would 
provide an appropriate alternative treatment to corticosteroids in this setting. 
1.2 
Rationale for the Use of Calcineurin Inhibitors in FSGS  
Calcineurin inhibitors are suggested for use in FSGS as second line treatment after failure of 
remission with steroid treatment and as first line treatment in patients with relative 
contraindications to steroids. In addition to well-characterized immunomodulatory effects, 
CNIs have been demonstrated to have direct beneficial effects on podocytes that are likely 
mechanisms of amelioration of proteinuria in podocytopathies, including FSGS. 
1.2.1 Mechanism of Action of CNIs and Potential for Treatment Benefit in 
FSGS 
Calcineurin inhibitors have beneficial effects in diseases characterized by disorders of the 
immune system and in the prevention of rejection after solid organ transplantation by inhibiting 
activation of nuclear factor of activated T-cell (NFAT) with subsequent regulation of the 
production of T-cell cytokines [9]. Recently, several investigations have demonstrated that 
CNIs have non-immunologic effects that contribute to their anti-proteinuric effects in 
podocytopathies. 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 protected from degradation. Calcineurin dephosphorylates synaptopodin 
allowing its degradation, with subsequent alteration of the actin cytoskeleton, disruption of the 
glomerular filtration barrier, and proteinuria. Expression of activated calcineurin in podocytes 
leads to proteinuria. Thus, by inhibiting calcineurin, CNIs exert a specific anti-proteinuric 
effect by preventing the degradation of the podocyte stabilizing protein synaptopodin [10,11]. 
In addition to effects on synaptopodin, cyclosporine has been found to stabilize other 
components of the actin cytoskeleton, i.e., cofilin-1 and nephrin. Podocyte apoptosis can be 
induced in the rat purine aminonucleoside model [12]. Shen et al [13] demonstrated that 
cyclosporine and tacrolimus reduced podocyte apoptosis in the rat purine aminonucleoside 
model. In addition, inhibition of NFAT signaling in the podocyte by CNIs may ameliorate 
podocyte injury [14]. Wakamatsu et al [15] evaluated the effects of tacrolimus in a nephrotic 
rat model (anti-nephrin antibody-induced nephropathy). Utilizing immunohistological 
analyses of rat and human kidneys, these investigators demonstrated that calcineurin is an 
element of the slit diaphragm and associated with nephrin, a critical component of the slit 
diaphragm. In the nephrotic rat model, they demonstrated that calcineurin distribution was 
altered and calcineurin activity was increased; these abnormalities were prevented by 
administration of tacrolimus, with amelioration of proteinuria. As noted in Section 1.1, 


 
 
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Background of the Disease and Treatment Options, calcineurin may also contribute to TGF-β-
induced fibrosis. 
In summary, CNIs, in addition to their immunomodulatory effects have been demonstrated to 
have direct beneficial effects on podocytes via multiple mechanisms. These effects are likely 
mechanisms of amelioration of proteinuria in podocytopathies, including FSGS. 
1.2.2 Clinical Studies of CNIs in FSGS  
The KDIGO guidelines suggest CNIs for use in the first line treatment of FSGS in patients 
who are intolerant or have contraindications to corticosteroid use [8]. There are no prospective, 
randomized trials of CNIs (either cyclosporine or tacrolimus) used as first line treatment in 
adult patients (or children) with FSGS. Limited retrospective observational data support their 
use in this setting; a recent treatment review [16] cites two studies: Duncan et al [17] and 
Goumenos et al [18]. 
In a single study center by Duncan et al [17], 6 patients with biopsy-proven FSGS and 
nephrotic syndrome, who had been previously treated with angiotensin converting enzyme 
inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), but not immunosuppression 
(including corticosteroids), were treated with tacrolimus and followed prospectively. The mean 
duration of nephrotic syndrome prior to treatment with tacrolimus was 13.6 months (standard 
deviation (SD) 11.8); baseline urine protein was 11.0 g/day (SD 4.5) and baseline estimated 
glomerular filtration rate (eGFR) was 71.7 mL/min/1.73 m2 (SD 22.4). After approximately 12 
months of follow-up, all 6 patients achieved remission, defined as normalization of serum 
albumin and resolution of edema. Mean urine protein decreased from 11.0 g/day (SD 4.5) to 
2.8 g/day (SD 2.5). Reportedly, no patients relapsed after attaining remission. 
In a retrospective review by Goumenos et al [18], 51 patients with biopsy-proven FSGS, 
proteinuria >1 g/day, and serum creatinine <2.5 mg/dL, were followed for 5 years. Of the 51 
patients, 26 were treated with conservative management (including ACEIs and other anti-
hypertensives) and 25 were treated with immunosuppressive drugs, including prednisolone 
alone (9 patients, treated for 16 months, 8 with nephrotic syndrome), prednisolone and 
azathioprine (6 patients, treated for 18 months, 5 with nephrotic syndrome) and prednisolone 
(0.5 mg/kg/day) and cyclosporine (10 patients, treated for 25 months, 7 with nephrotic 
syndrome). No patients received cyclosporine monotherapy. Treatment assignment was 
reportedly based on renal impairment and degree of proteinuria. Remission of nephrotic 
syndrome (both complete remission (defined as urine protein <0.3 g/day) and partial remission 
(defined as urine protein between 0.3 and 3 g/day)) occurred in 5/8 patients treated with 
prednisolone alone, 4/5 patients treated with prednisolone and azathioprine, and 6/7 patients 
treated with prednisolone and cyclosporine. 
Evidence to support the use of CNIs in adult patients who are steroid resistant includes 
randomized clinical trials as well as observational data. A Cochrane Review published in 2008 


 
 
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[19] identified one blinded controlled study (Cattran et al, 1999 [20]) which evaluated the 
effect of cyclosporine on remission of proteinuria and ESRD in steroid-resistant adult patients 
with nephrotic syndrome. This study was a single blind, randomized, placebo-controlled trial 
in which 26 patients were treated with cyclosporine and low dose prednisone and 23 patients 
were treated with placebo and low-dose prednisone. Complete remission (urine protein 
≤0.3 g/day with stable renal function) or partial remission (50% reduction and ≤3.5 g/day with 
stable renal function) occurred in 69% of the cyclosporine group and 4% of the placebo group 
at 26 weeks (p<0.001). At 4 years, the renal survival rate was 72% in the cyclosporine group 
and 49% in the placebo group. 
Laurin et al [21] performed a meta-analysis of studies evaluating the effects of CNIs in primary 
FSGS. They did not identify any trials in which CNIs were used as first-line treatment. Six 
randomized controlled trials and two retrospective cohort studies were included in their review. 
They performed a pooled analysis of the effect of cyclosporine on proteinuria remission; the 
relative risk of complete or partial remission was 7.0 (95% confidence interval (CI): 2.9, 16.8) 
compared with the control group. 
It has been noted in treatment reviews that cyclosporine use in steroid-resistant patients is 
associated with a high relapse rate (e.g., 43 to 50% in a 2003 review by Cattran [22]). In an 
NIH-sponsored trial, FSGS-CT, 138 patients (adults and children) with biopsy-proven FSGS 
(assessed as steroid resistant and urine protein creatine ratio (UPCR) >1 g/g) were randomized 
to cyclosporine (n=72) or a combination of pulse dexamethasone (DEX) and mycophenolate 
mofetil (MMF) (n=66) [23,24]. Treatment was administered for 12 months and patients were 
followed until Week 78. Steroid resistance was defined as failure to achieve sustained UPCR 
≤1.0 g/g after a minimal treatment duration of 4 weeks. All patients were treated with low-
dose prednisone and either an ACEI or ARB. There was no difference between the groups in 
the primary endpoint (mean score of a 6-level categorical assessment of remission of 
proteinuria at Week 52): 46% of the CsA group and 33% of the MMF/DEX group had at least 
a partial remission at Week 52. In patients who achieved at least a partial remission at Week 52, 
relapse (defined as UPCR >2.0 g/g after the withdrawal of medication at Week 52) was 
reported for 33% (11/33) in the CsA group and 18% (4/22) in the MMF/DEX group. These 
data are difficult to interpret as 28% of patients in the CsA group had baseline UPCR <2.0 g/g. 
Moreover, the definition of steroid resistance in this study is not consistent with standard 
definition of steroid resistance for adults and the data are not presented separately for adults 
and children. 
In a follow-up publication of a post-hoc analysis, Hogg et al [25] examined the outcomes in 
patients who achieved complete or partial remission after 26 weeks, completed 52 weeks of 
treatment, and had follow-up information through 78 weeks. In the cyclosporine group, the 
analysis included 22 of the 39 patients who were reported to have at least partial remission at 
Week 26 in the earlier publication, and 20 of the 26 patients in the MMF/DEX group. The 
authors report that, in the CsA patients, the mean eGFR decreased at Weeks 26 and 52 (17% 


 
 
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decrease and 19% decrease compared to baseline, respectively), and increased by 16% from 
Week 52 to Week 78. 
There are few studies examining the use of tacrolimus in patients with FSGS. In one study 
[26], 
decrease 
in 
proteinuria 
was 
similar 
in 
18 
patients 
treated 
with 
cyclophosphamide/prednisone and 15 patients treated with tacrolimus/prednisone, both after 6 
months of treatment and at the completion of a 6-month follow-up period. Baseline renal 
function was not recorded and there appeared to be stability of renal function between 6 months 
and 12 months. Therefore, it is difficult to assess the treatment benefit of tacrolimus from this 
study. 
In summary, the available data, although largely from retrospective studies, support a treatment 
benefit of cyclosporine in steroid-resistant patients. There is little data supporting the benefit 
of cyclosporine as first line treatment. It has been reported that the relapse rate is high following 
discontinuation of treatment; however, it is difficult to interpret the data reported by Gipson et 
al [23,24] and Hogg et al [25] with respect to the effect of cyclosporine on renal function and 
proteinuria over 12 months and subsequent improvement in renal function and proteinuria after 
withdrawal, and the reported relapse rate. The study failed to recruit the target number of 
patients, the criteria for steroid resistance were not consistent with standard definitions, and 
the changes in proteinuria and renal function were not completely reported. However, it 
appears that there was a significant decrease in proteinuria at both Weeks 26 and 52. While the 
post-treatment effect on eGFR is not completely clear, the data suggest some increase in eGFR 
after withdrawal of treatment. The relevance of these findings to the long-term effect of VCS 
is not clear. 
1.2.3 Voclosporin 
Voclosporin is a next generation CNI currently under development for use in FSGS and lupus 
nephritis (LN). Voclosporin is structurally similar to 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 VCS 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 
VCS as compared to CsA, has led to better PK/PD predictability. 
During the development of this investigational product, the legacy names of voclosporin, VCS, 
and ISA247 are referenced in discussions related to historical usage. In the Phase 3 LN clinical 
development program, the name of the investigational product is referred to as Orelvo, the 
proposed trade name. However, for the FSGS clinical development programs, the name of the 
investigational product will be referred to as voclosporin or VCS. All legacy names and the 


 
 
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proposed trade name should all be considered interchangeable unless specifically identified as 
different. 
Prior to the FSGS clinical development program, over 2,400 subjects have received 
investigational products containing VCS in 15 Phase 1, and 12 Phase 2/3 clinical studies in the 
indications of LN, transplant rejection, psoriasis and non-infectious uveitis. Detailed data for 
these clinical studies are presented in the IB [9].  
1.2.3.1 Pharmacokinetic Considerations 
Voclosporin approximates linear multiexponential PKs. Exposure to VCS was dose-related 
with maximum concentrations occurring ≤2 hours with a t1/2 of ≥30 hours. Drug accumulation 
was minor with accumulation factors of approximately 2 hours after twice daily (BID) dosing. 
Administration of VCS 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 VCS 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 Cmax and an 18-fold increase in AUC0-12 for VCS. Concomitant administration of 
rifampin, an inducer of CYP3A4/5, resulted in a decrease in exposure to VCS. 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 VCS. Concomitant administration of VCS and 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 VCS. Concomitant administration of digoxin, a P-gp substrate, 
resulted in statistically significant increases in digoxin Cmax and AUC0-24 and a decrease in 
clearance. Therefore, concomitant administration of P-gp substrates with VCS 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 Potential Toxicities of CNIs 
Increased blood pressure (BP) and renal dysfunction are well known potential toxicities of 
CNIs that are dose-related, reversible, and generally responsive to dose reduction or temporary 
interruption of treatment [27].  
Voclosporin has been studied in numerous disease states. In clinical studies of VCS in LN [9], 
a small proportion of VCS-treated subjects experienced an early drop of ≥30% in eGFR; 


 
 
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however, that proportion then remained 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 treatment 
in 1 (1.1%) placebo subject, 7 (7.9%) VCS low-dose (23.7 mg BID) subjects and 5 (5.7%) 
VCS high-dose (39.5 mg BID) subjects. There were more TEAEs of hypertension seen in the 
VCS-treated subjects compared to placebo; however, overall mean systolic and diastolic BP 
decreased in all groups, without statistically significant differences seen between groups. 
Overall, only 1 (1.1%) subject, in the VCS high-dose group, had a TEAE of hypertension that 
resulted in permanent discontinuation of study treatment.  
There was also evidence of an increased incidence of TEAEs over placebo and with increased 
dose of VCS in the System Organ Classes of Infections and Infestations, Gastrointestinal 
Disorders, and Vascular Disorders. 
 


 
 
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2. RATIONALE 
The rationale for the development of VCS and the range of dose is to introduce a novel CNI to 
the population of patients with FSGS, with meaningful efficacy while minimizing toxicities 
common to other CNIs. In clinical studies, a favorable efficacy/safety profile for VCS has been 
demonstrated in the prevention of renal transplant rejection and in Phase 2 studies in LN. 
As evaluated in nonclinical and clinical studies (healthy volunteers, moderate to severe 
psoriasis, renal transplantation, and uveitis) VCS is well tolerated and exhibits adverse events 
(AEs) that are typical of other CNIs yet seen to a lesser extent than those seen historically with 
other CNIs. 
The aim of the current study is to investigate whether VCS is able to reduce disease activity 
over a treatment period of 24 weeks. Subjects with histologic evidence of primary FSGS with 
proteinuria will be eligible to enter the study. Efficacy will be assessed by the ability of VCS 
to reduce the level of proteinuria (as measured by UPCR) while demonstrating an acceptable 
safety profile. The primary endpoint of this study will be complete or partial remission of 
proteinuria at 24 weeks. 
2.1 
Dose Rationale 
This Phase 2 study is designed to initially evaluate the treatment benefit of VCS 23.7 mg BID 
in the first Cohort of 10 subjects. The selection of this VCS dose for the first Cohort (see 
Section 7, Study Treatments) was based on the previous experience with this drug in the Phase 
2 LN study (AURA-LV). In AURA-LV, subjects were administered VCS 23.7 mg BID, VCS 
39.5 mg BID, or matching placebo. Low-dose VCS was significantly superior to placebo in 
the proportion of subjects achieving complete renal response at Week 24 (p=0.045). At Week 
48, complete remission rates in both the low-dose (49.4%) and high-dose (39.8%) VCS groups 
demonstrated statistically significant superiority compared to the placebo (23.9%) group, 
(p<0.001, p=0.026, respectively). There was no increase in efficacy with the higher dose and 
no significant differences between the two VCS groups in achievement of renal response.  
This study is also designed to evaluate a further dose level of VCS, this dose may be higher or 
lower than the initial 23.7 mg BID dosing. When the first 6 subjects in Cohort 1 have completed 
12 weeks of treatment with VCS, the top line efficacy and safety data will be analyzed to 
determine the dose level for Cohort 2. The maximum dose possible for Cohort 2 will be 39.5 
mg (5 capsules) BID. 
To minimize safety concerns, a cautious dose-escalation design starting with a minimal dose 
of one capsule (7.9 mg) per day will be employed for all subjects (see Section 7.1.2, Dosing 
Guidelines).  
The protocol contains provisions for management of dose (including rules for stopping 
treatment with study mediation) based on safety concerns in particular, BP and renal function. 


 
 
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The safety data from the use of VCS in LN demonstrates that these risks are dose-related, 
reversible, and can be managed by dose reduction and temporary interruption.   
Furthermore, VCS will be administered as fixed doses without the use of therapeutic drug 
monitoring. Population PK analyses of VCS concentrations from the clinical development 
program (including healthy subjects, subjects with renal impairment, subjects with hepatic 
impairment, renal transplant, plaque psoriasis, and LN) demonstrated that weight did not have 
a significant effect on the PK of VCS [9].  


 
 
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3. STUDY OBJECTIVES 
3.1 
Primary Objective 
• To assess the efficacy of VCS in achieving complete or partial remission of proteinuria 
after 24 weeks of therapy in subjects with FSGS. 
3.2 
Secondary Objective 
• To assess the safety and tolerability of VCS over 24 weeks in subjects with FSGS. 
3.3 
Endpoints 
All primary and secondary endpoints will be assessed overall and for each individual cohort. 
3.3.1 Primary Endpoint 
Proportion of subjects with remission of proteinuria at Week 24 based on the following 
parameters: 
• Complete remission: UPCR of <0.3 mg/mg 
OR 
• Partial remission: UPCR ≥0.3 mg/mg and <3.0 mg/mg with >50% reduction in UPCR 
from baseline 
3.3.2 Secondary Endpoints 
• Proportion of subjects with complete remission or partial remission of proteinuria at Weeks 
8 and 12 
• Proportion of subjects with complete remission of proteinuria at Weeks 8, 12, and 24 
• Proportion of subjects with UPCR <0.5 mg/mg at Weeks 8, 12, and 24 
• Proportion of subjects with partial remission of proteinuria at Weeks 8, 12, and 24 
• Time to first occurrence of complete or partial remission of proteinuria 
• Time to first occurrence of complete remission of proteinuria 
• Time to first occurrence of partial remission of proteinuria 
• Time to first occurrence of 50% reduction in UPCR from baseline 
• Duration of UPCR <0.3 mg/mg 


 
 
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• Change from baseline in UPCR at each time point 
• Proportion of subjects with a confirmed >30% decrease from baseline in eGFR (utilizing 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) at each time 
point  
• Proportion of subjects with a confirmed >30% increase in eGFR from the final visit 
(Week 24 or last on-treatment visit, for subjects who discontinue prematurely) to the 
second Safety Follow-up visit (Visit 10) 
• Change in UPCR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10) 
• Change in eGFR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10)  
• Change from baseline in serum creatinine, serum albumin, and eGFR at each time point 
• Quality of life (QoL) assessments 
− 
Mean change in Patient Reported Outcome Measurement Information System 
(PROMIS) measures at Week 24 
− 
Change from baseline in Kidney Disease Quality of Life-Short Form 
(KDQOL-SFTM) score at Week 24 
• Safety and tolerability over 24 weeks 
• Renal biopsy: descriptive analyses of changes in histopathology will be evaluated in post-
treatment (24 weeks) renal biopsies in a subset of patients 
• Change from baseline to Week 4 and 24 in the following biomarkers:  
− 
Urine nephrin 
− 
Urine synaptopodin 
− 
Serum TGF-β 


 
 
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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 2, open-label, multicenter, prospective, 24-week, exploratory cohort study to 
assess the efficacy and safety of two dose levels of VCS in achieving complete or partial 
remission of proteinuria in treatment-naïve subjects with biopsy-confirmed primary FSGS. 
Subjects who have provided a signed and dated informed consent will be screened into the 
study. Subjects will be assigned a unique subject number which will be used to identify them 
throughout the study. The duration of the screening period will be approximately 4 weeks to 
10 weeks (allowing for visit windows (14±3 days) for each stability assessment) to ensure that 
subjects meet eligibility criteria, including renal disease stability assessments. If a subject has 
not had a renal biopsy within the 3-month (prior to screening) required timeframe for study 
eligibility, one may be performed to assess eligibility into the study, 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 to 
receive treatment with VCS. The first 10 subjects will be enrolled into Cohort 1, at a starting 
dose of 7.9 mg BID for Week 1, 15.8 mg BID for Week 2, and a target dose of 23.7 mg BID 
for Weeks 3 to 24. The first dose of study treatment should occur in the morning on Day 2, the 
day after dispensing. Subjects will be contacted by telephone at the end of Week 1 and Week 
2 to be reminded to increase their dose as per Section 7.1.2.1, Voclosporin Study Treatment. 
Evaluable safety and tolerability from the first six subjects from Cohort 1 are required in order 
to determine the dose level for Cohort 2. The dose selected may be higher or lower than 23.7 
mg BID.The maximum dose possible for Cohort 2 will be 39.5 mg (5 capsules) BID. Dosing 
in this group will follow the same cautious approach as Cohort 1, with at a starting dose of 7.9 
mg BID for Week 1, 15.8 mg BID for Week 2, 23.7 mg BID for Week 3 and a maximum dose 
of 39.5 mg BID for Weeks 4 to 24. 
Doses and dose increments smaller than anticipated or an intermediate dose may be proposed 
for Cohort 2 based on the safety and tolerability results from the Cohort 1.  
All subjects will return for assessment of efficacy and safety at Weeks 2, 4, 8, 12, 18, and 24. 
See Schedule of Events, for detailed information regarding visits.  
All subjects, completed or withdrawn from the study, will complete the End of Treatment/Early 
Termination assessments (Visit 8) at Week 24, or at the time of withdrawal, and should attend 
two Safety Follow-up visits at 1 and 2 weeks after completion of treatment (i.e., at Week 25 
(Visit 9) and Week 26 (Visit 10)) (or 7 and 14 days, respectively, following withdrawal) 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. 


 
 
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4.2 
Duration of Subject Participation and Study 
The expected duration of subject participation is up to 36 weeks. The duration of the screening 
period will be approximately 4 weeks to 10 weeks (allowing for visit windows)  and the 
treatment duration is 24 weeks, with further Safety Follow-up visits at 1 and 2 weeks after last 
dose (completion or withdrawal). 


 
 
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5. SELECTION, WITHDRAWAL OF SUBJECTS AND PERMANENT 
DISCONTINUATION OF DRUG 
5.1 
Number of Subjects 
It is anticipated that approximately 20 subjects will be recruited 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 years (or legal age of consent if >18 
years) to 75 years of age, inclusive, at the time of consent. 
3. Primary FSGS diagnosed by renal biopsy within 3 months prior to the screening visit (see 
Appendix 3). 
4. At initial screening assessment and at last qualifying assessment during screening period 
prior to baseline, FSGS subjects must have urine protein creatinine ratio (UPCR) ≥3.0 
mg/mg, serum albumin <3.2 g/dL AND must be treatment-naïve, defined as subjects who 
have not received systemic steroids, cytotoxic or other systemic immunosuppressant 
treatment, and are not expected to require treatment with these medications during the 
study. 
5. All subjects should be treated with ACEIs and/or ARBs unless they have documented 
intolerance or contraindication to these medications. Doses of these agents must be stable 
for at least 2 weeks prior to baseline, with BP ≤150/90 mmHg at the baseline visit (Visit 2). 
a) Subjects with nephrotic edema may be treated with diuretics during the screening 
period. Volume status should be optimized based on the clinical judgment of the 
Investigator and the doses of diuretics must be stable in the 2 weeks prior to baseline. 
b) At the discretion of the Investigator, subjects with hyperlipidemia may be treated with 
lipid-lowering agents (e.g., statins) in accordance with standard clinical practice. Doses 
must be stable in the 2 weeks prior to baseline. 
6. Stable proteinuria, renal function, and BP during the 2 weeks prior to baseline, as assessed 
by the Investigator. Substantial changes in UPCR, eGFR, and/or BP during the screening 
period may be due to treatments administered (e.g., ACEIs and ARBs); and, therefore, may 
interfere with study assessments or outcomes, or may place the subject at increased risk. 
These subjects must be discussed with the medical monitor prior to initiation of study 
treatment. 


 
 
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7. Women of childbearing potential must have a negative serum pregnancy test prior to 
dispensing study treatment. 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. Clinical or histologic evidence of secondary FSGS. 
3. Histologic evidence of collapsing variant FSGS. 
4. eGFR as calculated by the CKD-EPI equation of ≤30 mL/minute/1.73 m2 at initial 
screening assessment or ≤45 mL/minute/1.73 m2 at last qualifying assessment during 
screening period prior to baseline. 
5. Currently taking or expected to require any of the prohibited medications listed in the 
protocol (see Section 7.6.1, Prohibited Medications) at screening or during the study. This 
includes prohibited medications prior to screening as specified in the protocol. 
6. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or expected to 
require dialysis during the study period. 
7. A previous renal transplant or planned renal transplant during the study. 
8. Body mass index >40 kg/m2. 
9. Family history of nephrotic syndrome. 
10. Any known hypersensitivity or contraindication to cyclosporine, or components of any 
cyclosporine drug product. 
11.  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. 


 
 
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• Current or past 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. 
12. Other clinically significant active medical conditions, such as: 
• Severe cardiovascular disease including congestive heart failure, history of cardiac 
dysrhythmia or congenital long QT syndrome. Subjects with 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 are excluded. 
• Liver dysfunction: aspartate aminotransferase, alanine aminotransferase, or bilirubin ≥2.5 
times the upper limit of normal at last qualifying assessment during screening period prior 
to baseline. 
• Chronic obstructive pulmonary disease or asthma requiring oral steroids. 
• Bone marrow insufficiency: white blood cell count <2,500/mm3, absolute neutrophil count 
<1.3 × 103/μL, and/or thrombocytopenia (platelet count <50,000/mm3) at screening or at 
last qualifying assessment during screening period prior to baseline. 
• Current infection requiring intravenous (IV) antibiotics. 
13. Any overlapping autoimmune condition for which the condition or the treatment of the 
condition may affect the study assessments or outcomes (e.g., any condition for which 
additional immunosuppression, including systemic corticosteroids, and/or cytotoxic 
therapy is indicated). Overlapping conditions for which the condition or treatment is not 
expected to affect assessments or outcomes are not excluded. 
14. No vaccines using live organisms, virus or bacterial, are allowed during screening and 
while taking the study treatment. 
15. 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. 
16. 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. 


 
 
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17. Subjects who are pregnant, breast feeding or, if of childbearing potential, not using 
adequate contraceptive precautions. 
18. 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. 
19. Subjects treated in a previous VCS clinical study. 
5.4 
Adequate/Effective Contraception 
Women of childbearing potential must have a negative serum pregnancy test during 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, 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, reproductively competent men are required to use condoms during treatment 
and for at least 6 weeks after cessation of study treatment. In addition, female partners of male 
subjects are recommended to use an effective contraception during their partner’s treatment 
and for at least 6 weeks after the last dose of study treatment. Male subjects are to refrain from 
making sperm donations during treatment and for at least 6 weeks after cessation of study 
treatment. 
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.  
Barrier methods (e.g., condoms, diaphragm, or cervical cap/sponge) when used alone are not 
considered highly 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 and documented throughout the study 
period in order to confirm the method used is considered effective. 


 
 
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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 8), if possible. If 
possible, the subject should also be advised to come for the two Safety Follow-up visits (Visit 9 
and Visit 10) at 1 and 2 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 withdrawal as “withdrawal of consent.” Withdrawn subjects 
will not be replaced. 
5.6 
Discontinuation of Study Treatment 
Discontinuation of study treatment does not necessarily constitute withdrawal from the study.   
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.  
If possible, subjects who are permanently discontinued from study treatment before the 
Week 24 visit should undergo all study assessments up to and including the Week 24 (or Early 
Termination Visit – Visit 8) and Safety Follow-up visits where appropriate. All subjects that 
discontinue study treatment should attend at least 2 further assessments after the last dose of 
study drug.  
Guidance on when study treatment must be discontinued is in Section 7.4, Voclosporin Dose 
Modification.  
5.6.1 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 discontinued 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 discontinued 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 
Not applicable. 


 
 
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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 
Pharmaceuticals Inc (Aurinia). 
7.1.1 Voclosporin – Study Treatment 
Company Code: 
 
Chemical Name: 
 
Empirical Formula: 
 
Generic Name: 
Voclosporin 
Dosage Form: 
Softgel capsules 
Strength: 
7.9 mg of VCS per softgel capsule 
Manufacturer: 
 
7.1.2 Dosing Guidelines 
7.1.2.1 Voclosporin 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. 
The dosing of VCS for Cohort 1 will be as follows: 
• Week 1: 1 capsule (7.9 mg) orally (PO), BID 
• Week 2: 2 capsules (15.8 mg) PO, BID 


 
 
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• Weeks 3 to 24 – Week 24: 3 capsules (23.7 mg) PO, BID 
Evaluable safety and tolerability data from the first six subjects from Cohort 1 are required in 
order to make the decision to escalate to a higher dose level for Cohort 2. The selected dose 
may be higher or lower than 23.7 mg BID. The maximum dose possible for Cohort 2 will be 
39.5 mg (5 capsules) BID.  Should this dose be selected the following dosing regimen will be 
followed: 
• Week 1: 1 capsule (7.9 mg) PO, BID 
• Week 2: 2 capsules (15.8 mg) PO, BID 
• Week 3: 3 capsules (23.7 mg) PO, BID 
• Week 4: 5 capsules (39.5 mg) PO, BID 
All subjects will be contacted by telephone at the end of Week 1 and Week 2 (and Week 3, if 
applicable) to be reminded to increase their dose. 
All unused study treatment (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 
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 
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. 
7.3 
Site Supply, Storage, Accountability 
7.3.1 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. 


 
 
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7.3.2 Storage 
Voclosporin softgel 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. 
7.3.3 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 
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, one 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’s approval of 
the process and forward the certificate of destruction to Aurinia. 
7.4 
Voclosporin Dose Modification 
7.4.1 Discontinuation of Study Therapy Due to Non-response 
During the treatment period, any case where the subject experiencing a worsening of 
proteinuria, or no improvement in proteinuria from baseline, once the highest permitted dose 
of study drug has been achieved, should be discussed with the Medical Monitor.  Subjects may 
be allowed to add treatment with corticosteroids (IV or oral) while continuing with study drug, 
or may be discontinued from study treatment and transitioned to standard of care treatment 


 
 
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7.4.2 Deterioration in Renal Function 
Serum creatinine and eGFR utilizing the CKD-EPI formula, as reported by the central 
laboratory, will be used for the assessment of renal function at every visit including 
unscheduled visits.  
It is recognized that eGFR may be unreliable at higher values (>100 mL/min/1.73 m2). FSGS 
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 [28], with or without kidney 
damage.  
7.4.2.1 Decrease in eGFR >30% and eGFR <90 mL/min/1.73 m2 
During the treatment period, any subject experiencing a >30% decrease in eGFR from baseline 
(baseline eGFR is defined as the last assessment prior to first dose of study treatment) to <90 
mL/min/1.73 m2, will have study treatment interrupted until a repeat test can be performed 
(unscheduled visit to be completed within 48 hours). If the decrease is confirmed at the 
unscheduled visit  and not due to potential contributing factors (e.g., high baseline eGFR, the 
addition or modification of non-steroidal anti-inflammatory drugs (NSAIDs), ACEIs, ARBs, 
a concurrent state of dehydration, overdosing with study treatment, renal flare, etc.), the case 
should be discussed with the Medical Monitor, the study treatment should continue to be 
withheld, and eGFR retested within 48 hours. (Note: doses of ACEIs, ARBs, diuretics, and/or 
lipid lowering therapy are to remain stable throughout the study.) 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. 
7.4.2.2 Decrease in eGFR ≤30% and eGFR <90 mL/min/1.73 m2 
During the treatment period, any subject having a ≤30% reduction in eGFR to 
<90 mL/min/1.73 m2 should have the influence of potential contributing factors (as described 
in Section 7.4.2.1 Decrease in eGFR >30% and eGFR <90 mL/min/1.73 m2) ruled out and 
appropriate corrective action taken. Any subject having a >20 to ≤30% reduction compared to 
baseline in eGFR to <90 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 should 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. 
7.4.2.3 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. 


 
 
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7.5 
Procedures for Overdose 
Based on clinical experience with VCS, 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. 
7.6 
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. 
7.6.1 Prohibited Medications 
The following medications cannot be taking during the study: 
• Systemic corticosteroids (oral or IV) unless approved by the Medical Monitor 
• Cytotoxic or other systemic immunosuppressants  
• Initiation of new treatment or change in dosage of ARBs and/or ACE inhibitors within 
2 weeks prior to baseline  
• Vaccines using live organisms, viral or bacterial 
• 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 5 contains a summary of additional treatment and food restrictions. 
7.6.2 Allowed Concomitant Medications 
These medications are permitted during the study: 
• Doses of ACEIs and/or ARBs as described in the Inclusion Criteria (see Section 5.2, 
Inclusion Criteria) 


 
 
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• Doses of diuretics as described in the Inclusion Criteria (see Section 5.2, Inclusion 
Criteria)  
• Doses of statins as described in the Inclusion Criteria (see Section 5.2, Inclusion 
Criteria) 
• Topical steroids (e.g., nose, scalp, skin, inhaled) 
• Herbal supplements can be used with caution and with approval by the Medical 
Monitor 
Treatments which may be used as medically indicated, according to the judgment of the 
Investigator can be found in Appendix 4. 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 5. 
7.7 
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, the mean 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 withheld, an unscheduled visit 
arranged within 48 hours for repeat BP assessment, 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 [9]. 
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 (FMV) and from standard 
urinalysis results. If the FMV is for some reason not available at Day 1, Week 12 or Week 24, 
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 1) will 
be drawn in accordance with the Schedule of Events. 
Table 1 
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) 
All  
 
Differential (absolute and %) 
 Bands 
 Basophils 
 Eosinophils 
 Lymphocytes 
 Monocytes 
 Neutrophils 
All 
 


 
 
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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 
All  
 
Cholesterol (total, HDL, and LDL) & 
triglycerides 
Creatine kinase 
Day 1 and Week 24 
 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
All 
Glycosylated hemoglobin (HbA1c) 
Day 1 and Week 24 
Lactic dehydrogenase (LDH) 
Magnesium 
All 
Phosphorous, inorganic 
Day 1 and Week 24 
Potassium 
Protein, total 
Sodium 
All 
Urinalysis and urine 
microscopy 
Complete urinalysis (to include urine protein, 
creatinine, blood, urine microscopy).  
All except for stability 
assessment visits during the 
screening period 
FMV urine 
collection 
FMV will be performed to analyze UPCR.  
All 
24-hour urine 
UPCR 
Day 1, Week 12 and Week 24 
Note that 24-hour urine 
collection should be scheduled so 
as not to coincide with the FMV 
sampling due on the day of the 
study visit 


 
 
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Test Type 
Test Parameters 
Collection at Visits 
Pregnancy Test 
For females of childbearing potential.  
Serum pregnancy test to be 
evaluated at central laboratory at 
Screening, and Week 24; urine 
pregnancy test will be performed 
locally at all other applicable 
visits. 
Serology 
Cytomegalovirus 
Hepatitis A, B, and C 
Hepatitis B surface antigen (HBsAg) 
Screening (including stability 
assessments) 
 
Special Tests 
Estimated glomerular filtration rate (eGFR) 
All 
Biomarkers 
Urine nephrin 
Urine synaptopodin 
Serum TGF-β 
Day 1, Week 4 and Week 24 
Notes: FMV=first morning void; HDL=High-density lipoprotein; LDL=Low-density lipoprotein; UPCR=urine protein creatinine ratio. 
 
The total amount of blood that will be collected during the study from an individual subject is 
approximately 200 mL over 34 weeks. 
For details on whether laboratory abnormalities should be reported as AEs and on the 
follow-up required in such cases, see Section 10.2.4 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 FSGS-related manifestations which will 
also be recorded. A complete physical examination will be conducted at the initial screening 
assessment, 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. 
 


 
 
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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 heart rate (HR) 
• Body temperature (°C or °F) 
• Weight (kg) 
• Height (cm) 
To avoid variability, the same method of obtaining body temperature should be used 
throughout the study. 
At stability assessments, BP only will be included. 
Height will be recorded at the initial screening assessment only.  
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 mean BP measure is  >130/80 mmHg (determined 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 7.7, 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 the initial screening assessment, Day 1, and Week 24. 


 
 
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9.1.4.1 Procedures to Manage a Treatment-Emergent Increase in QTcF 
In the event that a subject has a corrected QT interval duration corrected for heart rate using 
method of Fridericia (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,  study treatment will be 
discontinued and the subject followed until the QTcF value either returns to baseline 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 QoL Assessments 
Assessments for QoL will be conducted at Day 1, Week 24, Week 25 and Week 26. 
The PROMIS assesses physical function, pain interference, and fatigue. See Appendix 6. 
The KDQOL-SFTM survey is a kidney disease-specific measure of QoL that assesses general 
health, kidney disease and its effects on daily life, and satisfaction with care. See Appendix 7. 
9.1.6 Voclosporin Pharmacokinetic and Biomarker Assessment 
Blood samples for PK assessments will be taken at Week 4 and Week 24. PK samples will be 
drawn prior to study treatment dosing (trough sample), and at 1, 2 and 4 hours post-dose. These 
samples will be analyzed for VCS. Should a subject experience a serious adverse event (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 treatment, further PK samples are not required. 
Blood and urine samples for biomarker assessments will be taken at Day 1, Week 4 and Week 
24, samples will be collected prior to study treatment dosing.  
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 


 
 
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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 and Stability Assessment Procedures 
The duration of the screening period will be approximately 4 weeks to 10 weeks (allowing for 
visit windows)and will consist of an initial screening assessment and 2 to 4 stability 
assessments to ensure that subjects meet eligibility criteria. 
The initial screening assessment will include provision of informed consent; complete physical 
examination; medical history (including FSGS history); vital signs measurements, including 
weight and height; 12-lead ECG; blood and urine sample collection for central laboratory 
assessments, urinalysis, and urine microscopy; FMV urine collection (for determination of 
UPCR); a serum pregnancy test (for women of childbearing potential); and review of prior and 
concomitant medications and entry criteria. Any AEs which occur after informed consent will 
be recorded.  
Stability assessments will occur at 14-day intervals (±3 days) with the first assessment 
approximately 2 weeks after the initial screening assessment visit. Stability assessments 1 and 
2 are mandatory; assessments 3 and 4 are optional if additional time is required for the subject’s 
clinical status to stabilize. These stability assessment visits will include BP determination; 
blood sample collection for central laboratory assessments; FMV urine collection (for 
determination of UPCR); a serum pregnancy test (for women of childbearing potential); review 
of any AEs; and review of concomitant medications and entry criteria.  
These renal disease stability assessments will be evaluated to ensure eligibility with respect to 
entry criteria for UPCR and eGFR. 
Note that the laboratory assessments and FMV results of the last stability assessment will be 
used as the qualifying values for eligibility.  
FMV urine samples (for determination of UPCR) will be collected at all visits during the 
screening period and must be returned and the results evaluated prior to Baseline/Day 1. If the 
FMV is for some reason not available at Day 1, Week 12 or Week 24, 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 samples will be drawn according to Table 1. 
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. 


 
 
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Women of childbearing potential must have a negative serum pregnancy test result before 
baseline.  
If a subject has not met the requirements in Inclusion Criteria #3 due to not having renal biopsy 
result within the required time frame, a renal biopsy can be performed as per local procedures, 
after signing the study consent, provided the results can be obtained and reviewed prior to 
baseline. 
9.2.2 Treatment Procedures 
Only subjects who meet all of the inclusion and none of the exclusion criteria will be eligible 
for study treatment.  
Study medication will be dispensed per the Schedule of Events, beginning on Day 1. Subjects 
will take their first dose of study medication on Day 2. Women of childbearing potential must 
have a negative serum pregnancy test during Screening and a negative urine pregnancy test 
result on Day 1 prior to dispensing of study treatment.  
Subjects in Cohort 1, will be contacted by telephone at the end of Week 1 as a reminder to 
increase their dose to 2 capsules (15.8 mg) BID for 1 week, starting at Week 2. Subjects will 
be contacted again by telephone at the end of Week 2 as a reminder to increase their dose to 3 
capsules (23.7 mg) BID, starting at Week 3, for the remainder of the treatment period (see 
Section 7.1.2.1, Voclosporin Study Treatment).  
Subjects in Cohort 2, will also be contacted by telephone at the end of each week, as required 
up to the end of Week 3, as a reminder to increase their dose of study medication to the 
maximum dose selected for the second cohort. 
Subjects will complete all assessments per the Schedule of Events at Day 1 and at Weeks 2, 4, 
8, 12 and 18.  
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: 
• PROMIS and KDQOL-SFTM QoL questionnaires will be answered by the subject, as 
first study procedure, at Day 1/Baseline. 
• Abbreviated physical examination at Day 1. 
• Vital signs including weight. 
• Standard 12-lead ECG at Day 1. 


 
 
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• Blood and urine sample collection for analysis at central laboratory. 
• FMV urine sample collection. 
• Urine pregnancy testing at Day 1 (before dispensing study treatment)  
• AEs. 
• Concomitant medication. 
• Returned capsule count and drug accountability (except Day 1). 
9.2.3 End of Study (or Early Termination) Procedures 
On completion of treatment at Week 24 or earlier if subject is withdrawn, all assessments for 
Visit 8 (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: 
• PROMIS and KDQOL-SFTM QoL  
• Abbreviated physical examination  
• Vital signs including weight 
• Standard 12-lead ECG 
• Blood and urine sample collection for analysis at central laboratory 
• FMV urine sample collection 
• Serum pregnancy testing 
• Pharmacokinetic and biomarker sampling 
• AEs 
• Concomitant medication 
• Returned capsule count and drug accountability 
• Repeat renal biopsy may be performed on a subset of patients 


 
 
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• Confirmation of completion/discontinuation 
9.2.4 Follow-up Procedures 
All subjects who complete the study or withdraw before Week 24 will be followed up at 1 
week (±3 days) and 2 weeks (±3 days) after their last study treatment dose to collect any new 
AEs and concomitant medications. These 2 visits (Visit 9 and Visit 10) will be conducted as 
in-clinic visits. 
Assessments for the follow-up visit are as follows: 
• PROMIS and KDQOL-SFTM QoL 
• Vital signs including weight 
• Blood and urine sample collection for analysis at central laboratory  
• FMV urine sample collection 
• Concomitant medication 
• AEs 
• Confirmation of completed follow-up visit 
9.2.5 Unscheduled Visit 
Unscheduled visits may be performed during the course of the study for safety reasons. . Only 
the data relevant to the purpose of the visit will be collected in the source documents and eCRF. 
Additionally, unscheduled visits will be registered in the electronic data capture (EDC) system.  
An unscheduled visit is requested in the following cases: 
• After dose reduction at any time during the study (unscheduled visit within 2 weeks)  
• QTcF value exceeding 500 msec, or an increase >60 msec from baseline, where the 
ECG will be repeated (confirmed) at an unscheduled visit within 24 hours  
• Decrease in eGFR >30% compared to baseline (unscheduled visit within 48 hours), or 
a decrease in eGFR >20-30% compared to baseline (unscheduled visit within 
approximately 2 weeks) 
• Symptomatic hypertension: Systolic BP is ≥165 mmHg or diastolic BP is ≥105 mmHg 
with symptoms of hypertension, see Section 7.7 (unscheduled visit within 48 hours)  


 
 
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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 
one 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 
events will also usually be considered serious. 
Hospitalizations that have been scheduled prior to the subject signing the informed consent 
form (ICF), although not recorded as SAEs, must be documented in the subject’s source 
documents. A renal biopsy performed as part of the study to verify eligibility will not be 
considered an SAE. Any complication experienced during a renal 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 ability to function. 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. 
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 


 
 
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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 treatment 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 treatment 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. 
10.2.4 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. 


 
 
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If the Investigator considers such an AE as serious it must be reported as an SAE. 
10.2.5 Abuse, Misuse, Overdose and Medication Error 
All AEs of special interest such as study drug 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 observed from time of signing of the ICF will be recorded in the subject's source 
documentation. This applies to all AEs regardless of presumed relationship to the study drug. 
For screen failure subjects, any AEs and SAEs occurring during the screening period (after 
informed consent) will be recorded in the subject’s source documentation only and will not be 
collected on the eCRF. Adverse events leading to discontinuation of study drug must be 
collected. 
If any AE is reported, the date of onset, relationship to study treatment, relationship to disease 
under study, 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 one 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 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. Note that for screen 
failure subjects, any AEs and SAEs occurring during the screening period will be recorded in 
the subject’s source documentation only. For enrolled subjects (i.e., those who successfully 
complete screening), the AE reporting period ends at the second Safety Follow-up visit 
(Visit 10). 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. 


 
 
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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 
For screen failure subjects, any SAEs occurring during the screening period (after informed 
consent) will be recorded in the subject’s source documentation only and will not be collected 
on the eCRF. 
For enrolled subjects (i.e., those who successfully complete screening), 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 drug or 
relationship to disease under study. For enrolled subjects, all SAEs will be recorded in the AE 
section of the subject’s eCRF and source documentation. 
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: 
 
If notification is made via email or fax, site staff must enter the SAE information into the 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 or relationship to disease 
under study, 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. 


 
 
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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 9) 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 drug-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 Institutional Review Board (IRB)/Ethics Committee 
(EC)/Independent Ethics Committee (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. 


 
 
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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.  
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 
Not applicable. 


 
 
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12. DATA AND SAFETY MONITORING BOARD PROCEDURES 
Not applicable. 


 
 
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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 approximately 20 subjects, 10 subjects in each of 2 cohorts.  
As this is an exploratory study, sample size calculations are not required. Descriptive statistics 
will be used and the results will only be hypothesis-generating. 
13.3 Populations 
13.3.1 Intent-to-Treat Population 
The intent-to-treat (ITT) population will consist of all enrolled subjects (non-screening 
failures) and will be used for all efficacy analyses. 
13.3.2 Safety Set 
The safety set will consist of all subjects who have taken at least 1 dose of study treatment.  
13.3.3 Per-protocol Set 
The per-protocol set (PPS) 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 SAP. 
13.4 Datasets 
Assessments taken at each visit will be analyzed using 2 different datasets. The first will be 
the observed cases dataset whereby all values collected will contribute to the dataset. A second 
dataset will be used for summaries and analyses incorporating data carried forward from a 
subject’s last known value. This dataset will be referred to as the last observation carried 
forward dataset and as such, all subjects with any post-baseline efficacy assessment will 
contribute to the Week 24 analyses. 
13.5 Background and Demographic Characteristics 
Demographic and clinical disease characteristics will be summarized.  


 
 
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13.6 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, SD, median, minimum, 
and maximum) and frequency tables.  
13.7 Concomitant Therapy 
All concomitant medications will be coded by the World Health Organization Anatomical 
Therapeutic Chemical (ATC) Drug Reference List classification. The version used will be 
provided in the clinical study report. 
13.8 Efficacy Evaluations 
Primary and secondary endpoints will be assessed overall and for each individual cohort. 
13.8.1 Primary Endpoint 
The primary endpoint is the proportion of subjects with remission of proteinuria at Week 24 
based on the following parameters: 
• Complete remission: UPCR of <0.3 mg/mg 
OR 
• Partial remission: UPCR ≥0.3 mg/mg and <3.0 mg/mg with >50% reduction in UPCR 
from baseline 
13.8.2 Secondary Endpoints 
The following are defined as secondary endpoints: 
• Proportion of subjects with complete remission or partial remission of proteinuria at Weeks 
8 and 12 
• Proportion of subjects with complete remission of proteinuria at Weeks 8, 12, and 24 
• Proportion of subjects with UPCR <0.5 mg/mg at Weeks 8, 12, and 24 
• Proportion of subjects with partial remission of proteinuria at Weeks 8, 12, and 24 
• Time to first occurrence of complete or partial remission of proteinuria 
• Time to first occurrence of complete remission of proteinuria 


 
 
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• Time to first occurrence of partial remission of proteinuria 
• Time to first occurrence of 50% reduction in UPCR from baseline 
• Duration of UPCR <0.3 mg/mg 
• Change from baseline in UPCR at each time point 
• Proportion of subjects with a confirmed >30% decrease from baseline in eGFR (utilizing 
the CKD-EPI formula) at each time point (Baseline eGFR is defined as the last assessment 
prior to first dose of study treatment)  
• Proportion of subjects with a confirmed >30% increase in eGFR from the final visit (Week 
24 or last on-treatment visit, for subjects who discontinue prematurely) to the second Safety 
Follow-up visit (Visit 10) 
• Change in UPCR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10)  
• Change in eGFR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10) 
• Change from baseline in serum creatinine, serum albumin, and eGFR at each time point 
• QoL assessments 
− 
Mean change in PROMIS measures at Week 24 
− 
Change from baseline in KDQOL-SFTM score at Week 24 
• Safety and tolerability over 24 weeks 
• Renal biopsy: descriptive analyses of changes in histopathology will be evaluated in post-
treatment (24 weeks) renal biopsies in a subset of patients 
• Change from baseline to Week 4 and 24 in the following biomarkers:  
− 
Urine nephrin 
− 
Urine synaptopodin 
− 
Serum TGF-β 
 


 
 
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13.9 Statistical and Analytical Methods 
All statistical analyses relating to the primary and secondary objectives will be undertaken at 
study closure and will incorporate all available data. 
In order to aid dose decisions for cohort 2, an analysis of the first 6 subjects in cohort 1 will be 
undertaken once the 6th subject reaches week 12. 
Given the small sample size, all analyses will be descriptive in nature.  
Binary remission endpoints will be summarized using counts and proportions while continuous 
data will be summarized using means, SDs, medians, minimums and maximums. Kaplan-
Meier methodology will be used for the analysis of time-to endpoints.  Confidence intervals 
for proportions may be calculated but it is recognized that such intervals, being based on 20 
patients, will be very wide. As an example, the 95% Clopper-Pearson CI for a proportion of 
30% based on 20 patients is (11.9%, 54.3%). 
The analysis of the primary endpoint, complete or partial remission of proteinuria at Week 24, 
will be conducted on the ITT population and confirmed with the PPS (if applicable). Remission 
of proteinuria will be summarized and an exact 2-sided 95% CI for the remission rate will be 
calculated. 
The analyses of the secondary endpoints will incorporate the use of 2-sided 95% CIs and are 
described below:  
• Binary endpoints will be summarized using counts and proportions along with exact 
2-sided 95% CIs.  
• Endpoints measured as a time-to-event will be displayed using Kaplan-Meier 
methodology. Median time-to-event along with 2-sided 95% CIs will be displayed.  
• Other endpoints will be summarized by visit. Absolute values and differences between 
baseline and each time point up to and including Week 24 will be summarized using means 
and 2-sided 95% CIs. Changes between last on treatment value and post treatment follow-
up will also be summarized.   
Given the nature of the study, additional exploratory analysis will be undertaken as appropriate. 
This may include the reporting of individual case studies. 
13.10 Safety Evaluations 
Specific safety endpoints are as follows: 
• Biochemical (including liver function tests) and hematological laboratory tests 


 
 
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• 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 visit, and as change from baseline. 
Adverse events and diseases 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 and up until 14 
days after last dose will be considered TEAEs, though all AEs after informed consent will be 
recorded. SAEs occurring at any time after informed consent and prior to first study medication 
will be listed.  
All prior and concomitant medications will be summarized using preferred terms and ATC 
Level 2. 
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. 
13.11 Interim Analyses 
There will be no full interim analysis. 
13.12 Other Evaluations 
13.12.1 Pharmacokinetics 
Estimates of VCS 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 [28] and the ICH guidelines for GCP [29]. 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 IRB/EC/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. These 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 
protocol and the completeness, consistency, and accuracy of the data being entered on them. 


 
 
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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) must agree 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 termination 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. 
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 [31]. 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 [32] 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. 
D'Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 
2011;365(25):2398-411. 
2. 
Kikuchi M, Wickman L, Hodgin JB, Wiggins RC. Podometrics as a potential clinical 
tool for glomerular disease management. Semin Nephrol. 2015;35(3):245-55. 
3. 
Konigshausen E, Sellin L. Circulating permeability factors in primary focal segmental 
glomerulosclerosis: 
a 
review 
of 
proposed 
candidates. 
Biomed 
Res 
Int. 
2016;2016:3765608. 
4. 
Reggiani F, Ponticelli C. Focal segmental glomerular sclerosis: do not overlook the 
role of immune response. J Nephrol. 2016;29(4):525-34. 
5. 
Kim JH, Kim BK, Moon KC, Hong HK, Lee HS. Activation of the TGF-beta/Smad 
signaling 
pathway 
in 
focal 
segmental 
glomerulosclerosis. 
Kidney 
Int. 
2003;64(5):1715-21. 
6. 
Yamamoto T, Noble NA, Cohen AH, Nast CC, Hishida A, Gold LI, et al. Expression 
of transforming growth factor-beta isoforms in human glomerular diseases. Kidney Int. 
1996;49(2):461-9. 
7. 
Liao R, Liu Q, Zheng Z, Fan J, Peng W, Kong Q, et al. Tacrolimus protects podocytes 
from injury in lupus nephritis partly by stabilizing the cytoskeleton and inhibiting 
podocyte apoptosis. PLoS One. 2015;10(7):1-16. 
8. 
Kidney disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work 
Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl. 
2012;2:139-274. 
9. 
Investigator’s brochure – Voclosporin - Focal Segmental Glomerulosclerosis. Version 
1.0. Aurinia Pharmaceutical Inc. 2018Feb5. 
10. 
Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, et al. The 
actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of 
cyclosporine A. Nat Med. 2008 Sep;14(9):931-8. 
11. 
Mathieson PW. Proteinuria and immunity - an overstated relationship? N Engl J Med. 
2008 Dec 4;359(23):2492-4. 
12. 
Li X, Zhang X, Li X, Wang X, Wang S, Ding J. Cyclosporine A protects podocytes via 
stabilization of cofilin-1 expression in the unphosphorylated state. Exp Biol Med 
(Maywood). 2014;239(8):922-36. 
13. 
Shen X, Jiang H, Ying M, Xie Z, Li X, Wang H, et al. Calcineurin inhibitors 
cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin 
aminonucleoside in rodent models. Sci Rep. 2016;6:32087. 


 
 
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14. 
Mallipattu SK, He JC. The podocyte as a direct target for treatment of glomerular 
disease? Am J Physiol Renal Physiol. 2016;311(1):F46-51. 
15. 
Wakamatsu A, Fukusumi Y, Hasegawa E, Tomita M, Watanabe T, Narita I, et al. Role 
of calcineurin (CN) in kidney glomerular podocyte: CN inhibitor ameliorated 
proteinuria by inhibiting the redistribution of CN at the slit diaphragm. Physiol Rep. 
2016;4(6). 
16. 
Beaudreuil S, Lorenzo HK, Elias M, Nnang Obada E, Charpentier B, Durrbach A. 
Optimal management of primary focal segmental glomerulosclerosis in adults. Int J 
Nephrol Renovasc Dis. 2017;10:97-107. 
17. 
Duncan N, Dhaygude A, Owen J, Cairns TD, Griffith M, McLean AG, et al. Treatment 
of focal and segmental glomerulosclerosis in adults with tacrolimus monotherapy. 
Nephrol Dial Transplant. 2004;19(12):3062-7. 
18. 
Goumenos DS, Tsagalis G, El Nahas AM, Shortland JR, Davlouros P, Vlachojannis 
JG, 
et 
al. 
Immunosuppressive 
treatment 
of 
idiopathic 
focal 
segmental 
glomerulosclerosis: a five-year follow-up study. Nephron Clin Pract. 2006;104(2):c75-
82. 
19. 
Braun N, Schmutzler F, Lange C, Perna A, Remuzzi G, Risler T, et al. 
Immunosuppressive treatment for focal segmental glomerulosclerosis in adults. The 
Cochrane database of systematic reviews. 2008(3):CD003233. 
20. 
Cattran DC, Appel GB, Hebert LA, Hunsicker LG, Pohl MA, Hoy WE, et al. A 
randomized trial of cyclosporine in patients with steroid-resistant focal segmental 
glomerulosclerosis. North America Nephrotic Syndrome Study Group. Kidney Int. 
1999;56(6):2220-6. 
21. 
Laurin L-P, Nachman PH, Foster BJ. Calcineurin inhibitors in the treatment of primary 
focal segmental glomerulosclerosis: a systematic review and meta-analysis of the 
literature. Can J Kidney Health Dis. 2017;4:1-14. 
22. 
Cattran DC. Cyclosporine in the treatment of idiopathic focal segmental 
glomerulosclerosis. Semin Nephrol. 2003;23(2):234-41. 
23. 
Gipson DS, Trachtman H, Kaskel FJ, Radeva MK, Gassman J, Greene TH, et al. 
Clinical trials treating focal segmental glomerulosclerosis should measure patient 
quality of life. Kidney Int. 2011;79(6):678-85. 
24. 
Gipson DS, Trachtman H, Kaskel FJ, Greene TH, Radeva MK, Gassman JJ, et al. 
Clinical trial of focal segmental glomerulosclerosis in children and young adults. 
Kidney Int. 2011;80(8):868-78. 
25. 
Hogg RJ, Friedman A, Greene T, Radeva M, Budisavljevic MN, Gassman J, et al. 
Renal function and proteinuria after successful immunosuppressive therapies in 
patients with FSGS. Clin J Am Soc Nephrol. 2013;8(2):211-8. 


 
 
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26. 
Ren H, Shen P, Li X, Pan X, Zhang W, Chen N. Tacrolimus versus cyclophosphamide 
in steroid-dependent or steroid-resistant focal segmental glomerulosclerosis: a 
randomized controlled trial. Am J Nephrol. 2013;37(1):84-90. 
27. 
Wiseman AC. Immunosuppressive medications. Clin J Am Soc Nephrol. 2016 
Feb;11:332-43. 
28. 
KDOQI clinical practice guidelines for chronic kidney disease: evaluation, 
classification, and stratification, 2002. [assessed 2014 Sep 2]. Available from: 
http://www2.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm.  
29. 
World Medical Association Declaration of Helsinki. Ethical principles for medical 
research involving human subjects. 2013 Oct. 
30. 
ICH Harmonised Tripartite Guideline.: Guideline for good clinical practice. E6 (R1) 
1996 Jun 10. 
31. 
Pharmaceutical Research and Manufacturers of America [Internet]. PhRMA principles 
and guidelines: public disclosure of clinical trial results. 2009. Available from: 
Available from:  https://www.phrma.org/codes-and-guidelines/phrma-principles-on-
conduct-of-clinical-trials. 
32. 
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. 
33. 
Reiser J, Fervenza FC, Sethi S. Epidemiology, classification, and pathogenesis of focal 
segmental glomeruloschlerosis. UpToDate.com [Internet]. 2017 Jul 6 [cited 2018 Feb 
12]. Available from: https://www.uptodate.com 
 
 


 
 
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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 
after the screening period (including stabilization visits) in this trial (see Section 7.6.1, 
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 
Classification of FSGS 
The epidemiology, classification and pathogenesis of FSGS has been reviewed by Reiser et al, 
2017 [33]. 
According to this review, FSGS “is a histologic lesion, rather than a specific disease entity, 
that is commonly found to underlie the nephrotic syndrome in adults and children, particularly 
in the United States, Brazil, and many other countries. FSGS is characterized by the presence 
of sclerosis in parts (segmental) of some (focal) glomeruli on light microscopic examination 
of a kidney biopsy specimen.”  
According to this review, FSGS can be classified into the following etiologies, based upon the 
known and/or postulated causes of this histologic pattern: 
• “Primary or idiopathic FSGS, which most often presents with the nephrotic syndrome.”  
• “Secondary FSGS, which most often presents with non-nephrotic proteinuria and, 
commonly, some degree of renal insufficiency. This category most commonly refers to 
FSGS that develops as an adaptive response to glomerular hypertrophy or hyperfiltration. 
This includes disorders associated with a reduced renal mass and/or renal vasodilation, 
such as unilateral renal agenesis. In addition, a nonspecific pattern of secondary FSGS can 
result from scarring produced by a previous injury (due to a variety of conditions, including 
active IgA nephropathy, vasculitis, and LN). Other secondary causes of FSGS include 
drugs and toxins (including heroin, interferon, and pamidronate) and viral infections 
(particularly HIV).” 
• “Genetic causes of FSGS, which may present early in childhood with massive proteinuria 
and nephrotic syndrome or in adolescence or adulthood with less massive proteinuria.”  
Biopsy and diagnosis: According to Reiser et al, “precise quantification of sclerotic glomeruli 
requires three-dimensional morphometric analysis of entire glomeruli and the examination of 
sufficient glomeruli to ensure that the biopsy specimen is representative of glomeruli in the 
whole kidney. Kidney biopsies with few glomeruli (i.e., fewer than 15) cannot confidently 
exclude the diagnosis of FSGS, and, due to sampling error, some cases will be misclassified 
as minimal change disease.” 
“In patients who are found to have a FSGS lesion by light microscopy, the following approach 
can be used to distinguish between those with primary and secondary FSGS: 


 
 
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• Patients who present with nephrotic syndrome (ie, urine protein excretion >3.5 g/day and 
hypoalbuminemia), who exhibit extensive foot process effacement (≥80 percent) on EM 
[electron microscopic] examination, and who have no identifiable risk factors associated 
with secondary FSGS (eg, viral infection, drugs) most likely have primary FSGS, although 
genetic forms of FSGS lesions cannot always be excluded with confidence. Thus, primary 
FSGS is always a diagnosis of exclusion. 
• Patients who present with subnephrotic (ie, <3.5 g/day in an adult) or nephrotic-range 
proteinuria and a normal serum albumin concentration (ie, without nephrotic syndrome) 
and segmental foot process effacement (<80 percent) on EM [electron microscopic] 
examination most likely have secondary FSGS.” 
 
 


 
 
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Appendix 4 
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. 
• At the discretion of the Investigator, subjects with hyperlipidemia may be treated with 
lipid lowering agents (e.g., statins) in accordance with standard clinical practice. Doses 
must be stable in the 2 weeks prior to baseline. 
• Subjects with nephrotic edema may be treated with diuretics during the screening 
period. Volume status should be optimized based on the clinical judgment of the 
Investigator and the doses of diuretics must be stable in the 2 weeks prior to baseline. 
• ACEIs, ARBs, and aliskerin and other therapies are recommended, as per standard 
guidelines, but if used their dose must be stable throughout the study. Subjects 
receiving ACEIs or ARBs must be on a stable dose for at least 2 weeks prior to baseline.  


 
 
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• In the case of uncontrolled hypertension (systolic BP >165 mmHg or 
diastolic >105 mmHg on two successive measurements), the addition of a diuretic or 
calcium channel blocker only are permitted, together with dose decreases or 
interruption of study treatment per the instructions in Section 7.7, Increased Blood 
Pressure.  
 
 


 
 
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Appendix 5 
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 VCS 
metabolism 
ACEIs and ARBs 
Stable dose for at least 2 
weeks prior to baseline 
Change or 
commencement 
prohibited 
Interfere with 
primary endpoint 
assessment 
Foods 
Grapefruit and grapefruit 
juice 
 
24 hours 
 
Prohibited 
 
May affect the 
metabolism of VCS 
Notes:  ACEI=Angiotensin converting enzyme inhibitor; ARB=Angiotensin receptor blocker; NSAID=Non-steroidal anti-inflammatory 
drug; P-gp=P-glycoprotein; VCS=Voclosporin. 
 
 


 
 
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Appendix 6 
PROMIS QoL Assessment 
The PROMIS QoL assessment includes three questionnaires: 
• Physical Function – Short Form 10a (PROMIS® Item Bank v2.0) 
• Fatigue – Short Form 8a (PROMIS® Item Bank v1.0) 
• Pain Interference – Short Form 8a (PROMIS® Item Bank v1.0)  


 
 
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Appendix 7 
KDQOL-SFTM QoL Assessment Version 1.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Kidney Disease and Quality of Life™ Short Form  (KDQOL-SF™)
English Version 1.3
Copyright © 1993, 1994, 1995 by RAND and the University of Arizona
Your Health
– and –
Well-Being
Kidney Disease and Quality of Life (KDQOL-SF™ 1.3)
This survey asks for your views about your health. This information
will help keep track of how you feel and how well you are able to do
your usual activities.
Thank you for completing these questions!


Study of Quality of Life
For Patients on Dialysis
What is the purpose of the study?
This study is being carried out in cooperation with physicians and their patients.  The
purpose is to assess the quality of life of patients with kidney disease.
What will I be asked to do?
For this study, we want you to complete a survey today about your health, how you
feel and your background.
Confidentiality of information?
We do not ask for your name.  Your answers will be combined with those of other
participants in reporting the findings of the study.  Any information that would permit
identification of you will be regarded as strictly confidential.  In addition, all
information collected will be used only for purposes of the study, and will not be
disclosed or released for any other purpose without your prior consent.
How will participation benefit me?
The information you provide will tell us how you feel about your care and further
understanding about the effects of medical care on the health of patients.  This
information will help to evaluate the care delivered.
Do I have to take part?
You do not have to fill out the survey and you can refuse to answer any question.
Your decision to participate will not affect your opportunity to receive care.


Page 1
Your Health
This survey includes a wide variety of questions about your health and
your life.  We are interested in how you feel about each of these issues.
1. In general, would you say your health is:  [Mark an 
 in the one box
that best describes your answer.]
Excellent
Very good
Good
Fair
Poor
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
2. Compared to one year ago, how would you rate your health in
general now?
Much better
now than
one year
ago
Somewhat
better now
than one
year ago
About the
same as
one year
ago
Somewhat
worse now
than one
year ago
Much
worse now
than one
year ago
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5


Page 2
3. The following items are about activities you might do during a
typical day.  Does your health now limit you in these activities?  If so,
how much?  [Mark an 
 in a box on each line.]
Yes,
limited a
lot
Yes,
limited a
little
No, not
limited
at all
a
Vigorous activities, such as running, lifting
heavy objects, participating in strenuous
sports ............................................................
M
M
M
 1.........
 2 ........
 3
b
Moderate activities, such as moving a table,
pushing a vacuum cleaner, bowling, or
playing golf ....................................................
 1.........
 2 ........
 3
c
Lifting or carrying groceries ............................
 1.........
 2 ........
 3
d
Climbing several flights of stairs ......................
 1.........
 2 ........
 3
e
Climbing one flight of stairs.............................
 1.........
 2 ........
 3
f
Bending, kneeling, or stooping ........................
 1.........
 2 ........
 3
g
Walking more than a mile
 1.........
 2 ........
 3
h
Walking several blocks ...................................
 1.........
 2 ........
 3
i
Walking one block..........................................
 1.........
 2 ........
 3
j
Bathing or dressing yourself............................
 1.........
 2 ........
 3


Page 3
4. During the past 4 weeks, have you had any of the following problems
with your work or other regular daily activities as a result of your
physical health?
Yes
No
M
M
a
Cut down the amount of time you spent on work
or other activities ................................................
 1.........
 2
b
Accomplished less than you would like................
 1.........
 2
c
Were limited in the kind of work or other
activities.............................................................
 1.........
 2
d
Had difficulty performing the work or other
activities (for example, it took extra effort)...........
 1.........
 2
5. During the past 4 weeks, have you had any of the following problems
with your work or other regular daily activities as a result of any
emotional problems (such as feeling depressed or anxious)?
Yes
No
M
M
a
Cut down the amount of time you spent on work
or other activities ................................................
 1.........
 2
b
Accomplished less than you would like................
 1.........
 2
c
Didn’t do work or other activities as carefully as
usual..................................................................
 1.........
 2


Page 4
6. During the past 4 weeks, to what extent has your physical health or
emotional problems interfered with your normal social activities with
family, friends, neighbors, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
7. How much bodily pain have you had during the past 4 weeks?
None
Very
mild
Mild
Moderate
Severe
Very
severe
M
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
  
 6
8. During the past 4 weeks, how much did pain interfere with your
normal work (including both work outside the home and
housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5


Page 5
9.
These questions are about how you feel and how things have been
with you during the past 4 weeks.  For each question, please give
the one answer that comes closest to the way you have been feeling.
How much of the time during the past 4 weeks…
All
 of the
time
Most
of the
time
A good
bit
 of the
time
Some
of the
time
A little
of the
time
None
of the
time
M
M
M
M
M
M
a
Did you feel full of
pep?.............................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
b
Have you been a very
nervous person? ...........
 1........
 2 .......
 3........
 4 .......
 5.......
 6
c
Have you felt so down
in the dumps that
nothing could cheer
you up?........................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
d
Have you felt calm and
peaceful?......................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
e
Did you have a lot of
energy? ........................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
f
Have you felt
downhearted and blue? .
 1........
 2 .......
 3........
 4 .......
 5.......
 6
g
Did you feel worn out?..
 1........
 2 .......
 3........
 4 .......
 5.......
 6
h
Have you been a
happy person?..............
 1........
 2 .......
 3........
 4 .......
 5.......
 6
i
Did you feel tired?........
 1........
 2 .......
 3........
 4 .......
 5.......
 6


Page 6
10. During the past 4 weeks, how much of the time has your physical
health or emotional problems interfered with your social activities
(like visiting with friends, relatives, etc.)?
All
of the time
Most
of the time
Some
of the time
A little
of the time
None
of the time
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
11. Please choose the answer that best describes how true or false each
of the following statements is for you.
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false
a 
I seem to get sick
a little easier than
other people ..........
M
M
M
M
M
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
b
I am as healthy as
anybody I know ....
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
c
I expect my health
to get worse ..........
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
d
My health is
excellent................
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5


Page 7
Your Kidney Disease
12. How true or false is each of the following statements for you?
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false
a 
My kidney
disease interferes
too much with my
life ........................
M
M
M
M
M
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
b
Too much of my
time is spent
dealing with my
kidney disease.......
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
c
I feel frustrated
dealing with my
kidney disease.......
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
d
I feel like a burden
on my family .........
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5


Page 8
13. These questions are about how you feel and how things have been
going during the past 4 weeks.  For each question, please give the
one answer that comes closest to the way you have been feeling.
How much of the time during the past 4 weeks…
None
of the
time
A little
of the
time
Some
of the
time
A good
bit of
the
time
Most
of the
time
All of
the
time
a
Did you isolate your-
self from people
around you?.................
M
M
M
M
M
M
 1 .......
 2.......
 3........
 4 .......
 5........
 6
b
Did you react slowly
to things that were said
or done?.......................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
c
Did you act irritable
toward those around
you?.............................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
d
Did you have difficulty
concentrating or
thinking?.......................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
e
Did you get along well
with other people? ........
 1 .......
 2.......
 3........
 4 .......
 5........
 6
f
Did you become
confused? ....................
 1 .......
 2.......
 3........
 4 .......
 5........
 6


Page 9
14. During the past 4 weeks, to what extent were you bothered by each
of the following?
Not at all
bothered
Somewhat
bothered
Moderately
bothered
Very much
bothered
Extremely
bothered
M
M
M
M
M
a
Soreness in your
muscles?...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
b
Chest pain? ...........
 1 ............
 2 ...........
 3 ............
 4...........
 5
c
Cramps? ...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
d
Itchy skin?.............
 1 ............
 2 ...........
 3 ............
 4...........
 5
e
Dry skin?...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
f
Shortness of
breath?..................
 1 ............
 2 ...........
 3 ............
 4...........
 5
g
Faintness or
dizziness?..............
 1 ............
 2 ...........
 3 ............
 4...........
 5
h
Lack of appetite?...
 1 ............
 2 ...........
 3 ............
 4...........
 5
i
Washed out or
drained?................
 1 ............
 2 ...........
 3 ............
 4...........
 5
j
Numbness in
hands or feet?........
 1 ............
 2 ...........
 3 ............
 4...........
 5
k
Nausea or upset
stomach?...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
l
(Hemodialysis patient only)
Problems with
your access site? ...
 1 ............
 2 ...........
 3 ............
 4...........
 5
m
(Peritoneal dialysis patient only)
Problems with
your catheter site?..
 1 ............
 2 ...........
 3 ............
 4...........
 5


Page 10
Effects of Kidney Disease on Your Daily Life
15. Some people are bothered by the effects of kidney disease on their
daily life, while others are not.  How much does kidney disease
bother you in each of the following areas?
Not at all
bothered
Somewhat
bothered
Moderately
bothered
Very much
bothered
Extremely
bothered
M
M
M
M
M
a
Fluid restriction?....
 1 ............
 2 ...........
 3 ............
 4...........
 5
b
Dietary restriction?.
 1 ............
 2 ...........
 3 ............
 4...........
 5
c
Your ability to
work around the
house? ..................
 1 ............
 2 ...........
 3 ............
 4...........
 5
d
Your ability to
travel? ...................
 1 ............
 2 ...........
 3 ............
 4...........
 5
e
Being dependent
on doctors and
other medical
staff?.....................
 1 ............
 2 ...........
 3 ............
 4...........
 5
f
Stress or worries
caused by kidney
disease? ................
 1 ............
 2 ...........
 3 ............
 4...........
 5
g
Your sex life?........
 1 ............
 2 ...........
 3 ............
 4...........
 5
h
Your personal
appearance? ..........
 1 ............
 2 ...........
 3 ............
 4...........
 5


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Page 12
17. For the following question, please rate your sleep using a scale
ranging from 0 representing “very bad” to 10 representing “very
good.”
If you think your sleep is half-way between “very bad” and “very
good,” please mark the box under the number 5.  If you think you
sleep is one level better than 5, mark the box under 6.  If you think
your sleep is one level worse than 5, mark the box under 4 (and so
on).
On a scale from 0 to 10, how would you rate your sleep overall?
[Mark an 
 in one box.]
Very bad
Very good
M
M
0
1
2
3
4
5
6
7
8
9
10


Page 13
18. How often during the past 4 weeks did you...
None
of the
time
A little
of the
time
Some
of the
time
A good
bit of
the
time
Most
of the
time
All of
the
time
a
Awaken during the
night and have trouble
falling asleep again?.......
M
M
M
M
M
M
 1 .......
 2.......
 3........
 4 ......
 5.......
 6
b
Get the amount of
sleep you need?............
 1 .......
 2.......
 3........
 4 ......
 5.......
 6
c
Have trouble staying
awake during the day?...
 1 .......
 2.......
 3........
 4 ......
 5.......
 6
19. Concerning your family and friends, how satisfied are you with...
Very
dissatisfied
Somewhat
dissatisfied
Somewhat
satisfied
Very
satisfied
a
The amount of time
you are able to spend
with your family and
friends?........................
M
M
M
M
 1...............
 2 ..............
 3...............
 4
b
The support you
receive from your
family and friends?........
 1...............
 2 ..............
 3...............
 4


Page 14
20. During the past 4 weeks, did you work at a paying job?
Yes
No
M
M
  
 1
  
 2
21. Does your health keep you from working at a paying job?
Yes
No
M
M
  
 1
  
 2
22. Overall, how would you rate your health?
Worst possible
(as bad or worse
 than being dead)
Half-way
between worst
and best
Best
possible
M
M
M
0
1
2
3
4
5
6
7
8
9
10


Page 15
Satisfaction With Care
23. Think about the care you receive for kidney dialysis.  In terms of
your satisfaction, how would you rate the friendliness and interest
shown in you as a person?
Very
poor
Poor
Fair
Good
Very
good
Excellent
The Best
M
M
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
  
 6
  
 7
24. How true or false is each of the following statements?
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false
a 
Dialysis staff
encourage me to
be as independent
as possible ............
M
M
M
M
M
 1 ...........
 2 ...........
 3 ...........
 4 ............
 5
b
Dialysis staff
support me in
coping with my
kidney disease.......
 1 ...........
 2 ...........
 3 ...........
 4 ............
 5
Thank you for completing these questions!

Prot_SAP_003.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. 
 
 
An Open-Label Dose-Exploration Cohort Study Evaluating the 
Efficacy and Safety of Voclosporin in Achieving Complete or 
Partial Remission of Proteinuria in Subjects with Focal 
Segmental Glomerulosclerosis  
 
Clinical Protocol Number: 
AUR-VCS-2017-03 
 
 
Study Name: 
AURONA 
 
 
Date: 
20 December 2019 
 
 
Version Number: 
4.0 (Amendment 3) 
 
 
Previous Protocol Versions 
Version 1.0, 27 April 2018 
 
Version 2.0 (Amendment 1), 23 November 2018 
 
Version 3.0 (Amendment 2), 31 May 2019 
 
 
 
 
IND Number: 
137,905 
 
 
 
 
 
 
 
 
 
 
 


 
 
AUR-VCS-2017-03 Version 4.0 (Amendment 3) 
Confidential 
20 December 2019 
 
 
Page 2 of 111 
 
NAMES AND ADDRESSES 
 
Sponsor 
Name: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Tel: 
 
 
24 Hour: 
 
 
 
Chief Medical Officer 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
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: 
 
 
 




 
 
AUR-VCS-2017-03 Version 4.0 (Amendment 3) 
Confidential 
20 December 2019 
 
 
Page 4 of 111 
 
INVESTIGATOR AGREEMENT FORM 
I have read the attached protocol titled: An Open-Label Dose-Exploration Cohort Study 
Evaluating the Efficacy and Safety of Voclosporin in Achieving Complete or Partial Remission 
of Proteinuria in Subjects with Focal Segmental Glomerulosclerosis 
Version Number/Date: Version 4.0 (Amendment 3) / 20 December 2019 
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. 
 
 
 
<insert name> 
Principal Investigator 
 
Date (e.g., DD Month Year) 
 


 
 
AUR-VCS-2017-03 Version 4.0 (Amendment 3) 
Confidential 
20 December 2019 
 
 
Page 5 of 111 
 
SYNOPSIS 
Title: 
An Open-Label, Dose-exploration, Cohort Study Evaluating the Efficacy and Safety 
of Voclosporin in Achieving Complete or Partial Remission of Proteinuria in 
Subjects with Focal Segmental Glomerulosclerosis 
Short Title: 
AURONA 
Study Product: 
Voclosporin  
Indication: 
Focal Segmental Glomerulosclerosis 
Phase: 
2 
Sponsor: 
Aurinia Pharmaceuticals Inc. 
Study Code: 
AUR-VCS-2017-03 
Objectives: 
Primary Objective: 
• 
To assess the efficacy of voclosporin in achieving complete or partial remission 
of proteinuria after 24 weeks of therapy in subjects with focal segmental 
glomerulosclerosis (FSGS).  
Secondary Objective: 
• 
To assess the safety and tolerability of voclosporin over 24 weeks in subjects 
with FSGS. 
Design: 
Open-label, 24-week, multicenter, exploratory cohort study of voclosporin. 
Treatment: 
Investigational Treatment: 
Voclosporin softgel capsules containing 7.9 mg drug. Up to 10 subjects will be 
enrolled into Cohort 1 and take voclosporin 23.7 mg orally (PO), twice daily (BID). 
The dose level of voclosporin for Cohort 2 (at least 10 subjects) will be determined 
by analysis of efficacy and safety data at Week 12 from the first 5-6 subjects in 
Cohort 1. 
Inclusion Criteria: 
1. Written informed consent before any study-specific procedures are performed. 
2. Male or female subjects with a minimum age of 18 years (or legal age of consent 
if >18 years) to 75 years of age, inclusive, at the time of consent. 
3. Primary FSGS diagnosed by renal biopsy within 6 months prior to the screening 
visit. Biopsy results over 6 months prior to screening may be permitted following 
review with the Medical Monitor to confirm eligibility. 


 
 
AUR-VCS-2017-03 Version 4.0 (Amendment 3) 
Confidential 
20 December 2019 
 
 
Page 6 of 111 
 
Inclusion Criteria 
(cont’d): 
4. At initial screening assessment and at last qualifying assessment during 
screening period prior to baseline, FSGS subjects must have a urine protein 
creatinine ratio (UPCR) of ≥2.0 mg/mg. Subjects can be treatment-naïve or 
receiving steroid treatment (oral or IV) for FSGS. Subjects taking steroids must 
show signs of improvement in proteinuria, defined as at least a 20% 
improvement in UPCR from initiation of steroids to the last stability assessment 
prior to baseline. Subjects who have discontinued steroid treatment due to poor 
tolerability may be considered for the study. Subjects should also have a serum 
albumin level of ≤3.2 g/dL at screening and at the last qualifying assessment 
prior to baseline; subjects with serum albumin >3.2 g/dL may be included 
following review to confirm primary FSGS and after discussion with the Medical 
Monitor. 
5. All subjects should be treated with angiotensin converting enzyme inhibitors 
(ACEIs) and/or angiotensin receptor blockers (ARBs) unless they have 
documented intolerance or contraindication to these medications. Doses of these 
agents must be stable for at least 2 weeks prior to baseline, with blood pressure 
(BP) ≤150/90 mmHg at the baseline visit (Visit 2). 
a) Subjects with nephrotic edema may be treated with diuretics during the 
screening period. Volume status should be optimized based on the clinical 
judgment of the Investigator and the doses of diuretics must be stable for at 
least 2 weeks prior to baseline. 
b) At the discretion of the Investigator, subjects with hyperlipidemia may be 
treated with lipid-lowering agents (e.g., statins) in accordance with standard 
clinical practice. Doses must be stable for at least 2 weeks prior to baseline. 
6. Stable proteinuria, renal function, and BP for at least 2 weeks prior to baseline, 
as assessed by the Investigator. Changes in UPCR, estimated glomerular 
filtration rate (eGFR), and/or BP during the screening period may be due to 
treatments administered (e.g., ACEIs and ARBs); and, therefore, may interfere 
with study assessments or outcomes, or may place the subject at increased risk. 
All subjects must be discussed with the Medical Monitor prior to initiation of 
study treatment. 
7. Women of childbearing potential must have a negative serum pregnancy test 
prior to dispensing study treatment. Two effective forms of contraception must 
be used simultaneously unless abstinence is the chosen method. Subjects must 
use effective contraception during the study. 
Exclusion Criteria: 
 
1. Subjects unable or unwilling to give written informed consent and/or to comply 
with study procedures. 
2. Clinical or histologic evidence of secondary FSGS. 
3. Histologic evidence of collapsing variant FSGS. 
4. eGFR as calculated by the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation of ≤30 mL/minute/1.73 m2 at initial screening assessment 
or ≤45 mL/minute/1.73 m2 at last qualifying assessment during screening period 
prior to baseline. 
 


 
 
AUR-VCS-2017-03 Version 4.0 (Amendment 3) 
Confidential 
20 December 2019 
 
 
Page 7 of 111 
 
Exclusion Criteria 
(cont’d): 
 
5. Currently taking or expected to require any of the prohibited medications listed 
in the protocol at screening or during the study. This includes prior use of 
cytotoxic or other immunosuppressant treatment for FSGS. Subjects who have 
discontinued steroid treatment due to lack of response are excluded from the 
study. 
6. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or 
expected to require dialysis during the study period. 
7. A previous renal transplant or planned renal transplant during the study. 
8. Body mass index >40 kg/m2 at last stability assessment. 
9. Family history of nephrotic syndrome. 
10. Any known hypersensitivity or contraindication to cyclosporine, or components 
of any cyclosporine drug product. 
11. 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. 
• 
Current or past 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. 
12. Other clinically significant active medical conditions, such as: 
• 
Severe cardiovascular disease including congestive heart failure, history of 
cardiac dysrhythmia or congenital long QT syndrome. Subjects with 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 are excluded. 
• 
Liver dysfunction: aspartate aminotransferase, alanine aminotransferase, or 
bilirubin ≥2.5 times the upper limit of normal at last qualifying assessment 
during screening period prior to baseline. 
• 
Chronic obstructive pulmonary disease or asthma requiring oral steroids. 


 
 
AUR-VCS-2017-03 Version 4.0 (Amendment 3) 
Confidential 
20 December 2019 
 
 
Page 8 of 111 
 
Exclusion Criteria 
(cont’d): 
 
• 
Bone marrow insufficiency: white blood cell count <2,500/mm3, absolute 
neutrophil count <1.3 × 103/μL, and/or thrombocytopenia (platelet count 
<50,000/mm3) at screening or at last qualifying assessment during screening 
period prior to baseline. 
• 
Current infection requiring intravenous antibiotics. 
13. Any overlapping autoimmune condition for which the condition or the treatment 
of the condition may affect the study assessments or outcomes (e.g., any 
condition for which additional immunosuppression, including systemic 
corticosteroids, and/or cytotoxic therapy is indicated). Overlapping conditions 
for which the condition or treatment is not expected to affect assessments or 
outcomes are not excluded. 
14. No vaccines using live organisms, viral or bacterial, are allowed during 
screening and while taking the study treatment. 
15. 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. 
16. 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. 
17. Subjects who are pregnant, breast feeding or, if of childbearing potential, not 
using adequate contraceptive precautions. 
18. 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. 
19. Subjects treated in a previous voclosporin clinical study. 
Primary Endpoint: 
Proportion of subjects with remission of proteinuria at Week 24, assessed overall and 
for each individual cohort, based on the following parameters: 
• 
Complete remission: UPCR of <0.3 mg/mg 
OR 
• 
Partial remission: UPCR ≥0.3 mg/mg and <3.0 mg/mg with >50% reduction in 
UPCR from baseline 
Secondary 
Endpoints: 
The following secondary endpoints will be assessed overall and for each individual 
cohort: 
• 
Proportion of subjects with complete remission or partial remission of 
proteinuria at Weeks 8 and 12 
• 
Proportion of subjects with complete remission of proteinuria at Weeks 8, 12, 
and 24 
• 
Proportion of subjects with UPCR <0.5 mg/mg at Weeks 8, 12, and 24 
• 
Proportion of subjects with partial remission of proteinuria at Weeks 8, 12, and 
24 


 
 
AUR-VCS-2017-03 Version 4.0 (Amendment 3) 
Confidential 
20 December 2019 
 
 
Page 9 of 111 
 
Secondary 
Endpoints (cont’d): 
• 
Time to first occurrence of complete or partial remission of proteinuria 
• 
Time to first occurrence of complete remission of proteinuria 
• 
Time to first occurrence of partial remission of proteinuria 
• 
Time to first occurrence of 50% reduction in UPCR from baseline 
• 
Duration of UPCR <0.3 mg/mg 
• 
Change from baseline in UPCR at each time point 
• 
Proportion of subjects with a confirmed >30% decrease from baseline in eGFR 
(utilizing the CKD-EPI formula) at each time point  
• 
Proportion of subjects with a confirmed >30% increase in eGFR from the final 
visit (Week 24 or last on-treatment visit, for subjects who discontinue 
prematurely) to the second Safety Follow-up visit (Visit 10) 
• 
Change in UPCR from the final visit (Week 24 or last on-treatment visit, for 
subjects who discontinue prematurely) to the second Safety Follow-up visit 
(Visit 10)  
• 
Change in eGFR from the final visit (Week 24 or last on-treatment visit, for 
subjects who discontinue prematurely) to the second Safety Follow-up visit 
(Visit 10) 
• 
Change from baseline in serum creatinine, serum albumin, and eGFR at each 
time point 
• 
Quality of life assessments 
− 
Mean change in Patient Reported Outcome Measurement Information 
System (PROMIS) measures at Week 24 
− 
Change from baseline in Kidney Disease Quality of Life-Short Form 
(KDQOL-SFTM) score at Week 24 
• 
Safety and tolerability over 24 weeks 
• 
Renal biopsy: descriptive analyses of changes in histopathology will be 
evaluated in post-treatment (24 weeks) renal biopsies in a subset of patients 
• 
Change from baseline to Weeks 4 and 24 in the following biomarkers:  
− 
Urine nephrin 
− 
Urine synaptopodin 
− 
Serum transforming growth factor beta 


 
 
AUR-VCS-2017-03 Version 4.0 (Amendment 3) 
Confidential 
20 December 2019 
 
 
Page 10 of 111 
 
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. Subjects will be assigned a unique subject number which will 
be used to identify them throughout the study. If a subject has not had a renal 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 the end of screening. The duration of the screening period will be 
approximately 4 weeks to 10 weeks (allowing for visit windows) to ensure that 
subjects meet eligibility criteria, including renal disease stability assessments.  
The first 5-10 subjects meeting the required eligibility criteria will be assigned to 
Cohort 1 and will receive voclosporin according to the following dosing regimen: 
• 
Week 1: 1 capsule (7.9 mg) PO, BID 
• 
Week 2: 2 capsules (15.8 mg) PO, BID 
• 
Week 3 – Week 24: 3 capsules (23.7 mg) PO, BID 
Appropriate sponsor personnel (including the medical monitor) and the investigator 
will jointly decide whether to continue with the dose escalation for each subject.  
When the first 5 or 6 subjects in Cohort 1 have completed 12 weeks of treatment with 
voclosporin, the top line efficacy and safety data will be analyzed to determine the 
dose level for Cohort 2. The selected dose may be higher or lower than 23.7 mg BID. 
The maximum dose possible for Cohort 2 will be 39.5 mg (5 capsules) BID. Should 
this dose be selected the following dosing regimen will be followed: 
• 
Week 1: 1 capsule (7.9 mg) PO, BID 
• 
Week 2: 2 capsules (15.8 mg) PO, BID 
• 
Week 3: 3 capsules (23.7 mg) PO, BID 
• 
Week 4 – Week 24: 5 capsules (39.5 mg) PO, BID 
Evaluable safety and tolerability data at Week 12 from the first 5-6 subjects from 
Cohort 1 are required in order to make the decision to escalate to a higher dose level 
for Cohort 2.  
As a guidance, the dose will not be escalated if any of following criteria are met in 
the first 5 or 6 subjects from Cohort 1, unless it was obvious that the occurrence was 
not related to the administration of voclosporin: 
• 
Severe adverse events (SAEs) of same character in ≥2 subjects. 
• 
Clinically significant decrease in eGFR in ≥5 subjects. 
• 
Clinically significant laboratory abnormalities of same character in 
≥5 subjects. 
• 
Clinically significant abnormalities of electrolytes in ≥4 subjects. 
• 
Clinically significant changes in vital signs of same character in ≥4 subjects. 


 
 
AUR-VCS-2017-03 Version 4.0 (Amendment 3) 
Confidential 
20 December 2019 
 
 
Page 11 of 111 
 
Procedures (cont’d) 
Doses and dose increments smaller than anticipated may be proposed for Cohort 2 
based on the safety and tolerability results from the Cohort 1.  
All subjects will complete dosing through 24 weeks of study treatment and will have 
2 Safety Follow-Up visits, 1 and 2 weeks after completion of treatment (i.e., at Week 
25 and Week 26). Subjects who permanently discontinue study treatment before the 
Week 24 visit will return for all remaining study visits and assessments, including 
the 2 Safety Follow-Up visits, unless they have withdrawn consent. 
Sample Size: 
As this is an exploratory study, sample size calculations are not required. It is 
estimated that approximately 20 subjects will be recruited, with up to 10 subjects in 
Cohort 1 and at least 10 subjects in Cohort 2. 
Statistical Methods: 
Analysis: 
All statistical analyses relating to the primary and secondary objectives will be 
undertaken at study closure and will incorporate all available data. 
Given the small sample size, all analyses will be descriptive in nature. Confidence 
intervals (CIs) for proportions may be calculated but it is recognized that such 
intervals, being based on 20 patients, will be very wide. As an example, the 95% 
Clopper-Pearson CI for a proportion of 30% based on 20 patients is (11.9%, 54.3%). 
Populations:  
The efficacy analysis will be based on intent-to-treat (ITT) principles and will include 
all enrolled subjects (non-screening failures). 
The per-protocol data set will include the subset of subjects in the ITT set who do not 
have any major protocol violations (to be defined). 
The safety analysis set will consist of all subjects who receive at least 1 dose of study 
treatment. 
Methods: 
Top line efficacy (change from Baseline in UPCR) and safety data (AEs, eGFR, 
ECGs and vital signs) for the first 5 or 6 subjects in Cohort 1 completing 12 weeks 
of study treatment will be reviewed and based on those data the commencement of 
enrollment and the target dose for Cohort 2 will be determined. 
The analysis of the primary endpoint, complete or partial remission of proteinuria at 
Week 24, will be conducted on the ITT set and confirmed with the per-protocol set 
(if applicable). Remission of proteinuria will be summarized and an exact 2-sided 
95% CI for the remission rate will be calculated.  
The analyses of the secondary endpoints will incorporate the use of 2-sided 95% CIs 
and are described below:  
• 
Binary endpoints will be summarized using exact 2-sided 95% CIs.  
• 
Endpoints measured as a time-to-event will be displayed using Kaplan-Meier 
methodology. Median time-to-event along with 2-sided 95% CIs will be 
displayed.  


 
 
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Statistical Methods 
(cont’d) 
• 
Other endpoints will be summarized by visit. Absolute values and differences 
between baseline and each time point up to and including Week 24 will be 
summarized using means and 2-sided 95% CIs. Changes between last on 
treatment value and post treatment follow-up will also be summarized. 
Safety Endpoints:  
Adverse events will be aggregated by System Organ Class and preferred term and 
presented as summary tables.  
Laboratory values, 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. 
Exploratory analyses will be undertaken should the data suggest areas worthy of 
further investigation. 


 
 
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STUDY SCHEMA 
 
 
 
Notes: 
BID=Twice daily; VCS=Voclosporin. 


 
 
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AUR-VCS-2017-03 SCHEDULE OF EVENTS 
Visit 
Visit 1 
Screening Period 
Visit 2 
Baseline 
Visit 3 
Visits 4-5 
Visit 6 
Visit 7 
Visit 8 
End of 
Treatment/ 
Early 
Termination 
Visit 9 
Safety 
Follow-up 
Visit 10 
Safety 
Follow-up 
Day/Week 
Screening to Day -1 
Day 1 
(Within 1 
Wk Post 
Qualifying 
Assessment) 
Wk 2 
(±3 Days) 
Wks 4, 8 
(±3 Days) 
Wk 12 
(±3 Days) 
Wk 18 
(±5 Days) 
Wk 24 
(±7 Days) 
Wk 25 
(±3 Days) or 
Premature 
Disc. +7 Days 
Wk 26 
(±3 Days) or 
Premature 
Disc. +14 Days  
Screening 
Visit(1) 
Stability 
Assessments 1 & 
2, Optional 3 & 
4(1) 
Informed consent 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
 
 
 
 
 
 
 
 
 
 
Renal biopsy(2) 
 
 
 
 
 
 
 
(2) 
 
 
Medical history and 
demography 
 
 
 
 
 
 
 
 
 
 
Physical exam(3) 
 
 
 
 
 
 
 
 
 
 
Vital signs(4) 
 
 
 
 
 
 
 
 
 
 
ECG(5) 
 
 
 
 
 
 
 
 
 
 
Laboratory 
assessments(6)  
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics(7) 
 
 
 
 
 
 
 
 
 
 
Urinalysis and urine 
microscopy 
 
 
 
 
 
 
 
 
 
 
FMV urine collection(8) 
 
 
 
 
 
 
 
 
 
 
24-hour urine(9) 
 
 
 
 
 
 
 
 
 
 
QoL(10) 
 
 
 
 
 
 
 
 
 
 
Pregnancy test(11) 
 
 
 
 
 
 
 
 
 
 
Adverse events 
(12) 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
Dispense study 
medication/ 
compliance(13) 
 
 
 
 
 
 
 
(14) 
 
 
First dose of study 
medication 
 
 
(15) 
 
 
 
 
 
 
 


 
 
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1 
Stability assessments to occur at 14-day intervals (± 3 days) with first assessment approximately 2 weeks after the screening visit. Stability assessments 1 and 2 are mandatory; assessments 3 and 4 
are optional if additional time is required for the subject’s clinical status to stabilize. Note that the laboratory assessments and FMV results of the last stability assessment will be used as the 
qualifying values for eligibility. Enrollment of eligible subjects must occur within 1 week of the final stability assessment.  
2 
If a subject has not had a recent renal biopsy, one may be performed to assess eligibility for the study provided informed consent has been given. The biopsy must have been performed 6 months 
prior to the screening visit. Biopsy results over 6 months prior to screening may be permitted following review with the Medical Monitor to confirm eligibility. Repeat renal biopsies may be done at 
Week 24 in a subset of subjects at selected sites.  
3 
Complete physical exam at screening; abbreviated exam at all other visits. 
4 
BP, pulse, temperature, weight, and height. Height included at initial screening assessment only. At stability assessments, BP only will be included. 
5 
In the event that a subject is noted to have a QTcF value exceeding 500 msec, or an increase of >60 msec from baseline, the ECG should be repeated within 24 hours. Further details provided in the 
study protocol. 
6 
Laboratory assessments will be performed according to the schedule in the study protocol. Subjects must be fasting for at least 8-12 hours at Baseline and at end of study/early termination visit.  
7 
Pharmacokinetic assessments will be done at Weeks 4 and 24. PK samples will be drawn prior to study treatment dosing (trough sample), and at 1, 2 and 4 hours post-dose. In the event a subject 
experiences an SAE or requires a dose modification or is withdrawn from treatment, a voclosporin sample should be taken, with a trough sample preferred. 
8 
The UPCR will be calculated both from the FMV and from standard urinalysis results. If the FMV 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. 
9 
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. 
10 Patient Reported Outcome Measurement Information system (PROMIS) and Kidney Disease Quality of Life-Short Form (KDQOL-SFTM). 
11 Serum pregnancy test to be evaluated at central laboratory at Screening and Week 24; urine pregnancy test will be performed locally at all other visits as applicable. 
12 If screening visit occurs on the same day as informed consent, any findings are to be recorded as Medical History. Any change since the date of signed consent and/or during the screening period 
would be considered an AE. 
13 Subjects in Cohort 1, will be contacted by telephone at the end of Week 1 as a reminder to increase their dose to 2 capsules (15.8 mg) BID for 1 week, starting at Week 2. Subjects will be contacted 
again by telephone at the end of Week 2 as a reminder to increase their dose to 3 capsules (23.7 mg) BID, starting at Week 3, for the remainder of the treatment period. Subjects in Cohort 2, will also 
be contacted at the end of each week (as required) up to Week 4, as a reminder to increase their dose to the maximum selected for Cohort 2. 
14 Compliance only. 
15 First dose of study medication should occur in the morning the day after dispensing. 
Notes: Subjects who discontinue therapy will be requested to attend their regularly scheduled study visits to the end of the study. 
 
AE = Adverse event; BID = Twice daily; BP = Blood pressure; Disc. = Discontinuation; ECG = Electrocardiogram; FMV = First morning void; Min = Minimum; QoL = Quality of life; 
 
QTcF = QT interval duration corrected for heart rate using method of Fridericia; SAE = Serious adverse event; Wk= Week. 
 
 
 


 
 
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TABLE OF CONTENTS 
Page 
NAMES AND ADDRESSES ...................................................................................................2 
DECLARATION OF SPONSOR ...........................................................................................3 
INVESTIGATOR AGREEMENT FORM ............................................................................4 
SYNOPSIS ................................................................................................................................5 
STUDY SCHEMA .................................................................................................................13 
AUR-VCS-2017-03 SCHEDULE OF EVENTS ..................................................................14 
TABLE OF CONTENTS ......................................................................................................16 
LIST OF TABLES .................................................................................................................20 
LIST OF APPENDICES .......................................................................................................20 
LIST OF ABBREVIATIONS ...............................................................................................21 
1. 
INTRODUCTION AND BACKGROUND ..................................................................24 
1.1 
Background of the Disease and Treatment Options ....................................................24 
1.1.1 
Limitations of Current Treatment .............................................................................25 
1.2 
Rationale for the Use of Calcineurin Inhibitors in FSGS ............................................26 
1.2.1 
Mechanism of Action of CNIs and Potential for Treatment Benefit in FSGS .........26 
1.2.2 
Clinical Studies of CNIs in FSGS ............................................................................27 
1.2.3 
Voclosporin ...............................................................................................................29 
1.2.3.1 
Pharmacokinetic Considerations ............................................................................30 
1.2.4 
Potential Toxicities of CNIs .....................................................................................30 
2. 
RATIONALE .................................................................................................................32 
2.1 
Dose Rationale .............................................................................................................32 
3. 
STUDY OBJECTIVES ..................................................................................................34 
3.1 
Primary Objective ........................................................................................................34 
3.2 
Secondary Objective ....................................................................................................34 
3.3 
Endpoints .....................................................................................................................34 
3.3.1 
Primary Endpoint ......................................................................................................34 
3.3.2 
Secondary Endpoints ................................................................................................34 
4. 
INVESTIGATIONAL PLAN .......................................................................................36 
4.1 
Overall Study Design ...................................................................................................36 
4.2 
Duration of Subject Participation and Study ...............................................................37 
5. 
SELECTION, 
WITHDRAWAL 
OF 
SUBJECTS 
AND 
PERMANENT 
DISCONTINUATION OF DRUG ................................................................................38 


 
 
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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 of Study Treatment Due to an Adverse Event................................42 
6. 
RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES ..............44 
7. 
STUDY TREATMENTS ...............................................................................................45 
7.1 
Dosage Forms/Formulation .........................................................................................45 
7.1.1 
Voclosporin – Study Treatment ................................................................................45 
7.1.2 
Dosing Guidelines.....................................................................................................45 
7.1.2.1 
Voclosporin ............................................................................................................45 
7.1.2.2 
Corticosteroids .......................................................................................................46 
7.2 
Package and Labeling ..................................................................................................47 
7.3 
Site Supply, Storage, Accountability ...........................................................................47 
7.3.1 
Site Supply ................................................................................................................47 
7.3.2 
Storage ......................................................................................................................47 
7.3.3 
Accountability ...........................................................................................................47 
7.4 
Voclosporin Dose Modification ...................................................................................48 
7.4.1 
Discontinuation of Study Therapy Due to Non-response .........................................48 
7.4.2 
Deterioration in Renal Function ...............................................................................48 
7.4.2.1 
Decrease in eGFR >30% and eGFR <90 mL/min/1.73 m2 ....................................48 
7.4.2.2 
Decrease in eGFR ≤30% and eGFR <90 mL/min/1.73 m2 ....................................49 
7.4.2.3 
Recovery of eGFR .................................................................................................49 
7.5 
Procedures for Overdose ..............................................................................................49 
7.6 
Prohibited Therapy and Concomitant Treatment .........................................................49 
7.6.1 
Prohibited Medications .............................................................................................50 
7.6.2 
Allowed Concomitant Medications ..........................................................................50 
7.7 
Increased Blood Pressure .............................................................................................51 
8. 
RISKS/PRECAUTIONS ...............................................................................................52 
9. 
STUDY PROCEDURES ...............................................................................................53 
9.1 
Description of Study Assessments ...............................................................................53 
9.1.1 
Laboratory Assessments ...........................................................................................53 
9.1.1.1 
Evaluation of Biomarkers ......................................................................................55 
9.1.2 
Physical Examinations ..............................................................................................55 
9.1.3 
Vital Signs.................................................................................................................56 
9.1.3.1 
Blood Pressure Management .................................................................................56 
9.1.4 
Standard 12-lead Electrocardiogram ........................................................................56 
9.1.4.1 
Procedures to Manage a Treatment-Emergent Increase in QTcF ..........................57 


 
 
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9.1.5 
QoL Assessments ......................................................................................................57 
9.1.6 
Voclosporin Pharmacokinetic and Biomarker Assessment ......................................57 
9.2 
Schedule of Assessments .............................................................................................57 
9.2.1 
Screening Visit and Stability Assessment Procedures ..............................................58 
9.2.2 
Treatment Procedures ...............................................................................................59 
9.2.3 
End of Study (or Early Termination) Procedures .....................................................60 
9.2.4 
Follow-up Procedures ...............................................................................................61 
9.2.5 
Unscheduled Visit .....................................................................................................61 
10. EVALUATION, RECORDING AND REPORTING OF AES AND SAES .............62 
10.1 
Definitions....................................................................................................................62 
10.1.1 
Adverse Event ...........................................................................................................62 
10.1.2 
Adverse Drug Reaction .............................................................................................62 
10.1.3 
Serious Adverse Event ..............................................................................................62 
10.1.4 
Suspected Unexpected Serious Adverse Reaction ....................................................63 
10.2 
Adverse Event Descriptors ..........................................................................................63 
10.2.1 
Intensity/Severity Categorization .............................................................................63 
10.2.2 
Causal Relationship Categorization ..........................................................................63 
10.2.3 
Outcome Categorization ...........................................................................................64 
10.2.4 
Clinical Laboratory Evaluations ...............................................................................64 
10.2.5 
Abuse, Misuse, Overdose and Medication Error ......................................................65 
10.3 
Reporting Procedure for AEs, SAEs, and Pregnancy ..................................................65 
10.3.1 
Adverse Events .........................................................................................................65 
10.3.2 
Serious Adverse Events ............................................................................................66 
10.3.3 
Pregnancy..................................................................................................................67 
11. CLINICAL ENDPOINTS COMMITTEE ..................................................................69 
12. DATA AND SAFETY MONITORING BOARD PROCEDURES ...........................70 
13. STATISTICAL ANALYSIS .........................................................................................71 
13.1 
Statistical Methods .......................................................................................................71 
13.2 
Sample Size and Power Calculations ...........................................................................71 
13.3 
Populations ...................................................................................................................71 
13.3.1 
Intent-to-Treat Set .....................................................................................................71 
13.3.2 
Safety Set ..................................................................................................................71 
13.3.3 
Per-protocol Set ........................................................................................................71 
13.4 
Datasets ........................................................................................................................71 
13.5 
Background and Demographic Characteristics ............................................................71 
13.6 
Study Treatment ...........................................................................................................72 
13.7 
Concomitant Therapy...................................................................................................72 
13.8 
Efficacy Evaluations ....................................................................................................72 
13.8.1 
Primary Endpoint ......................................................................................................72 
13.8.2 
Secondary Endpoints ................................................................................................72 


 
 
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13.9 
Statistical and Analytical Methods ..............................................................................74 
13.10 Safety Evaluations .......................................................................................................74 
13.11 Interim Analyses ..........................................................................................................75 
13.12 Other Evaluations.........................................................................................................75 
13.12.1 Pharmacokinetics ......................................................................................................75 
14. ETHICAL CONDUCT OF THE STUDY ...................................................................76 
14.1 
Informed Consent.........................................................................................................76 
14.2 
Institutional Review Board or EC/IEC ........................................................................76 
15. QUALITY CONTROL AND QUALITY ASSURANCE ...........................................77 
16. ADMINISTRATIVE PROCEDURES .........................................................................78 
16.1 
Sponsor’s Responsibilities ...........................................................................................78 
16.1.1 
Study Supplies ..........................................................................................................78 
16.1.2 
Insurance ...................................................................................................................78 
16.1.3 
Study Monitoring ......................................................................................................78 
16.2 
Investigator’s Responsibilities .....................................................................................79 
16.2.1 
Reporting and Recording of Data .............................................................................79 
16.2.2 
Investigator Training.................................................................................................79 
16.2.3 
Source Documentation ..............................................................................................79 
17. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE 
TERMINATION OF THE STUDY .............................................................................80 
17.1 
Protocol Waivers, Deviations and Violations ..............................................................80 
17.2 
Study Termination .......................................................................................................80 
18. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ......................81 
19. REFERENCES ...............................................................................................................82 
 


 
 
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LIST OF TABLES 
Page 
Table 1 
Review of Laboratory Assessments .................................................................53 
 
LIST OF APPENDICES 
Page 
Appendix 1 
Drug Therapy for the Treatment of Hypertension ...........................................85 
Appendix 2 
Measurement of Blood Pressure ......................................................................86 
Appendix 3 
Classification of FSGS .....................................................................................87 
Appendix 4 
Conversion Table for Oral Corticosteroids ......................................................89 
Appendix 5 
Expanded List of Allowed Concomitant Medications .....................................90 
Appendix 6 
Summary of Treatment and Food Restrictions ................................................92 
Appendix 7 
PROMIS QoL Assessment ..............................................................................93 
Appendix 8 
KDQOL-SFTM QoL Assessment Version 1.3 ..................................................94 
  
 
 
 


 
 
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LIST OF ABBREVIATIONS 
ACEI 
Angiotensin converting enzyme inhibitor 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ARB 
Angiotensin receptor blocker 
ATC 
Anatomical Therapeutic Chemical 
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 
Aurinia 
Aurinia Pharmaceuticals Inc. 
BID 
Twice daily 
BP 
Blood pressure 
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 
DEX 
Dexamethasone 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End-stage renal disease 
FMV 
First morning void 
FSGS 
Focal Segmental Glomerulosclerosis 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 


 
 
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GMP 
Good Manufacturing Practice 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISA247 
Voclosporin 
ITT 
Intent-to-treat 
IV 
Intravenous 
KDIGO 
Kidney Disease: Improving Global Outcomes 
KDQOL-SFTM 
Kidney Disease Quality of Life-Short Form 
LN 
Lupus nephritis 
MMF 
Mycophenolate mofetil 
NSAID 
Non-steroidal anti-inflammatory drug 
OR 
Odds ratio 
PD 
Pharmacodynamic 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PO 
Orally 
PPS 
Per-protocol set 
PROMIS 
Patient Reported Outcome Measurement Information System  
QoL 
Quality of life 
QTcF 
QT interval duration corrected for heart rate using method of 
Fridericia 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
t1/2 
Terminal elimination half-life 


 
 
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TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TGF-β 
Transforming growth factor beta 
UPCR 
Urine protein creatinine ratio 


 
 
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1. INTRODUCTION AND BACKGROUND 
1.1 
Background of the Disease and Treatment Options  
Focal segmental glomerulosclerosis (FSGS) is diagnosed by characteristic glomerular findings 
of podocyte injury evidenced by findings from immunofluorescence and electron microscopy 
following renal biopsy. The disease is categorized as primary (i.e., idiopathic FSGS) or 
secondary (e.g., adaptive changes resulting from glomerular hyperfiltration in conditions such 
as reflux nephropathy, obesity, and reduced nephron mass; drug-induced FSGS; and FSGS 
associated with viral diseases) [1].  
The predominate clinical feature of primary FSGS is proteinuria, typically with signs and 
laboratory 
abnormalities 
associated 
with 
nephrotic 
syndrome 
(i.e., 
total 
urine 
protein >3.5 g/day, edema, hypoalbuminemia, and hypercholesterolemia) [1]. Patients may 
experience renal dysfunction which can progress to end-stage renal disease (ESRD). 
Reportedly 50%-60% of patients have nephrotic syndrome at presentation, and approximately 
50% of adult patients with idiopathic nephrotic syndrome are diagnosed with FSGS [1]. The 
amount of proteinuria at presentation and lack of response to treatment are correlated with 
progression to ESRD. FSGS is more common in males than in females and, in racially diverse 
populations, more common in black patients than in white patients [1]. 
Several published reviews have summarized the histopathologic features of FSGS and 
mechanisms of podocyte injury, disruption of the glomerular filtration barrier, and progression 
of renal dysfunction, e.g., D’Agati [1] and Kikuchi et al [2].  
The glomerular filtration barrier consists of glomerular endothelial cells, the glomerular 
basement membrane, and epithelial cells (podocytes). There is a complex interaction between 
these elements; the podocyte is not only a critical part of the structure, providing structural 
support to glomerular capillary, but also plays a role in maintaining the glomerular basement 
membrane and slit diaphragm proteins that permit filtration of water and small molecules and 
retention of large molecules and cells. Light microscopy findings include a segmental pattern 
of mesangial sclerosis occurring in some (i.e., focal), but not all glomeruli, without typical 
features of other proteinuric glomerulopathies. Immunofluorescence microscopy does not 
reveal immune deposits. The primary pathophysiologic mechanism of FSGS is reflected in 
electron microscopy findings, which include typical abnormalities of podocyte morphology, 
i.e., diffuse podocyte foot process effacement. In FSGS, as in other podocytopathies, these 
abnormalities disrupt the glomerular filtration barrier, resulting in protein leakage. 
The etiology of primary (idiopathic) FSGS is not known and is likely multifactorial. Based on 
indirect evidence, development of FSGS has been attributed to circulating factors (e.g., 
cytokines such as cardiotrophin-like cytokine 1, anti-CD40 (podocyte-B7-1 antigen) antibody, 
apolipoprotein A-Ib (ApoA-Ib) and serum soluble urokinase-type plasminogen activator 
receptor (suPAR)) which may mediate glomerular permeability. FSGS recurs in transplanted 


 
 
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kidneys, and proteinuria can be reduced by plasmapheresis in these patients; plasma and sera 
from FSGS patients have induced proteinuria in rats and in isolated rat glomeruli [3]. Several 
immune mechanisms have also been postulated to contribute to progressive glomerular damage 
subsequent to the initial podocyte injury, including cellular immunity and autoimmune 
reactivity [4].  
Elevated levels of transforming growth factor-beta (TGF-β) have been implicated in the 
pathogenesis of FSGS and have been reported in numerous tissues of patients with FSGS 
including the tubule-interstitium and the glomerular epithelial cells [5,6]. Calcineurin α, one 
of the calcineurin isoforms, is involved in broad cellular tasks including protein folding and 
regulation of TGF-β expression. The use of an immunosuppressive agent that increases TGF-β 
levels may have a negative long-term impact on renal fibrosis, whereas the use of an 
immunosuppressive agent that either decreases or has no impact on TGF-β levels may stabilize 
presently existing renal fibrosis. Concerning the podocyte, Liao et al [7] showed that in a 
murine (MRL/lpr) model, the calcineurin inhibitor (CNI) tacrolimus may decrease TGF-β-
induced podocyte apoptosis, suggesting that calcineurin may play a role in the progression of 
renal disease, thereby suggesting a potential mechanism of CNI benefit.   
1.1.1 Limitations of Current Treatment 
The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for 
Glomerulonephritis [8] provides Level 2C (low) and 2D (very low) suggestions for the 
treatment of primary FSGS: Corticosteroids are suggested as initial treatment at a daily single 
dose of 1 mg/kg (maximum 80 mg) or 2 mg/kg (maximum 120 mg) (Level 2C), to be 
administered for a minimum of 4 weeks and maximum of 16 weeks, as tolerated, or until 
complete remission has been achieved, whichever is earlier (Level 2D). Calcineurin inhibitors 
are suggested for use in FSGS as second-line treatment after failure of remission with steroid 
treatment and as first-line treatment in patients with relative contraindications to steroids. 
(Level 2D) (see Section 1.2.1, Mechanism of Action of CNIs and Potential for Treatment 
Benefit in FSGS). Up to 50% of patients fail to respond to corticosteroids [1]. Earlier use of 
CNIs in primary FSGS, as initial treatment at the time of diagnosis, would avoid the risks of 
corticosteroid use, and may result in proteinuria remission, as well as potentially decrease the 
risk of progression to ESRD. 
The potential benefit of voclosporin in treatment-naïve FSGS patients is supported by the 
mechanism of action of CNIs (see Section 1.2.1, Mechanism of Action of CNIs and Potential 
for Treatment Benefit in FSGS) and clinical data suggesting benefit in steroid-resistant patients 
(see Section 1.2.2, Clinical Studies of CNIs in FSGS), as well as potential advantages of 
voclosporin over cyclosporine (i.e., increased potency demonstrated in nonclinical studies with 
voclosporin, more predictable pharmacokinetic (PK)/pharmacodynamic (PD) profile 
(obviating the need for therapeutic drug monitoring), and a potentially improved safety profile 
compared to cyclosporine A (CsA)) (see FSGS Investigator’s Brochure (IB) [9]). These data, 
with the demonstrated efficacy in renal response (including reduction in proteinuria), suggest 


 
 
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that voclosporin may benefit patients with FSGS. Although treatment guidelines suggest 
corticosteroids as first line therapy in these patients [8], there are no data to support the use of 
corticosteroids instead of CNIs in this setting. Corticosteroids are associated with significant 
toxicities, and if voclosporin demonstrates treatment benefit and an acceptable safety profile, 
it would provide an appropriate alternative treatment to corticosteroids in this setting. 
1.2 
Rationale for the Use of Calcineurin Inhibitors in FSGS  
Calcineurin inhibitors are suggested for use in FSGS as second line treatment after failure of 
remission with steroid treatment and as first line treatment in patients with relative 
contraindications to steroids. In addition to well-characterized immunomodulatory effects, 
CNIs have been demonstrated to have direct beneficial effects on podocytes that are likely 
mechanisms of amelioration of proteinuria in podocytopathies, including FSGS. 
1.2.1 Mechanism of Action of CNIs and Potential for Treatment Benefit in 
FSGS 
Calcineurin inhibitors have beneficial effects in diseases characterized by disorders of the 
immune system and in the prevention of rejection after solid organ transplantation by inhibiting 
activation of nuclear factor of activated T-cell (NFAT) with subsequent regulation of the 
production of T-cell cytokines [9]. Recently, several investigations have demonstrated that 
CNIs have non-immunologic effects that contribute to their anti-proteinuric effects in 
podocytopathies. 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 protected from degradation. Calcineurin dephosphorylates synaptopodin 
allowing its degradation, with subsequent alteration of the actin cytoskeleton, disruption of the 
glomerular filtration barrier, and proteinuria. Expression of activated calcineurin in podocytes 
leads to proteinuria. Thus, by inhibiting calcineurin, CNIs exert a specific anti-proteinuric 
effect by preventing the degradation of the podocyte stabilizing protein synaptopodin [10,11]. 
In addition to effects on synaptopodin, cyclosporine has been found to stabilize other 
components of the actin cytoskeleton, i.e., cofilin-1 and nephrin. Podocyte apoptosis can be 
induced in the rat purine aminonucleoside model [12]. Shen et al [13] demonstrated that 
cyclosporine and tacrolimus reduced podocyte apoptosis in the rat purine aminonucleoside 
model. In addition, inhibition of NFAT signaling in the podocyte by CNIs may ameliorate 
podocyte injury [14]. Wakamatsu et al [15] evaluated the effects of tacrolimus in a nephrotic 
rat model (anti-nephrin antibody-induced nephropathy). Utilizing immunohistological 
analyses of rat and human kidneys, these investigators demonstrated that calcineurin is an 
element of the slit diaphragm and associated with nephrin, a critical component of the slit 
diaphragm. In the nephrotic rat model, they demonstrated that calcineurin distribution was 
altered and calcineurin activity was increased; these abnormalities were prevented by 
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Background of the Disease and Treatment Options, calcineurin may also contribute to TGF-β-
induced fibrosis. 
In summary, CNIs, in addition to their immunomodulatory effects have been demonstrated to 
have direct beneficial effects on podocytes via multiple mechanisms. These effects are likely 
mechanisms of amelioration of proteinuria in podocytopathies, including FSGS. 
1.2.2 Clinical Studies of CNIs in FSGS  
The KDIGO guidelines suggest CNIs for use in the first line treatment of FSGS in patients 
who are intolerant or have contraindications to corticosteroid use [8]. There are no prospective, 
randomized trials of CNIs (either cyclosporine or tacrolimus) used as first line treatment in 
adult patients (or children) with FSGS. Limited retrospective observational data support their 
use in this setting; a recent treatment review [16] cites two studies: Duncan et al [17] and 
Goumenos et al [18]. 
In a single study center by Duncan et al [17], 6 patients with biopsy-proven FSGS and 
nephrotic syndrome, who had been previously treated with angiotensin converting enzyme 
inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), but not immunosuppression 
(including corticosteroids), were treated with tacrolimus and followed prospectively. The mean 
duration of nephrotic syndrome prior to treatment with tacrolimus was 13.6 months (standard 
deviation (SD) 11.8); baseline urine protein was 11.0 g/day (SD 4.5) and baseline estimated 
glomerular filtration rate (eGFR) was 71.7 mL/min/1.73 m2 (SD 22.4). After approximately 
12 months of follow-up, all 6 patients achieved remission, defined as normalization of serum 
albumin and resolution of edema. Mean urine protein decreased from 11.0 g/day (SD 4.5) to 
2.8 g/day (SD 2.5). Reportedly, no patients relapsed after attaining remission. 
In a retrospective review by Goumenos et al [18], 51 patients with biopsy-proven FSGS, 
proteinuria >1 g/day, and serum creatinine <2.5 mg/dL, were followed for 5 years. Of the 
51 patients, 26 were treated with conservative management (including ACEIs and other anti-
hypertensives) and 25 were treated with immunosuppressive drugs, including prednisolone 
alone (9 patients, treated for 16 months, 8 with nephrotic syndrome), prednisolone and 
azathioprine (6 patients, treated for 18 months, 5 with nephrotic syndrome) and prednisolone 
(0.5 mg/kg/day) and cyclosporine (10 patients, treated for 25 months, 7 with nephrotic 
syndrome). No patients received cyclosporine monotherapy. Treatment assignment was 
reportedly based on renal impairment and degree of proteinuria. Remission of nephrotic 
syndrome (both complete remission (defined as urine protein <0.3 g/day) and partial remission 
(defined as urine protein between 0.3 and 3 g/day)) occurred in 5/8 patients treated with 
prednisolone alone, 4/5 patients treated with prednisolone and azathioprine, and 6/7 patients 
treated with prednisolone and cyclosporine. 
Evidence to support the use of CNIs in adult patients who are steroid resistant includes 
randomized clinical trials as well as observational data. A Cochrane Review published in 


 
 
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2008 [19] identified one blinded controlled study (Cattran et al, 1999 [20]) which evaluated 
the effect of cyclosporine on remission of proteinuria and ESRD in steroid-resistant adult 
patients with nephrotic syndrome. This study was a single blind, randomized, placebo-
controlled trial in which 26 patients were treated with cyclosporine and low dose prednisone 
and 23 patients were treated with placebo and low-dose prednisone. Complete remission (urine 
protein ≤0.3 g/day with stable renal function) or partial remission (50% reduction and ≤3.5 
g/day with stable renal function) occurred in 69% of the cyclosporine group and 4% of the 
placebo group at 26 weeks (p<0.001). At 4 years, the renal survival rate was 72% in the 
cyclosporine group and 49% in the placebo group. 
Laurin et al [21] performed a meta-analysis of studies evaluating the effects of CNIs in primary 
FSGS. They did not identify any trials in which CNIs were used as first-line treatment. Six 
randomized controlled trials and two retrospective cohort studies were included in their review. 
They performed a pooled analysis of the effect of cyclosporine on proteinuria remission; the 
relative risk of complete or partial remission was 7.0 (95% confidence interval (CI): 2.9, 16.8) 
compared with the control group. 
It has been noted in treatment reviews that cyclosporine use in steroid-resistant patients is 
associated with a high relapse rate (e.g., 43% to 50% in a 2003 review by Cattran [22]). In an 
NIH-sponsored trial, FSGS-CT, 138 patients (adults and children) with biopsy-proven FSGS 
(assessed as steroid resistant and urine protein creatine ratio (UPCR) >1 g/g) were randomized 
to cyclosporine (n=72) or a combination of pulse dexamethasone (DEX) and mycophenolate 
mofetil (MMF) (n=66) [23,24]. Treatment was administered for 12 months and patients were 
followed until Week 78. Steroid resistance was defined as failure to achieve sustained UPCR 
≤1.0 g/g after a minimal treatment duration of 4 weeks. All patients were treated with low-
dose prednisone and either an ACEI or ARB. There was no difference between the groups in 
the primary endpoint (mean score of a 6-level categorical assessment of remission of 
proteinuria at Week 52): 46% of the CsA group and 33% of the MMF/DEX group had at least 
a partial remission at Week 52. In patients who achieved at least a partial remission at Week 52, 
relapse (defined as UPCR >2.0 g/g after the withdrawal of medication at Week 52) was 
reported for 33% (11/33) in the CsA group and 18% (4/22) in the MMF/DEX group. These 
data are difficult to interpret as 28% of patients in the CsA group had baseline UPCR <2.0 g/g. 
Moreover, the definition of steroid resistance in this study is not consistent with standard 
definition of steroid resistance for adults and the data are not presented separately for adults 
and children. 
In a follow-up publication of a post-hoc analysis, Hogg et al [25] examined the outcomes in 
patients who achieved complete or partial remission after 26 weeks, completed 52 weeks of 
treatment, and had follow-up information through 78 weeks. In the cyclosporine group, the 
analysis included 22 of the 39 patients who were reported to have at least partial remission at 
Week 26 in the earlier publication, and 20 of the 26 patients in the MMF/DEX group. The 
authors report that, in the CsA patients, the mean eGFR decreased at Weeks 26 and 52 (17% 


 
 
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decrease and 19% decrease compared to baseline, respectively), and increased by 16% from 
Week 52 to Week 78. 
There are few studies examining the use of tacrolimus in patients with FSGS. In one study [26], 
decrease in proteinuria was similar in 18 patients treated with cyclophosphamide/prednisone 
and 15 patients treated with tacrolimus/prednisone, both after 6 months of treatment and at the 
completion of a 6-month follow-up period. Baseline renal function was not recorded and there 
appeared to be stability of renal function between 6 months and 12 months. Therefore, it is 
difficult to assess the treatment benefit of tacrolimus from this study. 
In summary, the available data, although largely from retrospective studies, support a treatment 
benefit of cyclosporine in steroid-resistant patients. There is little data supporting the benefit 
of cyclosporine as first line treatment. It has been reported that the relapse rate is high following 
discontinuation of treatment; however, it is difficult to interpret the data reported by 
Gipson et al [23,24] and Hogg et al [25] with respect to the effect of cyclosporine on renal 
function and proteinuria over 12 months and subsequent improvement in renal function and 
proteinuria after withdrawal, and the reported relapse rate. The study failed to recruit the target 
number of patients, the criteria for steroid resistance were not consistent with standard 
definitions, and the changes in proteinuria and renal function were not completely reported. 
However, it appears that there was a significant decrease in proteinuria at both Weeks 26 and 
52. While the post-treatment effect on eGFR is not completely clear, the data suggest some 
increase in eGFR after withdrawal of treatment. The relevance of these findings to the long-
term effect of voclosporin is not clear. 
1.2.3 Voclosporin 
Voclosporin is a next generation CNI currently under development for use in FSGS and lupus 
nephritis (LN). Voclosporin is structurally similar to 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 PK/PD predictability. 
During the development of this investigational product, the legacy names of voclosporin, VCS, 
and ISA247 are referenced in discussions related to historical usage. In the Phase 3 LN clinical 
development program, the name of the investigational product is referred to as Orelvo, the 
proposed trade name. However, for the FSGS clinical development programs, the name of the 
investigational product will be referred to as voclosporin. All legacy names and the proposed 
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Prior to the FSGS clinical development program, over 2,400 subjects have received 
investigational products containing voclosporin in 15 Phase 1, and 12 Phase 2/3 clinical studies 
in the indications of LN, transplant rejection, psoriasis and non-infectious uveitis. Detailed 
data for these clinical studies are presented in the IB [9].  
1.2.3.1 Pharmacokinetic Considerations 
Voclosporin approximates linear multiexponential PKs. Exposure to voclosporin was 
dose-related with maximum concentrations occurring ≤2 hours with a 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 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 Cmax and an 18-fold increase in 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 voclosporin. Concomitant administration 
of voclosporin and 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 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 Potential Toxicities of CNIs 
Increased blood pressure (BP) and renal dysfunction are well known potential toxicities of 
CNIs that are dose-related, reversible, and generally responsive to dose reduction or temporary 
interruption of treatment [27].  
Voclosporin has been studied in numerous disease states. In clinical studies of voclosporin in 
LN [9], a small proportion of voclosporin-treated subjects experienced an early drop of ≥30% 
in eGFR; however, that proportion then remained stable over time. None of these treatment-
emergent adverse events (TEAEs) were classed as serious. The majority of TEAEs of 


 
 
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decreased GFR were classed as mild or moderate, and resulted in permanent discontinuation 
of study treatment in 1 (1.1%) placebo subject, 7 (7.9%) voclosporin low-dose (23.7 mg BID) 
subjects and 5 (5.7%) voclosporin high-dose (39.5 mg BID) subjects. There were more TEAEs 
of hypertension seen in the voclosporin-treated subjects compared to placebo; however, overall 
mean systolic and diastolic 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 
treatment.  
There was also 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 Disorders, and Vascular Disorders. 
 


 
 
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2. RATIONALE 
The rationale for the development of voclosporin and the range of dose is to introduce a novel 
CNI to the population of patients with FSGS, with meaningful efficacy while minimizing 
toxicities common to other CNIs. In clinical studies, a favorable efficacy/safety profile for 
voclosporin has been demonstrated in the prevention of renal transplant rejection and in 
Phase 2 studies in LN. 
As evaluated in nonclinical and clinical studies (healthy volunteers, moderate to severe 
psoriasis, renal transplantation, and uveitis) voclosporin is well tolerated and exhibits adverse 
events (AEs) that are typical of other CNIs yet seen to a lesser extent than those seen 
historically with other CNIs. 
The aim of the current study is to investigate whether voclosporin is able to reduce disease 
activity over a treatment period of 24 weeks. Subjects with histologic evidence of primary 
FSGS with proteinuria will be eligible to enter the study. Efficacy will be assessed by the 
ability of voclosporin to reduce the level of proteinuria (as measured by UPCR) while 
demonstrating an acceptable safety profile. The primary endpoint of this study will be complete 
or partial remission of proteinuria at 24 weeks. 
2.1 
Dose Rationale 
This Phase 2 study is designed to initially evaluate the treatment benefit of voclosporin 23.7 mg 
BID in the first cohort of up to 10 subjects. The selection of this voclosporin dose for the first 
cohort (see Section 7, Study Treatments) was based on the previous experience with this drug 
in the Phase 2 LN study (AURA-LV). In AURA-LV, subjects were administered voclosporin 
23.7 mg BID, voclosporin 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). At Week 48, complete remission rates in both the low-dose 
(49.4%) and high-dose (39.8%) voclosporin groups demonstrated statistically significant 
superiority compared to the placebo (23.9%) group, (p<0.001, p=0.026, respectively). There 
was no increase in efficacy with the higher dose and no significant differences between the 
two voclosporin groups in achievement of renal response.  
This study is also designed to evaluate a further dose level of voclosporin, this dose may be 
higher or lower than the initial 23.7 mg BID dosing. When the first 5-6 subjects in Cohort 1 
have completed 12 weeks of treatment with voclosporin, the top line efficacy and safety data 
will be analyzed to determine the dose level for Cohort 2. The maximum dose possible for 
Cohort 2 will be 39.5 mg (5 capsules) BID. If the higher dose is selected for Cohort 2, subjects 
still receiving treatment in Cohort 1 may have their dose increased to 39.5 mg after Week 8 if 
they have not demonstrated meaningful benefit from the 23.7 mg BID dose per Investigator 
judgement and following discussion with the Medical Monitor. Subjects enrolled after the dose 
decision will receive voclosporin at 39.5 mg BID and be considered part of Cohort 2. 


 
 
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To minimize safety concerns, a cautious dose-escalation design starting with a minimal dose 
of one capsule (7.9 mg) per day will be employed for all subjects (see Section 7.1.2, Dosing 
Guidelines).  
The protocol contains provisions for management of dose (including rules for stopping 
treatment with study mediation) based on safety concerns in particular, BP and renal function. 
The safety data from the use of voclosporin in LN demonstrates that these risks are dose-related, 
reversible, and can be managed by dose reduction and temporary interruption.   
Furthermore, voclosporin will be administered as fixed doses 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, plaque psoriasis, and LN) demonstrated that weight 
did not have a significant effect on the PK of voclosporin [9].  


 
 
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3. STUDY OBJECTIVES 
3.1 
Primary Objective 
• To assess the efficacy of voclosporin in achieving complete or partial remission of 
proteinuria after 24 weeks of therapy in subjects with FSGS. 
3.2 
Secondary Objective 
• To assess the safety and tolerability of voclosporin over 24 weeks in subjects with FSGS. 
3.3 
Endpoints 
All primary and secondary endpoints will be assessed overall and for each individual cohort. 
3.3.1 Primary Endpoint 
Proportion of subjects with remission of proteinuria at Week 24 based on the following 
parameters: 
• Complete remission: UPCR of <0.3 mg/mg 
OR 
• Partial remission: UPCR ≥0.3 mg/mg and <3.0 mg/mg with >50% reduction in UPCR 
from baseline 
3.3.2 Secondary Endpoints 
• Proportion of subjects with complete remission or partial remission of proteinuria at Weeks 
8 and 12 
• Proportion of subjects with complete remission of proteinuria at Weeks 8, 12, and 24 
• Proportion of subjects with UPCR <0.5 mg/mg at Weeks 8, 12, and 24 
• Proportion of subjects with partial remission of proteinuria at Weeks 8, 12, and 24 
• Time to first occurrence of complete or partial remission of proteinuria 
• Time to first occurrence of complete remission of proteinuria 
• Time to first occurrence of partial remission of proteinuria 
• Time to first occurrence of 50% reduction in UPCR from baseline 
• Duration of UPCR <0.3 mg/mg 


 
 
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• Change from baseline in UPCR at each time point 
• Proportion of subjects with a confirmed >30% decrease from baseline in eGFR (utilizing 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) at each time 
point  
• Proportion of subjects with a confirmed >30% increase in eGFR from the final visit 
(Week 24 or last on-treatment visit, for subjects who discontinue prematurely) to the 
second Safety Follow-up visit (Visit 10) 
• Change in UPCR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10) 
• Change in eGFR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10)  
• Change from baseline in serum creatinine, serum albumin, and eGFR at each time point 
• Quality of life (QoL) assessments 
− 
Mean change in Patient Reported Outcome Measurement Information System 
(PROMIS) measures at Week 24 
− 
Change from baseline in Kidney Disease Quality of Life-Short Form (KDQOL-SFTM) 
score at Week 24 
• Safety and tolerability over 24 weeks 
• Renal biopsy: descriptive analyses of changes in histopathology will be evaluated in post-
treatment (24 weeks) renal biopsies in a subset of patients 
• Change from baseline to Week 4 and 24 in the following biomarkers:  
− 
Urine nephrin 
− 
Urine synaptopodin 
− 
Serum TGF-β 


 
 
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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 2, open-label, multicenter, prospective, 24-week, exploratory cohort study to 
assess the efficacy and safety of two dose levels of voclosporin in achieving complete or partial 
remission of proteinuria in subjects with biopsy-confirmed primary FSGS. Subjects who have 
provided a signed and dated informed consent will be screened into the study. Subjects will be 
assigned a unique subject number which will be used to identify them throughout the study. 
The duration of the screening period will be approximately 4 weeks to 10 weeks (allowing for 
visit windows (14±3 days) for each stability assessment) to ensure that subjects meet eligibility 
criteria, including renal disease stability assessments. If a subject has not had a renal biopsy 
within the 6-month (prior to screening) required timeframe for study eligibility, one may be 
performed to assess eligibility into the study, provided the subject has given consent and 
provided the results can be obtained and reviewed before baseline; biopsy results over 
6 months prior to screening may be permitted following review with the Medical Monitor. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible 
to receive treatment with voclosporin. Up to 10 subjects will be enrolled into Cohort 1, at a 
starting dose of 7.9 mg BID for Week 1, 15.8 mg BID for Week 2, and a target dose of 23.7 mg 
BID for Weeks 3 to 24. The first dose of study treatment should occur in the morning on Day 2, 
the day after dispensing. Subjects will be contacted by telephone at the end of Week 1 and 
Week 2 to be reminded to increase their dose as per Section 7.1.2.1, Voclosporin Study 
Treatment. 
Evaluable safety and tolerability from 12 weeks of treatment in the first 5-6 subjects from 
Cohort 1 are required in order to determine the dose level for Cohort 2. The dose selected may 
be higher or lower than 23.7 mg BID. The maximum dose possible for Cohort 2 will be 
39.5 mg (5 capsules) BID. Dosing in this group will follow the same cautious approach as 
Cohort 1, with at a starting dose of 7.9 mg BID for Week 1, 15.8 mg BID for Week 2, 
23.7 mg BID for Week 3 and a maximum dose of 39.5 mg BID for Weeks 4 to 24. 
Doses and dose increments smaller than anticipated or an intermediate dose may be proposed 
for Cohort 2 based on the safety and tolerability results from the Cohort 1.  
All subjects will return for assessment of efficacy and safety at Weeks 2, 4, 8, 12, 18, and 24. 
See Schedule of Events, for detailed information regarding visits.  
All subjects, completed or withdrawn from the study, will complete the End of Treatment/Early 
Termination assessments (Visit 8) at Week 24, or at the time of withdrawal, and should attend 
two Safety Follow-up visits at 1 and 2 weeks after completion of treatment (i.e., at Week 25 
(Visit 9) and Week 26 (Visit 10)) (or 7 and 14 days, respectively, following withdrawal) to 
collect any new AEs and concomitant medications. At the follow-up visit, UPCR and eGFR 


 
 
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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 up to 36 weeks. The duration of the screening 
period will be approximately 4 weeks to 10 weeks (allowing for visit windows) and the 
treatment duration is 24 weeks, with further Safety Follow-up visits at 1 and 2 weeks after last 
dose (completion or withdrawal). 


 
 
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5. SELECTION, WITHDRAWAL OF SUBJECTS AND PERMANENT 
DISCONTINUATION OF DRUG 
5.1 
Number of Subjects 
It is anticipated that approximately 20 subjects will be recruited 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 years (or legal age of consent if >18 
years) to 75 years of age, inclusive, at the time of consent. 
3. Primary FSGS diagnosed by renal biopsy within 6 months prior to the screening visit. 
Biopsy results over 6 months prior to screening may be permitted following review with 
the Medical Monitor to confirm eligibility (see Appendix 3). 
4. At initial screening assessment and at last qualifying assessment during screening period 
prior to baseline, FSGS subjects must have a urine protein creatinine ratio (UPCR) of 
≥2.0 mg/mg. Subjects can be treatment-naïve or receiving steroid treatment (oral or 
intravenous (IV)) for FSGS. Subjects taking steroids must show signs of improvement in 
proteinuria, defined as at least a 20% improvement in UPCR from initiation of steroids to 
the last stability assessment prior to baseline. Subjects who have discontinued steroid 
treatment due to poor tolerability may be considered for the study. Subjects should also 
have a serum albumin level of ≤3.2 g/dL at screening and at the last qualifying assessment 
prior to baseline; subjects with serum albumin >3.2 g/dL may be included following review 
to confirm primary FSGS and after discussion with the Medical Monitor. 
5. All subjects should be treated with ACEIs and/or ARBs unless they have documented 
intolerance or contraindication to these medications. Doses of these agents must be stable 
for at least 2 weeks prior to baseline, with BP ≤150/90 mmHg at the baseline visit (Visit 2). 
a) Subjects with nephrotic edema may be treated with diuretics during the screening 
period. Volume status should be optimized based on the clinical judgment of the 
Investigator and the doses of diuretics must be stable in the 2 weeks prior to baseline. 
b) At the discretion of the Investigator, subjects with hyperlipidemia may be treated with 
lipid-lowering agents (e.g., statins) in accordance with standard clinical practice. Doses 
must be stable in the 2 weeks prior to baseline. 


 
 
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6. Stable proteinuria, renal function, and BP during the 2 weeks prior to baseline, as assessed 
by the Investigator. Changes in UPCR, eGFR, and/or BP during the screening period may 
be due to treatments administered (e.g., ACEIs and ARBs); and, therefore, may interfere 
with study assessments or outcomes, or may place the subject at increased risk. All subjects 
must be discussed with the medical monitor prior to initiation of study treatment. 
7. Women of childbearing potential must have a negative serum pregnancy test prior to 
dispensing study treatment. 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. Clinical or histologic evidence of secondary FSGS. 
3. Histologic evidence of collapsing variant FSGS. 
4. eGFR as calculated by the CKD-EPI equation of ≤30 mL/minute/1.73 m2 at initial 
screening assessment or ≤45 mL/minute/1.73 m2 at last qualifying assessment during 
screening period prior to baseline. 
5. Currently taking or expected to require any of the prohibited medications listed in the 
protocol (see Section 7.6.1, Prohibited Medications) at screening or during the study. This 
includes prior use of cytotoxic or other immunosuppressant treatment for FSGS. Subjects 
who have discontinued steroid treatment due to lack of response are excluded from the 
study.   
6. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or expected to 
require dialysis during the study period. 
7. A previous renal transplant or planned renal transplant during the study. 
8. Body mass index >40 kg/m2 at last stability assessment. 
9. Family history of nephrotic syndrome. 
10. Any known hypersensitivity or contraindication to cyclosporine, or components of any 
cyclosporine drug product. 
11.  Current or medical history of: 
• Congenital or acquired immunodeficiency. 


 
 
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• 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. 
• Current or past 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. 
12. Other clinically significant active medical conditions, such as: 
• Severe cardiovascular disease including congestive heart failure, history of cardiac 
dysrhythmia or congenital long QT syndrome. Subjects with 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 are excluded. 
• Liver dysfunction: aspartate aminotransferase, alanine aminotransferase, or bilirubin 
≥2.5 times the upper limit of normal at last qualifying assessment during screening period 
prior to baseline. 
• Chronic obstructive pulmonary disease or asthma requiring oral steroids. 
• Bone marrow insufficiency: white blood cell count <2,500/mm3, absolute neutrophil count 
<1.3 × 103/μL, and/or thrombocytopenia (platelet count <50,000/mm3) at screening or at 
last qualifying assessment during screening period prior to baseline. 
• Current infection requiring IV antibiotics. 
13. Any overlapping autoimmune condition for which the condition or the treatment of the 
condition may affect the study assessments or outcomes (e.g., any condition for which 
additional immunosuppression, including systemic corticosteroids, and/or cytotoxic 
therapy is indicated). Overlapping conditions for which the condition or treatment is not 
expected to affect assessments or outcomes are not excluded. 


 
 
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14. No vaccines using live organisms, viral or bacterial, are allowed during screening and while 
taking the study treatment. 
15. 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. 
16. 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. 
17. Subjects who are pregnant, breast feeding or, if of childbearing potential, not using 
adequate contraceptive precautions. 
18. 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. 
19. Subjects treated in a previous voclosporin clinical study. 
5.4 
Adequate/Effective Contraception 
Women of childbearing potential must have a negative serum pregnancy test during 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, 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, reproductively competent men are required to use condoms during treatment 
and for at least 6 weeks after cessation of study treatment. In addition, female partners of male 
subjects are recommended to use an effective contraception during their partner’s treatment 
and for at least 6 weeks after the last dose of study treatment. Male subjects are to refrain from 
making sperm donations during treatment and for at least 6 weeks after cessation of study 
treatment. 
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.  
Barrier methods (e.g., condoms, diaphragm, or cervical cap/sponge) when used alone are not 
considered highly effective. 


 
 
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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 and documented 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 8), if possible. If 
possible, the subject should also be advised to come for the two Safety Follow-up visits (Visit 9 
and Visit 10) at 1 and 2 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 withdrawal as “withdrawal of consent.” Withdrawn subjects 
will not be replaced. 
5.6 
Discontinuation of Study Treatment 
Discontinuation of study treatment does not necessarily constitute withdrawal from the study.   
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.  
If possible, subjects who are permanently discontinued from study treatment before the 
Week 24 visit should undergo all study assessments up to and including the Week 24 (or Early 
Termination Visit – Visit 8) and Safety Follow-up visits where appropriate. All subjects that 
discontinue study treatment should attend at least 2 further assessments after the last dose of 
study drug.  
Guidance on when study treatment must be discontinued is in Section 7.4, Voclosporin Dose 
Modification.  
5.6.1 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 discontinued 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 


 
 
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is discontinued 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 
Not applicable. 


 
 
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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 
Pharmaceuticals Inc. (Aurinia). 
7.1.1 Voclosporin – 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 Dosing Guidelines 
7.1.2.1 Voclosporin 
Voclosporin 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. 
The dosing of voclosporin for Cohort 1 will be as follows: 
• Week 1: 1 capsule (7.9 mg) orally (PO), BID 
• Week 2: 2 capsules (15.8 mg) PO, BID 


 
 
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• Weeks 3 to 24: 3 capsules (23.7 mg) PO, BID 
Evaluable safety and tolerability data from 12 weeks of treatment in the first 5-6 subjects from 
Cohort 1 are required in order to make the decision to escalate to a higher dose level for Cohort 
2. The selected dose may be higher or lower than 23.7 mg BID. The maximum dose possible 
for Cohort 2 will be 39.5 mg (5 capsules) BID. Should this dose be selected the following 
dosing regimen will be followed: 
• Week 1: 1 capsule (7.9 mg) PO, BID 
• Week 2: 2 capsules (15.8 mg) PO, BID 
• Week 3: 3 capsules (23.7 mg) PO, BID 
• Weeks 4 to 24: 5 capsules (39.5 mg) PO, BID 
All subjects will be contacted by telephone at the end of Week 1 and Week 2 (and Week 3, if 
applicable) to be reminded to increase their dose. 
If the 39.5 mg dose is selected for Cohort 2, subjects still receiving treatment in Cohort 1 may 
have their dose increased to 39.5 mg BID after Week 8 per Investigator judgement and 
following discussion with the Medical Monitor. 
All unused study treatment (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. 
7.1.2.2 Corticosteroids 
Subjects entering the study with corticosteroids should have their steroid dose gradually 
titrated down until they achieve a daily dose of <10 mg/day prednisone by Week 12. The timing 
of the titration is at the discretion of the investigator, with a reduction of 5 mg/day every 
2 weeks recommended. If clinically indicated, steroid tapering may start during the stability 
assessment period. A dose level may be maintained for up to 4 weeks or increased per 
investigator judgement following discussion with the Medical Monitor. Refer to Appendix 4 
for a conversion table of various formulations of steroids. 
Corticosteroid treatment must be documented in the eCRF and source documentation. 
When clinically indicated, subjects are allowed to be completely titrated off oral 
corticosteroids. 


 
 
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Corticosteroids should not be re-started in a patient whose dose has been reduced to zero, or 
initiated during the study in treatment-naïve patients, without prior discussion with the Medical 
Monitor. 
7.2 
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 
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. 
7.3 
Site Supply, Storage, Accountability 
7.3.1 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. 
7.3.2 Storage 
Voclosporin softgel 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. 
7.3.3 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, one 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’s approval of 
the process and forward the certificate of destruction to Aurinia. 
7.4 
Voclosporin Dose Modification 
7.4.1 Discontinuation of Study Therapy Due to Non-response 
During the treatment period, any case where the subject experiences a worsening of 
proteinuria, or no improvement in proteinuria from baseline, once the highest permitted dose 
of study drug has been achieved, should be discussed with the Medical Monitor. Subjects may 
be allowed to add treatment with corticosteroids (IV or oral) while continuing with study drug, 
or may be discontinued from study treatment and transitioned to standard of care treatment. 
If the dose level of 39.5 mg BID is determined for Cohort 2, any subject still on treatment in 
Cohort 1 who has completed 8 weeks of treatment and shown no meaningful improvement in 
proteinuria may have their dose increased to 39.5 mg BID per Investigator judgement and 
following discussion with the Medical Monitor. 
7.4.2 Deterioration in Renal Function 
Serum creatinine and eGFR utilizing the CKD-EPI formula, as reported by the central 
laboratory, will be used for the assessment of renal function at every visit including 
unscheduled visits.  
It is recognized that eGFR may be unreliable at higher values (>100 mL/min/1.73 m2). FSGS 
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 [28], with or without kidney 
damage.  
7.4.2.1 Decrease in eGFR >30% and eGFR <90 mL/min/1.73 m2 
During the treatment period, any subject experiencing a >30% decrease in eGFR from baseline 
(baseline eGFR is defined as the last assessment prior to first dose of study treatment) to 
<90 mL/min/1.73 m2 will have study treatment interrupted until a repeat test can be performed 
(unscheduled visit to be completed within 48 hours). If the decrease is confirmed at the 


 
 
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unscheduled visit and not due to potential contributing factors (e.g., high baseline eGFR, the 
addition or modification of non-steroidal anti-inflammatory drugs (NSAIDs), ACEIs, ARBs, 
a concurrent state of dehydration, overdosing with study treatment, renal flare, etc.), the case 
should be discussed with the Medical Monitor, the study treatment should continue to be 
withheld, and eGFR retested within 48 hours. (Note: doses of ACEIs, ARBs, diuretics, and/or 
lipid lowering therapy are to remain stable throughout the study.) 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. 
7.4.2.2 Decrease in eGFR ≤30% and eGFR <90 mL/min/1.73 m2 
During the treatment period, any subject having a ≤30% reduction in eGFR to 
<90 mL/min/1.73 m2 should have the influence of potential contributing factors (as described 
in Section 7.4.2.1, Decrease in eGFR >30% and eGFR <90 mL/min/1.73 m2) ruled out and 
appropriate corrective action taken. Any subject having a >20 to ≤30% reduction compared to 
baseline in eGFR to <90 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 should 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. 
7.4.2.3 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. 
7.5 
Procedures for Overdose 
Based on clinical experience with voclosporin, 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. 
7.6 
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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7.6.1 Prohibited Medications 
The following medications cannot be taking during the study: 
• Cytotoxic or other systemic immunosuppressants  
• Initiation of new treatment or change in dosage of ARBs and/or ACE inhibitors within 
2 weeks prior to baseline  
• Vaccines using live organisms, viral or bacterial 
• 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 6 contains a summary of additional treatment and food restrictions. 
7.6.2 Allowed Concomitant Medications 
These medications are permitted during the study: 
• Systemic 
corticosteroids 
as 
described 
in 
the 
Inclusion 
Criteria 
(see 
Section 5.2, Inclusion Criteria) and following the corticosteroid dosing guidelines (see 
Section 7.1.2.2, Corticosteroids) 
• Doses of ACEIs and/or ARBs as described in the Inclusion Criteria (see Section 5.2, 
Inclusion Criteria) 
• Doses of diuretics as described in the Inclusion Criteria (see Section 5.2, Inclusion 
Criteria)  
• Doses of statins as described in the Inclusion Criteria (see Section 5.2, Inclusion 
Criteria) 
• Topical steroids (e.g., nose, scalp, skin, inhaled) 
• Herbal supplements can be used with caution and with approval by the Medical 
Monitor 
Treatments which may be used as medically indicated, according to the judgment of the 
Investigator can be found in Appendix 5. 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 6. 


 
 
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7.7 
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, the mean 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 withheld, an unscheduled visit 
arranged within 48 hours for repeat BP assessment, 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 [9]. 
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 (FMV) and from standard 
urinalysis results. If the FMV is for some reason not available at Day 1, Week 12 or Week 24, 
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 (Table 1) will be 
drawn in accordance with the Schedule of Events. 
Table 1 
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) 
All  
 
Differential (absolute and %) 
 Bands 
 Basophils 
 Eosinophils 
 Lymphocytes 
 Monocytes 
 Neutrophils 
All 
 


 
 
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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 
All  
 
Cholesterol (total, HDL, and LDL) & 
triglycerides 
Creatine kinase 
Day 1 and Week 24 
 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
All 
Glycosylated hemoglobin (HbA1c) 
Day 1 and Week 24 
Lactic dehydrogenase (LDH) 
Magnesium 
All 
Phosphorous, inorganic 
Day 1 and Week 24 
Potassium 
Protein, total 
Sodium 
All 
Urinalysis and urine 
microscopy 
Complete urinalysis (to include urine protein, 
creatinine, blood, urine microscopy).  
All except for stability 
assessment visits during the 
screening period 
FMV urine 
collection 
FMV will be performed to analyze UPCR.  
All 
24-hour urine 
UPCR 
Day 1, Week 12 and Week 24 
Note that 24-hour urine 
collection should be scheduled so 
as not to coincide with the FMV 
sampling due on the day of the 
study visit 


 
 
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Test Type 
Test Parameters 
Collection at Visits 
Pregnancy Test 
For females of childbearing potential.  
Serum pregnancy test to be 
evaluated at central laboratory at 
Screening, and Week 24; urine 
pregnancy test will be performed 
locally at all other applicable 
visits. 
Serology 
Cytomegalovirus 
Hepatitis A, B, and C 
Hepatitis B surface antigen (HBsAg) 
Screening (including stability 
assessments) 
 
Special Tests 
Estimated glomerular filtration rate (eGFR) 
All 
Biomarkers 
Urine nephrin 
Urine synaptopodin 
Serum TGF-β 
Day 1, Week 4 and Week 24 
Notes: FMV = First morning void; HDL = High-density lipoprotein; LDL = Low-density lipoprotein; UPCR = Urine protein creatinine 
ratio. 
 
The total amount of blood that will be collected during the study from an individual subject is 
approximately 200 mL over 34 weeks. 
For details on whether laboratory abnormalities should be reported as AEs and on the 
follow-up required in such cases, see Section 10.2.4, 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 FSGS-related manifestations which will 
also be recorded. A complete physical examination will be conducted at the initial screening 
assessment, 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. 
 


 
 
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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 heart rate (HR) 
• Body temperature (°C or °F) 
• Weight (kg) 
• Height (cm) 
To avoid variability, the same method of obtaining body temperature should be used 
throughout the study. 
At stability assessments, BP only will be included. 
Height will be recorded at the initial screening assessment only.  
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 mean BP measure is >130/80 mmHg (determined 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 7.7, 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 the initial screening assessment, Day 1, and Week 24. 


 
 
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9.1.4.1 Procedures to Manage a Treatment-Emergent Increase in QTcF 
In the event that a subject has a corrected QT interval duration corrected for heart rate using 
method of Fridericia (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, study treatment will be discontinued and 
the subject followed until the QTcF value either returns to baseline 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 QoL Assessments 
Assessments for QoL will be conducted at Day 1, Week 24, Week 25 and Week 26. 
The PROMIS assesses physical function, pain interference, and fatigue. See Appendix 7. 
The KDQOL-SFTM survey is a kidney disease-specific measure of QoL that assesses general 
health, kidney disease and its effects on daily life, and satisfaction with care. See Appendix 8. 
9.1.6 Voclosporin Pharmacokinetic and Biomarker Assessment 
Blood samples for PK assessments will be taken at Week 4 and Week 24. PK samples will be 
drawn prior to study treatment dosing (trough sample), and at 1, 2 and 4 hours post-dose. These 
samples will be analyzed for voclosporin. Should a subject experience a serious adverse event 
(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 treatment, further PK samples are not required. 
Blood and urine samples for biomarker assessments will be taken at Day 1, Week 4 and Week 
24, samples will be collected prior to study treatment dosing.  
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 
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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 and Stability Assessment Procedures 
The duration of the screening period will be approximately 4 weeks to 10 weeks (allowing for 
visit windows) and will consist of an initial screening assessment and 2 to 4 stability 
assessments to ensure that subjects meet eligibility criteria. 
The initial screening assessment will include provision of informed consent; complete physical 
examination; medical history (including FSGS history); vital signs measurements, including 
weight and height; 12-lead ECG; blood and urine sample collection for central laboratory 
assessments, urinalysis, and urine microscopy; FMV urine collection (for determination of 
UPCR); a serum pregnancy test (for women of childbearing potential); and review of prior and 
concomitant medications and entry criteria. Following these assessments and if clinically 
indicated, subjects receiving steroids may start reducing their steroid dose as described in the 
corticosteroid dosing guidelines (see Section 7.1.2.2, Corticosteroids). Any AEs which occur 
after informed consent will be recorded.  
Stability assessments will occur at 14-day intervals (±3 days) with the first assessment 
approximately 2 weeks after the initial screening assessment visit. Stability assessments 1 and 
2 are mandatory; assessments 3 and 4 are optional if additional time is required for the subject’s 
clinical status to stabilize. These stability assessment visits will include BP determination; 
blood sample collection for central laboratory assessments; FMV urine collection (for 
determination of UPCR); a serum pregnancy test (for women of childbearing potential); review 
of any AEs; and review of concomitant medications and entry criteria.  
These renal disease stability assessments will be evaluated to ensure eligibility with respect to 
entry criteria for UPCR and eGFR. 
Note that the laboratory assessments and FMV results of the last stability assessment will be 
used as the qualifying values for eligibility.  
FMV urine samples (for determination of UPCR) will be collected at all visits during the 
screening period and must be returned and the results evaluated prior to Baseline/Day 1. If the 
FMV is for some reason not available at Day 1, Week 12 or Week 24, 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 samples will be drawn according to Table 1. 
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. 


 
 
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Women of childbearing potential must have a negative serum pregnancy test result before 
baseline.  
If a subject has not met the requirements in Inclusion Criteria #3 due to not having renal biopsy 
result within the required time frame, a renal biopsy can be performed as per local procedures, 
after signing the study consent, provided the results can be obtained and reviewed prior to 
baseline. 
9.2.2 Treatment Procedures 
Only subjects who meet all of the inclusion and none of the exclusion criteria will be eligible 
for study treatment.  
Study medication will be dispensed per the Schedule of Events, beginning on Day 1. Subjects 
will take their first dose of study medication on Day 2. Women of childbearing potential must 
have a negative serum pregnancy test during Screening and a negative urine pregnancy test 
result on Day 1 prior to dispensing of study treatment.  
Subjects in Cohort 1, will be contacted by telephone at the end of Week 1 as a reminder to 
increase their dose to 2 capsules (15.8 mg) BID for 1 week, starting at Week 2. Subjects will 
be contacted again by telephone at the end of Week 2 as a reminder to increase their dose to 
3 capsules (23.7 mg) BID, starting at Week 3, for the remainder of the treatment period (see 
Section 7.1.2.1, Voclosporin).  
Subjects in Cohort 2, will also be contacted by telephone at the end of each week, as required 
up to the end of Week 3, as a reminder to increase their dose of study medication to the 
maximum dose selected for the second cohort. 
Subjects will complete all assessments per the Schedule of Events at Day 1 and at Weeks 2, 4, 
8, 12 and 18.  
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: 
• PROMIS and KDQOL-SFTM QoL questionnaires will be answered by the subject, as 
first study procedure, at Day 1/Baseline. 
• Abbreviated physical examination at Day 1. 
• Vital signs including weight. 
• Standard 12-lead ECG at Day 1. 


 
 
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• Blood and urine sample collection for analysis at central laboratory. 
• FMV urine sample collection. 
• Urine pregnancy testing at Day 1 (before dispensing study treatment)  
• AEs. 
• Concomitant medication. 
• Returned capsule count and drug accountability (except Day 1). 
9.2.3 End of Study (or Early Termination) Procedures 
On completion of treatment at Week 24 or earlier if subject is withdrawn, all assessments for 
Visit 8 (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: 
• PROMIS and KDQOL-SFTM QoL  
• Abbreviated physical examination  
• Vital signs including weight 
• Standard 12-lead ECG 
• Blood and urine sample collection for analysis at central laboratory 
• FMV urine sample collection 
• Serum pregnancy testing 
• Pharmacokinetic and biomarker sampling 
• AEs 
• Concomitant medication 
• Returned capsule count and drug accountability 
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• Confirmation of completion/discontinuation 
9.2.4 Follow-up Procedures 
All subjects who complete the study or withdraw before Week 24 will be followed up at 1 week 
(±3 days) and 2 weeks (±3 days) after their last study treatment dose to collect any new AEs 
and concomitant medications. These 2 visits (Visit 9 and Visit 10) will be conducted as 
in-clinic visits. 
Assessments for the follow-up visit are as follows: 
• PROMIS and KDQOL-SFTM QoL 
• Vital signs including weight 
• Blood and urine sample collection for analysis at central laboratory  
• FMV urine sample collection 
• Concomitant medication 
• AEs 
• Confirmation of completed follow-up visit 
9.2.5 Unscheduled Visit 
Unscheduled visits may be performed during the course of the study for safety reasons. . Only 
the data relevant to the purpose of the visit will be collected in the source documents and eCRF. 
Additionally, unscheduled visits will be registered in the electronic data capture (EDC) system.  
An unscheduled visit is requested in the following cases: 
• After dose reduction at any time during the study (unscheduled visit within 2 weeks)  
• QTcF value exceeding 500 msec, or an increase >60 msec from baseline, where the 
ECG will be repeated (confirmed) at an unscheduled visit within 24 hours  
• Decrease in eGFR >30% compared to baseline (unscheduled visit within 48 hours), or 
a decrease in eGFR >20-30% compared to baseline (unscheduled visit within 
approximately 2 weeks) 
• Symptomatic hypertension: Systolic BP is ≥165 mmHg or diastolic BP is ≥105 mmHg 
with symptoms of hypertension, see Section 7.7, Increased Blood Pressure 
(unscheduled visit within 48 hours)  


 
 
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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 
one 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 
events will also usually be considered serious.    
Hospitalizations that have been scheduled prior to the subject signing the informed consent 
form (ICF), although not recorded as SAEs, must be documented in the subject’s source 
documents. A renal biopsy performed as part of the study to verify eligibility will not be 
considered an SAE. Any complication experienced during a renal 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 ability to function. 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. 
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 


 
 
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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 treatment 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 treatment 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. 
10.2.4 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. 


 
 
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If the Investigator considers such an AE as serious it must be reported as an SAE. 
10.2.5 Abuse, Misuse, Overdose and Medication Error 
All AEs of special interest such as study drug 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 observed from time of signing of the ICF will be recorded in the subject's source 
documentation. This applies to all AEs regardless of presumed relationship to the study drug. 
For screen failure subjects, any AEs and SAEs occurring during the screening period (after 
informed consent) will be recorded in the subject’s source documentation only and will not be 
collected on the eCRF. Adverse events leading to discontinuation of study drug must be 
collected. 
If any AE is reported, the date of onset, relationship to study treatment, relationship to disease 
under study, 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 one 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 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. Note that for screen 
failure subjects, any AEs and SAEs occurring during the screening period will be recorded in 
the subject’s source documentation only. For enrolled subjects (i.e., those who successfully 
complete screening), the AE reporting period ends at the second Safety Follow-up visit 
(Visit 10). 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. 


 
 
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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 
For screen failure subjects, any SAEs occurring during the screening period (after informed 
consent) will be recorded in the subject’s source documentation only and will not be collected 
on the eCRF. 
For enrolled subjects (i.e., those who successfully complete screening), 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 drug or 
relationship to disease under study. For enrolled subjects, all SAEs will be recorded in the AE 
section of the subject’s eCRF and source documentation. 
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: 
. 
If notification is made via email or fax, site staff must enter the SAE information into the 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, whichever is 
longer. No formal study visit is required but Investigators must report any SAEs that occur 
during this 30-day period using the SAE reporting form provided; these will be entered into 
the safety database only. 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 or relationship to disease 
under study, 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. 


 
 
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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 9) 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 drug-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 Institutional Review Board (IRB)/Ethics Committee 
(EC)/Independent Ethics Committee (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. 


 
 
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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.  
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 
Not applicable. 


 
 
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12. DATA AND SAFETY MONITORING BOARD PROCEDURES 
Not applicable. 


 
 
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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 approximately 20 subjects, with up to 10 subjects in Cohort 1 and 
at least 10 subjects in Cohort 2.  
As this is an exploratory study, sample size calculations are not required. Descriptive statistics 
will be used and the results will only be hypothesis-generating. 
13.3 Populations 
13.3.1 Intent-to-Treat Set 
The intent-to-treat (ITT) set will consist of all enrolled subjects (non-screening failures) and 
will be used for all efficacy analyses. 
13.3.2 Safety Set 
The safety set will consist of all subjects who have taken at least 1 dose of study treatment.  
13.3.3 Per-protocol Set 
The per-protocol set (PPS) will consist of all subjects eligible from the ITT set who do not 
have any major protocol violations. Major protocol violations will be defined in the SAP. 
13.4 Datasets 
Assessments taken at each visit will be analyzed using 2 different datasets. The first will be 
the observed cases dataset whereby all values collected will contribute to the dataset. A second 
dataset will be used for summaries and analyses incorporating data carried forward from a 
subject’s last known value. This dataset will be referred to as the last observation carried 
forward dataset and as such, all subjects with any post-baseline efficacy assessment will 
contribute to the Week 24 analyses. 
13.5 Background and Demographic Characteristics 
Demographic and clinical disease characteristics will be summarized.  


 
 
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13.6 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, SD, median, minimum, 
and maximum) and frequency tables.  
13.7 Concomitant Therapy 
All concomitant medications will be coded by the World Health Organization Anatomical 
Therapeutic Chemical (ATC) Drug Reference List classification. The version used will be 
provided in the clinical study report. 
13.8 Efficacy Evaluations 
Primary and secondary endpoints will be assessed overall and for each individual cohort. 
13.8.1 Primary Endpoint 
The primary endpoint is the proportion of subjects with remission of proteinuria at Week 24 
based on the following parameters: 
• Complete remission: UPCR of <0.3 mg/mg 
OR 
• Partial remission: UPCR ≥0.3 mg/mg and <3.0 mg/mg with >50% reduction in UPCR 
from baseline 
13.8.2 Secondary Endpoints 
The following are defined as secondary endpoints: 
• Proportion of subjects with complete remission or partial remission of proteinuria at Weeks 
8 and 12 
• Proportion of subjects with complete remission of proteinuria at Weeks 8, 12, and 24 
• Proportion of subjects with UPCR <0.5 mg/mg at Weeks 8, 12, and 24 
• Proportion of subjects with partial remission of proteinuria at Weeks 8, 12, and 24 
• Time to first occurrence of complete or partial remission of proteinuria 
• Time to first occurrence of complete remission of proteinuria 


 
 
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• Time to first occurrence of partial remission of proteinuria 
• Time to first occurrence of 50% reduction in UPCR from baseline 
• Duration of UPCR <0.3 mg/mg 
• Change from baseline in UPCR at each time point 
• Proportion of subjects with a confirmed >30% decrease from baseline in eGFR (utilizing 
the CKD-EPI formula) at each time point (Baseline eGFR is defined as the last assessment 
prior to first dose of study treatment)  
• Proportion of subjects with a confirmed >30% increase in eGFR from the final visit (Week 
24 or last on-treatment visit, for subjects who discontinue prematurely) to the second Safety 
Follow-up visit (Visit 10) 
• Change in UPCR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10)  
• Change in eGFR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10) 
• Change from baseline in serum creatinine, serum albumin, and eGFR at each time point 
• QoL assessments 
− 
Mean change in PROMIS measures at Week 24 
− 
Change from baseline in KDQOL-SFTM score at Week 24 
• Safety and tolerability over 24 weeks 
• Renal biopsy: descriptive analyses of changes in histopathology will be evaluated in post-
treatment (24 weeks) renal biopsies in a subset of patients 
• Change from baseline to Week 4 and 24 in the following biomarkers:  
− 
Urine nephrin 
− 
Urine synaptopodin 
− 
Serum TGF-β 


 
 
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13.9 Statistical and Analytical Methods 
All statistical analyses relating to the primary and secondary objectives will be undertaken at 
study closure and will incorporate all available data. 
In order to aid dose decisions for Cohort 2, an analysis of the first 5 or 6 subjects in Cohort 1 
will be undertaken once the 5th or 6th subject reaches Week 12. 
Given the small sample size, all analyses will be descriptive in nature.  
Binary remission endpoints will be summarized using counts and proportions while continuous 
data will be summarized using means, SDs, medians, minimums and maximums. Kaplan-
Meier methodology will be used for the analysis of time-to endpoints. Confidence intervals for 
proportions may be calculated but it is recognized that such intervals, being based on 
20 patients, will be very wide. As an example, the 95% Clopper-Pearson CI for a proportion 
of 30% based on 20 patients is (11.9%, 54.3%). 
The analysis of the primary endpoint, complete or partial remission of proteinuria at Week 24, 
will be conducted on the ITT set and confirmed with the PPS (if applicable). Remission of 
proteinuria will be summarized and an exact 2-sided 95% CI for the remission rate will be 
calculated. 
The analyses of the secondary endpoints will incorporate the use of 2-sided 95% CIs and are 
described below:  
• Binary endpoints will be summarized using counts and proportions along with exact 
2-sided 95% CIs.  
• Endpoints measured as a time-to-event will be displayed using Kaplan-Meier methodology. 
Median time-to-event along with 2-sided 95% CIs will be displayed.  
• Other endpoints will be summarized by visit. Absolute values and differences between 
baseline and each time point up to and including Week 24 will be summarized using means 
and 2-sided 95% CIs. Changes between last on treatment value and post treatment 
follow-up will also be summarized.   
Given the nature of the study, additional exploratory analysis will be undertaken as appropriate. 
This may include the reporting of individual case studies. 
13.10 Safety Evaluations 
Specific safety endpoints are as follows: 
• Biochemical (including liver function tests) and hematological laboratory tests 


 
 
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• 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 visit, and as change from baseline. 
Adverse events and diseases 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 and up until 14 days 
after last dose will be considered TEAEs, though all AEs after informed consent will be 
recorded. SAEs occurring at any time after informed consent and prior to first study medication 
will be listed.  
All prior and concomitant medications will be summarized using preferred terms and ATC 
Level 2. 
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. 
13.11 Interim Analyses 
There will be no full interim analysis. 
13.12 Other Evaluations 
13.12.1 Pharmacokinetics 
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. 


 
 
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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 [28] and the ICH guidelines for GCP [29]. 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 IRB/EC/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. These 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 
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 


 
 
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verify the entries on the eCRF. The Investigator (or his/her deputy) must agree 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 termination 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. 
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 [31]. 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 [32] 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. 
D'Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 
2011;365(25):2398-411. 
2. 
Kikuchi M, Wickman L, Hodgin JB, Wiggins RC. Podometrics as a potential clinical 
tool for glomerular disease management. Semin Nephrol. 2015;35(3):245-55. 
3. 
Konigshausen E, Sellin L. Circulating permeability factors in primary focal segmental 
glomerulosclerosis: 
a 
review 
of 
proposed 
candidates. 
Biomed 
Res 
Int. 
2016;2016:3765608. 
4. 
Reggiani F, Ponticelli C. Focal segmental glomerular sclerosis: do not overlook the 
role of immune response. J Nephrol. 2016;29(4):525-34. 
5. 
Kim JH, Kim BK, Moon KC, Hong HK, Lee HS. Activation of the TGF-beta/Smad 
signaling 
pathway 
in 
focal 
segmental 
glomerulosclerosis. 
Kidney 
Int. 
2003;64(5):1715-21. 
6. 
Yamamoto T, Noble NA, Cohen AH, Nast CC, Hishida A, Gold LI, et al. Expression 
of transforming growth factor-beta isoforms in human glomerular diseases. Kidney Int. 
1996;49(2):461-9. 
7. 
Liao R, Liu Q, Zheng Z, Fan J, Peng W, Kong Q, et al. Tacrolimus protects podocytes 
from injury in lupus nephritis partly by stabilizing the cytoskeleton and inhibiting 
podocyte apoptosis. PLoS One. 2015;10(7):1-16. 
8. 
Kidney disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work 
Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl. 
2012;2:139-274. 
9. 
Investigator’s brochure – Voclosporin - Focal Segmental Glomerulosclerosis. Version 
3.0. Aurinia Pharmaceutical Inc. 23 October 2019. 
10. 
Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, et al. The 
actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of 
cyclosporine A. Nat Med. 2008 Sep;14(9):931-8. 
11. 
Mathieson PW. Proteinuria and immunity - an overstated relationship? N Engl J Med. 
2008 Dec 4;359(23):2492-4. 
12. 
Li X, Zhang X, Li X, Wang X, Wang S, Ding J. Cyclosporine A protects podocytes via 
stabilization of cofilin-1 expression in the unphosphorylated state. Exp Biol Med 
(Maywood). 2014;239(8):922-36. 
13. 
Shen X, Jiang H, Ying M, Xie Z, Li X, Wang H, et al. Calcineurin inhibitors 
cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin 
aminonucleoside in rodent models. Sci Rep. 2016;6:32087. 


 
 
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14. 
Mallipattu SK, He JC. The podocyte as a direct target for treatment of glomerular 
disease? Am J Physiol Renal Physiol. 2016;311(1):F46-51. 
15. 
Wakamatsu A, Fukusumi Y, Hasegawa E, Tomita M, Watanabe T, Narita I, et al. Role 
of calcineurin (CN) in kidney glomerular podocyte: CN inhibitor ameliorated 
proteinuria by inhibiting the redistribution of CN at the slit diaphragm. Physiol Rep. 
2016;4(6). 
16. 
Beaudreuil S, Lorenzo HK, Elias M, Nnang Obada E, Charpentier B, Durrbach A. 
Optimal management of primary focal segmental glomerulosclerosis in adults. Int J 
Nephrol Renovasc Dis. 2017;10:97-107. 
17. 
Duncan N, Dhaygude A, Owen J, Cairns TD, Griffith M, McLean AG, et al. Treatment 
of focal and segmental glomerulosclerosis in adults with tacrolimus monotherapy. 
Nephrol Dial Transplant. 2004;19(12):3062-7. 
18. 
Goumenos DS, Tsagalis G, El Nahas AM, Shortland JR, Davlouros P, Vlachojannis 
JG, 
et 
al. 
Immunosuppressive 
treatment 
of 
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focal 
segmental 
glomerulosclerosis: a five-year follow-up study. Nephron Clin Pract. 2006;104(2):c75-
82. 
19. 
Braun N, Schmutzler F, Lange C, Perna A, Remuzzi G, Risler T, et al. 
Immunosuppressive treatment for focal segmental glomerulosclerosis in adults. The 
Cochrane database of systematic reviews. 2008(3):CD003233. 
20. 
Cattran DC, Appel GB, Hebert LA, Hunsicker LG, Pohl MA, Hoy WE, et al. A 
randomized trial of cyclosporine in patients with steroid-resistant focal segmental 
glomerulosclerosis. North America Nephrotic Syndrome Study Group. Kidney Int. 
1999;56(6):2220-6. 
21. 
Laurin L-P, Nachman PH, Foster BJ. Calcineurin inhibitors in the treatment of primary 
focal segmental glomerulosclerosis: a systematic review and meta-analysis of the 
literature. Can J Kidney Health Dis. 2017;4:1-14. 
22. 
Cattran DC. Cyclosporine in the treatment of idiopathic focal segmental 
glomerulosclerosis. Semin Nephrol. 2003;23(2):234-41. 
23. 
Gipson DS, Trachtman H, Kaskel FJ, Radeva MK, Gassman J, Greene TH, et al. 
Clinical trials treating focal segmental glomerulosclerosis should measure patient 
quality of life. Kidney Int. 2011;79(6):678-85. 
24. 
Gipson DS, Trachtman H, Kaskel FJ, Greene TH, Radeva MK, Gassman JJ, et al. 
Clinical trial of focal segmental glomerulosclerosis in children and young adults. 
Kidney Int. 2011;80(8):868-78. 
25. 
Hogg RJ, Friedman A, Greene T, Radeva M, Budisavljevic MN, Gassman J, et al. 
Renal function and proteinuria after successful immunosuppressive therapies in 
patients with FSGS. Clin J Am Soc Nephrol. 2013;8(2):211-8. 


 
 
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26. 
Ren H, Shen P, Li X, Pan X, Zhang W, Chen N. Tacrolimus versus cyclophosphamide 
in steroid-dependent or steroid-resistant focal segmental glomerulosclerosis: a 
randomized controlled trial. Am J Nephrol. 2013;37(1):84-90. 
27. 
Wiseman AC. Immunosuppressive medications. Clin J Am Soc Nephrol. 2016 
Feb;11:332-43. 
28. 
KDOQI clinical practice guidelines for chronic kidney disease: evaluation, 
classification, and stratification, 2002. [assessed 2014 Sep 2]. Available from: 
http://www2.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm.  
29. 
World Medical Association Declaration of Helsinki. Ethical principles for medical 
research involving human subjects. 2013 Oct. 
30. 
ICH Harmonised Tripartite Guideline.: Guideline for good clinical practice. E6 (R1) 
1996 Jun 10. 
31. 
Pharmaceutical Research and Manufacturers of America [Internet]. PhRMA principles 
and guidelines: public disclosure of clinical trial results. 2009. Available from: 
Available from: https://www.phrma.org/codes-and-guidelines/phrma-principles-on-
conduct-of-clinical-trials. 
32. 
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. 
33. 
Reiser J, Fervenza FC, Sethi S. Epidemiology, classification, and pathogenesis of focal 
segmental glomeruloschlerosis. UpToDate.com [Internet]. 2017 Jul 6 [cited 2018 Feb 
12]. Available from: https://www.uptodate.com. 
 
 


 
 
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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 
after the screening period (including stabilization visits) in this trial (see Section 7.6.1, 
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 
Classification of FSGS 
The epidemiology, classification and pathogenesis of FSGS has been reviewed by Reiser et al, 
2017 [33]. 
According to this review, FSGS “is a histologic lesion, rather than a specific disease entity, 
that is commonly found to underlie the nephrotic syndrome in adults and children, particularly 
in the United States, Brazil, and many other countries. FSGS is characterized by the presence 
of sclerosis in parts (segmental) of some (focal) glomeruli on light microscopic examination 
of a kidney biopsy specimen.”  
According to this review, FSGS can be classified into the following etiologies, based upon the 
known and/or postulated causes of this histologic pattern: 
• “Primary or idiopathic FSGS, which most often presents with the nephrotic syndrome.”  
• “Secondary FSGS, which most often presents with non-nephrotic proteinuria and, 
commonly, some degree of renal insufficiency. This category most commonly refers to 
FSGS that develops as an adaptive response to glomerular hypertrophy or hyperfiltration. 
This includes disorders associated with a reduced renal mass and/or renal vasodilation, 
such as unilateral renal agenesis. In addition, a nonspecific pattern of secondary FSGS can 
result from scarring produced by a previous injury (due to a variety of conditions, including 
active IgA nephropathy, vasculitis, and LN). Other secondary causes of FSGS include 
drugs and toxins (including heroin, interferon, and pamidronate) and viral infections 
(particularly HIV).” 
• “Genetic causes of FSGS, which may present early in childhood with massive proteinuria 
and nephrotic syndrome or in adolescence or adulthood with less massive proteinuria.”  
Biopsy and diagnosis: According to Reiser et al, “precise quantification of sclerotic glomeruli 
requires three-dimensional morphometric analysis of entire glomeruli and the examination of 
sufficient glomeruli to ensure that the biopsy specimen is representative of glomeruli in the 
whole kidney. Kidney biopsies with few glomeruli (i.e., fewer than 15) cannot confidently 
exclude the diagnosis of FSGS, and, due to sampling error, some cases will be misclassified 
as minimal change disease.” 
“In patients who are found to have a FSGS lesion by light microscopy, the following approach 
can be used to distinguish between those with primary and secondary FSGS: 


 
 
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• Patients who present with nephrotic syndrome (ie, urine protein excretion >3.5 g/day and 
hypoalbuminemia), who exhibit extensive foot process effacement (≥80 percent) on EM 
[electron microscopic] examination, and who have no identifiable risk factors associated 
with secondary FSGS (eg, viral infection, drugs) most likely have primary FSGS, although 
genetic forms of FSGS lesions cannot always be excluded with confidence. Thus, primary 
FSGS is always a diagnosis of exclusion. 
• Patients who present with subnephrotic (ie, <3.5 g/day in an adult) or nephrotic-range 
proteinuria and a normal serum albumin concentration (ie, without nephrotic syndrome) 
and segmental foot process effacement (<80 percent) on EM [electron microscopic] 
examination most likely have secondary FSGS.” 
 
 


 
 
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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 
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. 
• At the discretion of the Investigator, subjects with hyperlipidemia may be treated with 
lipid lowering agents (e.g., statins) in accordance with standard clinical practice. Doses 
must be stable in the 2 weeks prior to baseline. 
• Subjects with nephrotic edema may be treated with diuretics during the screening 
period. Volume status should be optimized based on the clinical judgment of the 
Investigator and the doses of diuretics must be stable in the 2 weeks prior to baseline. 
• ACEIs, ARBs, and aliskerin and other therapies are recommended, as per standard 
guidelines, but if used their dose must be stable throughout the study. Subjects 
receiving ACEIs or ARBs must be on a stable dose for at least 2 weeks prior to baseline.  


 
 
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• In the case of uncontrolled hypertension (systolic BP >165 mmHg or 
diastolic >105 mmHg on two successive measurements), the addition of a diuretic or 
calcium channel blocker only are permitted, together with dose decreases or 
interruption of study treatment per the instructions in Section 7.7, Increased Blood 
Pressure.  
 
 


 
 
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Appendix 6 
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 voclosporin 
metabolism 
ACEIs and ARBs 
Stable dose for at least 2 
weeks prior to baseline 
Change or 
commencement 
prohibited 
Interfere with 
primary endpoint 
assessment 
Foods 
Grapefruit and grapefruit 
juice 
 
24 hours 
 
Prohibited 
 
May affect the 
metabolism of 
voclosporin 
Notes:  ACEI = Angiotensin converting enzyme inhibitor; ARB = Angiotensin receptor blocker; NSAID = Non-steroidal anti-inflammatory 
drug; P-gp = P-glycoprotein. 
 
 


 
 
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Appendix 7 
PROMIS QoL Assessment 
The PROMIS QoL assessment includes three questionnaires: 
• Physical Function – Short Form 10a (PROMIS® Item Bank v2.0) 
• Fatigue – Short Form 8a (PROMIS® Item Bank v1.0) 
• Pain Interference – Short Form 8a (PROMIS® Item Bank v1.0)  
 
 
 
 
 


 
 
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Appendix 8 
KDQOL-SFTM QoL Assessment Version 1.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Kidney Disease and Quality of Life™ Short Form  (KDQOL-SF™)
English Version 1.3
Copyright © 1993, 1994, 1995 by RAND and the University of Arizona
Your Health
– and –
Well-Being
Kidney Disease and Quality of Life (KDQOL-SF™ 1.3)
This survey asks for your views about your health. This information
will help keep track of how you feel and how well you are able to do
your usual activities.
Thank you for completing these questions!
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Study of Quality of Life
For Patients on Dialysis
What is the purpose of the study?
This study is being carried out in cooperation with physicians and their patients.  The
purpose is to assess the quality of life of patients with kidney disease.
What will I be asked to do?
For this study, we want you to complete a survey today about your health, how you
feel and your background.
Confidentiality of information?
We do not ask for your name.  Your answers will be combined with those of other
participants in reporting the findings of the study.  Any information that would permit
identification of you will be regarded as strictly confidential.  In addition, all
information collected will be used only for purposes of the study, and will not be
disclosed or released for any other purpose without your prior consent.
How will participation benefit me?
The information you provide will tell us how you feel about your care and further
understanding about the effects of medical care on the health of patients.  This
information will help to evaluate the care delivered.
Do I have to take part?
You do not have to fill out the survey and you can refuse to answer any question.
Your decision to participate will not affect your opportunity to receive care.
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Page 1
Your Health
This survey includes a wide variety of questions about your health and
your life.  We are interested in how you feel about each of these issues.
1. In general, would you say your health is:  [Mark an 
 in the one box
that best describes your answer.]
Excellent
Very good
Good
Fair
Poor
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
2. Compared to one year ago, how would you rate your health in
general now?
Much better
now than
one year
ago
Somewhat
better now
than one
year ago
About the
same as
one year
ago
Somewhat
worse now
than one
year ago
Much
worse now
than one
year ago
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
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Page 2
3. The following items are about activities you might do during a
typical day.  Does your health now limit you in these activities?  If so,
how much?  [Mark an 
 in a box on each line.]
Yes,
limited a
lot
Yes,
limited a
little
No, not
limited
at all
a
Vigorous activities, such as running, lifting
heavy objects, participating in strenuous
sports ............................................................
M
M
M
 1.........
 2 ........
 3
b
Moderate activities, such as moving a table,
pushing a vacuum cleaner, bowling, or
playing golf ....................................................
 1.........
 2 ........
 3
c
Lifting or carrying groceries ............................
 1.........
 2 ........
 3
d
Climbing several flights of stairs ......................
 1.........
 2 ........
 3
e
Climbing one flight of stairs.............................
 1.........
 2 ........
 3
f
Bending, kneeling, or stooping ........................
 1.........
 2 ........
 3
g
Walking more than a mile
 1.........
 2 ........
 3
h
Walking several blocks ...................................
 1.........
 2 ........
 3
i
Walking one block..........................................
 1.........
 2 ........
 3
j
Bathing or dressing yourself............................
 1.........
 2 ........
 3
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Page 3
4. During the past 4 weeks, have you had any of the following problems
with your work or other regular daily activities as a result of your
physical health?
Yes
No
M
M
a
Cut down the amount of time you spent on work
or other activities ................................................
 1.........
 2
b
Accomplished less than you would like................
 1.........
 2
c
Were limited in the kind of work or other
activities.............................................................
 1.........
 2
d
Had difficulty performing the work or other
activities (for example, it took extra effort)...........
 1.........
 2
5. During the past 4 weeks, have you had any of the following problems
with your work or other regular daily activities as a result of any
emotional problems (such as feeling depressed or anxious)?
Yes
No
M
M
a
Cut down the amount of time you spent on work
or other activities ................................................
 1.........
 2
b
Accomplished less than you would like................
 1.........
 2
c
Didn’t do work or other activities as carefully as
usual..................................................................
 1.........
 2
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Page 4
6. During the past 4 weeks, to what extent has your physical health or
emotional problems interfered with your normal social activities with
family, friends, neighbors, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
7. How much bodily pain have you had during the past 4 weeks?
None
Very
mild
Mild
Moderate
Severe
Very
severe
M
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
  
 6
8. During the past 4 weeks, how much did pain interfere with your
normal work (including both work outside the home and
housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
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Page 5
9.
These questions are about how you feel and how things have been
with you during the past 4 weeks.  For each question, please give
the one answer that comes closest to the way you have been feeling.
How much of the time during the past 4 weeks…
All
 of the
time
Most
of the
time
A good
bit
 of the
time
Some
of the
time
A little
of the
time
None
of the
time
M
M
M
M
M
M
a
Did you feel full of
pep?.............................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
b
Have you been a very
nervous person? ...........
 1........
 2 .......
 3........
 4 .......
 5.......
 6
c
Have you felt so down
in the dumps that
nothing could cheer
you up?........................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
d
Have you felt calm and
peaceful?......................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
e
Did you have a lot of
energy? ........................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
f
Have you felt
downhearted and blue? .
 1........
 2 .......
 3........
 4 .......
 5.......
 6
g
Did you feel worn out?..
 1........
 2 .......
 3........
 4 .......
 5.......
 6
h
Have you been a
happy person?..............
 1........
 2 .......
 3........
 4 .......
 5.......
 6
i
Did you feel tired?........
 1........
 2 .......
 3........
 4 .......
 5.......
 6
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Page 6
10. During the past 4 weeks, how much of the time has your physical
health or emotional problems interfered with your social activities
(like visiting with friends, relatives, etc.)?
All
of the time
Most
of the time
Some
of the time
A little
of the time
None
of the time
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
11. Please choose the answer that best describes how true or false each
of the following statements is for you.
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false
a 
I seem to get sick
a little easier than
other people ..........
M
M
M
M
M
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
b
I am as healthy as
anybody I know ....
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
c
I expect my health
to get worse ..........
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
d
My health is
excellent................
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
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Page 7
Your Kidney Disease
12. How true or false is each of the following statements for you?
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false
a 
My kidney
disease interferes
too much with my
life ........................
M
M
M
M
M
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
b
Too much of my
time is spent
dealing with my
kidney disease.......
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
c
I feel frustrated
dealing with my
kidney disease.......
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
d
I feel like a burden
on my family .........
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
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Page 8
13. These questions are about how you feel and how things have been
going during the past 4 weeks.  For each question, please give the
one answer that comes closest to the way you have been feeling.
How much of the time during the past 4 weeks…
None
of the
time
A little
of the
time
Some
of the
time
A good
bit of
the
time
Most
of the
time
All of
the
time
a
Did you isolate your-
self from people
around you?.................
M
M
M
M
M
M
 1 .......
 2.......
 3........
 4 .......
 5........
 6
b
Did you react slowly
to things that were said
or done?.......................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
c
Did you act irritable
toward those around
you?.............................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
d
Did you have difficulty
concentrating or
thinking?.......................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
e
Did you get along well
with other people? ........
 1 .......
 2.......
 3........
 4 .......
 5........
 6
f
Did you become
confused? ....................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
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Page 9
14. During the past 4 weeks, to what extent were you bothered by each
of the following?
Not at all
bothered
Somewhat
bothered
Moderately
bothered
Very much
bothered
Extremely
bothered
M
M
M
M
M
a
Soreness in your
muscles?...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
b
Chest pain? ...........
 1 ............
 2 ...........
 3 ............
 4...........
 5
c
Cramps? ...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
d
Itchy skin?.............
 1 ............
 2 ...........
 3 ............
 4...........
 5
e
Dry skin?...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
f
Shortness of
breath?..................
 1 ............
 2 ...........
 3 ............
 4...........
 5
g
Faintness or
dizziness?..............
 1 ............
 2 ...........
 3 ............
 4...........
 5
h
Lack of appetite?...
 1 ............
 2 ...........
 3 ............
 4...........
 5
i
Washed out or
drained?................
 1 ............
 2 ...........
 3 ............
 4...........
 5
j
Numbness in
hands or feet?........
 1 ............
 2 ...........
 3 ............
 4...........
 5
k
Nausea or upset
stomach?...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
l
(Hemodialysis patient only)
Problems with
your access site? ...
 1 ............
 2 ...........
 3 ............
 4...........
 5
m
(Peritoneal dialysis patient only)
Problems with
your catheter site?..
 1 ............
 2 ...........
 3 ............
 4...........
 5
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Page 10
Effects of Kidney Disease on Your Daily Life
15. Some people are bothered by the effects of kidney disease on their
daily life, while others are not.  How much does kidney disease
bother you in each of the following areas?
Not at all
bothered
Somewhat
bothered
Moderately
bothered
Very much
bothered
Extremely
bothered
M
M
M
M
M
a
Fluid restriction?....
 1 ............
 2 ...........
 3 ............
 4...........
 5
b
Dietary restriction?.
 1 ............
 2 ...........
 3 ............
 4...........
 5
c
Your ability to
work around the
house? ..................
 1 ............
 2 ...........
 3 ............
 4...........
 5
d
Your ability to
travel? ...................
 1 ............
 2 ...........
 3 ............
 4...........
 5
e
Being dependent
on doctors and
other medical
staff?.....................
 1 ............
 2 ...........
 3 ............
 4...........
 5
f
Stress or worries
caused by kidney
disease? ................
 1 ............
 2 ...........
 3 ............
 4...........
 5
g
Your sex life?........
 1 ............
 2 ...........
 3 ............
 4...........
 5
h
Your personal
appearance? ..........
 1 ............
 2 ...........
 3 ............
 4...........
 5
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Page 12
17. For the following question, please rate your sleep using a scale
ranging from 0 representing “very bad” to 10 representing “very
good.”
If you think your sleep is half-way between “very bad” and “very
good,” please mark the box under the number 5.  If you think you
sleep is one level better than 5, mark the box under 6.  If you think
your sleep is one level worse than 5, mark the box under 4 (and so
on).
On a scale from 0 to 10, how would you rate your sleep overall?
[Mark an 
 in one box.]
Very bad
Very good
M
M
0
1
2
3
4
5
6
7
8
9
10
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Page 13
18. How often during the past 4 weeks did you...
None
of the
time
A little
of the
time
Some
of the
time
A good
bit of
the
time
Most
of the
time
All of
the
time
a
Awaken during the
night and have trouble
falling asleep again?.......
M
M
M
M
M
M
 1 .......
 2.......
 3........
 4 ......
 5.......
 6
b
Get the amount of
sleep you need?............
 1 .......
 2.......
 3........
 4 ......
 5.......
 6
c
Have trouble staying
awake during the day?...
 1 .......
 2.......
 3........
 4 ......
 5.......
 6
19. Concerning your family and friends, how satisfied are you with...
Very
dissatisfied
Somewhat
dissatisfied
Somewhat
satisfied
Very
satisfied
a
The amount of time
you are able to spend
with your family and
friends?........................
M
M
M
M
 1...............
 2 ..............
 3...............
 4
b
The support you
receive from your
family and friends?........
 1...............
 2 ..............
 3...............
 4
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Page 14
20. During the past 4 weeks, did you work at a paying job?
Yes
No
M
M
  
 1
  
 2
21. Does your health keep you from working at a paying job?
Yes
No
M
M
  
 1
  
 2
22. Overall, how would you rate your health?
Worst possible
(as bad or worse
 than being dead)
Half-way
between worst
and best
Best
possible
M
M
M
0
1
2
3
4
5
6
7
8
9
10
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Page 15
Satisfaction With Care
23. Think about the care you receive for kidney dialysis.  In terms of
your satisfaction, how would you rate the friendliness and interest
shown in you as a person?
Very
poor
Poor
Fair
Good
Very
good
Excellent
The Best
M
M
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
  
 6
  
 7
24. How true or false is each of the following statements?
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false
a 
Dialysis staff
encourage me to
be as independent
as possible ............
M
M
M
M
M
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b
Dialysis staff
support me in
coping with my
kidney disease.......
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Thank you for completing these questions!
AUR-VCS-2017-03 – Version 4.0 (Amendment 3) 
20 December 2019
Confidential 
Page 111 of 111

Prot_SAP_000.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. 
 
 
An Open-Label Dose-Exploration Cohort Study Evaluating the 
Efficacy and Safety of Voclosporin in Achieving Complete or 
Partial Remission of Proteinuria in Subjects with Focal 
Segmental Glomerulosclerosis  
 
Clinical Protocol Number: 
AUR-VCS-2017-03 
 
 
Study Name: 
AURONA 
 
 
Date: 
27 April 2018 
 
 
Version Number: 
1.0 
 
 
IND Number: 
137,905 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Page 2 of 110 
 
NAMES AND ADDRESSES 
 
Sponsor 
Name: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Tel: 
 
 
24 Hour: 
 
 
 
Chief Medical Officer 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
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: An Open-Label Dose-Exploration Cohort Study Evaluating the Efficacy and Safety of 
Voclosporin in Achieving Complete or Partial Remission of Proteinuria in Subjects with Focal 
Segmental Glomerulosclerosis 
Version Number/Date: 1.0/27 April 2018 
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 
 
 
 
Chief Medical Officer 
 
Date (e.g., DD Month Year) 
 
 
 
Vice President, Quality and Regulatory 
Affairs 
 
Date (e.g., DD Month Year) 
 
27 Apr 2018
27APR2018


 
 
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Page 4 of 110 
 
INVESTIGATOR AGREEMENT FORM 
I have read the attached protocol titled: An Open-Label Dose-Exploration Cohort Study 
Evaluating the Efficacy and Safety of Voclosporin in Achieving Complete or Partial Remission 
of Proteinuria in Subjects with Focal Segmental Glomerulosclerosis 
Version Number/Date: 1.0/27 April 2018 
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. 
 
 
 
<insert name> 
Principal Investigator 
 
Date (e.g., DD Month Year) 
 


 
 
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Page 5 of 110 
 
SYNOPSIS 
Title: 
An Open-Label, Dose-exploration, Cohort Study Evaluating the Efficacy and Safety 
of Voclosporin in Achieving Complete or Partial Remission of Proteinuria in 
Subjects with Focal Segmental Glomerulosclerosis 
Short Title: 
AURONA 
Study Product: 
Voclosporin  
Indication: 
Focal Segmental Glomerulosclerosis 
Phase: 
2 
Sponsor: 
Aurinia Pharmaceuticals Inc. 
Study Code: 
AUR-VCS-2017-03 
Objectives: 
Primary Objective: 
• 
To assess the efficacy of voclosporin (VCS) in achieving complete or partial 
remission of proteinuria after 24 weeks of therapy in subjects with focal 
segmental glomerulosclerosis (FSGS).  
Secondary Objective: 
• 
To assess the safety and tolerability of VCS over 24 weeks in subjects with 
FSGS. 
Design: 
Open-label, 24-week, multicenter, exploratory cohort study of VCS. 
Treatment: 
Investigational Treatment: 
Voclosporin softgel capsules containing 7.9 mg drug. Approximately 10 subjects will 
be enrolled into Cohort 1 and take VCS 23.7 mg orally (PO), twice daily (BID). 
The dose level of VCS for Cohort 2 (approximately 10 subjects) will be determined 
by analysis of efficacy and safety data at Week 12 from the first 6 subjects in 
Cohort 1. 
Inclusion Criteria: 
1. Written informed consent before any study-specific procedures are performed. 
2. Male or female subjects with a minimum age of 18 years (or legal age of consent 
if >18 years) to 75 years of age, inclusive, at the time of consent. 
3. Primary FSGS diagnosed by renal biopsy within 4 months prior to end of 
screening. 
4. At initial screening assessment and at last qualifying assessment during 
screening period prior to baseline, FSGS subjects must have urine protein 
creatinine ratio (UPCR) ≥3.0 mg/mg, serum albumin <3.2 mg/dL AND must be 
treatment-naïve, defined as subjects who have not received systemic steroids, 
cytotoxic or other systemic immunosuppressant treatment, and are not expected 
to require treatment with these medications during the study. 


 
 
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Page 6 of 110 
 
Inclusion Criteria 
(cont’d): 
5. All subjects should be treated with angiotensin converting enzyme inhibitors 
(ACEIs) and/or angiotensin receptor blockers (ARBs) unless they have 
documented intolerance or contraindication to these medications. Doses of these 
agents must be stable for at least 2 weeks prior to baseline, with blood pressure 
(BP) ≤150/90 mmHg at the baseline visit (Visit 2). 
a) Subjects with nephrotic edema may be treated with diuretics during the 
screening period. Volume status should be optimized based on the clinical 
judgment of the Investigator and the doses of diuretics must be stable for at 
least 2 weeks prior to baseline. 
b) At the discretion of the Investigator, subjects with hyperlipidemia may be 
treated with lipid-lowering agents (e.g., statins) in accordance with standard 
clinical practice. Doses must be stable for at least 2 weeks prior to baseline. 
6. Stable proteinuria, renal function, and BP for at least 2 weeks prior to baseline, 
as assessed by the Investigator. Substantial changes in UPCR, estimated 
glomerular filtration rate (eGFR), and/or BP during the screening period may be 
due to treatments administered (e.g., ACEIs and ARBs); and, therefore, may 
interfere with study assessments or outcomes, or may place the subject at 
increased risk. These subjects must be discussed with the medical monitor prior 
to initiation of study treatment. 
7. Women of childbearing potential must have a negative serum pregnancy test 
prior to dispensing study treatment. Two effective forms of contraception must 
be used simultaneously unless abstinence is the chosen method. Subjects must 
use effective contraception during the study. 
Exclusion Criteria: 
1. Subjects unable or unwilling to give written informed consent and/or to comply 
with study procedures. 
2. Clinical or histologic evidence of secondary FSGS. 
3. Histologic evidence of collapsing variant FSGS. 
4. eGFR as calculated by the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation of ≤30 mL/minute/1.73 m2 at initial screening assessment 
or ≤45 mL/minute/1.73 m2 at last qualifying assessment during screening period 
prior to baseline. 
5. Currently taking or expected to require any of the prohibited medications listed 
in the protocol at screening or during the study. This includes prohibited 
medications prior to screening as specified in the protocol. 
6. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or 
expected to require dialysis during the study period. 
7. A previous renal transplant or planned renal transplant during the study. 
8. Body mass index >40 kg/m2. 
9. Family history of nephrotic syndrome. 
10. Any known hypersensitivity or contraindication to cyclosporine, or components 
of any cyclosporine drug product. 


 
 
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Exclusion Criteria 
(cont’d): 
11. 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. 
• 
Current or past 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. 
12. Other clinically significant active medical conditions, such as: 
• 
Severe cardiovascular disease including congestive heart failure, history of 
cardiac dysrhythmia or congenital long QT syndrome. Subjects with 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 are excluded. 
• 
Liver dysfunction: aspartate aminotransferase, alanine aminotransferase, or 
bilirubin ≥2.5 times the upper limit of normal at last qualifying assessment 
during screening period prior to baseline. 
• 
Chronic obstructive pulmonary disease or asthma requiring oral steroids. 
• 
Bone marrow insufficiency: white blood cell count <2,500/mm3, absolute 
neutrophil count <1.3 × 103/μL, and/or thrombocytopenia (platelet count 
<50,000/mm3) at screening or at last qualifying assessment during screening 
period prior to baseline. 
• 
Current infection requiring intravenous antibiotics. 
13. Any overlapping autoimmune condition for which the condition or the treatment 
of the condition may affect the study assessments or outcomes (e.g., any 
condition for which additional immunosuppression, including systemic 
corticosteroids, and/or cytotoxic therapy is indicated). Overlapping conditions 
for which the condition or treatment is not expected to affect assessments or 
outcomes are not excluded. 
14. No vaccines using live organisms, virus or bacterial, are allowed during 
screening and while taking the study treatment. 


 
 
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Exclusion Criteria 
(cont’d): 
15. 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. 
16. 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. 
17. Subjects who are pregnant, breast feeding or, if of childbearing potential, not 
using adequate contraceptive precautions. 
18. 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. 
19. Subjects treated in a previous VCS clinical study. 
Primary Endpoint: 
Proportion of subjects with remission of proteinuria at Week 24, assessed overall and 
for each individual cohort, based on the following parameters: 
• 
Complete remission: UPCR of <0.3 mg/mg 
OR 
• 
Partial remission: UPCR ≥0.3 mg/mg and <3.0 mg/mg with >50% reduction in 
UPCR from baseline 
Secondary 
Endpoints: 
The following secondary endpoints will be assessed overall and for each individual 
cohort: 
• 
Proportion of subjects with complete remission or partial remission of 
proteinuria at Weeks 8 and 12 
• 
Proportion of subjects with complete remission of proteinuria at Weeks 8, 12, 
and 24 
• 
Proportion of subjects with UPCR <0.5 mg/mg at Weeks 8, 12, and 24 
• 
Proportion of subjects with partial remission of proteinuria at Weeks 8, 12, and 
24 
• 
Time to first occurrence of complete or partial remission of proteinuria 
• 
Time to first occurrence of complete remission of proteinuria 
• 
Time to first occurrence of partial remission of proteinuria 
• 
Time to first occurrence of 50% reduction in UPCR from baseline 
• 
Duration of UPCR <0.3 mg/mg 
• 
Change from baseline in UPCR at each time point 
• 
Proportion of subjects with a confirmed >30% decrease from baseline in eGFR 
(utilizing the CKD-EPI formula) at each time point  
• 
Proportion of subjects with a confirmed >30% increase in eGFR from the final 
visit (Week 24 or last on-treatment visit, for subjects who discontinue 
prematurely) to the second Safety Follow-up visit (Visit 10) 


 
 
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Secondary 
Endpoints (cont’d): 
• 
Change in UPCR from the final visit (Week 24 or last on-treatment visit, for 
subjects who discontinue prematurely) to the second Safety Follow-up visit 
(Visit 10)  
• 
Change in eGFR from the final visit (Week 24 or last on-treatment visit, for 
subjects who discontinue prematurely) to the second Safety Follow-up visit 
(Visit 10) 
• 
Change from baseline in serum creatinine, serum albumin, and eGFR at each 
time point 
• 
Quality of life assessments 
− 
Mean change in Patient Reported Outcome Measurement Information 
System (PROMIS) measures at Week 24 
− 
Change from baseline in Kidney Disease Quality of Life-Short Form 
(KDQOL-SFTM) score at Week 24 
• 
Safety and tolerability over 24 weeks 
• 
Renal biopsy: descriptive analyses of changes in histopathology will be 
evaluated in post-treatment (24 weeks) renal biopsies in a subset of patients 
• 
Change from baseline to Weeks 4 and 24 in the following biomarkers:  
− 
Urine nephrin 
− 
Urine synaptopodin 
− 
Serum transforming growth factor beta 
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. Subjects will be assigned a unique subject number which will 
be used to identify them throughout the study. If a subject has not had a renal 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 the end of screening. The screening period will be between 4 and 8 
weeks long to ensure that subjects meet eligibility criteria, including renal disease 
stability assessments.  
The first 10 subjects meeting the required eligibility criteria will be assigned to 
Cohort 1 and will receive VCS according to the following dosing regimen: 
• 
Week 1: 1 capsule (7.9 mg) PO, BID 
• 
Week 2: 2 capsules (15.8 mg) PO, BID 
• 
Week 3 – Week 24: 3 capsules (23.7 mg) PO, BID 
Appropriate sponsor personnel (including the medical monitor) and the investigator 
will jointly decide whether to continue with the dose escalation for each subject.  


 
 
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When the first 6 subjects in Cohort 1 have completed 12 weeks of treatment with 
VCS, the top line efficacy and safety data will be analyzed to determine the dose level 
for Cohort 2. The selected dose may be higher or lower than 23.7 mg BID. The 
maximum dose possible for Cohort 2 will be 39.5 mg (5 capsules) BID.  Should this 
dose be selected the following dosing regimen will be followed: 
• 
Week 1: 1 capsule (7.9 mg) PO, BID 
• 
Week 2: 2 capsules (15.8 mg) PO, BID 
• 
Week 3: 3 capsules (23.7 mg) PO, BID 
• 
Week 4: 5 capsules (39.5 mg) PO, BID 
Evaluable safety and tolerability data at Week 12 from the first six subjects from 
Cohort 1 are required in order to make the decision to escalate to a higher dose level 
for Cohort 2.  
As a guidance, the dose will not be escalated if any of following criteria are met in 
the first 6 subjects from Cohort 1, unless it was obvious that the occurrence was not 
related to the administration of VCS: 
• 
Severe adverse events (SAEs) of same character in ≥2 subjects. 
• 
Clinically significant decrease in eGFR in ≥5 subjects. 
• 
Clinically significant laboratory abnormalities of same character in ≥
5 subjects. 
• 
Clinically significant abnormalities of electrolytes in ≥4 subjects. 
• 
Clinically significant changes in vital signs of same character in ≥4 
subjects. 
Doses and dose increments smaller than anticipated may be proposed for Cohort 2 
based on the safety and tolerability results from the Cohort 1.  
All subjects will complete dosing through 24 weeks of study treatment and will have 
2 Safety Follow-Up visits, 1 and 2 weeks after completion of treatment (i.e., at Week 
25 and Week 26). Subjects who permanently discontinue study treatment before the 
Week 24 visit will return for all remaining study visits and assessments, including 
the 2 Safety Follow-Up visits, unless they have withdrawn consent. 
Sample Size: 
As this is an exploratory study, sample size calculations are not required. It is 
estimated that approximately 20 subjects will be recruited, with approximately 10 
subjects in both of Cohorts 1 and 2. 


 
 
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Statistical Methods: 
Analysis: 
All statistical analyses relating to the primary and secondary objectives will be 
undertaken at study closure and will incorporate all available data. 
Given the small sample size, all analyses will be descriptive in nature. Confidence 
intervals (CIs) for proportions may be calculated but it is recognized that such 
intervals, being based on 20 patients, will be very wide. As an example, the 95% 
Clopper-Pearson CI for a proportion of 30% based on 20 patients is (11.9%, 54.3%). 
Populations:  
The efficacy analysis will be based on intent-to-treat (ITT) principles and will include 
all enrolled subjects (non-screening failures). 
The per-protocol data set will include the subset of subjects in the ITT population 
who do not have any major protocol violations (to be defined). 
The safety analysis set will consist of all subjects who receive at least 1 dose of study 
treatment. 
Methods: 
Top line efficacy (change from Baseline in UPCR) and safety data (AEs, eGFR, 
ECGs and vital signs) for the first 6 subjects in Cohort 1 completing 12 weeks of 
study treatment, will be reviewed and based on those data the commencement of 
enrolment and the target dose for Cohort 2 will be determined. 
The analysis of the primary endpoint, complete or partial remission of proteinuria at 
Week 24, will be conducted on the ITT population and confirmed with the per-
protocol population (if applicable). Remission of proteinuria will be summarized and 
an exact 2-sided 95% CI for the remission rate will be calculated.  
The analyses of the secondary endpoints will incorporate the use of 2-sided 95% CIs 
and are described below:  
• 
Binary endpoints will be summarized using exact 2-sided 95% CIs.  
• 
Endpoints measured as a time-to-event will be displayed using Kaplan-Meier 
methodology. Median time-to-event along with 2-sided 95% CIs will be 
displayed.  
• 
Other endpoints will be summarized by visit. Absolute values and differences 
between baseline and each time point up to and including Week 24 will be 
summarized using means and 2-sided 95% CIs. Changes between last on 
treatment value and post treatment follow-up will also be summarized. 
Safety Endpoints:  
Adverse events will be aggregated by System Organ Class and preferred term and 
presented as summary tables.  
Laboratory values, 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. 
Exploratory analyses will be undertaken should the data suggest areas worthy of 
further investigation. 


 
 
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STUDY SCHEMA 
 
 
 
Notes: 
BID=Twice daily; VCS=Voclosporin. 


 
 
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Page 13 of 110 
 
AUR-VCS-2018-01 SCHEDULE OF EVENTS 
Visit 
Visit 1 
Screening Period 
Visit 2 
Baseline 
Visit 3 
Visits 4-5 
Visit 6 
Visit 7 
Visit 8 
End of 
Treatment/ 
Early 
Termination 
Visit 9 
Safety 
Follow-up 
Visit 10 
Safety 
Follow-up 
Day/Week 
Day -56 to Day -1 
Day 1 
(Within 1 
Wk Post 
Qualifying 
Assessment) 
Wk 2 
(±3 Days) 
Wks 4, 8 
(±3 Days) 
Wk 12 
(±3 Days) 
Wk 18 
(±5 Days) 
Wk 24 
(±7 Days) 
Wk 25 
(±3 Days) or 
Premature 
Disc. +7 Days 
Wk 26 
(±3 Days) or 
Premature 
Disc. +14 Days  
Screening 
Visit(1) 
Stability 
Assessments 1 & 
2, Optional 3 & 
4(1) 
Informed consent 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
 
 
 
 
 
 
 
 
 
 
Renal biopsy(2) 
 
 
 
 
 
 
 
(2) 
 
 
Medical history and 
demography 
 
 
 
 
 
 
 
 
 
 
Physical exam(3) 
 
 
 
 
 
 
 
 
 
 
Vital signs(4) 
 
 
 
 
 
 
 
 
 
 
ECG(5) 
 
 
 
 
 
 
 
 
 
 
Laboratory 
assessments(6)  
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics(7) 
 
 
 
 
 
 
 
 
 
 
Urinalysis and urine 
microscopy 
 
 
 
 
 
 
 
 
 
 
FMV urine collection(8) 
 
 
 
 
 
 
 
 
 
 
24-hour urine(9) 
 
 
 
 
 
 
 
 
 
 
QoL(10) 
 
 
 
 
 
 
 
 
 
 
Pregnancy test(11) 
 
 
 
 
 
 
 
 
 
 
Adverse events 
(12) 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
Dispense study 
medication/ 
compliance(13) 
 
 
 
 
 
 
 
(14) 
 
 
First dose of study 
medication 
 
 
(15) 
 
 
 
 
 
 
 


 
 
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Page 14 of 110 
 
1 
Stability assessments to occur at a minimum of 14-day intervals with first assessment 2 weeks after the screening visit. Stability assessments 1 and 2 are mandatory; assessments 3 and 4 are optional 
if additional time is required for the subject’s clinical status to stabilize. Note that the laboratory assessments and FMV results of the last stability assessment will be used as the qualifying values for 
eligibility.  
2 
If a subject has not had a recent renal biopsy, one may be performed to assess eligibility for the study provided informed consent has been given. The biopsy must have been performed within 4 
months of end of screening. Repeat renal biopsies may be done at Week 24 in a subset of subjects at selected sites. 
3 
Complete physical exam at screening; abbreviated exam at all other visits. 
4 
BP, pulse, temperature, weight, and height. Height included at initial screening assessment only. At stability assessments, BP only will be included. 
5 
In the event that a subject is noted to have a QTcF value exceeding 500 msec, or an increase of >60 msec from baseline, the ECG should be repeated. Further details provided in the study protocol. 
6 
Laboratory assessments will be performed according to the schedule in the study protocol. Subjects must be fasting for at least 8-12 hours at Baseline and at end of study/early termination visit.  
7 
Pharmacokinetic assessments will be done at Weeks 4 and 24. PK samples will be drawn prior to study treatment dosing (trough sample), and at 1, 2 and 4 hours post-dose. In the event a subject 
experiences an SAE or requires a dose modification or is withdrawn from treatment, a VCS sample should be taken, with a trough sample preferred. 
8 
The UPCR will be calculated both from the FMV and from standard urinalysis results. If the FMV 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. 
9 
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. 
10 Patient Reported Outcome Measurement Information system (PROMIS) and Kidney Disease Quality of Life-Short Form (KDQOL-SFTM). 
11 Serum pregnancy test to be evaluated at central laboratory at Screening and Week 24; urine pregnancy test will be performed locally at all other visits as applicable. 
12 If screening visit occurs on the same day as informed consent, any findings are to be recorded as Medical History. Any change since the date of signed consent and/or during the screening period 
would be considered an AE. 
13 Subjects in Cohort 1, will be contacted by telephone at the end of Week 1 as a reminder to increase their dose to 2 capsules (15.8 mg) BID for 1 week, starting at Week 2. Subjects will be contacted 
again by telephone at the end of Week 2 as a reminder to increase their dose to 3 capsules (23.7 mg) BID, starting at Week 3, for the remainder of the treatment period.  Subjects in Cohort 2, will 
also be contacted at the end of each week (as required) up to Week 4, as a reminder to increase their dose to the maximum selected for Cohort 2. 
14 Compliance only. 
15 First dose of study medication should occur in the morning the day after dispensing. 
Notes: Subjects who discontinue therapy will be requested to attend their regularly scheduled study visits to the end of the study. 
 
AE=Adverse event; BID=Twice dialy; BP=Blood pressure; Disc.=Discontinuation; ECG=Electrocardiogram; FMV=First morning void; Min=Minimum; QoL=Quality of life; QTcF=QT 
interval duration corrected for heart rate using method of Fridericia; SAE=Serious adverse event; VCS=Voclosporin; Wk=Week. 
 
 
 


 
 
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TABLE OF CONTENTS 
Page 
NAMES AND ADDRESSES ...................................................................................................2 
DECLARATION OF SPONSOR ...........................................................................................3 
INVESTIGATOR AGREEMENT FORM ............................................................................4 
SYNOPSIS ................................................................................................................................5 
STUDY SCHEMA .................................................................................................................12 
AUR-VCS-2018-01 SCHEDULE OF EVENTS ..................................................................13 
TABLE OF CONTENTS ......................................................................................................15 
LIST OF TABLES .................................................................................................................19 
LIST OF APPENDICES .......................................................................................................19 
LIST OF ABBREVIATIONS ...............................................................................................20 
1. 
INTRODUCTION AND BACKGROUND ..................................................................23 
1.1 
Background of the Disease and Treatment Options ....................................................23 
1.1.1 
Limitations of Current Treatment .............................................................................24 
1.2 
Rationale for the Use of Calcineurin Inhibitors in FSGS ............................................25 
1.2.1 
Mechanism of Action of CNIs and Potential for Treatment Benefit in FSGS .........25 
1.2.2 
Clinical Studies of CNIs in FSGS ............................................................................26 
1.2.3 
Voclosporin ...............................................................................................................28 
1.2.3.1 
Pharmacokinetic Considerations ............................................................................29 
1.2.4 
Potential Toxicities of CNIs .....................................................................................29 
2. 
RATIONALE .................................................................................................................31 
2.1 
Dose Rationale .............................................................................................................31 
3. 
STUDY OBJECTIVES ..................................................................................................33 
3.1 
Primary Objective ........................................................................................................33 
3.2 
Secondary Objective ....................................................................................................33 
3.3 
Endpoints .....................................................................................................................33 
3.3.1 
Primary Endpoint ......................................................................................................33 
3.3.2 
Secondary Endpoints ................................................................................................33 
4. 
INVESTIGATIONAL PLAN .......................................................................................35 
4.1 
Overall Study Design ...................................................................................................35 
4.2 
Duration of Subject Participation and Study ...............................................................36 
5. 
SELECTION, 
WITHDRAWAL 
OF 
SUBJECTS 
AND 
PERMANENT 
DISCONTINUATION OF DRUG ................................................................................37 


 
 
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5.1 
Number of Subjects......................................................................................................37 
5.2 
Inclusion Criteria .........................................................................................................37 
5.3 
Exclusion Criteria ........................................................................................................38 
5.4 
Adequate/Effective Contraception ...............................................................................40 
5.5 
Withdrawal of Subjects ................................................................................................41 
5.6 
Discontinuation of Study Treatment ............................................................................41 
5.6.1 
Discontinuation of Study Treatment Due to an Adverse Event................................41 
6. 
RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES ..............42 
7. 
STUDY TREATMENTS ...............................................................................................43 
7.1 
Dosage Forms/Formulation .........................................................................................43 
7.1.1 
Voclosporin – Study Treatment ................................................................................43 
7.1.2 
Dosing Guidelines.....................................................................................................43 
7.1.2.1 
Voclosporin Study Treatment ................................................................................43 
7.2 
Package and Labeling ..................................................................................................44 
7.3 
Site Supply, Storage, Accountability ...........................................................................44 
7.3.1 
Site Supply ................................................................................................................44 
7.3.2 
Storage ......................................................................................................................45 
7.3.3 
Accountability ...........................................................................................................45 
7.4 
Voclosporin Dose Modification ...................................................................................45 
7.4.1 
Discontinuation of Study Therapy Due to Non-response .........................................45 
7.4.2 
Deterioration in Renal Function ...............................................................................45 
7.4.2.1 
Decrease in eGFR >30% and eGFR <90 mL/min/1.73 m2 ....................................46 
7.4.2.2 
Decrease in eGFR ≤30% and eGFR <90 mL/min/1.73 m2 ....................................46 
7.4.2.3 
Recovery of eGFR .................................................................................................46 
7.5 
Procedures for Overdose ..............................................................................................46 
7.6 
Prohibited Therapy and Concomitant Treatment .........................................................47 
7.6.1 
Prohibited Medications .............................................................................................47 
7.6.2 
Allowed Concomitant Medications ..........................................................................47 
7.7 
Increased Blood Pressure .............................................................................................48 
8. 
RISKS/PRECAUTIONS ...............................................................................................49 
9. 
STUDY PROCEDURES ...............................................................................................50 
9.1 
Description of Study Assessments ...............................................................................50 
9.1.1 
Laboratory Assessments ...........................................................................................50 
9.1.1.1 
Evaluation of Biomarkers ......................................................................................52 
9.1.2 
Physical Examinations ..............................................................................................52 
9.1.3 
Vital Signs.................................................................................................................53 
9.1.3.1 
Blood Pressure Management .................................................................................53 
9.1.4 
Standard 12-lead Electrocardiogram ........................................................................53 
9.1.4.1 
Procedures to Manage a Treatment-Emergent Increase in QTcF ..........................53 
9.1.5 
QoL Assessments ......................................................................................................54 


 
 
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9.1.6 
Voclosporin Pharmacokinetic and Biomarker Assessment ......................................54 
9.2 
Schedule of Assessments .............................................................................................54 
9.2.1 
Screening Visit and Stability Assessment Procedures ..............................................54 
9.2.2 
Treatment Procedures ...............................................................................................56 
9.2.3 
End of Study (or Early Discontinuation) Procedures ...............................................57 
9.2.4 
Follow-up Procedures ...............................................................................................57 
9.2.5 
Unscheduled Visit .....................................................................................................58 
10. EVALUATION, RECORDING AND REPORTING OF AES AND SAES .............59 
10.1 
Definitions....................................................................................................................59 
10.1.1 
Adverse Event ...........................................................................................................59 
10.1.2 
Adverse Drug Reaction .............................................................................................59 
10.1.3 
Serious Adverse Event ..............................................................................................59 
10.1.4 
Suspected Unexpected Serious Adverse Reaction....................................................60 
10.2 
Adverse Event Descriptors ..........................................................................................60 
10.2.1 
Intensity/Severity Categorization .............................................................................60 
10.2.2 
Causal Relationship Categorization ..........................................................................60 
10.2.3 
Outcome Categorization ...........................................................................................61 
10.2.4 
Clinical Laboratory Evaluations ...............................................................................61 
10.2.5 
Abuse, Misuse, Overdose and Medication Error ......................................................62 
10.3 
Reporting Procedure for AEs, SAEs, and Pregnancy ..................................................62 
10.3.1 
Adverse Events .........................................................................................................62 
10.3.2 
Serious Adverse Events ............................................................................................63 
10.3.3 
Pregnancy..................................................................................................................64 
11. CLINICAL ENDPOINTS COMMITTEE ..................................................................66 
12. DATA AND SAFETY MONITORING BOARD PROCEDURES ...........................67 
13. STATISTICAL ANALYSIS .........................................................................................68 
13.1 
Statistical Methods .......................................................................................................68 
13.2 
Sample Size and Power Calculations ...........................................................................68 
13.3 
Populations ...................................................................................................................68 
13.3.1 
Intent-to-Treat Population.........................................................................................68 
13.3.2 
Safety Set ..................................................................................................................68 
13.3.3 
Per-protocol Set ........................................................................................................68 
13.4 
Datasets ........................................................................................................................68 
13.5 
Background and Demographic Characteristics ............................................................68 
13.6 
Study Treatment ...........................................................................................................69 
13.7 
Concomitant Therapy...................................................................................................69 
13.8 
Efficacy Evaluations ....................................................................................................69 
13.8.1 
Primary Endpoint ......................................................................................................69 
13.8.2 
Secondary Endpoints ................................................................................................69 
13.9 
Statistical and Analytical Methods ..............................................................................71 


 
 
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13.10 Safety Evaluations .......................................................................................................71 
13.11 Interim Analyses ..........................................................................................................72 
13.12 Other Evaluations.........................................................................................................72 
13.12.1 Pharmacokinetics ......................................................................................................72 
14. ETHICAL CONDUCT OF THE STUDY ...................................................................73 
14.1 
Informed Consent.........................................................................................................73 
14.2 
Institutional Review Board or EC/IEC ........................................................................73 
15. QUALITY CONTROL AND QUALITY ASSURANCE ...........................................74 
16. ADMINISTRATIVE PROCEDURES .........................................................................75 
16.1 
Sponsor’s Responsibilities ...........................................................................................75 
16.1.1 
Study Supplies ..........................................................................................................75 
16.1.2 
Insurance ...................................................................................................................75 
16.1.3 
Study Monitoring ......................................................................................................75 
16.2 
Investigator’s Responsibilities .....................................................................................76 
16.2.1 
Reporting and Recording of Data .............................................................................76 
16.2.2 
Investigator Training.................................................................................................76 
16.2.3 
Source Documentation ..............................................................................................76 
17. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE 
TERMINATION OF THE STUDY .............................................................................77 
17.1 
Protocol Waivers, Deviations and Violations ..............................................................77 
17.2 
Study Termination .......................................................................................................77 
18. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ......................78 
19. REFERENCES ...............................................................................................................79 
 


 
 
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LIST OF TABLES 
Page 
Table 1 
Review of Laboratory Assessments .................................................................50 
 
LIST OF APPENDICES 
Appendix 1 
Drug Therapy for the Treatment of Hypertension ...........................................82 
Appendix 2 
Measurement of Blood Pressure ......................................................................83 
Appendix 3 
Classification of FSGS .....................................................................................84 
Appendix 4 
Expanded List of Allowed Concomitant Medications .....................................86 
Appendix 5 
Summary of Treatment and Food Restrictions ................................................88 
Appendix 6 
PROMIS QoL Assessment ..............................................................................89 
Appendix 7 
KDQOL-SFTM QoL Assessment Version 1.3 ..................................................91 
  
 
 
 


 
 
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LIST OF ABBREVIATIONS 
ACEI 
Angiotensin converting enzyme inhibitor 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ARB 
Angiotensin receptor blocker 
ATC 
Anatomical Therapeutic Chemical 
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 
Aurinia 
Aurinia Pharmaceuticals Inc. 
BID 
Twice daily 
BP 
Blood pressure 
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 
DEX 
Dexamethasone 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End-stage renal disease 
FMV 
First morning void 
FSGS 
Focal Segmental Glomerulosclerosis 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 


 
 
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GMP 
Good Manufacturing Practice 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISA247 
Voclosporin 
ITT 
Intent-to-treat 
IV 
Intravenous 
KDIGO 
Kidney Disease: Improving Global Outcomes 
KDQOL-SFTM 
Kidney Disease Quality of Life-Short Form 
LN 
Lupus nephritis 
MMF 
Mycophenolate mofetil 
NSAID 
Non-steroidal anti-inflammatory drug 
OR 
Odds ratio 
PD 
Pharmacodynamic 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PO 
Orally 
PPS 
Per-protocol set 
PROMIS 
Patient Reported Outcome Measurement Information System  
QoL 
Quality of life 
QTcF 
QT interval duration corrected for heart rate using method of 
Fridericia 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
t1/2 
Terminal elimination half-life 


 
 
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TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TGF-β 
Transforming growth factor beta 
UPCR 
Urine protein creatinine ratio 


 
 
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1. INTRODUCTION AND BACKGROUND 
1.1 
Background of the Disease and Treatment Options  
Focal segmental glomerulosclerosis (FSGS) is diagnosed by characteristic glomerular findings 
of podocyte injury evidenced by findings from immunofluorescence and electron microscopy 
following renal biopsy. The disease is categorized as primary (i.e., idiopathic FSGS) or 
secondary (e.g., adaptive changes resulting from glomerular hyperfiltration in conditions such 
as reflux nephropathy, obesity, and reduced nephron mass; drug-induced FSGS; and FSGS 
associated with viral diseases) [1].  
The predominate clinical feature of primary FSGS is proteinuria, typically with signs and 
laboratory abnormalities associated with nephrotic syndrome (i.e., total urine protein >3.5 
g/day, edema, hypoalbuminemia, and hypercholesterolemia) [1]. Patients may experience 
renal dysfunction which can progress to end-stage renal disease (ESRD). Reportedly 50-60% 
of patients have nephrotic syndrome at presentation, and approximately 50% of adult patients 
with idiopathic nephrotic syndrome are diagnosed with FSGS [1]. The amount of proteinuria 
at presentation and lack of response to treatment are correlated with progression to ESRD. 
FSGS is more common in males than in females and, in racially diverse populations, more 
common in black patients than in white patients [1]. 
Several published reviews have summarized the histopathologic features of FSGS and 
mechanisms of podocyte injury, disruption of the glomerular filtration barrier, and progression 
of renal dysfunction, e.g., D’Agati [1] and Kikuchi et al [2].  
The glomerular filtration barrier consists of glomerular endothelial cells, the glomerular 
basement membrane, and epithelial cells (podocytes). There is a complex interaction between 
these elements; the podocyte is not only a critical part of the structure, providing structural 
support to glomerular capillary, but also plays a role in maintaining the glomerular basement 
membrane and slit diaphragm proteins that permit filtration of water and small molecules and 
retention of large molecules and cells. Light microscopy findings include a segmental pattern 
of mesangial sclerosis occurring in some (i.e., focal), but not all glomeruli, without typical 
features of other proteinuric glomerulopathies. Immunofluorescence microscopy does not 
reveal immune deposits. The primary pathophysiologic mechanism of FSGS is reflected in 
electron microscopy findings, which include typical abnormalities of podocyte morphology, 
i.e., diffuse podocyte foot process effacement. In FSGS, as in other podocytopathies, these 
abnormalities disrupt the glomerular filtration barrier, resulting in protein leakage. 
The etiology of primary (idiopathic) FSGS is not known and is likely multifactorial. Based on 
indirect evidence, development of FSGS has been attributed to circulating factors (e.g., 
cytokines such as cardiotrophin-like cytokine 1, anti-CD40 (podocyte-B7-1 antigen) antibody, 
apolipoprotein A-Ib (ApoA-Ib) and serum soluble urokinase-type plasminogen activator 
receptor (suPAR)) which may mediate glomerular permeability. FSGS recurs in transplanted 


 
 
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kidneys, and proteinuria can be reduced by plasmapheresis in these patients; plasma and sera 
from FSGS patients have induced proteinuria in rats and in isolated rat glomeruli [3]. Several 
immune mechanisms have also been postulated to contribute to progressive glomerular damage 
subsequent to the initial podocyte injury, including cellular immunity and autoimmune 
reactivity [4].  
Elevated levels of transforming growth factor-beta (TGF-β) have been implicated in the 
pathogenesis of FSGS and have been reported in numerous tissues of patients with FSGS 
including the tubule-interstitium and the glomerular epithelial cells [5,6]. Calcineurin α, one 
of the calcineurin isoforms, is involved in broad cellular tasks including protein folding and 
regulation of TGF-β expression. The use of an immunosuppressive agent that increases TGF-
β levels may have a negative long-term impact on renal fibrosis, whereas the use of an 
immunosuppressive agent that either decreases or has no impact on TGF-β levels may stabilize 
presently existing renal fibrosis. Concerning the podocyte, Liao et al [7] showed that in a 
murine (MRL/lpr) model, the calcineurin inhibitor (CNI) tacrolimus may decrease TGF-β-
induced podocyte apoptosis, suggesting that calcineurin may play a role in the progression of 
renal disease, thereby suggesting a potential mechanism of CNI benefit.   
1.1.1 
Limitations of Current Treatment 
The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for 
Glomerulonephritis [8] provides Level 2C (low) and 2D (very low) suggestions for the 
treatment of primary FSGS: Corticosteroids are suggested as initial treatment at a daily single 
dose of 1 mg/kg (maximum 80 mg) or 2 mg/kg (maximum 120 mg) (Level 2C), to be 
administered for a minimum of 4 weeks and maximum of 16 weeks, as tolerated, or until 
complete remission has been achieved, whichever is earlier (Level 2D). Calcineurin inhibitors 
are suggested for use in FSGS as second-line treatment after failure of remission with steroid 
treatment and as first-line treatment in patients with relative contraindications to steroids. 
(Level 2D) (see Section 1.2.1, Mechanism of Action of CNIs and Potential for Treatment 
Benefit in FSGS). Up to 50% of patients fail to respond to corticosteroids [1]. Earlier use of 
CNIs in primary FSGS, as initial treatment at the time of diagnosis, would avoid the risks of 
corticosteroid use, and may result in proteinuria remission, as well as potentially decrease the 
risk of progression to ESRD. 
The potential benefit of voclosporin (VCS) in treatment-naïve FSGS patients is supported by 
the mechanism of action of CNIs (see Section 1.2.1, Mechanism of Action of CNIs and 
Potential for Treatment Benefit in FSGS) and clinical data suggesting benefit in steroid-
resistant patients (see Section 1.2.2, Clinical Studies of CNIs in FSGS), as well as potential 
advantages of VCS over cyclosporine (i.e., increased potency demonstrated in nonclinical 
studies with VCS, more predictable pharmacokinetic (PK)/pharmacodynamic (PD) profile 
(obviating the need for therapeutic drug monitoring), and a potentially improved safety profile 
compared to cyclosporine A (CsA)) (see FSGS Investigator’s Brochure (IB) [9]). These data, 
with the demonstrated efficacy in renal response (including reduction in proteinuria), suggest 


 
 
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that VCS may benefit patients with FSGS. Although treatment guidelines suggest 
corticosteroids as first line therapy in these patients [8], there are no data to support the use of 
corticosteroids instead of CNIs in this setting. Corticosteroids are associated with significant 
toxicities, and if VCS demonstrates treatment benefit and an acceptable safety profile, it would 
provide an appropriate alternative treatment to corticosteroids in this setting. 
1.2 
Rationale for the Use of Calcineurin Inhibitors in FSGS  
Calcineurin inhibitors are suggested for use in FSGS as second line treatment after failure of 
remission with steroid treatment and as first line treatment in patients with relative 
contraindications to steroids. In addition to well-characterized immunomodulatory effects, 
CNIs have been demonstrated to have direct beneficial effects on podocytes that are likely 
mechanisms of amelioration of proteinuria in podocytopathies, including FSGS. 
1.2.1 Mechanism of Action of CNIs and Potential for Treatment Benefit in 
FSGS 
Calcineurin inhibitors have beneficial effects in diseases characterized by disorders of the 
immune system and in the prevention of rejection after solid organ transplantation by inhibiting 
activation of nuclear factor of activated T-cell (NFAT) with subsequent regulation of the 
production of T-cell cytokines [9]. Recently, several investigations have demonstrated that 
CNIs have non-immunologic effects that contribute to their anti-proteinuric effects in 
podocytopathies. 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 protected from degradation. Calcineurin dephosphorylates synaptopodin 
allowing its degradation, with subsequent alteration of the actin cytoskeleton, disruption of the 
glomerular filtration barrier, and proteinuria. Expression of activated calcineurin in podocytes 
leads to proteinuria. Thus, by inhibiting calcineurin, CNIs exert a specific anti-proteinuric 
effect by preventing the degradation of the podocyte stabilizing protein synaptopodin [10,11]. 
In addition to effects on synaptopodin, cyclosporine has been found to stabilize other 
components of the actin cytoskeleton, i.e., cofilin-1 and nephrin. Podocyte apoptosis can be 
induced in the rat purine aminonucleoside model [12]. Shen et al [13] demonstrated that 
cyclosporine and tacrolimus reduced podocyte apoptosis in the rat purine aminonucleoside 
model. In addition, inhibition of NFAT signaling in the podocyte by CNIs may ameliorate 
podocyte injury [14]. Wakamatsu et al [15] evaluated the effects of tacrolimus in a nephrotic 
rat model (anti-nephrin antibody-induced nephropathy). Utilizing immunohistological 
analyses of rat and human kidneys, these investigators demonstrated that calcineurin is an 
element of the slit diaphragm and associated with nephrin, a critical component of the slit 
diaphragm. In the nephrotic rat model, they demonstrated that calcineurin distribution was 
altered and calcineurin activity was increased; these abnormalities were prevented by 
administration of tacrolimus, with amelioration of proteinuria. As noted in Section 1.1, 


 
 
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Background of the Disease and Treatment Options, calcineurin may also contribute to TGF-β-
induced fibrosis. 
In summary, CNIs, in addition to their immunomodulatory effects have been demonstrated to 
have direct beneficial effects on podocytes via multiple mechanisms. These effects are likely 
mechanisms of amelioration of proteinuria in podocytopathies, including FSGS. 
1.2.2 Clinical Studies of CNIs in FSGS  
The KDIGO guidelines suggest CNIs for use in the first line treatment of FSGS in patients 
who are intolerant or have contraindications to corticosteroid use [8]. There are no prospective, 
randomized trials of CNIs (either cyclosporine or tacrolimus) used as first line treatment in 
adult patients (or children) with FSGS. Limited retrospective observational data support their 
use in this setting; a recent treatment review [16] cites two studies: Duncan et al [17] and 
Goumenos et al [18]. 
In a single study center by Duncan et al [17], 6 patients with biopsy-proven FSGS and 
nephrotic syndrome, who had been previously treated with angiotensin converting enzyme 
inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), but not immunosuppression 
(including corticosteroids), were treated with tacrolimus and followed prospectively. The mean 
duration of nephrotic syndrome prior to treatment with tacrolimus was 13.6 months (standard 
deviation (SD) 11.8); baseline urine protein was 11.0 g/day (SD 4.5) and baseline estimated 
glomerular filtration rate (eGFR) was 71.7 mL/min/1.73 m2 (SD 22.4). After approximately 12 
months of follow-up, all 6 patients achieved remission, defined as normalization of serum 
albumin and resolution of edema. Mean urine protein decreased from 11.0 g/day (SD 4.5) to 
2.8 g/day (SD 2.5). Reportedly, no patients relapsed after attaining remission. 
In a retrospective review by Goumenos et al [18], 51 patients with biopsy-proven FSGS, 
proteinuria >1 g/day, and serum creatinine <2.5 mg/dL, were followed for 5 years. Of the 51 
patients, 26 were treated with conservative management (including ACEIs and other anti-
hypertensives) and 25 were treated with immunosuppressive drugs, including prednisolone 
alone (9 patients, treated for 16 months, 8 with nephrotic syndrome), prednisolone and 
azathioprine (6 patients, treated for 18 months, 5 with nephrotic syndrome) and prednisolone 
(0.5 mg/kg/day) and cyclosporine (10 patients, treated for 25 months, 7 with nephrotic 
syndrome). No patients received cyclosporine monotherapy. Treatment assignment was 
reportedly based on renal impairment and degree of proteinuria. Remission of nephrotic 
syndrome (both complete remission (defined as urine protein <0.3 g/day) and partial remission 
(defined as urine protein between 0.3 and 3 g/day)) occurred in 5/8 patients treated with 
prednisolone alone, 4/5 patients treated with prednisolone and azathioprine, and 6/7 patients 
treated with prednisolone and cyclosporine. 
Evidence to support the use of CNIs in adult patients who are steroid resistant includes 
randomized clinical trials as well as observational data. A Cochrane Review published in 2008 


 
 
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[19] identified one blinded controlled study (Cattran et al, 1999 [20]) which evaluated the 
effect of cyclosporine on remission of proteinuria and ESRD in steroid-resistant adult patients 
with nephrotic syndrome. This study was a single blind, randomized, placebo-controlled trial 
in which 26 patients were treated with cyclosporine and low dose prednisone and 23 patients 
were treated with placebo and low-dose prednisone. Complete remission (urine protein 
≤0.3 g/day with stable renal function) or partial remission (50% reduction and ≤3.5 g/day with 
stable renal function) occurred in 69% of the cyclosporine group and 4% of the placebo group 
at 26 weeks (p<0.001). At 4 years, the renal survival rate was 72% in the cyclosporine group 
and 49% in the placebo group. 
Laurin et al [21] performed a meta-analysis of studies evaluating the effects of CNIs in primary 
FSGS. They did not identify any trials in which CNIs were used as first-line treatment. Six 
randomized controlled trials and two retrospective cohort studies were included in their review. 
They performed a pooled analysis of the effect of cyclosporine on proteinuria remission; the 
relative risk of complete or partial remission was 7.0 (95% confidence interval (CI): 2.9, 16.8) 
compared with the control group. 
It has been noted in treatment reviews that cyclosporine use in steroid-resistant patients is 
associated with a high relapse rate (e.g., 43 to 50% in a 2003 review by Cattran [22]). In an 
NIH-sponsored trial, FSGS-CT, 138 patients (adults and children) with biopsy-proven FSGS 
(assessed as steroid resistant and urine protein creatine ratio (UPCR) >1 g/g) were randomized 
to cyclosporine (n=72) or a combination of pulse dexamethasone (DEX) and mycophenolate 
mofetil (MMF) (n=66) [23,24]. Treatment was administered for 12 months and patients were 
followed until Week 78. Steroid resistance was defined as failure to achieve sustained UPCR 
≤1.0 g/g after a minimal treatment duration of 4 weeks. All patients were treated with low-
dose prednisone and either an ACEI or ARB. There was no difference between the groups in 
the primary endpoint (mean score of a 6-level categorical assessment of remission of 
proteinuria at Week 52): 46% of the CsA group and 33% of the MMF/DEX group had at least 
a partial remission at Week 52. In patients who achieved at least a partial remission at Week 52, 
relapse (defined as UPCR >2.0 g/g after the withdrawal of medication at Week 52) was 
reported for 33% (11/33) in the CsA group and 18% (4/22) in the MMF/DEX group. These 
data are difficult to interpret as 28% of patients in the CsA group had baseline UPCR <2.0 g/g. 
Moreover, the definition of steroid resistance in this study is not consistent with standard 
definition of steroid resistance for adults and the data are not presented separately for adults 
and children. 
In a follow-up publication of a post-hoc analysis, Hogg et al [25] examined the outcomes in 
patients who achieved complete or partial remission after 26 weeks, completed 52 weeks of 
treatment, and had follow-up information through 78 weeks. In the cyclosporine group, the 
analysis included 22 of the 39 patients who were reported to have at least partial remission at 
Week 26 in the earlier publication, and 20 of the 26 patients in the MMF/DEX group. The 
authors report that, in the CsA patients, the mean eGFR decreased at Weeks 26 and 52 (17% 


 
 
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decrease and 19% decrease compared to baseline, respectively), and increased by 16% from 
Week 52 to Week 78. 
There are few studies examining the use of tacrolimus in patients with FSGS. In one study 
[26], 
decrease 
in 
proteinuria 
was 
similar 
in 
18 
patients 
treated 
with 
cyclophosphamide/prednisone and 15 patients treated with tacrolimus/prednisone, both after 6 
months of treatment and at the completion of a 6-month follow-up period. Baseline renal 
function was not recorded and there appeared to be stability of renal function between 6 months 
and 12 months. Therefore, it is difficult to assess the treatment benefit of tacrolimus from this 
study. 
In summary, the available data, although largely from retrospective studies, support a treatment 
benefit of cyclosporine in steroid-resistant patients. There is little data supporting the benefit 
of cyclosporine as first line treatment. It has been reported that the relapse rate is high following 
discontinuation of treatment; however, it is difficult to interpret the data reported by Gipson et 
al [23,24] and Hogg et al [25] with respect to the effect of cyclosporine on renal function and 
proteinuria over 12 months and subsequent improvement in renal function and proteinuria after 
withdrawal, and the reported relapse rate. The study failed to recruit the target number of 
patients, the criteria for steroid resistance were not consistent with standard definitions, and 
the changes in proteinuria and renal function were not completely reported. However, it 
appears that there was a significant decrease in proteinuria at both Weeks 26 and 52. While the 
post-treatment effect on eGFR is not completely clear, the data suggest some increase in eGFR 
after withdrawal of treatment. The relevance of these findings to the long-term effect of VCS 
is not clear. 
1.2.3 Voclosporin 
Voclosporin is a next generation CNI currently under development for use in FSGS and lupus 
nephritis (LN). Voclosporin is structurally similar to 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 VCS 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 
VCS as compared to CsA, has led to better PK/PD predictability. 
During the development of this investigational product, the legacy names of voclosporin, VCS, 
and ISA247 are referenced in discussions related to historical usage. In the Phase 3 LN clinical 
development program, the name of the investigational product is referred to as Orelvo, the 
proposed trade name. However, for the FSGS clinical development programs, the name of the 
investigational product will be referred to as voclosporin or VCS. All legacy names and the 


 
 
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proposed trade name should all be considered interchangeable unless specifically identified as 
different. 
Prior to the FSGS clinical development program, over 2,400 subjects have received 
investigational products containing VCS in 15 Phase 1, and 12 Phase 2/3 clinical studies in the 
indications of LN, transplant rejection, psoriasis and non-infectious uveitis. Detailed data for 
these clinical studies are presented in the IB [9].  
1.2.3.1 Pharmacokinetic Considerations 
Voclosporin approximates linear multiexponential PKs. Exposure to VCS was dose-related 
with maximum concentrations occurring ≤2 hours with a t1/2 of ≥30 hours. Drug accumulation 
was minor with accumulation factors of approximately 2 hours after twice daily (BID) dosing. 
Administration of VCS 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 VCS 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 Cmax and an 18-fold increase in AUC0-12 for VCS. Concomitant administration of 
rifampin, an inducer of CYP3A4/5, resulted in a decrease in exposure to VCS. 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 VCS. Concomitant administration of VCS and 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 VCS. Concomitant administration of digoxin, a P-gp substrate, 
resulted in statistically significant increases in digoxin Cmax and AUC0-24 and a decrease in 
clearance. Therefore, concomitant administration of P-gp substrates with VCS 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 Potential Toxicities of CNIs 
Increased blood pressure (BP) and renal dysfunction are well known potential toxicities of 
CNIs that are dose-related, reversible, and generally responsive to dose reduction or temporary 
interruption of treatment [27].  
Voclosporin has been studied in numerous disease states. In clinical studies of VCS in LN [9], 
a small proportion of VCS-treated subjects experienced an early drop of ≥30% in eGFR; 


 
 
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however, that proportion then remained 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 treatment 
in 1 (1.1%) placebo subject, 7 (7.9%) VCS low-dose (23.7 mg BID) subjects and 5 (5.7%) 
VCS high-dose (39.5 mg BID) subjects. There were more TEAEs of hypertension seen in the 
VCS-treated subjects compared to placebo; however, overall mean systolic and diastolic BP 
decreased in all groups, without statistically significant differences seen between groups. 
Overall, only 1 (1.1%) subject, in the VCS high-dose group, had a TEAE of hypertension that 
resulted in permanent discontinuation of study treatment.  
There was also evidence of an increased incidence of TEAEs over placebo and with increased 
dose of VCS in the System Organ Classes of Infections and Infestations, Gastrointestinal 
Disorders, and Vascular Disorders. 
 


 
 
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2. RATIONALE 
The rationale for the development of VCS and the range of dose is to introduce a novel CNI to 
the population of patients with FSGS, with meaningful efficacy while minimizing toxicities 
common to other CNIs. In clinical studies, a favorable efficacy/safety profile for VCS has been 
demonstrated in the prevention of renal transplant rejection and in Phase 2 studies in LN. 
As evaluated in nonclinical and clinical studies (healthy volunteers, moderate to severe 
psoriasis, renal transplantation, and uveitis) VCS is well tolerated and exhibits adverse events 
(AEs) that are typical of other CNIs yet seen to a lesser extent than those seen historically with 
other CNIs. 
The aim of the current study is to investigate whether VCS is able to reduce disease activity 
over a treatment period of 24 weeks. Subjects with histologic evidence of primary FSGS with 
proteinuria will be eligible to enter the study. Efficacy will be assessed by the ability of VCS 
to reduce the level of proteinuria (as measured by UPCR) while demonstrating an acceptable 
safety profile. The primary endpoint of this study will be complete or partial remission of 
proteinuria at 24 weeks. 
2.1 
Dose Rationale 
This Phase 2 study is designed to initially evaluate the treatment benefit of VCS 23.7 mg BID 
in the first Cohort of 10 subjects. The selection of this VCS dose for the first Cohort (see 
Section 7, Study Treatments) was based on the previous experience with this drug in the Phase 
2 LN study (AURA-LV). In AURA-LV, subjects were administered VCS 23.7 mg BID, VCS 
39.5 mg BID, or matching placebo. Low-dose VCS was significantly superior to placebo in 
the proportion of subjects achieving complete renal response at Week 24 (p=0.045). At Week 
48, complete remission rates in both the low-dose (49.4%) and high-dose (39.8%) VCS groups 
demonstrated statistically significant superiority compared to the placebo (23.9%) group, 
(p<0.001, p=0.026, respectively). There was no increase in efficacy with the higher dose and 
no significant differences between the two VCS groups in achievement of renal response.  
This study is also designed to evaluate a further dose level of VCS, this dose may be higher or 
lower than the initial 23.7 mg BID dosing. When the first 6 subjects in Cohort 1 have completed 
12 weeks of treatment with VCS, the top line efficacy and safety data will be analyzed to 
determine the dose level for Cohort 2. The maximum dose possible for Cohort 2 will be 39.5 
mg (5 capsules) BID. 
To minimize safety concerns, a cautious dose-escalation design starting with a minimal dose 
of one capsule (7.9 mg) per day will be employed for all subjects (see Section 7.1.2, Dosing 
Guidelines).  
The protocol contains provisions for management of dose (including rules for stopping 
treatment with study mediation) based on safety concerns in particular, BP and renal function. 


 
 
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The safety data from the use of VCS in LN demonstrates that these risks are dose-related, 
reversible, and can be managed by dose reduction and temporary interruption.   
Furthermore, VCS will be administered as fixed doses without the use of therapeutic drug 
monitoring. Population PK analyses of VCS concentrations from the clinical development 
program (including healthy subjects, subjects with renal impairment, subjects with hepatic 
impairment, renal transplant, plaque psoriasis, and LN) demonstrated that weight did not have 
a significant effect on the PK of VCS [9].  


 
 
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3. STUDY OBJECTIVES 
3.1 
Primary Objective 
• To assess the efficacy of VCS in achieving complete or partial remission of proteinuria 
after 24 weeks of therapy in subjects with FSGS. 
3.2 
Secondary Objective 
• To assess the safety and tolerability of VCS over 24 weeks in subjects with FSGS. 
3.3 
Endpoints 
All primary and secondary endpoints will be assessed overall and for each individual cohort. 
3.3.1 Primary Endpoint 
Proportion of subjects with remission of proteinuria at Week 24 based on the following 
parameters: 
• Complete remission: UPCR of <0.3 mg/mg 
OR 
• Partial remission: UPCR ≥0.3 mg/mg and <3.0 mg/mg with >50% reduction in UPCR 
from baseline 
3.3.2 Secondary Endpoints 
• Proportion of subjects with complete remission or partial remission of proteinuria at Weeks 
8 and 12 
• Proportion of subjects with complete remission of proteinuria at Weeks 8, 12, and 24 
• Proportion of subjects with UPCR <0.5 mg/mg at Weeks 8, 12, and 24 
• Proportion of subjects with partial remission of proteinuria at Weeks 8, 12, and 24 
• Time to first occurrence of complete or partial remission of proteinuria 
• Time to first occurrence of complete remission of proteinuria 
• Time to first occurrence of partial remission of proteinuria 
• Time to first occurrence of 50% reduction in UPCR from baseline 
• Duration of UPCR <0.3 mg/mg 


 
 
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• Change from baseline in UPCR at each time point 
• Proportion of subjects with a confirmed >30% decrease from baseline in eGFR (utilizing 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) at each time 
point  
• Proportion of subjects with a confirmed >30% increase in eGFR from the final visit 
(Week 24 or last on-treatment visit, for subjects who discontinue prematurely) to the 
second Safety Follow-up visit (Visit 10) 
• Change in UPCR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10) 
• Change in eGFR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10)  
• Change from baseline in serum creatinine, serum albumin, and eGFR at each time point 
• Quality of life (QoL) assessments 
− 
Mean change in Patient Reported Outcome Measurement Information System 
(PROMIS) measures at Week 24 
− 
Change from baseline in Kidney Disease Quality of Life-Short Form 
(KDQOL-SFTM) score at Week 24 
• Safety and tolerability over 24 weeks 
• Renal biopsy: descriptive analyses of changes in histopathology will be evaluated in post-
treatment (24 weeks) renal biopsies in a subset of patients 
• Change from baseline to Week 4 and 24 in the following biomarkers:  
− 
Urine nephrin 
− 
Urine synaptopodin 
− 
Serum TGF-β 


 
 
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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 2, open-label, multicenter, prospective, 24-week, exploratory cohort study to 
assess the efficacy and safety of two dose levels of VCS in achieving complete or partial 
remission of proteinuria in treatment-naïve subjects with biopsy-confirmed primary FSGS. 
Subjects who have provided a signed and dated informed consent will be screened into the 
study up to 56 days before Baseline/Day 1. Subjects will be assigned a unique subject number 
which will be used to identify them throughout the study. The screening period will be up to 8 
weeks long to ensure that subjects meet eligibility criteria, including renal disease stability 
assessments. If a subject has not had a renal biopsy within the 4-month required timeframe for 
study eligibility, one may be performed to assess eligibility into the study, 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 
to receive treatment with VCS. The first 10 subjects will be enrolled into Cohort 1, at a starting 
dose of 7.9 mg BID for Week 1, 15.8 mg BID for Week 2, and a target dose of 23.7 mg BID 
for Weeks 3 to 24. The first dose of study treatment should occur in the morning on Day 2, the 
day after dispensing. Subjects will be contacted by telephone at the end of Week 1 and Week 
2 to be reminded to increase their dose as per Section 7.1.2.1, Voclosporin Study Treatment. 
Evaluable safety and tolerability from the first six subjects from Cohort 1 are required in order 
to determine the dose level for Cohort 2. The dose selected may be higher or lower than 23.7 
mg BID.The maximum dose possible for Cohort 2 will be 39.5 mg (5 capsules) BID. Dosing 
in this group will follow the same cautious approach as Cohort 1, with at a starting dose of 7.9 
mg BID for Week 1, 15.8 mg BID for Week 2, 23.7 mg BID for Week 3 and a maximum dose 
of 39.5 mg BID for Weeks 4 to 24. 
Doses and dose increments smaller than anticipated or an intermediate dose may be proposed 
for Cohort 2 based on the safety and tolerability results from the Cohort 1.  
All subjects will return for assessment of efficacy and safety at Weeks 2, 4, 8, 12, 18, and 24. 
See Schedule of Events, for detailed information regarding visits.  
All subjects, completed or withdrawn, will complete the End of Treatment/Early Termination 
assessments (Visit 8) at Week 24, or at the time of early termination, and should attend two 
Safety Follow-up visits at 1 and 2 weeks after completion of treatment (i.e., at Week 25 (Visit 
9) and Week 26 (Visit 10)) (or 7 and 14 days, respectively, following premature 
discontinuation) 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. 


 
 
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4.2 
Duration of Subject Participation and Study 
The expected duration of subject participation is approximately 34 weeks. The screening 
period is up to 8 weeks and the treatment duration is 24 weeks, with further Safety Follow-up 
visits at 1 and 2 weeks after last dose (completion or early termination). 


 
 
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5. SELECTION, WITHDRAWAL OF SUBJECTS AND PERMANENT 
DISCONTINUATION OF DRUG 
5.1 
Number of Subjects 
It is anticipated that approximately 20 subjects will be recruited 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 years (or legal age of consent if >18 
years) to 75 years of age, inclusive, at the time of consent. 
3. Primary FSGS diagnosed by renal biopsy within 4 months prior to end of screening (see 
Appendix 3). 
4. At initial screening assessment and at last qualifying assessment during screening period 
prior to baseline, FSGS subjects must have urine protein creatinine ratio (UPCR) ≥3.0 
mg/mg, serum albumin <3.2 mg/dL AND must be treatment-naïve, defined as subjects who 
have not received systemic steroids, cytotoxic or other systemic immunosuppressant 
treatment, and are not expected to require treatment with these medications during the 
study. 
5. All subjects should be treated with ACEIs and/or ARBs unless they have documented 
intolerance or contraindication to these medications. Doses of these agents must be stable 
for at least 2 weeks prior to baseline, with BP ≤150/90 mmHg at the baseline visit (Visit 2). 
a) Subjects with nephrotic edema may be treated with diuretics during the screening 
period. Volume status should be optimized based on the clinical judgment of the 
Investigator and the doses of diuretics must be stable in the 2 weeks prior to baseline. 
b) At the discretion of the Investigator, subjects with hyperlipidemia may be treated with 
lipid-lowering agents (e.g., statins) in accordance with standard clinical practice. Doses 
must be stable in the 2 weeks prior to baseline. 
6. Stable proteinuria, renal function, and BP during the 2 weeks prior to baseline, as assessed 
by the Investigator. Substantial changes in UPCR, eGFR, and/or BP during the screening 
period may be due to treatments administered (e.g., ACEIs and ARBs); and, therefore, may 
interfere with study assessments or outcomes, or may place the subject at increased risk. 
These subjects must be discussed with the medical monitor prior to initiation of study 
treatment. 


 
 
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7. Women of childbearing potential must have a negative serum pregnancy test prior to 
dispensing study treatment. 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. Clinical or histologic evidence of secondary FSGS. 
3. Histologic evidence of collapsing variant FSGS. 
4. eGFR as calculated by the CKD-EPI equation of ≤30 mL/minute/1.73 m2 at initial 
screening assessment or ≤45 mL/minute/1.73 m2 at last qualifying assessment during 
screening period prior to baseline. 
5. Currently taking or expected to require any of the prohibited medications listed in the 
protocol (see Section 7.6.1, Prohibited Medications) at screening or during the study. This 
includes prohibited medications prior to screening as specified in the protocol. 
6. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or expected to 
require dialysis during the study period. 
7. A previous renal transplant or planned renal transplant during the study. 
8. Body mass index >40 kg/m2. 
9. Family history of nephrotic syndrome. 
10. Any known hypersensitivity or contraindication to cyclosporine, or components of any 
cyclosporine drug product. 
11.  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. 


 
 
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• Current or past 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. 
12. Other clinically significant active medical conditions, such as: 
• Severe cardiovascular disease including congestive heart failure, history of cardiac 
dysrhythmia or congenital long QT syndrome. Subjects with 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 are excluded. 
• Liver dysfunction: aspartate aminotransferase, alanine aminotransferase, or bilirubin ≥2.5 
times the upper limit of normal at last qualifying assessment during screening period prior 
to baseline. 
• Chronic obstructive pulmonary disease or asthma requiring oral steroids. 
• Bone marrow insufficiency: white blood cell count <2,500/mm3, absolute neutrophil count 
<1.3 × 103/μL, and/or thrombocytopenia (platelet count <50,000/mm3) at screening or at 
last qualifying assessment during screening period prior to baseline. 
• Current infection requiring intravenous (IV) antibiotics. 
13. Any overlapping autoimmune condition for which the condition or the treatment of the 
condition may affect the study assessments or outcomes (e.g., any condition for which 
additional immunosuppression, including systemic corticosteroids, and/or cytotoxic 
therapy is indicated). Overlapping conditions for which the condition or treatment is not 
expected to affect assessments or outcomes are not excluded. 
14. No vaccines using live organisms, virus or bacterial, are allowed during screening and 
while taking the study treatment. 
15. 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. 
16. 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. 


 
 
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17. Subjects who are pregnant, breast feeding or, if of childbearing potential, not using 
adequate contraceptive precautions. 
18. 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. 
19. Subjects treated in a previous VCS clinical study. 
5.4 
Adequate/Effective Contraception 
Women of childbearing potential must have a negative serum pregnancy test during 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, 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 6 weeks after cessation of study treatment. In 
addition, female partners of male subjects are recommended to use an effective contraception 
during their partner’s treatment and for at least 6 weeks after the last dose of study treatment. 
Male subjects are to refrain from making sperm donations during treatment and for at least 
6 weeks after cessation of study treatment. 
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.  
Barrier methods (e.g., condoms, diaphragm, or cervical cap/sponge) when used alone are not 
considered highly 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 and documented throughout the study 
period in order to confirm the method used is considered effective. 


 
 
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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 8), if possible. If 
possible, the subject should also be advised to come for the two Safety Follow-up visits (Visit 9 
and Visit 10) at 1 and 2 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 withdrawal 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 permanently discontinued from study 
treatment before the Week 24 visit should undergo all study assessments, if possible, up to and 
including both the Week 24 (or Early Termination Visit – Visit 8), and the two Safety Follow-
up visits at 1 and 2 weeks after last dose. Guidance on when study treatment must be 
discontinued is in Section 7.4, Voclosporin Dose Modification.  
5.6.1 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 discontinued 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 discontinued 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 
Not applicable. 


 
 
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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 
Pharmaceuticals Inc (Aurinia). 
7.1.1 Voclosporin – Study Treatment 
Company Code: 
 
Chemical Name: 
 
Empirical Formula: 
 
Generic Name: 
Voclosporin 
Dosage Form: 
Softgel capsules 
Strength: 
7.9 mg of VCS per softgel capsule 
Manufacturer: 
 
7.1.2 Dosing Guidelines 
7.1.2.1 Voclosporin 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. 
The dosing of VCS for Cohort 1 will be as follows: 
• Week 1: 1 capsule (7.9 mg) orally (PO), BID 
• Week 2: 2 capsules (15.8 mg) PO, BID 


 
 
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• Weeks 3 to 24 – Week 24: 3 capsules (23.7 mg) PO, BID 
Evaluable safety, tolerability and pharmacokinetic data from the first six subjects from Cohort 
1 are required in order to make the decision to escalate to a higher dose level for Cohort 2. The 
selected dose may be higher or lower than 23.7 mg BID. The maximum dose possible for 
Cohort 2 will be 39.5 mg (5 capsules) BID.  Should this dose be selected the following dosing 
regimen will be followed: 
• Week 1: 1 capsule (7.9 mg) PO, BID 
• Week 2: 2 capsules (15.8 mg) PO, BID 
• Week 3: 3 capsules (23.7 mg) PO, BID 
• Week 4: 5 capsules (39.5 mg) PO, BID 
All subjects will be contacted by telephone at the end of Week 1 and Week 2 (and Week 3, if 
applicable) to be reminded to increase their dose. 
All unused study treatment (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 
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 
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. 
7.3 
Site Supply, Storage, Accountability 
7.3.1 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. 


 
 
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7.3.2 Storage 
Voclosporin softgel 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. 
7.3.3 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 
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, one 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’s approval of 
the process and forward the certificate of destruction to Aurinia. 
7.4 
Voclosporin Dose Modification 
7.4.1 Discontinuation of Study Therapy Due to Non-response 
During the treatment period, any subject experiencing a worsening of proteinuria from baseline 
may be discontinued from study treatment. The case should be discussed with the Medical 
Monitor, and the subject should be transitioned to standard of care treatment 
7.4.2 Deterioration in Renal Function 
Serum creatinine and eGFR utilizing the CKD-EPI formula, as reported by the central 
laboratory, will be used for the assessment of renal function at every visit including 
unscheduled visits.  


 
 
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It is recognized that eGFR may be unreliable at higher values (>100 mL/min/1.73 m2). FSGS 
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 [28], with or without kidney 
damage.  
7.4.2.1 Decrease in eGFR >30% and eGFR <90 mL/min/1.73 m2 
During the treatment period, any subject experiencing a >30% decrease in eGFR from baseline 
(baseline eGFR is defined as the last assessment prior to first dose of study treatment) to <90 
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), ACEIs, ARBs, a concurrent state of dehydration, 
overdosing with study treatment, renal flare, etc.), the case should be discussed with the 
Medical Monitor, the study treatment should be withheld, and eGFR retested within 48 hours. 
(Note: doses of ACEIs, ARBs, diuretics, and/or lipid lowering therapy are to remain stable 
throughout the study.) 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. 
7.4.2.2 Decrease in eGFR ≤30% and eGFR <90 mL/min/1.73 m2 
During the treatment period, any subject having a ≤30% reduction in eGFR to 
<90 mL/min/1.73 m2 should have the influence of potential contributing factors (as described 
in Section 7.4.2.1 Decrease in eGFR >30% and eGFR <90 mL/min/1.73 m2) ruled out and 
appropriate corrective action taken. Any subject having a >20 to ≤30% reduction compared to 
baseline in eGFR to <90 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 should 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. 
7.4.2.3 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. 
7.5 
Procedures for Overdose 
Based on clinical experience with VCS, 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, 


 
 
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and all other expected AEs, should be based on symptoms, with care taken to rule out other 
causes. 
7.6 
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. 
7.6.1 Prohibited Medications 
The following medications cannot be taking during the study: 
• Systemic corticosteroids (oral or IV) unless approved by the Medical Monitor 
• Cytotoxic or other systemic immunosuppressants  
• Initiation of new treatment or change in dosage of ARBs and/or ACE inhibitors within 
2 weeks prior to baseline  
• Vaccines using live organisms, viral or bacterial 
• 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 5 contains a summary of additional treatment and food restrictions. 
7.6.2 Allowed Concomitant Medications 
These medications are permitted during the study: 
• Doses of ACEIs and/or ARBs as described in the Inclusion Criteria (see Section 5.2, 
Inclusion Criteria) 
• Doses of diuretics as described in the Inclusion Criteria (see Section 5.2, Inclusion 
Criteria)  
• Doses of statins as described in the Inclusion Criteria (see Section 5.2, Inclusion 
Criteria) 
• Topical steroids (e.g., nose, scalp, skin, inhaled) 


 
 
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• Herbal supplements can be used with caution and with approval by the Medical 
Monitor 
Treatments which may be used as medically indicated, according to the judgment of the 
Investigator can be found in Appendix 4. 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 5. 
7.7 
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 withheld, 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 [9]. 
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 (FMV) and from standard 
urinalysis results. If the FMV is for some reason not available at Day 1, Week 12 or Week 24, 
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 1) will 
be drawn in accordance with the Schedule of Events. 
Table 1 
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) 
All  
 
Differential (absolute and %) 
 Bands 
 Basophils 
 Eosinophils 
 Lymphocytes 
 Monocytes 
 Neutrophils 
All 
 


 
 
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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 
All  
 
Cholesterol (total, HDL, and LDL) & 
triglycerides 
Creatine kinase 
Day 1 and Week 24 
 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
All 
Glycosylated hemoglobin (HbA1c) 
Day 1 and Week 24 
Lactic dehydrogenase (LDH) 
Magnesium 
All 
Phosphorous, inorganic 
Day 1 and Week 24 
Potassium 
Protein, total 
Sodium 
All 
Urinalysis and urine 
microscopy 
Complete urinalysis (to include urine protein, 
creatinine, blood, urine microscopy).  
All except for stability 
assessment visits during the 
screening period 
FMV urine 
collection 
FMV will be performed to analyze UPCR.  
All 
24-hour urine 
UPCR 
Day 1, Week 12 and Week 24 
Note that 24-hour urine 
collection should be scheduled so 
as not to coincide with the FMV 
sampling due on the day of the 
study visit 


 
 
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Test Type 
Test Parameters 
Collection at Visits 
Pregnancy Test 
For females of childbearing potential.  
Serum pregnancy test to be 
evaluated at central laboratory at 
Screening, and Week 24; urine 
pregnancy test will be performed 
locally at all other applicable 
visits. 
Serology 
Cytomegalovirus 
Hepatitis A, B, and C 
Hepatitis B surface antigen (HBsAg) 
Screening (including stability 
assessments) 
 
Special Tests 
Estimated glomerular filtration rate (eGFR) 
All 
Biomarkers 
Urine nephrin 
Urine synaptopodin 
Serum TGF-β 
Day 1, Week 4 and Week 24 
Notes: FMV=first morning void; HDL=High-density lipoprotein; LDL=Low-density lipoprotein; UPCR=urine protein creatinine ratio. 
 
The total amount of blood that will be collected during the study from an individual subject is 
approximately 200 mL over 34 weeks. 
For details on whether laboratory abnormalities should be reported as AEs and on the 
follow-up required in such cases, see Section 10.2.4 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 FSGS-related manifestations which will 
also be recorded. A complete physical examination will be conducted at the initial screening 
assessment, 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 
be recorded at the initial screening assessment. 


 
 
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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 heart rate (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 7.7, 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 the initial screening assessment, Day 1, and Week 24. 
9.1.4.1 Procedures to Manage a Treatment-Emergent Increase in QTcF 
In the event that a subject has a corrected QT interval duration corrected for heart rate using 
method of Fridericia (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 


 
 
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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 QoL Assessments 
Assessments for QoL will be conducted at Day 1, Week 24, Week 25 and Week 26. 
The PROMIS assesses physical function, pain interference, and fatigue. See Appendix 6. 
The KDQOL-SFTM survey is a kidney disease-specific measure of QoL that assesses general 
health, kidney disease and its effects on daily life, and satisfaction with care. See Appendix 7. 
9.1.6 Voclosporin Pharmacokinetic and Biomarker Assessment 
Blood samples for PK assessments will be taken at Week 4 and Week 24. PK samples will be 
drawn prior to study treatment dosing (trough sample), and at 1, 2 and 4 hours post-dose. These 
samples will be analyzed for VCS. Should a subject experience a serious adverse event (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 treatment, further PK samples are not required. 
Blood and urine samples for biomarker assessments will be taken at Day 1, Week 4 and Week 
24, samples will be collected prior to study treatment dosing.  
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 and Stability Assessment Procedures 
The screening period will be up to 8 weeks long to ensure that subjects meet eligibility criteria, 
including renal disease stability assessments, and will consist of an initial screening assessment 
and 2 to 4 stability assessments conducted between Day -56 to Day -1. 


 
 
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The initial screening assessment will include provision of informed consent; complete physical 
examination; medical history (including FSGS history); vital signs measurements, including 
weight and height; 12-lead ECG; blood and urine sample collection for central laboratory 
assessments, urinalysis, and urine microscopy; FMV urine collection (for determination of 
UPCR); a serum pregnancy test (for women of childbearing potential); and review of prior and 
concomitant medications and entry criteria. Any AEs which occur after informed consent will 
be recorded.  
Stability assessments will occur at a minimum of 14-day intervals with the first assessment 
2 weeks after the initial screening assessment visit. Stability assessments 1 and 2 are 
mandatory; assessments 3 and 4 are optional if additional time is required for the subject’s 
clinical status to stabilize. These stability assessment visits will include BP determination; 
blood sample collection for central laboratory assessments; FMV urine collection (for 
determination of UPCR); a serum pregnancy test (for women of childbearing potential); review 
of any AEs; and review of concomitant medications and entry criteria.  
These renal disease stability assessments will be evaluated to ensure eligibility with respect to 
entry criteria for UPCR and eGFR. 
Note that the laboratory assessments and FMV results of the last stability assessment will be 
used as the qualifying values for eligibility.  
FMV urine samples (for determination of UPCR) will be collected at all visits during the 
screening period and must be returned and the results evaluated prior to Baseline/Day 1. If the 
FMV is for some reason not available at Day 1, Week 12 or Week 24, 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 samples will be drawn according to Table 1. 
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 must have a negative serum pregnancy test result before 
baseline.  
If a subject has not met the requirements in Inclusion Criteria #3 due to not having renal biopsy 
result within the required time frame, a renal biopsy can be performed as per local procedures, 
after signing the study consent, provided the results can be obtained and reviewed prior to 
baseline. 


 
 
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9.2.2 Treatment Procedures 
Only subjects who meet all of the inclusion and none of the exclusion criteria will be eligible 
for study treatment.  
Study medication will be dispensed per the Schedule of Events, beginning on Day 1. Subjects 
will take their first dose of study medication on Day 2. Women of childbearing potential must 
have a negative serum pregnancy test during Screening and a negative urine pregnancy test 
result on Day 1 prior to dispensing of study treatment.  
Subjects in Cohort 1, will be contacted by telephone at the end of Week 1 as a reminder to 
increase their dose to 2 capsules (15.8 mg) BID for 1 week, starting at Week 2. Subjects will 
be contacted again by telephone at the end of Week 2 as a reminder to increase their dose to 3 
capsules (23.7 mg) BID, starting at Week 3, for the remainder of the treatment period (see 
Section 7.1.2.1, Voclosporin Study Treatment).  
Subjects in Cohort 2, will also be contacted by telephone at the end of each week, as required 
up to the end of Week 3, as a reminder to increase their dose of study medication to the 
maximum dose selected for the second cohort. 
Subjects will complete all assessments per the Schedule of Events at Day 1 and at Weeks 2, 4, 
8, 12 and 18.  
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: 
• PROMIS and KDQOL-SFTM QoL questionnaires will be answered by the subject, as 
first study procedure, at Day 1/Baseline. 
• Abbreviated physical examination at Day 1. 
• Vital signs including weight. 
• Standard 12-lead ECG at Day 1. 
• Blood and urine sample collection for analysis at central laboratory. 
• FMV urine sample collection. 
• Urine pregnancy testing at Day 1 (before dispensing study treatment)  
• AEs. 


 
 
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• Concomitant medication. 
• Returned capsule count and drug accountability (except Day 1). 
9.2.3 End of Study (or Early Discontinuation) Procedures 
On completion of treatment at Week 24 or earlier if subject is discontinued/withdrawn early, 
all assessments for Visit 8 (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: 
• PROMIS and KDQOL-SFTM QoL  
• Abbreviated physical examination  
• Vital signs including weight 
• Standard 12-lead ECG 
• Blood and urine sample collection for analysis at central laboratory 
• FMV urine sample collection 
• Serum pregnancy testing 
• Pharmacokinetic and biomarker sampling 
• AEs 
• Concomitant medication 
• Returned capsule count and drug accountability 
• Repeat renal biopsy may be performed on a subset of patients 
• Confirmation of completion/discontinuation 
9.2.4 Follow-up Procedures 
All subjects who complete the study or discontinue study treatment before Week 24 will be 
followed up at 1 week (±3 days) and 2 weeks (±3 days) after their last study treatment dose to 
collect any new AEs and concomitant medications. These 2 visits (Visit 9 and Visit 10) will 
be conducted as in-clinic visits. 


 
 
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Assessments for the follow-up visit are as follows: 
• PROMIS and KDQOL-SFTM QoL 
• Vital signs including weight 
• Blood and urine sample collection for analysis at central laboratory  
• FMV urine sample collection 
• Concomitant medication 
• AEs 
• Confirmation of completed follow-up visit 
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. 
Additionally, unscheduled visits will be registered in the electronic data capture (EDC) system. 
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 


 
 
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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 
one 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 that have been scheduled prior to the subject signing the informed consent 
form (ICF), although not recorded as SAEs, must be documented in the subject’s source 
documents. A renal biopsy performed as part of the study to verify eligibility will not be 
considered an SAE. Any complication experienced during a renal 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. 
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 


 
 
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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 treatment 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 treatment 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. 
10.2.4 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. 


 
 
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If the Investigator considers such an AE as serious it must be reported as an SAE. 
10.2.5 Abuse, Misuse, Overdose and Medication Error 
All AEs of special interest such as study drug 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 observed from time of signing of the ICF will be recorded in the subject's source 
documentation. This applies to all AEs regardless of presumed relationship to the study drug. 
For screen failure subjects, any AEs and SAEs occurring during the screening period (after 
informed consent) will be recorded in the subject’s source documentation only and will not be 
collected on the eCRF. Adverse events leading to discontinuation of study drug must be 
collected. 
If any AE is reported, the date of onset, relationship to study treatment, relationship to disease 
under study, 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 one 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 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. Note that for screen 
failure subjects, any AEs and SAEs occurring during the screening period will be recorded in 
the subject’s source documentation only. For enrolled subjects (i.e., those who successfully 
complete screening), the AE reporting period ends at the second Safety Follow-up visit 
(Visit 10). 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. 


 
 
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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 
For screen failure subjects, any SAEs occurring during the screening period (after informed 
consent) will be recorded in the subject’s source documentation only and will not be collected 
on the eCRF. 
For enrolled subjects (i.e., those who successfully complete screening), 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 drug or 
relationship to disease under study. For enrolled subjects, all SAEs will be recorded in the AE 
section of the subject’s eCRF and source documentation. 
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: 
 
If notification is made via email or fax, site staff must enter the SAE information into the 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 or relationship to disease 
under study, 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. 


 
 
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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 9) 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 drug-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 Institutional Review Board (IRB)/Ethics Committee 
(EC)/Independent Ethics Committee (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. 


 
 
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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.  
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 
Not applicable. 


 
 
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12. DATA AND SAFETY MONITORING BOARD PROCEDURES 
Not applicable. 


 
 
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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 approximately 20 subjects, 10 subjects in each of 2 cohorts.  
As this is an exploratory study, sample size calculations are not required. Descriptive statistics 
will be used and the results will only be hypothesis-generating. 
13.3 Populations 
13.3.1 Intent-to-Treat Population 
The intent-to-treat (ITT) population will consist of all enrolled subjects (non-screening 
failures) and will be used for all efficacy analyses. 
13.3.2 Safety Set 
The safety set will consist of all subjects who have taken at least 1 dose of study treatment.  
13.3.3 Per-protocol Set 
The per-protocol set (PPS) 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 SAP. 
13.4 Datasets 
Assessments taken at each visit will be analyzed using 2 different datasets. The first will be 
the observed cases dataset whereby all values collected will contribute to the dataset. A second 
dataset will be used for summaries and analyses incorporating data carried forward from a 
subject’s last known value. This dataset will be referred to as the last observation carried 
forward dataset and as such, all subjects with any post-baseline efficacy assessment will 
contribute to the Week 24 analyses. 
13.5 Background and Demographic Characteristics 
Demographic and clinical disease characteristics will be summarized.  


 
 
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13.6 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, SD, median, minimum, 
and maximum) and frequency tables.  
13.7 Concomitant Therapy 
All concomitant medications will be coded by the World Health Organization Anatomical 
Therapeutic Chemical (ATC) Drug Reference List classification. The version used will be 
provided in the clinical study report. 
13.8 Efficacy Evaluations 
Primary and secondary endpoints will be assessed overall and for each individual cohort. 
13.8.1 Primary Endpoint 
The primary endpoint is the proportion of subjects with remission of proteinuria at Week 24 
based on the following parameters: 
• Complete remission: UPCR of <0.3 mg/mg 
OR 
• Partial remission: UPCR ≥0.3 mg/mg and <3.0 mg/mg with >50% reduction in UPCR 
from baseline 
13.8.2 Secondary Endpoints 
The following are defined as secondary endpoints: 
• Proportion of subjects with complete remission or partial remission of proteinuria at Weeks 
8 and 12 
• Proportion of subjects with complete remission of proteinuria at Weeks 8, 12, and 24 
• Proportion of subjects with UPCR <0.5 mg/mg at Weeks 8, 12, and 24 
• Proportion of subjects with partial remission of proteinuria at Weeks 8, 12, and 24 
• Time to first occurrence of complete or partial remission of proteinuria 
• Time to first occurrence of complete remission of proteinuria 


 
 
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• Time to first occurrence of partial remission of proteinuria 
• Time to first occurrence of 50% reduction in UPCR from baseline 
• Duration of UPCR <0.3 mg/mg 
• Change from baseline in UPCR at each time point 
• Proportion of subjects with a confirmed >30% decrease from baseline in eGFR (utilizing 
the CKD-EPI formula) at each time point (Baseline eGFR is defined as the last assessment 
prior to first dose of study treatment)  
• Proportion of subjects with a confirmed >30% increase in eGFR from the final visit (Week 
24 or last on-treatment visit, for subjects who discontinue prematurely) to the second Safety 
Follow-up visit (Visit 10) 
• Change in UPCR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10)  
• Change in eGFR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10) 
• Change from baseline in serum creatinine, serum albumin, and eGFR at each time point 
• QoL assessments 
− 
Mean change in PROMIS measures at Week 24 
− 
Change from baseline in KDQOL-SFTM score at Week 24 
• Safety and tolerability over 24 weeks 
• Renal biopsy: descriptive analyses of changes in histopathology will be evaluated in post-
treatment (24 weeks) renal biopsies in a subset of patients 
• Change from baseline to Week 4 and 24 in the following biomarkers:  
− 
Urine nephrin 
− 
Urine synaptopodin 
− 
Serum TGF-β 
 


 
 
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13.9 Statistical and Analytical Methods 
All statistical analyses relating to the primary and secondary objectives will be undertaken at 
study closure and will incorporate all available data. 
In order to aid dose decisions for cohort 2, an analysis of the first 6 subjects in cohort 1 will be 
undertaken once the 6th subject reaches week 12. 
Given the small sample size, all analyses will be descriptive in nature.  
Binary remission endpoints will be summarized using counts and proportions while continuous 
data will be summarized using means, SDs, medians, minimums and maximums. Kaplan-
Meier methodology will be used for the analysis of time-to endpoints.  Confidence intervals 
for proportions may be calculated but it is recognized that such intervals, being based on 20 
patients, will be very wide. As an example, the 95% Clopper-Pearson CI for a proportion of 
30% based on 20 patients is (11.9%, 54.3%). 
The analysis of the primary endpoint, complete or partial remission of proteinuria at Week 24, 
will be conducted on the ITT population and confirmed with the PPS (if applicable). Remission 
of proteinuria will be summarized and an exact 2-sided 95% CI for the remission rate will be 
calculated. 
The analyses of the secondary endpoints will incorporate the use of 2-sided 95% CIs and are 
described below:  
• Binary endpoints will be summarized using counts and proportions along with exact 
2-sided 95% CIs.  
• Endpoints measured as a time-to-event will be displayed using Kaplan-Meier 
methodology. Median time-to-event along with 2-sided 95% CIs will be displayed.  
• Other endpoints will be summarized by visit. Absolute values and differences between 
baseline and each time point up to and including Week 24 will be summarized using means 
and 2-sided 95% CIs. Changes between last on treatment value and post treatment follow-
up will also be summarized.   
Given the nature of the study, additional exploratory analysis will be undertaken as appropriate. 
This may include the reporting of individual case studies. 
13.10 Safety Evaluations 
Specific safety endpoints are as follows: 
• Biochemical (including liver function tests) and hematological laboratory tests 


 
 
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• 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 visit, and as change from baseline. 
Adverse events and diseases 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 and up until 14 
days after last dose will be considered TEAEs, though all AEs after informed consent will be 
recorded. SAEs occurring at any time after informed consent and prior to first study medication 
will be listed.  
All prior and concomitant medications will be summarized using preferred terms and ATC 
Level 2. 
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. 
13.11 Interim Analyses 
There will be no full interim analysis. 
13.12 Other Evaluations 
13.12.1 Pharmacokinetics 
Estimates of VCS 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 [28] and the ICH guidelines for GCP [29]. 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 IRB/EC/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. These 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 
protocol and the completeness, consistency, and accuracy of the data being entered on them. 


 
 
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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) must agree 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. 
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 [31]. 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 [32] 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. 
D'Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 
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tool for glomerular disease management. Semin Nephrol. 2015;35(3):245-55. 
3. 
Konigshausen E, Sellin L. Circulating permeability factors in primary focal segmental 
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Reggiani F, Ponticelli C. Focal segmental glomerular sclerosis: do not overlook the 
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Yamamoto T, Noble NA, Cohen AH, Nast CC, Hishida A, Gold LI, et al. Expression 
of transforming growth factor-beta isoforms in human glomerular diseases. Kidney Int. 
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7. 
Liao R, Liu Q, Zheng Z, Fan J, Peng W, Kong Q, et al. Tacrolimus protects podocytes 
from injury in lupus nephritis partly by stabilizing the cytoskeleton and inhibiting 
podocyte apoptosis. PLoS One. 2015;10(7):1-16. 
8. 
Kidney disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work 
Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl. 
2012;2:139-274. 
9. 
Investigator’s brochure – Voclosporin - Focal Segmental Glomerulosclerosis. Version 
1.0. Aurinia Pharmaceutical Inc. 2018Feb5. 
10. 
Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, et al. The 
actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of 
cyclosporine A. Nat Med. 2008 Sep;14(9):931-8. 
11. 
Mathieson PW. Proteinuria and immunity - an overstated relationship? N Engl J Med. 
2008 Dec 4;359(23):2492-4. 
12. 
Li X, Zhang X, Li X, Wang X, Wang S, Ding J. Cyclosporine A protects podocytes via 
stabilization of cofilin-1 expression in the unphosphorylated state. Exp Biol Med 
(Maywood). 2014;239(8):922-36. 
13. 
Shen X, Jiang H, Ying M, Xie Z, Li X, Wang H, et al. Calcineurin inhibitors 
cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin 
aminonucleoside in rodent models. Sci Rep. 2016;6:32087. 


 
 
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14. 
Mallipattu SK, He JC. The podocyte as a direct target for treatment of glomerular 
disease? Am J Physiol Renal Physiol. 2016;311(1):F46-51. 
15. 
Wakamatsu A, Fukusumi Y, Hasegawa E, Tomita M, Watanabe T, Narita I, et al. Role 
of calcineurin (CN) in kidney glomerular podocyte: CN inhibitor ameliorated 
proteinuria by inhibiting the redistribution of CN at the slit diaphragm. Physiol Rep. 
2016;4(6). 
16. 
Beaudreuil S, Lorenzo HK, Elias M, Nnang Obada E, Charpentier B, Durrbach A. 
Optimal management of primary focal segmental glomerulosclerosis in adults. Int J 
Nephrol Renovasc Dis. 2017;10:97-107. 
17. 
Duncan N, Dhaygude A, Owen J, Cairns TD, Griffith M, McLean AG, et al. Treatment 
of focal and segmental glomerulosclerosis in adults with tacrolimus monotherapy. 
Nephrol Dial Transplant. 2004;19(12):3062-7. 
18. 
Goumenos DS, Tsagalis G, El Nahas AM, Shortland JR, Davlouros P, Vlachojannis 
JG, 
et 
al. 
Immunosuppressive 
treatment 
of 
idiopathic 
focal 
segmental 
glomerulosclerosis: a five-year follow-up study. Nephron Clin Pract. 2006;104(2):c75-
82. 
19. 
Braun N, Schmutzler F, Lange C, Perna A, Remuzzi G, Risler T, et al. 
Immunosuppressive treatment for focal segmental glomerulosclerosis in adults. The 
Cochrane database of systematic reviews. 2008(3):CD003233. 
20. 
Cattran DC, Appel GB, Hebert LA, Hunsicker LG, Pohl MA, Hoy WE, et al. A 
randomized trial of cyclosporine in patients with steroid-resistant focal segmental 
glomerulosclerosis. North America Nephrotic Syndrome Study Group. Kidney Int. 
1999;56(6):2220-6. 
21. 
Laurin L-P, Nachman PH, Foster BJ. Calcineurin inhibitors in the treatment of primary 
focal segmental glomerulosclerosis: a systematic review and meta-analysis of the 
literature. Can J Kidney Health Dis. 2017;4:1-14. 
22. 
Cattran DC. Cyclosporine in the treatment of idiopathic focal segmental 
glomerulosclerosis. Semin Nephrol. 2003;23(2):234-41. 
23. 
Gipson DS, Trachtman H, Kaskel FJ, Radeva MK, Gassman J, Greene TH, et al. 
Clinical trials treating focal segmental glomerulosclerosis should measure patient 
quality of life. Kidney Int. 2011;79(6):678-85. 
24. 
Gipson DS, Trachtman H, Kaskel FJ, Greene TH, Radeva MK, Gassman JJ, et al. 
Clinical trial of focal segmental glomerulosclerosis in children and young adults. 
Kidney Int. 2011;80(8):868-78. 
25. 
Hogg RJ, Friedman A, Greene T, Radeva M, Budisavljevic MN, Gassman J, et al. 
Renal function and proteinuria after successful immunosuppressive therapies in 
patients with FSGS. Clin J Am Soc Nephrol. 2013;8(2):211-8. 


 
 
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27 April 2018 
Page 81 of 110 
 
26. 
Ren H, Shen P, Li X, Pan X, Zhang W, Chen N. Tacrolimus versus cyclophosphamide 
in steroid-dependent or steroid-resistant focal segmental glomerulosclerosis: a 
randomized controlled trial. Am J Nephrol. 2013;37(1):84-90. 
27. 
Wiseman AC. Immunosuppressive medications. Clin J Am Soc Nephrol. 2016 
Feb;11:332-43. 
28. 
KDOQI clinical practice guidelines for chronic kidney disease: evaluation, 
classification, and stratification, 2002. [assessed 2014 Sep 2]. Available from: 
http://www2.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm.  
29. 
World Medical Association Declaration of Helsinki. Ethical principles for medical 
research involving human subjects. 2013 Oct. 
30. 
ICH Harmonised Tripartite Guideline.: Guideline for good clinical practice. E6 (R1) 
1996 Jun 10. 
31. 
Pharmaceutical Research and Manufacturers of America [Internet]. PhRMA principles 
and guidelines: public disclosure of clinical trial results. 2009. Available from: 
Available from:  https://www.phrma.org/codes-and-guidelines/phrma-principles-on-
conduct-of-clinical-trials. 
32. 
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. 
33. 
Reiser J, Fervenza FC, Sethi S. Epidemiology, classification, and pathogenesis of focal 
segmental glomeruloschlerosis. UpToDate.com [Internet]. 2017 Jul 6 [cited 2018 Feb 
12]. Available from: https://www.uptodate.com 
 
 


 
 
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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 7.6.1, 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 
Classification of FSGS 
The epidemiology, classification and pathogenesis of FSGS has been reviewed by Reiser et al, 
2017 [33]. 
According to this review, FSGS “is a histologic lesion, rather than a specific disease entity, 
that is commonly found to underlie the nephrotic syndrome in adults and children, particularly 
in the United States, Brazil, and many other countries. FSGS is characterized by the presence 
of sclerosis in parts (segmental) of some (focal) glomeruli on light microscopic examination 
of a kidney biopsy specimen.”  
According to this review, FSGS can be classified into the following etiologies, based upon the 
known and/or postulated causes of this histologic pattern: 
• “Primary or idiopathic FSGS, which most often presents with the nephrotic syndrome.”  
• “Secondary FSGS, which most often presents with non-nephrotic proteinuria and, 
commonly, some degree of renal insufficiency. This category most commonly refers to 
FSGS that develops as an adaptive response to glomerular hypertrophy or hyperfiltration. 
This includes disorders associated with a reduced renal mass and/or renal vasodilation, 
such as unilateral renal agenesis. In addition, a nonspecific pattern of secondary FSGS can 
result from scarring produced by a previous injury (due to a variety of conditions, including 
active IgA nephropathy, vasculitis, and LN). Other secondary causes of FSGS include 
drugs and toxins (including heroin, interferon, and pamidronate) and viral infections 
(particularly HIV).” 
• “Genetic causes of FSGS, which may present early in childhood with massive proteinuria 
and nephrotic syndrome or in adolescence or adulthood with less massive proteinuria.”  
Biopsy and diagnosis: According to Reiser et al, “precise quantification of sclerotic glomeruli 
requires three-dimensional morphometric analysis of entire glomeruli and the examination of 
sufficient glomeruli to ensure that the biopsy specimen is representative of glomeruli in the 
whole kidney. Kidney biopsies with few glomeruli (i.e., fewer than 15) cannot confidently 
exclude the diagnosis of FSGS, and, due to sampling error, some cases will be misclassified 
as minimal change disease.” 
“In patients who are found to have a FSGS lesion by light microscopy, the following approach 
can be used to distinguish between those with primary and secondary FSGS: 


 
 
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• Patients who present with nephrotic syndrome (ie, urine protein excretion >3.5 g/day and 
hypoalbuminemia), who exhibit extensive foot process effacement (≥80 percent) on EM 
[electron microscopic] examination, and who have no identifiable risk factors associated 
with secondary FSGS (eg, viral infection, drugs) most likely have primary FSGS, although 
genetic forms of FSGS lesions cannot always be excluded with confidence. Thus, primary 
FSGS is always a diagnosis of exclusion. 
• Patients who present with subnephrotic (ie, <3.5 g/day in an adult) or nephrotic-range 
proteinuria and a normal serum albumin concentration (ie, without nephrotic syndrome) 
and segmental foot process effacement (<80 percent) on EM [electron microscopic] 
examination most likely have secondary FSGS.” 
 
 


 
 
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Appendix 4 
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. 
• At the discretion of the Investigator, subjects with hyperlipidemia may be treated with 
lipid lowering agents (e.g., statins) in accordance with standard clinical practice. Doses 
must be stable in the 2 weeks prior to baseline. 
• Subjects with nephrotic edema may be treated with diuretics during the screening 
period. Volume status should be optimized based on the clinical judgment of the 
Investigator and the doses of diuretics must be stable in the 2 weeks prior to baseline. 
• ACEIs, ARBs, and aliskerin and other therapies are recommended, as per standard 
guidelines, but if used their dose must be stable throughout the study. Subjects 
receiving ACEIs or ARBs must be on a stable dose for at least 2 weeks prior to baseline.  


 
 
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• In the case of uncontrolled hypertension (systolic BP >165 mmHg or 
diastolic >105 mmHg on two successive measurements), the addition of a diuretic or 
calcium channel blocker only are permitted, together with dose decreases or 
interruption of study treatment per the instructions in Section 7.7, Increased Blood 
Pressure.  
 
 


 
 
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Appendix 5 
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 VCS 
metabolism 
ACEIs and ARBs 
Stable dose for at least 2 
weeks prior to baseline 
Change or 
commencement 
prohibited 
Interfere with 
primary endpoint 
assessment 
Foods 
Grapefruit and grapefruit 
juice 
 
24 hours 
 
Prohibited 
 
May affect the 
metabolism of VCS 
Notes:  ACEI=Angiotensin converting enzyme inhibitor; ARB=Angiotensin receptor blocker; NSAID=Non-steroidal anti-inflammatory 
drug; P-gp=P-glycoprotein; VCS=Voclosporin. 
 
 


 
 
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Appendix 6 
PROMIS QoL Assessment 
The PROMIS QoL assessment includes three questionnaires: 
• Physical Function – Short Form 10a (PROMIS® Item Bank v2.0) 
• Fatigue – Short Form 8a (PROMIS® Item Bank v1.0) 
• Pain Interference – Short Form 8a (PROMIS® Item Bank v1.0)  


PROMIS® Item Bank v2.0 – Physical Function – Short Form 10a
  
 
 
  Page 1 of 1 
Physical Function – Short Form 10a 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PROMIS Item Bank v1.0 – Fatigue – Short Form 8a 
Fatigue – Short Form 8a
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
  Page 1 of 1 


PROMIS Item Bank v1.0 – Pain Interference – Short Form 8a 
Pain Interference – Short Form 8a
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
  Page 1 of 1 


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Appendix 7 
KDQOL-SFTM QoL Assessment Version 1.3 


Kidney Disease and Quality of Life™ Short Form  (KDQOL-SF™)
English Version 1.3
Copyright © 1993, 1994, 1995 by RAND and the University of Arizona
Your Health
– and –
Well-Being
Kidney Disease and Quality of Life (KDQOL-SF™ 1.3)
This survey asks for your views about your health. This information
will help keep track of how you feel and how well you are able to do
your usual activities.
Thank you for completing these questions!


Study of Quality of Life
For Patients on Dialysis
What is the purpose of the study?
This study is being carried out in cooperation with physicians and their patients.  The
purpose is to assess the quality of life of patients with kidney disease.
What will I be asked to do?
For this study, we want you to complete a survey today about your health, how you
feel and your background.
Confidentiality of information?
We do not ask for your name.  Your answers will be combined with those of other
participants in reporting the findings of the study.  Any information that would permit
identification of you will be regarded as strictly confidential.  In addition, all
information collected will be used only for purposes of the study, and will not be
disclosed or released for any other purpose without your prior consent.
How will participation benefit me?
The information you provide will tell us how you feel about your care and further
understanding about the effects of medical care on the health of patients.  This
information will help to evaluate the care delivered.
Do I have to take part?
You do not have to fill out the survey and you can refuse to answer any question.
Your decision to participate will not affect your opportunity to receive care.


Page 1
Your Health
This survey includes a wide variety of questions about your health and
your life.  We are interested in how you feel about each of these issues.
1. In general, would you say your health is:  [Mark an 
 in the one box
that best describes your answer.]
Excellent
Very good
Good
Fair
Poor
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
2. Compared to one year ago, how would you rate your health in
general now?
Much better
now than
one year
ago
Somewhat
better now
than one
year ago
About the
same as
one year
ago
Somewhat
worse now
than one
year ago
Much
worse now
than one
year ago
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5


Page 2
3. The following items are about activities you might do during a
typical day.  Does your health now limit you in these activities?  If so,
how much?  [Mark an 
 in a box on each line.]
Yes,
limited a
lot
Yes,
limited a
little
No, not
limited
at all
a
Vigorous activities, such as running, lifting
heavy objects, participating in strenuous
sports ............................................................
M
M
M
 1.........
 2 ........
 3
b
Moderate activities, such as moving a table,
pushing a vacuum cleaner, bowling, or
playing golf ....................................................
 1.........
 2 ........
 3
c
Lifting or carrying groceries ............................
 1.........
 2 ........
 3
d
Climbing several flights of stairs ......................
 1.........
 2 ........
 3
e
Climbing one flight of stairs.............................
 1.........
 2 ........
 3
f
Bending, kneeling, or stooping ........................
 1.........
 2 ........
 3
g
Walking more than a mile
 1.........
 2 ........
 3
h
Walking several blocks ...................................
 1.........
 2 ........
 3
i
Walking one block..........................................
 1.........
 2 ........
 3
j
Bathing or dressing yourself............................
 1.........
 2 ........
 3


Page 3
4. During the past 4 weeks, have you had any of the following problems
with your work or other regular daily activities as a result of your
physical health?
Yes
No
M
M
a
Cut down the amount of time you spent on work
or other activities ................................................
 1.........
 2
b
Accomplished less than you would like................
 1.........
 2
c
Were limited in the kind of work or other
activities.............................................................
 1.........
 2
d
Had difficulty performing the work or other
activities (for example, it took extra effort)...........
 1.........
 2
5. During the past 4 weeks, have you had any of the following problems
with your work or other regular daily activities as a result of any
emotional problems (such as feeling depressed or anxious)?
Yes
No
M
M
a
Cut down the amount of time you spent on work
or other activities ................................................
 1.........
 2
b
Accomplished less than you would like................
 1.........
 2
c
Didn’t do work or other activities as carefully as
usual..................................................................
 1.........
 2


Page 4
6. During the past 4 weeks, to what extent has your physical health or
emotional problems interfered with your normal social activities with
family, friends, neighbors, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
7. How much bodily pain have you had during the past 4 weeks?
None
Very
mild
Mild
Moderate
Severe
Very
severe
M
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
  
 6
8. During the past 4 weeks, how much did pain interfere with your
normal work (including both work outside the home and
housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5


Page 5
9.
These questions are about how you feel and how things have been
with you during the past 4 weeks.  For each question, please give
the one answer that comes closest to the way you have been feeling.
How much of the time during the past 4 weeks…
All
 of the
time
Most
of the
time
A good
bit
 of the
time
Some
of the
time
A little
of the
time
None
of the
time
M
M
M
M
M
M
a
Did you feel full of
pep?.............................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
b
Have you been a very
nervous person? ...........
 1........
 2 .......
 3........
 4 .......
 5.......
 6
c
Have you felt so down
in the dumps that
nothing could cheer
you up?........................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
d
Have you felt calm and
peaceful?......................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
e
Did you have a lot of
energy? ........................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
f
Have you felt
downhearted and blue? .
 1........
 2 .......
 3........
 4 .......
 5.......
 6
g
Did you feel worn out?..
 1........
 2 .......
 3........
 4 .......
 5.......
 6
h
Have you been a
happy person?..............
 1........
 2 .......
 3........
 4 .......
 5.......
 6
i
Did you feel tired?........
 1........
 2 .......
 3........
 4 .......
 5.......
 6


Page 6
10. During the past 4 weeks, how much of the time has your physical
health or emotional problems interfered with your social activities
(like visiting with friends, relatives, etc.)?
All
of the time
Most
of the time
Some
of the time
A little
of the time
None
of the time
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
11. Please choose the answer that best describes how true or false each
of the following statements is for you.
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false
a 
I seem to get sick
a little easier than
other people ..........
M
M
M
M
M
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
b
I am as healthy as
anybody I know ....
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
c
I expect my health
to get worse ..........
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
d
My health is
excellent................
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5


Page 7
Your Kidney Disease
12. How true or false is each of the following statements for you?
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false
a 
My kidney
disease interferes
too much with my
life ........................
M
M
M
M
M
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
b
Too much of my
time is spent
dealing with my
kidney disease.......
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
c
I feel frustrated
dealing with my
kidney disease.......
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
d
I feel like a burden
on my family .........
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5


Page 8
13. These questions are about how you feel and how things have been
going during the past 4 weeks.  For each question, please give the
one answer that comes closest to the way you have been feeling.
How much of the time during the past 4 weeks…
None
of the
time
A little
of the
time
Some
of the
time
A good
bit of
the
time
Most
of the
time
All of
the
time
a
Did you isolate your-
self from people
around you?.................
M
M
M
M
M
M
 1 .......
 2.......
 3........
 4 .......
 5........
 6
b
Did you react slowly
to things that were said
or done?.......................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
c
Did you act irritable
toward those around
you?.............................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
d
Did you have difficulty
concentrating or
thinking?.......................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
e
Did you get along well
with other people? ........
 1 .......
 2.......
 3........
 4 .......
 5........
 6
f
Did you become
confused? ....................
 1 .......
 2.......
 3........
 4 .......
 5........
 6


Page 9
14. During the past 4 weeks, to what extent were you bothered by each
of the following?
Not at all
bothered
Somewhat
bothered
Moderately
bothered
Very much
bothered
Extremely
bothered
M
M
M
M
M
a
Soreness in your
muscles?...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
b
Chest pain? ...........
 1 ............
 2 ...........
 3 ............
 4...........
 5
c
Cramps? ...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
d
Itchy skin?.............
 1 ............
 2 ...........
 3 ............
 4...........
 5
e
Dry skin?...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
f
Shortness of
breath?..................
 1 ............
 2 ...........
 3 ............
 4...........
 5
g
Faintness or
dizziness?..............
 1 ............
 2 ...........
 3 ............
 4...........
 5
h
Lack of appetite?...
 1 ............
 2 ...........
 3 ............
 4...........
 5
i
Washed out or
drained?................
 1 ............
 2 ...........
 3 ............
 4...........
 5
j
Numbness in
hands or feet?........
 1 ............
 2 ...........
 3 ............
 4...........
 5
k
Nausea or upset
stomach?...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
l
(Hemodialysis patient only)
Problems with
your access site? ...
 1 ............
 2 ...........
 3 ............
 4...........
 5
m
(Peritoneal dialysis patient only)
Problems with
your catheter site?..
 1 ............
 2 ...........
 3 ............
 4...........
 5


Page 10
Effects of Kidney Disease on Your Daily Life
15. Some people are bothered by the effects of kidney disease on their
daily life, while others are not.  How much does kidney disease
bother you in each of the following areas?
Not at all
bothered
Somewhat
bothered
Moderately
bothered
Very much
bothered
Extremely
bothered
M
M
M
M
M
a
Fluid restriction?....
 1 ............
 2 ...........
 3 ............
 4...........
 5
b
Dietary restriction?.
 1 ............
 2 ...........
 3 ............
 4...........
 5
c
Your ability to
work around the
house? ..................
 1 ............
 2 ...........
 3 ............
 4...........
 5
d
Your ability to
travel? ...................
 1 ............
 2 ...........
 3 ............
 4...........
 5
e
Being dependent
on doctors and
other medical
staff?.....................
 1 ............
 2 ...........
 3 ............
 4...........
 5
f
Stress or worries
caused by kidney
disease? ................
 1 ............
 2 ...........
 3 ............
 4...........
 5
g
Your sex life?........
 1 ............
 2 ...........
 3 ............
 4...........
 5
h
Your personal
appearance? ..........
 1 ............
 2 ...........
 3 ............
 4...........
 5


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Page 12
17. For the following question, please rate your sleep using a scale
ranging from 0 representing “very bad” to 10 representing “very
good.”
If you think your sleep is half-way between “very bad” and “very
good,” please mark the box under the number 5.  If you think you
sleep is one level better than 5, mark the box under 6.  If you think
your sleep is one level worse than 5, mark the box under 4 (and so
on).
On a scale from 0 to 10, how would you rate your sleep overall?
[Mark an 
 in one box.]
Very bad
Very good
M
M
0
1
2
3
4
5
6
7
8
9
10


Page 13
18. How often during the past 4 weeks did you...
None
of the
time
A little
of the
time
Some
of the
time
A good
bit of
the
time
Most
of the
time
All of
the
time
a
Awaken during the
night and have trouble
falling asleep again?.......
M
M
M
M
M
M
 1 .......
 2.......
 3........
 4 ......
 5.......
 6
b
Get the amount of
sleep you need?............
 1 .......
 2.......
 3........
 4 ......
 5.......
 6
c
Have trouble staying
awake during the day?...
 1 .......
 2.......
 3........
 4 ......
 5.......
 6
19. Concerning your family and friends, how satisfied are you with...
Very
dissatisfied
Somewhat
dissatisfied
Somewhat
satisfied
Very
satisfied
a
The amount of time
you are able to spend
with your family and
friends?........................
M
M
M
M
 1...............
 2 ..............
 3...............
 4
b
The support you
receive from your
family and friends?........
 1...............
 2 ..............
 3...............
 4


Page 14
20. During the past 4 weeks, did you work at a paying job?
Yes
No
M
M
  
 1
  
 2
21. Does your health keep you from working at a paying job?
Yes
No
M
M
  
 1
  
 2
22. Overall, how would you rate your health?
Worst possible
(as bad or worse
 than being dead)
Half-way
between worst
and best
Best
possible
M
M
M
0
1
2
3
4
5
6
7
8
9
10


Page 15
Satisfaction With Care
23. Think about the care you receive for kidney dialysis.  In terms of
your satisfaction, how would you rate the friendliness and interest
shown in you as a person?
Very
poor
Poor
Fair
Good
Very
good
Excellent
The Best
M
M
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
  
 6
  
 7
24. How true or false is each of the following statements?
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false
a 
Dialysis staff
encourage me to
be as independent
as possible ............
M
M
M
M
M
 1 ...........
 2 ...........
 3 ...........
 4 ............
 5
b
Dialysis staff
support me in
coping with my
kidney disease.......
 1 ...........
 2 ...........
 3 ...........
 4 ............
 5
Thank you for completing these questions!

Prot_SAP_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. 
 
 
An Open-Label Dose-Exploration Cohort Study Evaluating the 
Efficacy and Safety of Voclosporin in Achieving Complete or 
Partial Remission of Proteinuria in Subjects with Focal 
Segmental Glomerulosclerosis  
 
Clinical Protocol Number: 
AUR-VCS-2017-03 
 
 
Study Name: 
AURONA 
 
 
Date: 
31 May 2019 
 
 
Version Number: 
3.0 (Amendment 2) 
 
 
Previous Protocol Versions 
Version 1.0, 27 April 2018 
 
Version 2.0 (Amendment 1),  
23 November 2018 
 
 
 
 
IND Number: 
137,905 
 
 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


 
 
AUR-VCS-2017-03 Version 3.0 (Amendment 2) 
Confidential 
31 May 2019 
 
 
Page 2 of 111 
 
NAMES AND ADDRESSES 
 
Sponsor 
Name: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Tel: 
 
 
24 Hour: 
 
 
 
Chief Medical Officer 
Name: 
 
 
Company: 
Aurinia Pharmaceuticals Inc. 
 
Address: 
#1203 - 4464 Markham Street 
Victoria, BC 
V8Z 7X8 
Canada 
 
Email: 
 
 
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: 
 
 
 
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


 
 
AUR-VCS-2017-03 Version 3.0 (Amendment 2) 
Confidential 
31 May 2019 
 
 
Page 3 of 111 
 
DECLARATION OF SPONSOR 
Title: An Open-Label Dose-Exploration Cohort Study Evaluating the Efficacy and Safety of 
Voclosporin in Achieving Complete or Partial Remission of Proteinuria in Subjects with Focal 
Segmental Glomerulosclerosis 
Version Number/Date: Version 3.0 (Amendment 2) / 31 May 2019 
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 
 
 
 
Chief Medical Officer 
 
Date (e.g., DD Month Year) 
 
 
 
Vice President, Quality and Regulatory 
Affairs 
 
Date (e.g., DD Month Year) 
 
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4
31-May-19
31-May-19


 
 
AUR-VCS-2017-03 Version 3.0 (Amendment 2) 
Confidential 
31 May 2019 
 
 
Page 4 of 111 
 
INVESTIGATOR AGREEMENT FORM 
I have read the attached protocol titled: An Open-Label Dose-Exploration Cohort Study 
Evaluating the Efficacy and Safety of Voclosporin in Achieving Complete or Partial Remission 
of Proteinuria in Subjects with Focal Segmental Glomerulosclerosis 
Version Number/Date: Version 3.0 (Amendment 2) / 31 May 2019 
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. 
 
 
 
<insert name> 
Principal Investigator 
 
Date (e.g., DD Month Year) 
 
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


 
 
AUR-VCS-2017-03 Version 3.0 (Amendment 2) 
Confidential 
31 May 2019 
 
 
Page 5 of 111 
 
SYNOPSIS 
Title: 
An Open-Label, Dose-exploration, Cohort Study Evaluating the Efficacy and Safety 
of Voclosporin in Achieving Complete or Partial Remission of Proteinuria in 
Subjects with Focal Segmental Glomerulosclerosis 
Short Title: 
AURONA 
Study Product: 
Voclosporin  
Indication: 
Focal Segmental Glomerulosclerosis 
Phase: 
2 
Sponsor: 
Aurinia Pharmaceuticals Inc. 
Study Code: 
AUR-VCS-2017-03 
Objectives: 
Primary Objective: 
• 
To assess the efficacy of voclosporin in achieving complete or partial remission 
of proteinuria after 24 weeks of therapy in subjects with focal segmental 
glomerulosclerosis (FSGS).  
Secondary Objective: 
• 
To assess the safety and tolerability of voclosporin over 24 weeks in subjects 
with FSGS. 
Design: 
Open-label, 24-week, multicenter, exploratory cohort study of voclosporin. 
Treatment: 
Investigational Treatment: 
Voclosporin softgel capsules containing 7.9 mg drug. Approximately 10 subjects will 
be enrolled into Cohort 1 and take voclosporin 23.7 mg orally (PO), twice daily 
(BID). 
The dose level of voclosporin for Cohort 2 (approximately 10 subjects) will be 
determined by analysis of efficacy and safety data at Week 12 from the first 6 subjects 
in Cohort 1. 
Inclusion Criteria: 
1. Written informed consent before any study-specific procedures are performed. 
2. Male or female subjects with a minimum age of 18 years (or legal age of consent 
if >18 years) to 75 years of age, inclusive, at the time of consent. 
3. Primary FSGS diagnosed by renal biopsy within 6 months prior to the screening 
visit. Biopsy results over 6 months prior to screening may be permitted following 
review with the Medical Monitor to confirm eligibility. 
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


 
 
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Confidential 
31 May 2019 
 
 
Page 6 of 111 
 
Inclusion Criteria 
(cont’d): 
4. At initial screening assessment and at last qualifying assessment during 
screening period prior to baseline, FSGS subjects must have urine protein 
creatinine ratio (UPCR) ≥2.0 mg/mg, serum albumin ≤3.2 g/dL. Subjects can be 
treatment-naïve or receiving steroid treatment (oral or IV) for FSGS. Subjects 
taking steroids must show signs of improvement in proteinuria, defined as at 
least a 20% improvement in UPCR from initiation of steroids to the last stability 
assessment prior to baseline. Subjects who have discontinued steroid treatment 
due to poor tolerability may be considered for the study. 
5. All subjects should be treated with angiotensin converting enzyme inhibitors 
(ACEIs) and/or angiotensin receptor blockers (ARBs) unless they have 
documented intolerance or contraindication to these medications. Doses of these 
agents must be stable for at least 2 weeks prior to baseline, with blood pressure 
(BP) ≤150/90 mmHg at the baseline visit (Visit 2). 
a) Subjects with nephrotic edema may be treated with diuretics during the 
screening period. Volume status should be optimized based on the clinical 
judgment of the Investigator and the doses of diuretics must be stable for at 
least 2 weeks prior to baseline. 
b) At the discretion of the Investigator, subjects with hyperlipidemia may be 
treated with lipid-lowering agents (e.g., statins) in accordance with standard 
clinical practice. Doses must be stable for at least 2 weeks prior to baseline. 
6. Stable proteinuria, renal function, and BP for at least 2 weeks prior to baseline, 
as assessed by the Investigator. Changes in UPCR, estimated glomerular 
filtration rate (eGFR), and/or BP during the screening period may be due to 
treatments administered (e.g., ACEIs and ARBs); and, therefore, may interfere 
with study assessments or outcomes, or may place the subject at increased risk. 
All subjects must be discussed with the Medical Monitor prior to initiation of 
study treatment. 
7. Women of childbearing potential must have a negative serum pregnancy test 
prior to dispensing study treatment. Two effective forms of contraception must 
be used simultaneously unless abstinence is the chosen method. Subjects must 
use effective contraception during the study. 
Exclusion Criteria: 
1. Subjects unable or unwilling to give written informed consent and/or to comply 
with study procedures. 
2. Clinical or histologic evidence of secondary FSGS. 
3. Histologic evidence of collapsing variant FSGS. 
4. eGFR as calculated by the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation of ≤30 mL/minute/1.73 m2 at initial screening assessment 
or ≤45 mL/minute/1.73 m2 at last qualifying assessment during screening period 
prior to baseline. 
5. Currently taking or expected to require any of the prohibited medications listed 
in the protocol at screening or during the study. This includes prior use of 
cytotoxic or other immunosuppressant treatment for FSGS. Subjects who have 
discontinued steroid treatment due to lack of response are excluded from the 
study. 
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


 
 
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Confidential 
31 May 2019 
 
 
Page 7 of 111 
 
Exclusion Criteria 
(cont’d) 
6. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or 
expected to require dialysis during the study period. 
7. A previous renal transplant or planned renal transplant during the study. 
8. Body mass index >40 kg/m2 at last stability assessment. 
9. Family history of nephrotic syndrome. 
10. Any known hypersensitivity or contraindication to cyclosporine, or components 
of any cyclosporine drug product. 
11. 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. 
• 
Current or past 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. 
12. Other clinically significant active medical conditions, such as: 
• 
Severe cardiovascular disease including congestive heart failure, history of 
cardiac dysrhythmia or congenital long QT syndrome. Subjects with 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 are excluded. 
• 
Liver dysfunction: aspartate aminotransferase, alanine aminotransferase, or 
bilirubin ≥2.5 times the upper limit of normal at last qualifying assessment 
during screening period prior to baseline. 
• 
Chronic obstructive pulmonary disease or asthma requiring oral steroids. 
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


 
 
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Confidential 
31 May 2019 
 
 
Page 8 of 111 
 
Exclusion Criteria 
(cont’d): 
• 
Bone marrow insufficiency: white blood cell count <2,500/mm3, absolute 
neutrophil count <1.3 × 103/μL, and/or thrombocytopenia (platelet count 
<50,000/mm3) at screening or at last qualifying assessment during screening 
period prior to baseline. 
• 
Current infection requiring intravenous antibiotics. 
13. Any overlapping autoimmune condition for which the condition or the treatment 
of the condition may affect the study assessments or outcomes (e.g., any 
condition for which additional immunosuppression, including systemic 
corticosteroids, and/or cytotoxic therapy is indicated). Overlapping conditions 
for which the condition or treatment is not expected to affect assessments or 
outcomes are not excluded. 
14. No vaccines using live organisms, virus or bacterial, are allowed during 
screening and while taking the study treatment. 
15. 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. 
16. 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. 
17. Subjects who are pregnant, breast feeding or, if of childbearing potential, not 
using adequate contraceptive precautions. 
18. 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. 
19. Subjects treated in a previous voclosporin clinical study. 
Primary Endpoint: 
Proportion of subjects with remission of proteinuria at Week 24, assessed overall and 
for each individual cohort, based on the following parameters: 
• 
Complete remission: UPCR of <0.3 mg/mg 
OR 
• 
Partial remission: UPCR ≥0.3 mg/mg and <3.0 mg/mg with >50% reduction in 
UPCR from baseline 
Secondary 
Endpoints: 
The following secondary endpoints will be assessed overall and for each individual 
cohort: 
• 
Proportion of subjects with complete remission or partial remission of 
proteinuria at Weeks 8 and 12 
• 
Proportion of subjects with complete remission of proteinuria at Weeks 8, 12, 
and 24 
• 
Proportion of subjects with UPCR <0.5 mg/mg at Weeks 8, 12, and 24 
• 
Proportion of subjects with partial remission of proteinuria at Weeks 8, 12, and 
24 
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


 
 
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Confidential 
31 May 2019 
 
 
Page 9 of 111 
 
Secondary 
Endpoints (cont’d): 
• 
Time to first occurrence of complete or partial remission of proteinuria 
• 
Time to first occurrence of complete remission of proteinuria 
• 
Time to first occurrence of partial remission of proteinuria 
• 
Time to first occurrence of 50% reduction in UPCR from baseline 
• 
Duration of UPCR <0.3 mg/mg 
• 
Change from baseline in UPCR at each time point 
• 
Proportion of subjects with a confirmed >30% decrease from baseline in eGFR 
(utilizing the CKD-EPI formula) at each time point  
• 
Proportion of subjects with a confirmed >30% increase in eGFR from the final 
visit (Week 24 or last on-treatment visit, for subjects who discontinue 
prematurely) to the second Safety Follow-up visit (Visit 10) 
• 
Change in UPCR from the final visit (Week 24 or last on-treatment visit, for 
subjects who discontinue prematurely) to the second Safety Follow-up visit 
(Visit 10)  
• 
Change in eGFR from the final visit (Week 24 or last on-treatment visit, for 
subjects who discontinue prematurely) to the second Safety Follow-up visit 
(Visit 10) 
• 
Change from baseline in serum creatinine, serum albumin, and eGFR at each 
time point 
• 
Quality of life assessments 
− 
Mean change in Patient Reported Outcome Measurement Information 
System (PROMIS) measures at Week 24 
− 
Change from baseline in Kidney Disease Quality of Life-Short Form 
(KDQOL-SFTM) score at Week 24 
• 
Safety and tolerability over 24 weeks 
• 
Renal biopsy: descriptive analyses of changes in histopathology will be 
evaluated in post-treatment (24 weeks) renal biopsies in a subset of patients 
• 
Change from baseline to Weeks 4 and 24 in the following biomarkers:  
− 
Urine nephrin 
− 
Urine synaptopodin 
− 
Serum transforming growth factor beta 
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


 
 
AUR-VCS-2017-03 Version 3.0 (Amendment 2) 
Confidential 
31 May 2019 
 
 
Page 10 of 111 
 
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. Subjects will be assigned a unique subject number which will 
be used to identify them throughout the study. If a subject has not had a renal 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 the end of screening. The duration of the screening period will be 
approximately 4 weeks to 10 weeks (allowing for visit windows) to ensure that 
subjects meet eligibility criteria, including renal disease stability assessments.  
The first 10 subjects meeting the required eligibility criteria will be assigned to 
Cohort 1 and will receive voclosporin according to the following dosing regimen: 
• 
Week 1: 1 capsule (7.9 mg) PO, BID 
• 
Week 2: 2 capsules (15.8 mg) PO, BID 
• 
Week 3 – Week 24: 3 capsules (23.7 mg) PO, BID 
Appropriate sponsor personnel (including the medical monitor) and the investigator 
will jointly decide whether to continue with the dose escalation for each subject.  
When the first 6 subjects in Cohort 1 have completed 12 weeks of treatment with 
voclosporin, the top line efficacy and safety data will be analyzed to determine the 
dose level for Cohort 2. The selected dose may be higher or lower than 23.7 mg BID. 
The maximum dose possible for Cohort 2 will be 39.5 mg (5 capsules) BID. Should 
this dose be selected the following dosing regimen will be followed: 
• 
Week 1: 1 capsule (7.9 mg) PO, BID 
• 
Week 2: 2 capsules (15.8 mg) PO, BID 
• 
Week 3: 3 capsules (23.7 mg) PO, BID 
• 
Week 4 – Week 24: 5 capsules (39.5 mg) PO, BID 
Evaluable safety and tolerability data at Week 12 from the first six subjects from 
Cohort 1 are required in order to make the decision to escalate to a higher dose level 
for Cohort 2.  
As a guidance, the dose will not be escalated if any of following criteria are met in 
the first 6 subjects from Cohort 1, unless it was obvious that the occurrence was not 
related to the administration of voclosporin: 
• 
Severe adverse events (SAEs) of same character in ≥2 subjects. 
• 
Clinically significant decrease in eGFR in ≥5 subjects. 
• 
Clinically significant laboratory abnormalities of same character in 
≥5 subjects. 
• 
Clinically significant abnormalities of electrolytes in ≥4 subjects. 
• 
Clinically significant changes in vital signs of same character in ≥4 subjects. 
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


 
 
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Confidential 
31 May 2019 
 
 
Page 11 of 111 
 
Procedures (cont’d) 
Doses and dose increments smaller than anticipated may be proposed for Cohort 2 
based on the safety and tolerability results from the Cohort 1.  
All subjects will complete dosing through 24 weeks of study treatment and will have 
2 Safety Follow-Up visits, 1 and 2 weeks after completion of treatment (i.e., at Week 
25 and Week 26). Subjects who permanently discontinue study treatment before the 
Week 24 visit will return for all remaining study visits and assessments, including 
the 2 Safety Follow-Up visits, unless they have withdrawn consent. 
Sample Size: 
As this is an exploratory study, sample size calculations are not required. It is 
estimated that approximately 20 subjects will be recruited, with approximately 10 
subjects in both of Cohorts 1 and 2. 
Statistical Methods: 
Analysis: 
All statistical analyses relating to the primary and secondary objectives will be 
undertaken at study closure and will incorporate all available data. 
Given the small sample size, all analyses will be descriptive in nature. Confidence 
intervals (CIs) for proportions may be calculated but it is recognized that such 
intervals, being based on 20 patients, will be very wide. As an example, the 95% 
Clopper-Pearson CI for a proportion of 30% based on 20 patients is (11.9%, 54.3%). 
Populations:  
The efficacy analysis will be based on intent-to-treat (ITT) principles and will include 
all enrolled subjects (non-screening failures). 
The per-protocol data set will include the subset of subjects in the ITT set who do not 
have any major protocol violations (to be defined). 
The safety analysis set will consist of all subjects who receive at least 1 dose of study 
treatment. 
Methods: 
Top line efficacy (change from Baseline in UPCR) and safety data (AEs, eGFR, 
ECGs and vital signs) for the first 6 subjects in Cohort 1 completing 12 weeks of 
study treatment, will be reviewed and based on those data the commencement of 
enrolment and the target dose for Cohort 2 will be determined. 
The analysis of the primary endpoint, complete or partial remission of proteinuria at 
Week 24, will be conducted on the ITT set and confirmed with the per-protocol set 
(if applicable). Remission of proteinuria will be summarized and an exact 2-sided 
95% CI for the remission rate will be calculated.  
The analyses of the secondary endpoints will incorporate the use of 2-sided 95% CIs 
and are described below:  
• 
Binary endpoints will be summarized using exact 2-sided 95% CIs.  
• 
Endpoints measured as a time-to-event will be displayed using Kaplan-Meier 
methodology. Median time-to-event along with 2-sided 95% CIs will be 
displayed.  
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Statistical Methods 
(cont’d) 
• 
Other endpoints will be summarized by visit. Absolute values and differences 
between baseline and each time point up to and including Week 24 will be 
summarized using means and 2-sided 95% CIs. Changes between last on 
treatment value and post treatment follow-up will also be summarized. 
Safety Endpoints:  
Adverse events will be aggregated by System Organ Class and preferred term and 
presented as summary tables.  
Laboratory values, 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. 
Exploratory analyses will be undertaken should the data suggest areas worthy of 
further investigation. 
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STUDY SCHEMA 
 
 
 
Notes: 
BID=Twice daily; VCS=Voclosporin. 
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AUR-VCS-2017-03 SCHEDULE OF EVENTS 
Visit 
Visit 1 
Screening Period 
Visit 2 
Baseline 
Visit 3 
Visits 4-5 
Visit 6 
Visit 7 
Visit 8 
End of 
Treatment/ 
Early 
Termination 
Visit 9 
Safety 
Follow-up 
Visit 10 
Safety 
Follow-up 
Day/Week 
Screening to Day -1 
Day 1 
(Within 1 
Wk Post 
Qualifying 
Assessment) 
Wk 2 
(±3 Days) 
Wks 4, 8 
(±3 Days) 
Wk 12 
(±3 Days) 
Wk 18 
(±5 Days) 
Wk 24 
(±7 Days) 
Wk 25 
(±3 Days) or 
Premature 
Disc. +7 Days 
Wk 26 
(±3 Days) or 
Premature 
Disc. +14 Days  
Screening 
Visit(1) 
Stability 
Assessments 1 & 
2, Optional 3 & 
4(1) 
Informed consent 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
 
 
 
 
 
 
 
 
 
 
Renal biopsy(2) 
 
 
 
 
 
 
 
(2) 
 
 
Medical history and 
demography 
 
 
 
 
 
 
 
 
 
 
Physical exam(3) 
 
 
 
 
 
 
 
 
 
 
Vital signs(4) 
 
 
 
 
 
 
 
 
 
 
ECG(5) 
 
 
 
 
 
 
 
 
 
 
Laboratory 
assessments(6)  
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics(7) 
 
 
 
 
 
 
 
 
 
 
Urinalysis and urine 
microscopy 
 
 
 
 
 
 
 
 
 
 
FMV urine collection(8) 
 
 
 
 
 
 
 
 
 
 
24-hour urine(9) 
 
 
 
 
 
 
 
 
 
 
QoL(10) 
 
 
 
 
 
 
 
 
 
 
Pregnancy test(11) 
 
 
 
 
 
 
 
 
 
 
Adverse events 
(12) 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
Dispense study 
medication/ 
compliance(13) 
 
 
 
 
 
 
 
(14) 
 
 
First dose of study 
medication 
 
 
(15) 
 
 
 
 
 
 
 
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1 
Stability assessments to occur at 14-day intervals (± 3 days) with first assessment approximately 2 weeks after the screening visit. Stability assessments 1 and 2 are mandatory; assessments 3 and 4 
are optional if additional time is required for the subject’s clinical status to stabilize. Note that the laboratory assessments and FMV results of the last stability assessment will be used as the 
qualifying values for eligibility. Enrolment of eligibile subjects must occur within 1 week of the final stability assessment.  
2 
If a subject has not had a recent renal biopsy, one may be performed to assess eligibility for the study provided informed consent has been given. The biopsy must have been performed 6 months 
prior to the screening visit. Biopsy results over 6 months prior to screening may be permitted following review with the Medical Monitor to confirm eligibility. Repeat renal biopsies may be done at 
Week 24 in a subset of subjects at selected sites.  
3 
Complete physical exam at screening; abbreviated exam at all other visits. 
4 
BP, pulse, temperature, weight, and height. Height included at initial screening assessment only. At stability assessments, BP only will be included. 
5 
In the event that a subject is noted to have a QTcF value exceeding 500 msec, or an increase of >60 msec from baseline, the ECG should be repeated within 24 hours. Further details provided in the 
study protocol. 
6 
Laboratory assessments will be performed according to the schedule in the study protocol. Subjects must be fasting for at least 8-12 hours at Baseline and at end of study/early termination visit.  
7 
Pharmacokinetic assessments will be done at Weeks 4 and 24. PK samples will be drawn prior to study treatment dosing (trough sample), and at 1, 2 and 4 hours post-dose. In the event a subject 
experiences an SAE or requires a dose modification or is withdrawn from treatment, a voclosporin sample should be taken, with a trough sample preferred. 
8 
The UPCR will be calculated both from the FMV and from standard urinalysis results. If the FMV 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. 
9 
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. 
10 Patient Reported Outcome Measurement Information system (PROMIS) and Kidney Disease Quality of Life-Short Form (KDQOL-SFTM). 
11 Serum pregnancy test to be evaluated at central laboratory at Screening and Week 24; urine pregnancy test will be performed locally at all other visits as applicable. 
12 If screening visit occurs on the same day as informed consent, any findings are to be recorded as Medical History. Any change since the date of signed consent and/or during the screening period 
would be considered an AE. 
13 Subjects in Cohort 1, will be contacted by telephone at the end of Week 1 as a reminder to increase their dose to 2 capsules (15.8 mg) BID for 1 week, starting at Week 2. Subjects will be contacted 
again by telephone at the end of Week 2 as a reminder to increase their dose to 3 capsules (23.7 mg) BID, starting at Week 3, for the remainder of the treatment period. Subjects in Cohort 2, will also 
be contacted at the end of each week (as required) up to Week 4, as a reminder to increase their dose to the maximum selected for Cohort 2. 
14 Compliance only. 
15 First dose of study medication should occur in the morning the day after dispensing. 
Notes: Subjects who discontinue therapy will be requested to attend their regularly scheduled study visits to the end of the study. 
 
AE=Adverse event; BID=Twice dialy; BP=Blood pressure; Disc.=Discontinuation; ECG=Electrocardiogram; FMV=First morning void; Min=Minimum; QoL=Quality of life; QTcF=QT 
interval duration corrected for heart rate using method of Fridericia; SAE=Serious adverse event; Wk=Week. 
 
 
 
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TABLE OF CONTENTS 
Page 
NAMES AND ADDRESSES ...................................................................................................2 
DECLARATION OF SPONSOR ...........................................................................................3 
INVESTIGATOR AGREEMENT FORM ............................................................................4 
SYNOPSIS ................................................................................................................................5 
STUDY SCHEMA .................................................................................................................13 
AUR-VCS-2017-03 SCHEDULE OF EVENTS ..................................................................14 
TABLE OF CONTENTS ......................................................................................................16 
LIST OF TABLES .................................................................................................................20 
LIST OF APPENDICES .......................................................................................................20 
LIST OF ABBREVIATIONS ...............................................................................................21 
1. 
INTRODUCTION AND BACKGROUND ..................................................................24 
1.1 
Background of the Disease and Treatment Options ....................................................24 
1.1.1 
Limitations of Current Treatment .............................................................................25 
1.2 
Rationale for the Use of Calcineurin Inhibitors in FSGS ............................................26 
1.2.1 
Mechanism of Action of CNIs and Potential for Treatment Benefit in FSGS .........26 
1.2.2 
Clinical Studies of CNIs in FSGS ............................................................................27 
1.2.3 
Voclosporin ...............................................................................................................29 
1.2.3.1 
Pharmacokinetic Considerations ............................................................................30 
1.2.4 
Potential Toxicities of CNIs .....................................................................................30 
2. 
RATIONALE .................................................................................................................32 
2.1 
Dose Rationale .............................................................................................................32 
3. 
STUDY OBJECTIVES ..................................................................................................34 
3.1 
Primary Objective ........................................................................................................34 
3.2 
Secondary Objective ....................................................................................................34 
3.3 
Endpoints .....................................................................................................................34 
3.3.1 
Primary Endpoint ......................................................................................................34 
3.3.2 
Secondary Endpoints ................................................................................................34 
4. 
INVESTIGATIONAL PLAN .......................................................................................36 
4.1 
Overall Study Design ...................................................................................................36 
4.2 
Duration of Subject Participation and Study ...............................................................37 
5. 
SELECTION, 
WITHDRAWAL 
OF 
SUBJECTS 
AND 
PERMANENT 
DISCONTINUATION OF DRUG ................................................................................38 
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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 of Study Treatment Due to an Adverse Event................................42 
6. 
RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES ..............44 
7. 
STUDY TREATMENTS ...............................................................................................45 
7.1 
Dosage Forms/Formulation .........................................................................................45 
7.1.1 
Voclosporin – Study Treatment ................................................................................45 
7.1.2 
Dosing Guidelines.....................................................................................................45 
7.1.2.1 
Voclosporin Study Treatment ................................................................................45 
7.1.2.2 
Corticosteroids .......................................................................................................46 
7.2 
Package and Labeling ..................................................................................................47 
7.3 
Site Supply, Storage, Accountability ...........................................................................47 
7.3.1 
Site Supply ................................................................................................................47 
7.3.2 
Storage ......................................................................................................................47 
7.3.3 
Accountability ...........................................................................................................47 
7.4 
Voclosporin Dose Modification ...................................................................................48 
7.4.1 
Discontinuation of Study Therapy Due to Non-response .........................................48 
7.4.2 
Deterioration in Renal Function ...............................................................................48 
7.4.2.1 
Decrease in eGFR >30% and eGFR <90 mL/min/1.73 m2 ....................................48 
7.4.2.2 
Decrease in eGFR ≤30% and eGFR <90 mL/min/1.73 m2 ....................................49 
7.4.2.3 
Recovery of eGFR .................................................................................................49 
7.5 
Procedures for Overdose ..............................................................................................49 
7.6 
Prohibited Therapy and Concomitant Treatment .........................................................49 
7.6.1 
Prohibited Medications .............................................................................................49 
7.6.2 
Allowed Concomitant Medications ..........................................................................50 
7.7 
Increased Blood Pressure .............................................................................................50 
8. 
RISKS/PRECAUTIONS ...............................................................................................52 
9. 
STUDY PROCEDURES ...............................................................................................53 
9.1 
Description of Study Assessments ...............................................................................53 
9.1.1 
Laboratory Assessments ...........................................................................................53 
9.1.1.1 
Evaluation of Biomarkers ......................................................................................55 
9.1.2 
Physical Examinations ..............................................................................................55 
9.1.3 
Vital Signs.................................................................................................................56 
9.1.3.1 
Blood Pressure Management .................................................................................56 
9.1.4 
Standard 12-lead Electrocardiogram ........................................................................56 
9.1.4.1 
Procedures to Manage a Treatment-Emergent Increase in QTcF ..........................57 
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9.1.5 
QoL Assessments ......................................................................................................57 
9.1.6 
Voclosporin Pharmacokinetic and Biomarker Assessment ......................................57 
9.2 
Schedule of Assessments .............................................................................................57 
9.2.1 
Screening Visit and Stability Assessment Procedures ..............................................58 
9.2.2 
Treatment Procedures ...............................................................................................59 
9.2.3 
End of Study (or Early Termination) Procedures .....................................................60 
9.2.4 
Follow-up Procedures ...............................................................................................61 
9.2.5 
Unscheduled Visit .....................................................................................................61 
10. EVALUATION, RECORDING AND REPORTING OF AES AND SAES .............62 
10.1 
Definitions....................................................................................................................62 
10.1.1 
Adverse Event ...........................................................................................................62 
10.1.2 
Adverse Drug Reaction .............................................................................................62 
10.1.3 
Serious Adverse Event ..............................................................................................62 
10.1.4 
Suspected Unexpected Serious Adverse Reaction....................................................63 
10.2 
Adverse Event Descriptors ..........................................................................................63 
10.2.1 
Intensity/Severity Categorization .............................................................................63 
10.2.2 
Causal Relationship Categorization ..........................................................................63 
10.2.3 
Outcome Categorization ...........................................................................................64 
10.2.4 
Clinical Laboratory Evaluations ...............................................................................64 
10.2.5 
Abuse, Misuse, Overdose and Medication Error ......................................................65 
10.3 
Reporting Procedure for AEs, SAEs, and Pregnancy ..................................................65 
10.3.1 
Adverse Events .........................................................................................................65 
10.3.2 
Serious Adverse Events ............................................................................................66 
10.3.3 
Pregnancy..................................................................................................................67 
11. CLINICAL ENDPOINTS COMMITTEE ..................................................................69 
12. DATA AND SAFETY MONITORING BOARD PROCEDURES ...........................70 
13. STATISTICAL ANALYSIS .........................................................................................71 
13.1 
Statistical Methods .......................................................................................................71 
13.2 
Sample Size and Power Calculations ...........................................................................71 
13.3 
Populations ...................................................................................................................71 
13.3.1 
Intent-to-Treat Set .....................................................................................................71 
13.3.2 
Safety Set ..................................................................................................................71 
13.3.3 
Per-protocol Set ........................................................................................................71 
13.4 
Datasets ........................................................................................................................71 
13.5 
Background and Demographic Characteristics ............................................................71 
13.6 
Study Treatment ...........................................................................................................72 
13.7 
Concomitant Therapy...................................................................................................72 
13.8 
Efficacy Evaluations ....................................................................................................72 
13.8.1 
Primary Endpoint ......................................................................................................72 
13.8.2 
Secondary Endpoints ................................................................................................72 
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13.9 
Statistical and Analytical Methods ..............................................................................74 
13.10 Safety Evaluations .......................................................................................................74 
13.11 Interim Analyses ..........................................................................................................75 
13.12 Other Evaluations.........................................................................................................75 
13.12.1 Pharmacokinetics ......................................................................................................75 
14. ETHICAL CONDUCT OF THE STUDY ...................................................................76 
14.1 
Informed Consent.........................................................................................................76 
14.2 
Institutional Review Board or EC/IEC ........................................................................76 
15. QUALITY CONTROL AND QUALITY ASSURANCE ...........................................77 
16. ADMINISTRATIVE PROCEDURES .........................................................................78 
16.1 
Sponsor’s Responsibilities ...........................................................................................78 
16.1.1 
Study Supplies ..........................................................................................................78 
16.1.2 
Insurance ...................................................................................................................78 
16.1.3 
Study Monitoring ......................................................................................................78 
16.2 
Investigator’s Responsibilities .....................................................................................79 
16.2.1 
Reporting and Recording of Data .............................................................................79 
16.2.2 
Investigator Training.................................................................................................79 
16.2.3 
Source Documentation ..............................................................................................79 
17. PROCEDURE FOR MODIFICATION OF PROTOCOL OR PREMATURE 
TERMINATION OF THE STUDY .............................................................................80 
17.1 
Protocol Waivers, Deviations and Violations ..............................................................80 
17.2 
Study Termination .......................................................................................................80 
18. POLICY FOR PUBLICATION AND PRESENTATION OF DATA ......................81 
19. REFERENCES ...............................................................................................................82 
 
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LIST OF TABLES 
Page 
Table 1 
Review of Laboratory Assessments .................................................................53 
 
LIST OF APPENDICES 
Page 
Appendix 1 
Drug Therapy for the Treatment of Hypertension ...........................................85 
Appendix 2 
Measurement of Blood Pressure ......................................................................86 
Appendix 3 
Classification of FSGS .....................................................................................87 
Appendix 4 
Conversion Table for Oral Corticosteroids ......................................................89 
Appendix 5 
Expanded List of Allowed Concomitant Medications .....................................90 
Appendix 6 
Summary of Treatment and Food Restrictions ................................................92 
Appendix 7 
PROMIS QoL Assessment ..............................................................................93 
Appendix 8 
KDQOL-SFTM QoL Assessment Version 1.3 ..................................................94 
  
 
 
 
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LIST OF ABBREVIATIONS 
ACEI 
Angiotensin converting enzyme inhibitor 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ARB 
Angiotensin receptor blocker 
ATC 
Anatomical Therapeutic Chemical 
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 
Aurinia 
Aurinia Pharmaceuticals Inc. 
BID 
Twice daily 
BP 
Blood pressure 
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 
DEX 
Dexamethasone 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End-stage renal disease 
FMV 
First morning void 
FSGS 
Focal Segmental Glomerulosclerosis 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
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GMP 
Good Manufacturing Practice 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISA247 
Voclosporin 
ITT 
Intent-to-treat 
IV 
Intravenous 
KDIGO 
Kidney Disease: Improving Global Outcomes 
KDQOL-SFTM 
Kidney Disease Quality of Life-Short Form 
LN 
Lupus nephritis 
MMF 
Mycophenolate mofetil 
NSAID 
Non-steroidal anti-inflammatory drug 
OR 
Odds ratio 
PD 
Pharmacodynamic 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PO 
Orally 
PPS 
Per-protocol set 
PROMIS 
Patient Reported Outcome Measurement Information System  
QoL 
Quality of life 
QTcF 
QT interval duration corrected for heart rate using method of 
Fridericia 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
t1/2 
Terminal elimination half-life 
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TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TGF-β 
Transforming growth factor beta 
UPCR 
Urine protein creatinine ratio 
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1. INTRODUCTION AND BACKGROUND 
1.1 
Background of the Disease and Treatment Options  
Focal segmental glomerulosclerosis (FSGS) is diagnosed by characteristic glomerular findings 
of podocyte injury evidenced by findings from immunofluorescence and electron microscopy 
following renal biopsy. The disease is categorized as primary (i.e., idiopathic FSGS) or 
secondary (e.g., adaptive changes resulting from glomerular hyperfiltration in conditions such 
as reflux nephropathy, obesity, and reduced nephron mass; drug-induced FSGS; and FSGS 
associated with viral diseases) [1].  
The predominate clinical feature of primary FSGS is proteinuria, typically with signs and 
laboratory abnormalities associated with nephrotic syndrome (i.e., total urine protein >3.5 
g/day, edema, hypoalbuminemia, and hypercholesterolemia) [1]. Patients may experience 
renal dysfunction which can progress to end-stage renal disease (ESRD). Reportedly 50-60% 
of patients have nephrotic syndrome at presentation, and approximately 50% of adult patients 
with idiopathic nephrotic syndrome are diagnosed with FSGS [1]. The amount of proteinuria 
at presentation and lack of response to treatment are correlated with progression to ESRD. 
FSGS is more common in males than in females and, in racially diverse populations, more 
common in black patients than in white patients [1]. 
Several published reviews have summarized the histopathologic features of FSGS and 
mechanisms of podocyte injury, disruption of the glomerular filtration barrier, and progression 
of renal dysfunction, e.g., D’Agati [1] and Kikuchi et al [2].  
The glomerular filtration barrier consists of glomerular endothelial cells, the glomerular 
basement membrane, and epithelial cells (podocytes). There is a complex interaction between 
these elements; the podocyte is not only a critical part of the structure, providing structural 
support to glomerular capillary, but also plays a role in maintaining the glomerular basement 
membrane and slit diaphragm proteins that permit filtration of water and small molecules and 
retention of large molecules and cells. Light microscopy findings include a segmental pattern 
of mesangial sclerosis occurring in some (i.e., focal), but not all glomeruli, without typical 
features of other proteinuric glomerulopathies. Immunofluorescence microscopy does not 
reveal immune deposits. The primary pathophysiologic mechanism of FSGS is reflected in 
electron microscopy findings, which include typical abnormalities of podocyte morphology, 
i.e., diffuse podocyte foot process effacement. In FSGS, as in other podocytopathies, these 
abnormalities disrupt the glomerular filtration barrier, resulting in protein leakage. 
The etiology of primary (idiopathic) FSGS is not known and is likely multifactorial. Based on 
indirect evidence, development of FSGS has been attributed to circulating factors (e.g., 
cytokines such as cardiotrophin-like cytokine 1, anti-CD40 (podocyte-B7-1 antigen) antibody, 
apolipoprotein A-Ib (ApoA-Ib) and serum soluble urokinase-type plasminogen activator 
receptor (suPAR)) which may mediate glomerular permeability. FSGS recurs in transplanted 
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kidneys, and proteinuria can be reduced by plasmapheresis in these patients; plasma and sera 
from FSGS patients have induced proteinuria in rats and in isolated rat glomeruli [3]. Several 
immune mechanisms have also been postulated to contribute to progressive glomerular damage 
subsequent to the initial podocyte injury, including cellular immunity and autoimmune 
reactivity [4].  
Elevated levels of transforming growth factor-beta (TGF-β) have been implicated in the 
pathogenesis of FSGS and have been reported in numerous tissues of patients with FSGS 
including the tubule-interstitium and the glomerular epithelial cells [5,6]. Calcineurin α, one 
of the calcineurin isoforms, is involved in broad cellular tasks including protein folding and 
regulation of TGF-β expression. The use of an immunosuppressive agent that increases TGF-
β levels may have a negative long-term impact on renal fibrosis, whereas the use of an 
immunosuppressive agent that either decreases or has no impact on TGF-β levels may stabilize 
presently existing renal fibrosis. Concerning the podocyte, Liao et al [7] showed that in a 
murine (MRL/lpr) model, the calcineurin inhibitor (CNI) tacrolimus may decrease TGF-β-
induced podocyte apoptosis, suggesting that calcineurin may play a role in the progression of 
renal disease, thereby suggesting a potential mechanism of CNI benefit.   
1.1.1 Limitations of Current Treatment 
The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for 
Glomerulonephritis [8] provides Level 2C (low) and 2D (very low) suggestions for the 
treatment of primary FSGS: Corticosteroids are suggested as initial treatment at a daily single 
dose of 1 mg/kg (maximum 80 mg) or 2 mg/kg (maximum 120 mg) (Level 2C), to be 
administered for a minimum of 4 weeks and maximum of 16 weeks, as tolerated, or until 
complete remission has been achieved, whichever is earlier (Level 2D). Calcineurin inhibitors 
are suggested for use in FSGS as second-line treatment after failure of remission with steroid 
treatment and as first-line treatment in patients with relative contraindications to steroids. 
(Level 2D) (see Section 1.2.1, Mechanism of Action of CNIs and Potential for Treatment 
Benefit in FSGS). Up to 50% of patients fail to respond to corticosteroids [1]. Earlier use of 
CNIs in primary FSGS, as initial treatment at the time of diagnosis, would avoid the risks of 
corticosteroid use, and may result in proteinuria remission, as well as potentially decrease the 
risk of progression to ESRD. 
The potential benefit of voclosporin in treatment-naïve FSGS patients is supported by the 
mechanism of action of CNIs (see Section 1.2.1, Mechanism of Action of CNIs and Potential 
for Treatment Benefit in FSGS) and clinical data suggesting benefit in steroid-resistant patients 
(see Section 1.2.2, Clinical Studies of CNIs in FSGS), as well as potential advantages of 
voclosporin over cyclosporine (i.e., increased potency demonstrated in nonclinical studies with 
voclosporin, more predictable pharmacokinetic (PK)/pharmacodynamic (PD) profile 
(obviating the need for therapeutic drug monitoring), and a potentially improved safety profile 
compared to cyclosporine A (CsA)) (see FSGS Investigator’s Brochure (IB) [9]). These data, 
with the demonstrated efficacy in renal response (including reduction in proteinuria), suggest 
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that voclosporin may benefit patients with FSGS. Although treatment guidelines suggest 
corticosteroids as first line therapy in these patients [8], there are no data to support the use of 
corticosteroids instead of CNIs in this setting. Corticosteroids are associated with significant 
toxicities, and if voclosporin demonstrates treatment benefit and an acceptable safety profile, 
it would provide an appropriate alternative treatment to corticosteroids in this setting. 
1.2 
Rationale for the Use of Calcineurin Inhibitors in FSGS  
Calcineurin inhibitors are suggested for use in FSGS as second line treatment after failure of 
remission with steroid treatment and as first line treatment in patients with relative 
contraindications to steroids. In addition to well-characterized immunomodulatory effects, 
CNIs have been demonstrated to have direct beneficial effects on podocytes that are likely 
mechanisms of amelioration of proteinuria in podocytopathies, including FSGS. 
1.2.1 Mechanism of Action of CNIs and Potential for Treatment Benefit in 
FSGS 
Calcineurin inhibitors have beneficial effects in diseases characterized by disorders of the 
immune system and in the prevention of rejection after solid organ transplantation by inhibiting 
activation of nuclear factor of activated T-cell (NFAT) with subsequent regulation of the 
production of T-cell cytokines [9]. Recently, several investigations have demonstrated that 
CNIs have non-immunologic effects that contribute to their anti-proteinuric effects in 
podocytopathies. 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 protected from degradation. Calcineurin dephosphorylates synaptopodin 
allowing its degradation, with subsequent alteration of the actin cytoskeleton, disruption of the 
glomerular filtration barrier, and proteinuria. Expression of activated calcineurin in podocytes 
leads to proteinuria. Thus, by inhibiting calcineurin, CNIs exert a specific anti-proteinuric 
effect by preventing the degradation of the podocyte stabilizing protein synaptopodin [10,11]. 
In addition to effects on synaptopodin, cyclosporine has been found to stabilize other 
components of the actin cytoskeleton, i.e., cofilin-1 and nephrin. Podocyte apoptosis can be 
induced in the rat purine aminonucleoside model [12]. Shen et al [13] demonstrated that 
cyclosporine and tacrolimus reduced podocyte apoptosis in the rat purine aminonucleoside 
model. In addition, inhibition of NFAT signaling in the podocyte by CNIs may ameliorate 
podocyte injury [14]. Wakamatsu et al [15] evaluated the effects of tacrolimus in a nephrotic 
rat model (anti-nephrin antibody-induced nephropathy). Utilizing immunohistological 
analyses of rat and human kidneys, these investigators demonstrated that calcineurin is an 
element of the slit diaphragm and associated with nephrin, a critical component of the slit 
diaphragm. In the nephrotic rat model, they demonstrated that calcineurin distribution was 
altered and calcineurin activity was increased; these abnormalities were prevented by 
administration of tacrolimus, with amelioration of proteinuria. As noted in Section 1.1, 
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Background of the Disease and Treatment Options, calcineurin may also contribute to TGF-β-
induced fibrosis. 
In summary, CNIs, in addition to their immunomodulatory effects have been demonstrated to 
have direct beneficial effects on podocytes via multiple mechanisms. These effects are likely 
mechanisms of amelioration of proteinuria in podocytopathies, including FSGS. 
1.2.2 Clinical Studies of CNIs in FSGS  
The KDIGO guidelines suggest CNIs for use in the first line treatment of FSGS in patients 
who are intolerant or have contraindications to corticosteroid use [8]. There are no prospective, 
randomized trials of CNIs (either cyclosporine or tacrolimus) used as first line treatment in 
adult patients (or children) with FSGS. Limited retrospective observational data support their 
use in this setting; a recent treatment review [16] cites two studies: Duncan et al [17] and 
Goumenos et al [18]. 
In a single study center by Duncan et al [17], 6 patients with biopsy-proven FSGS and 
nephrotic syndrome, who had been previously treated with angiotensin converting enzyme 
inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), but not immunosuppression 
(including corticosteroids), were treated with tacrolimus and followed prospectively. The mean 
duration of nephrotic syndrome prior to treatment with tacrolimus was 13.6 months (standard 
deviation (SD) 11.8); baseline urine protein was 11.0 g/day (SD 4.5) and baseline estimated 
glomerular filtration rate (eGFR) was 71.7 mL/min/1.73 m2 (SD 22.4). After approximately 12 
months of follow-up, all 6 patients achieved remission, defined as normalization of serum 
albumin and resolution of edema. Mean urine protein decreased from 11.0 g/day (SD 4.5) to 
2.8 g/day (SD 2.5). Reportedly, no patients relapsed after attaining remission. 
In a retrospective review by Goumenos et al [18], 51 patients with biopsy-proven FSGS, 
proteinuria >1 g/day, and serum creatinine <2.5 mg/dL, were followed for 5 years. Of the 51 
patients, 26 were treated with conservative management (including ACEIs and other anti-
hypertensives) and 25 were treated with immunosuppressive drugs, including prednisolone 
alone (9 patients, treated for 16 months, 8 with nephrotic syndrome), prednisolone and 
azathioprine (6 patients, treated for 18 months, 5 with nephrotic syndrome) and prednisolone 
(0.5 mg/kg/day) and cyclosporine (10 patients, treated for 25 months, 7 with nephrotic 
syndrome). No patients received cyclosporine monotherapy. Treatment assignment was 
reportedly based on renal impairment and degree of proteinuria. Remission of nephrotic 
syndrome (both complete remission (defined as urine protein <0.3 g/day) and partial remission 
(defined as urine protein between 0.3 and 3 g/day)) occurred in 5/8 patients treated with 
prednisolone alone, 4/5 patients treated with prednisolone and azathioprine, and 6/7 patients 
treated with prednisolone and cyclosporine. 
Evidence to support the use of CNIs in adult patients who are steroid resistant includes 
randomized clinical trials as well as observational data. A Cochrane Review published in 2008 
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[19] identified one blinded controlled study (Cattran et al, 1999 [20]) which evaluated the 
effect of cyclosporine on remission of proteinuria and ESRD in steroid-resistant adult patients 
with nephrotic syndrome. This study was a single blind, randomized, placebo-controlled trial 
in which 26 patients were treated with cyclosporine and low dose prednisone and 23 patients 
were treated with placebo and low-dose prednisone. Complete remission (urine protein 
≤0.3 g/day with stable renal function) or partial remission (50% reduction and ≤3.5 g/day with 
stable renal function) occurred in 69% of the cyclosporine group and 4% of the placebo group 
at 26 weeks (p<0.001). At 4 years, the renal survival rate was 72% in the cyclosporine group 
and 49% in the placebo group. 
Laurin et al [21] performed a meta-analysis of studies evaluating the effects of CNIs in primary 
FSGS. They did not identify any trials in which CNIs were used as first-line treatment. Six 
randomized controlled trials and two retrospective cohort studies were included in their review. 
They performed a pooled analysis of the effect of cyclosporine on proteinuria remission; the 
relative risk of complete or partial remission was 7.0 (95% confidence interval (CI): 2.9, 16.8) 
compared with the control group. 
It has been noted in treatment reviews that cyclosporine use in steroid-resistant patients is 
associated with a high relapse rate (e.g., 43 to 50% in a 2003 review by Cattran [22]). In an 
NIH-sponsored trial, FSGS-CT, 138 patients (adults and children) with biopsy-proven FSGS 
(assessed as steroid resistant and urine protein creatine ratio (UPCR) >1 g/g) were randomized 
to cyclosporine (n=72) or a combination of pulse dexamethasone (DEX) and mycophenolate 
mofetil (MMF) (n=66) [23,24]. Treatment was administered for 12 months and patients were 
followed until Week 78. Steroid resistance was defined as failure to achieve sustained UPCR 
≤1.0 g/g after a minimal treatment duration of 4 weeks. All patients were treated with low-
dose prednisone and either an ACEI or ARB. There was no difference between the groups in 
the primary endpoint (mean score of a 6-level categorical assessment of remission of 
proteinuria at Week 52): 46% of the CsA group and 33% of the MMF/DEX group had at least 
a partial remission at Week 52. In patients who achieved at least a partial remission at Week 52, 
relapse (defined as UPCR >2.0 g/g after the withdrawal of medication at Week 52) was 
reported for 33% (11/33) in the CsA group and 18% (4/22) in the MMF/DEX group. These 
data are difficult to interpret as 28% of patients in the CsA group had baseline UPCR <2.0 g/g. 
Moreover, the definition of steroid resistance in this study is not consistent with standard 
definition of steroid resistance for adults and the data are not presented separately for adults 
and children. 
In a follow-up publication of a post-hoc analysis, Hogg et al [25] examined the outcomes in 
patients who achieved complete or partial remission after 26 weeks, completed 52 weeks of 
treatment, and had follow-up information through 78 weeks. In the cyclosporine group, the 
analysis included 22 of the 39 patients who were reported to have at least partial remission at 
Week 26 in the earlier publication, and 20 of the 26 patients in the MMF/DEX group. The 
authors report that, in the CsA patients, the mean eGFR decreased at Weeks 26 and 52 (17% 
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decrease and 19% decrease compared to baseline, respectively), and increased by 16% from 
Week 52 to Week 78. 
There are few studies examining the use of tacrolimus in patients with FSGS. In one study [26], 
decrease in proteinuria was similar in 18 patients treated with cyclophosphamide/prednisone 
and 15 patients treated with tacrolimus/prednisone, both after 6 months of treatment and at the 
completion of a 6-month follow-up period. Baseline renal function was not recorded and there 
appeared to be stability of renal function between 6 months and 12 months. Therefore, it is 
difficult to assess the treatment benefit of tacrolimus from this study. 
In summary, the available data, although largely from retrospective studies, support a treatment 
benefit of cyclosporine in steroid-resistant patients. There is little data supporting the benefit 
of cyclosporine as first line treatment. It has been reported that the relapse rate is high following 
discontinuation of treatment; however, it is difficult to interpret the data reported by Gipson et 
al [23,24] and Hogg et al [25] with respect to the effect of cyclosporine on renal function and 
proteinuria over 12 months and subsequent improvement in renal function and proteinuria after 
withdrawal, and the reported relapse rate. The study failed to recruit the target number of 
patients, the criteria for steroid resistance were not consistent with standard definitions, and 
the changes in proteinuria and renal function were not completely reported. However, it 
appears that there was a significant decrease in proteinuria at both Weeks 26 and 52. While the 
post-treatment effect on eGFR is not completely clear, the data suggest some increase in eGFR 
after withdrawal of treatment. The relevance of these findings to the long-term effect of 
voclosporin is not clear. 
1.2.3 Voclosporin 
Voclosporin is a next generation CNI currently under development for use in FSGS and lupus 
nephritis (LN). Voclosporin is structurally similar to 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 PK/PD predictability. 
During the development of this investigational product, the legacy names of voclosporin, VCS, 
and ISA247 are referenced in discussions related to historical usage. In the Phase 3 LN clinical 
development program, the name of the investigational product is referred to as Orelvo, the 
proposed trade name. However, for the FSGS clinical development programs, the name of the 
investigational product will be referred to as voclosporin. All legacy names and the proposed 
trade name should all be considered interchangeable unless specifically identified as different. 
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Prior to the FSGS clinical development program, over 2,400 subjects have received 
investigational products containing voclosporin in 15 Phase 1, and 12 Phase 2/3 clinical studies 
in the indications of LN, transplant rejection, psoriasis and non-infectious uveitis. Detailed 
data for these clinical studies are presented in the IB [9].  
1.2.3.1 Pharmacokinetic Considerations 
Voclosporin approximates linear multiexponential PKs. Exposure to voclosporin was 
dose-related with maximum concentrations occurring ≤2 hours with a 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 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 Cmax and an 18-fold increase in 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 voclosporin. Concomitant administration 
of voclosporin and 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 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 Potential Toxicities of CNIs 
Increased blood pressure (BP) and renal dysfunction are well known potential toxicities of 
CNIs that are dose-related, reversible, and generally responsive to dose reduction or temporary 
interruption of treatment [27].  
Voclosporin has been studied in numerous disease states. In clinical studies of voclosporin in 
LN [9], a small proportion of voclosporin-treated subjects experienced an early drop of ≥30% 
in eGFR; however, that proportion then remained stable over time. None of these treatment-
emergent adverse events (TEAEs) were classed as serious. The majority of TEAEs of 
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decreased GFR were classed as mild or moderate, and resulted in permanent discontinuation 
of study treatment in 1 (1.1%) placebo subject, 7 (7.9%) voclosporin low-dose (23.7 mg BID) 
subjects and 5 (5.7%) voclosporin high-dose (39.5 mg BID) subjects. There were more TEAEs 
of hypertension seen in the voclosporin-treated subjects compared to placebo; however, overall 
mean systolic and diastolic 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 
treatment.  
There was also 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 Disorders, and Vascular Disorders. 
 
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2. RATIONALE 
The rationale for the development of voclosporin and the range of dose is to introduce a novel 
CNI to the population of patients with FSGS, with meaningful efficacy while minimizing 
toxicities common to other CNIs. In clinical studies, a favorable efficacy/safety profile for 
voclosporin has been demonstrated in the prevention of renal transplant rejection and in Phase 
2 studies in LN. 
As evaluated in nonclinical and clinical studies (healthy volunteers, moderate to severe 
psoriasis, renal transplantation, and uveitis) voclosporin is well tolerated and exhibits adverse 
events (AEs) that are typical of other CNIs yet seen to a lesser extent than those seen 
historically with other CNIs. 
The aim of the current study is to investigate whether voclosporin is able to reduce disease 
activity over a treatment period of 24 weeks. Subjects with histologic evidence of primary 
FSGS with proteinuria will be eligible to enter the study. Efficacy will be assessed by the 
ability of voclosporin to reduce the level of proteinuria (as measured by UPCR) while 
demonstrating an acceptable safety profile. The primary endpoint of this study will be complete 
or partial remission of proteinuria at 24 weeks. 
2.1 
Dose Rationale 
This Phase 2 study is designed to initially evaluate the treatment benefit of voclosporin 23.7 
mg BID in the first Cohort of 10 subjects. The selection of this voclosporin dose for the first 
Cohort (see Section 7, Study Treatments) was based on the previous experience with this drug 
in the Phase 2 LN study (AURA-LV). In AURA-LV, subjects were administered voclosporin 
23.7 mg BID, voclosporin 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). At Week 48, complete remission rates in both the low-dose 
(49.4%) and high-dose (39.8%) voclosporin groups demonstrated statistically significant 
superiority compared to the placebo (23.9%) group, (p<0.001, p=0.026, respectively). There 
was no increase in efficacy with the higher dose and no significant differences between the 
two voclosporin groups in achievement of renal response.  
This study is also designed to evaluate a further dose level of voclosporin, this dose may be 
higher or lower than the initial 23.7 mg BID dosing. When the first 6 subjects in Cohort 1 have 
completed 12 weeks of treatment with voclosporin, the top line efficacy and safety data will 
be analyzed to determine the dose level for Cohort 2. The maximum dose possible for Cohort 
2 will be 39.5 mg (5 capsules) BID. 
To minimize safety concerns, a cautious dose-escalation design starting with a minimal dose 
of one capsule (7.9 mg) per day will be employed for all subjects (see Section 7.1.2, Dosing 
Guidelines).  
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The protocol contains provisions for management of dose (including rules for stopping 
treatment with study mediation) based on safety concerns in particular, BP and renal function. 
The safety data from the use of voclosporin in LN demonstrates that these risks are dose-related, 
reversible, and can be managed by dose reduction and temporary interruption.   
Furthermore, voclosporin will be administered as fixed doses 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, plaque psoriasis, and LN) demonstrated that weight 
did not have a significant effect on the PK of voclosporin [9].  
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3. STUDY OBJECTIVES 
3.1 
Primary Objective 
• To assess the efficacy of voclosporin in achieving complete or partial remission of 
proteinuria after 24 weeks of therapy in subjects with FSGS. 
3.2 
Secondary Objective 
• To assess the safety and tolerability of voclosporin over 24 weeks in subjects with FSGS. 
3.3 
Endpoints 
All primary and secondary endpoints will be assessed overall and for each individual cohort. 
3.3.1 Primary Endpoint 
Proportion of subjects with remission of proteinuria at Week 24 based on the following 
parameters: 
• Complete remission: UPCR of <0.3 mg/mg 
OR 
• Partial remission: UPCR ≥0.3 mg/mg and <3.0 mg/mg with >50% reduction in UPCR 
from baseline 
3.3.2 Secondary Endpoints 
• Proportion of subjects with complete remission or partial remission of proteinuria at Weeks 
8 and 12 
• Proportion of subjects with complete remission of proteinuria at Weeks 8, 12, and 24 
• Proportion of subjects with UPCR <0.5 mg/mg at Weeks 8, 12, and 24 
• Proportion of subjects with partial remission of proteinuria at Weeks 8, 12, and 24 
• Time to first occurrence of complete or partial remission of proteinuria 
• Time to first occurrence of complete remission of proteinuria 
• Time to first occurrence of partial remission of proteinuria 
• Time to first occurrence of 50% reduction in UPCR from baseline 
• Duration of UPCR <0.3 mg/mg 
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• Change from baseline in UPCR at each time point 
• Proportion of subjects with a confirmed >30% decrease from baseline in eGFR (utilizing 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) at each time 
point  
• Proportion of subjects with a confirmed >30% increase in eGFR from the final visit 
(Week 24 or last on-treatment visit, for subjects who discontinue prematurely) to the 
second Safety Follow-up visit (Visit 10) 
• Change in UPCR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10) 
• Change in eGFR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10)  
• Change from baseline in serum creatinine, serum albumin, and eGFR at each time point 
• Quality of life (QoL) assessments 
− 
Mean change in Patient Reported Outcome Measurement Information System 
(PROMIS) measures at Week 24 
− 
Change from baseline in Kidney Disease Quality of Life-Short Form (KDQOL-SFTM) 
score at Week 24 
• Safety and tolerability over 24 weeks 
• Renal biopsy: descriptive analyses of changes in histopathology will be evaluated in post-
treatment (24 weeks) renal biopsies in a subset of patients 
• Change from baseline to Week 4 and 24 in the following biomarkers:  
− 
Urine nephrin 
− 
Urine synaptopodin 
− 
Serum TGF-β 
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4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 2, open-label, multicenter, prospective, 24-week, exploratory cohort study to 
assess the efficacy and safety of two dose levels of voclosporin in achieving complete or partial 
remission of proteinuria in subjects with biopsy-confirmed primary FSGS. Subjects who have 
provided a signed and dated informed consent will be screened into the study. Subjects will be 
assigned a unique subject number which will be used to identify them throughout the study. 
The duration of the screening period will be approximately 4 weeks to 10 weeks (allowing for 
visit windows (14±3 days) for each stability assessment) to ensure that subjects meet eligibility 
criteria, including renal disease stability assessments. If a subject has not had a renal biopsy 
within the 6-month (prior to screening) required timeframe for study eligibility, one may be 
performed to assess eligibility into the study, provided the subject has given consent and 
provided the results can be obtained and reviewed before baseline; biopsy results over 6 
months prior to screening may be permitted following review with the Medical Monitor. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be eligible 
to receive treatment with voclosporin. The first 10 subjects will be enrolled into Cohort 1, at a 
starting dose of 7.9 mg BID for Week 1, 15.8 mg BID for Week 2, and a target dose of 23.7 
mg BID for Weeks 3 to 24. The first dose of study treatment should occur in the morning on 
Day 2, the day after dispensing. Subjects will be contacted by telephone at the end of Week 1 
and Week 2 to be reminded to increase their dose as per Section 7.1.2.1, Voclosporin Study 
Treatment. 
Evaluable safety and tolerability from the first six subjects from Cohort 1 are required in order 
to determine the dose level for Cohort 2. The dose selected may be higher or lower than 23.7 
mg BID.The maximum dose possible for Cohort 2 will be 39.5 mg (5 capsules) BID. Dosing 
in this group will follow the same cautious approach as Cohort 1, with at a starting dose of 7.9 
mg BID for Week 1, 15.8 mg BID for Week 2, 23.7 mg BID for Week 3 and a maximum dose 
of 39.5 mg BID for Weeks 4 to 24. 
Doses and dose increments smaller than anticipated or an intermediate dose may be proposed 
for Cohort 2 based on the safety and tolerability results from the Cohort 1.  
All subjects will return for assessment of efficacy and safety at Weeks 2, 4, 8, 12, 18, and 24. 
See Schedule of Events, for detailed information regarding visits.  
All subjects, completed or withdrawn from the study, will complete the End of Treatment/Early 
Termination assessments (Visit 8) at Week 24, or at the time of withdrawal, and should attend 
two Safety Follow-up visits at 1 and 2 weeks after completion of treatment (i.e., at Week 25 
(Visit 9) and Week 26 (Visit 10)) (or 7 and 14 days, respectively, following withdrawal) to 
collect any new AEs and concomitant medications. At the follow-up visit, UPCR and eGFR 
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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 up to 36 weeks. The duration of the screening 
period will be approximately 4 weeks to 10 weeks (allowing for visit windows) and the 
treatment duration is 24 weeks, with further Safety Follow-up visits at 1 and 2 weeks after last 
dose (completion or withdrawal). 
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5. SELECTION, WITHDRAWAL OF SUBJECTS AND PERMANENT 
DISCONTINUATION OF DRUG 
5.1 
Number of Subjects 
It is anticipated that approximately 20 subjects will be recruited 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 years (or legal age of consent if >18 
years) to 75 years of age, inclusive, at the time of consent. 
3. Primary FSGS diagnosed by renal biopsy within 6 months prior to the screening visit. 
Biopsy results over 6 months prior to screening may be permitted following review with 
the Medical Monitor to confirm eligibility (see Appendix 3). 
4. At initial screening assessment and at last qualifying assessment during screening period 
prior to baseline, FSGS subjects must have urine protein creatinine ratio (UPCR) ≥2.0 
mg/mg, serum albumin ≤3.2 g/dL. Subjects can be treatment-naïve or receiving steroid 
treatment (oral or IV) for FSGS. Subjects taking steroids must show signs of improvement 
in proteinuria, defined as at least a 20% improvement in UPCR from initiation of steroids 
to the last stability assessment prior to baseline. Subjects who have discontinued steroid 
treatment due to poor tolerability may be considered for the study.  
5. All subjects should be treated with ACEIs and/or ARBs unless they have documented 
intolerance or contraindication to these medications. Doses of these agents must be stable 
for at least 2 weeks prior to baseline, with BP ≤150/90 mmHg at the baseline visit (Visit 2). 
a) Subjects with nephrotic edema may be treated with diuretics during the screening 
period. Volume status should be optimized based on the clinical judgment of the 
Investigator and the doses of diuretics must be stable in the 2 weeks prior to baseline. 
b) At the discretion of the Investigator, subjects with hyperlipidemia may be treated with 
lipid-lowering agents (e.g., statins) in accordance with standard clinical practice. Doses 
must be stable in the 2 weeks prior to baseline. 
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6. Stable proteinuria, renal function, and BP during the 2 weeks prior to baseline, as assessed 
by the Investigator. Changes in UPCR, eGFR, and/or BP during the screening period may 
be due to treatments administered (e.g., ACEIs and ARBs); and, therefore, may interfere 
with study assessments or outcomes, or may place the subject at increased risk. All subjects 
must be discussed with the medical monitor prior to initiation of study treatment. 
7. Women of childbearing potential must have a negative serum pregnancy test prior to 
dispensing study treatment. 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. Clinical or histologic evidence of secondary FSGS. 
3. Histologic evidence of collapsing variant FSGS. 
4. eGFR as calculated by the CKD-EPI equation of ≤30 mL/minute/1.73 m2 at initial 
screening assessment or ≤45 mL/minute/1.73 m2 at last qualifying assessment during 
screening period prior to baseline. 
5. Currently taking or expected to require any of the prohibited medications listed in the 
protocol (see Section 7.6.1, Prohibited Medications) at screening or during the study. This 
includes prior use of cytotoxic or other immunosuppressant treatment for FSGS. Subjects 
who have discontinued steroid treatment due to lack of response are excluded from the 
study.   
6. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or expected to 
require dialysis during the study period. 
7. A previous renal transplant or planned renal transplant during the study. 
8. Body mass index >40 kg/m2 at last stability assessment. 
9. Family history of nephrotic syndrome. 
10. Any known hypersensitivity or contraindication to cyclosporine, or components of any 
cyclosporine drug product. 
11.  Current or medical history of: 
• Congenital or acquired immunodeficiency. 
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• 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. 
• Current or past 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. 
12. Other clinically significant active medical conditions, such as: 
• Severe cardiovascular disease including congestive heart failure, history of cardiac 
dysrhythmia or congenital long QT syndrome. Subjects with 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 are excluded. 
• Liver dysfunction: aspartate aminotransferase, alanine aminotransferase, or bilirubin ≥2.5 
times the upper limit of normal at last qualifying assessment during screening period prior 
to baseline. 
• Chronic obstructive pulmonary disease or asthma requiring oral steroids. 
• Bone marrow insufficiency: white blood cell count <2,500/mm3, absolute neutrophil count 
<1.3 × 103/μL, and/or thrombocytopenia (platelet count <50,000/mm3) at screening or at 
last qualifying assessment during screening period prior to baseline. 
• Current infection requiring intravenous (IV) antibiotics. 
13. Any overlapping autoimmune condition for which the condition or the treatment of the 
condition may affect the study assessments or outcomes (e.g., any condition for which 
additional immunosuppression, including systemic corticosteroids, and/or cytotoxic 
therapy is indicated). Overlapping conditions for which the condition or treatment is not 
expected to affect assessments or outcomes are not excluded. 
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14. No vaccines using live organisms, virus or bacterial, are allowed during screening and 
while taking the study treatment. 
15. 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. 
16. 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. 
17. Subjects who are pregnant, breast feeding or, if of childbearing potential, not using 
adequate contraceptive precautions. 
18. 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. 
19. Subjects treated in a previous voclosporin clinical study. 
5.4 
Adequate/Effective Contraception 
Women of childbearing potential must have a negative serum pregnancy test during 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, 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, reproductively competent men are required to use condoms during treatment 
and for at least 6 weeks after cessation of study treatment. In addition, female partners of male 
subjects are recommended to use an effective contraception during their partner’s treatment 
and for at least 6 weeks after the last dose of study treatment. Male subjects are to refrain from 
making sperm donations during treatment and for at least 6 weeks after cessation of study 
treatment. 
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.  
Barrier methods (e.g., condoms, diaphragm, or cervical cap/sponge) when used alone are not 
considered highly effective. 
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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 and documented 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 8), if possible. If 
possible, the subject should also be advised to come for the two Safety Follow-up visits (Visit 9 
and Visit 10) at 1 and 2 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 withdrawal as “withdrawal of consent.” Withdrawn subjects 
will not be replaced. 
5.6 
Discontinuation of Study Treatment 
Discontinuation of study treatment does not necessarily constitute withdrawal from the study.   
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.  
If possible, subjects who are permanently discontinued from study treatment before the 
Week 24 visit should undergo all study assessments up to and including the Week 24 (or Early 
Termination Visit – Visit 8) and Safety Follow-up visits where appropriate. All subjects that 
discontinue study treatment should attend at least 2 further assessments after the last dose of 
study drug.  
Guidance on when study treatment must be discontinued is in Section 7.4, Voclosporin Dose 
Modification.  
5.6.1 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 discontinued 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 
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is discontinued 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 
Not applicable. 
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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 
Pharmaceuticals Inc. (Aurinia). 
7.1.1 Voclosporin – 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 Dosing Guidelines 
7.1.2.1 Voclosporin 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. 
The dosing of voclosporin for Cohort 1 will be as follows: 
• Week 1: 1 capsule (7.9 mg) orally (PO), BID 
• Week 2: 2 capsules (15.8 mg) PO, BID 
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• Weeks 3 to 24 – Week 24: 3 capsules (23.7 mg) PO, BID 
Evaluable safety and tolerability data from the first six subjects from Cohort 1 are required in 
order to make the decision to escalate to a higher dose level for Cohort 2. The selected dose 
may be higher or lower than 23.7 mg BID. The maximum dose possible for Cohort 2 will be 
39.5 mg (5 capsules) BID. Should this dose be selected the following dosing regimen will be 
followed: 
• Week 1: 1 capsule (7.9 mg) PO, BID 
• Week 2: 2 capsules (15.8 mg) PO, BID 
• Week 3: 3 capsules (23.7 mg) PO, BID 
• Week 4: 5 capsules (39.5 mg) PO, BID 
All subjects will be contacted by telephone at the end of Week 1 and Week 2 (and Week 3, if 
applicable) to be reminded to increase their dose. 
All unused study treatment (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. 
7.1.2.2 Corticosteroids 
Subjects entering the study with corticosteroids should have their steroid dose gradually 
titrated down until they achieve a daily dose of <10 mg/day prednisone by Week 12. The timing 
of the titration is at the discretion of the investigator, with a reduction of 5 mg/day every 2 
weeks recommended. If clinically indicated, steroid tapering may start during the stability 
assessment period. A dose level may be maintained for up to 4 weeks or increased per 
investigator judgement following discussion with the Medical Monitor. Refer to Appendix 4 
for a conversion table of various formulations of steroids. 
Corticosteroid treatment must be documented in the eCRF and source documentation. 
When clinically indicated, subjects are allowed to be completely titrated off oral 
corticosteroids. 
Corticosteroids should not be re-started in a patient whose dose has been reduced to zero, or 
initiated during the study in treatment-naïve patients, without prior discussion with the Medical 
Monitor. 
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7.2 
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 
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. 
7.3 
Site Supply, Storage, Accountability 
7.3.1 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. 
7.3.2 Storage 
Voclosporin softgel 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. 
7.3.3 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 
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. 
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Each study site will maintain a drug inventory/dispensing record for all drugs dispensed and 
returned. At the end of the study, one 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’s approval of 
the process and forward the certificate of destruction to Aurinia. 
7.4 
Voclosporin Dose Modification 
7.4.1 Discontinuation of Study Therapy Due to Non-response 
During the treatment period, any case where the subject experiencing a worsening of 
proteinuria, or no improvement in proteinuria from baseline, once the highest permitted dose 
of study drug has been achieved, should be discussed with the Medical Monitor. Subjects may 
be allowed to add treatment with corticosteroids (IV or oral) while continuing with study drug, 
or may be discontinued from study treatment and transitioned to standard of care treatment 
7.4.2 Deterioration in Renal Function 
Serum creatinine and eGFR utilizing the CKD-EPI formula, as reported by the central 
laboratory, will be used for the assessment of renal function at every visit including 
unscheduled visits.  
It is recognized that eGFR may be unreliable at higher values (>100 mL/min/1.73 m2). FSGS 
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 [28], with or without kidney 
damage.  
7.4.2.1 Decrease in eGFR >30% and eGFR <90 mL/min/1.73 m2 
During the treatment period, any subject experiencing a >30% decrease in eGFR from baseline 
(baseline eGFR is defined as the last assessment prior to first dose of study treatment) to <90 
mL/min/1.73 m2, will have study treatment interrupted until a repeat test can be performed 
(unscheduled visit to be completed within 48 hours). If the decrease is confirmed at the 
unscheduled visit and not due to potential contributing factors (e.g., high baseline eGFR, the 
addition or modification of non-steroidal anti-inflammatory drugs (NSAIDs), ACEIs, ARBs, 
a concurrent state of dehydration, overdosing with study treatment, renal flare, etc.), the case 
should be discussed with the Medical Monitor, the study treatment should continue to be 
withheld, and eGFR retested within 48 hours. (Note: doses of ACEIs, ARBs, diuretics, and/or 
lipid lowering therapy are to remain stable throughout the study.) 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. 
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7.4.2.2 Decrease in eGFR ≤30% and eGFR <90 mL/min/1.73 m2 
During the treatment period, any subject having a ≤30% reduction in eGFR to 
<90 mL/min/1.73 m2 should have the influence of potential contributing factors (as described 
in Section 7.4.2.1, Decrease in eGFR >30% and eGFR <90 mL/min/1.73 m2) ruled out and 
appropriate corrective action taken. Any subject having a >20 to ≤30% reduction compared to 
baseline in eGFR to <90 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 should 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. 
7.4.2.3 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. 
7.5 
Procedures for Overdose 
Based on clinical experience with voclosporin, 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. 
7.6 
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. 
7.6.1 Prohibited Medications 
The following medications cannot be taking during the study: 
• Cytotoxic or other systemic immunosuppressants  
• Initiation of new treatment or change in dosage of ARBs and/or ACE inhibitors within 
2 weeks prior to baseline  
• Vaccines using live organisms, viral or bacterial 
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• 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 6 contains a summary of additional treatment and food restrictions. 
7.6.2 Allowed Concomitant Medications 
These medications are permitted during the study: 
• Systemic corticosteroids as described in the Inclusion Criteria (see Section 5.2, 
Inclusion Criteria) and following the corticosteroid dosing guidelines (see Section 
7.1.2.2, Corticosteroids) 
• Doses of ACEIs and/or ARBs as described in the Inclusion Criteria (see Section 5.2, 
Inclusion Criteria) 
• Doses of diuretics as described in the Inclusion Criteria (see Section 5.2, Inclusion 
Criteria)  
• Doses of statins as described in the Inclusion Criteria (see Section 5.2, Inclusion 
Criteria) 
• Topical steroids (e.g., nose, scalp, skin, inhaled) 
• Herbal supplements can be used with caution and with approval by the Medical 
Monitor 
Treatments which may be used as medically indicated, according to the judgment of the 
Investigator can be found in Appendix 5. 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 6. 
7.7 
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, the mean 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 
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(hemorrhages, papilledema)), study treatment should be withheld, an unscheduled visit 
arranged within 48 hours for repeat BP assessment, 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 [9]. 
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 (FMV) and from standard 
urinalysis results. If the FMV is for some reason not available at Day 1, Week 12 or Week 24, 
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 1) will 
be drawn in accordance with the Schedule of Events. 
Table 1 
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) 
All  
 
Differential (absolute and %) 
 Bands 
 Basophils 
 Eosinophils 
 Lymphocytes 
 Monocytes 
 Neutrophils 
All 
 
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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 
All  
 
Cholesterol (total, HDL, and LDL) & 
triglycerides 
Creatine kinase 
Day 1 and Week 24 
 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
All 
Glycosylated hemoglobin (HbA1c) 
Day 1 and Week 24 
Lactic dehydrogenase (LDH) 
Magnesium 
All 
Phosphorous, inorganic 
Day 1 and Week 24 
Potassium 
Protein, total 
Sodium 
All 
Urinalysis and urine 
microscopy 
Complete urinalysis (to include urine protein, 
creatinine, blood, urine microscopy).  
All except for stability 
assessment visits during the 
screening period 
FMV urine 
collection 
FMV will be performed to analyze UPCR.  
All 
24-hour urine 
UPCR 
Day 1, Week 12 and Week 24 
Note that 24-hour urine 
collection should be scheduled so 
as not to coincide with the FMV 
sampling due on the day of the 
study visit 
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Test Type 
Test Parameters 
Collection at Visits 
Pregnancy Test 
For females of childbearing potential.  
Serum pregnancy test to be 
evaluated at central laboratory at 
Screening, and Week 24; urine 
pregnancy test will be performed 
locally at all other applicable 
visits. 
Serology 
Cytomegalovirus 
Hepatitis A, B, and C 
Hepatitis B surface antigen (HBsAg) 
Screening (including stability 
assessments) 
 
Special Tests 
Estimated glomerular filtration rate (eGFR) 
All 
Biomarkers 
Urine nephrin 
Urine synaptopodin 
Serum TGF-β 
Day 1, Week 4 and Week 24 
Notes: FMV=first morning void; HDL=High-density lipoprotein; LDL=Low-density lipoprotein; UPCR=urine protein creatinine ratio. 
 
The total amount of blood that will be collected during the study from an individual subject is 
approximately 200 mL over 34 weeks. 
For details on whether laboratory abnormalities should be reported as AEs and on the 
follow-up required in such cases, see Section 10.2.4, 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 FSGS-related manifestations which will 
also be recorded. A complete physical examination will be conducted at the initial screening 
assessment, 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. 
 
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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 heart rate (HR) 
• Body temperature (°C or °F) 
• Weight (kg) 
• Height (cm) 
To avoid variability, the same method of obtaining body temperature should be used 
throughout the study. 
At stability assessments, BP only will be included. 
Height will be recorded at the initial screening assessment only.  
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 mean BP measure is >130/80 mmHg (determined 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 7.7, 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 the initial screening assessment, Day 1, and Week 24. 
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9.1.4.1 Procedures to Manage a Treatment-Emergent Increase in QTcF 
In the event that a subject has a corrected QT interval duration corrected for heart rate using 
method of Fridericia (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, study treatment will be discontinued and 
the subject followed until the QTcF value either returns to baseline 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 QoL Assessments 
Assessments for QoL will be conducted at Day 1, Week 24, Week 25 and Week 26. 
The PROMIS assesses physical function, pain interference, and fatigue. See Appendix 7. 
The KDQOL-SFTM survey is a kidney disease-specific measure of QoL that assesses general 
health, kidney disease and its effects on daily life, and satisfaction with care. See Appendix 8. 
9.1.6 Voclosporin Pharmacokinetic and Biomarker Assessment 
Blood samples for PK assessments will be taken at Week 4 and Week 24. PK samples will be 
drawn prior to study treatment dosing (trough sample), and at 1, 2 and 4 hours post-dose. These 
samples will be analyzed for voclosporin. Should a subject experience a serious adverse event 
(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 treatment, further PK samples are not required. 
Blood and urine samples for biomarker assessments will be taken at Day 1, Week 4 and Week 
24, samples will be collected prior to study treatment dosing.  
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 
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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 and Stability Assessment Procedures 
The duration of the screening period will be approximately 4 weeks to 10 weeks (allowing for 
visit windows) and will consist of an initial screening assessment and 2 to 4 stability 
assessments to ensure that subjects meet eligibility criteria. 
The initial screening assessment will include provision of informed consent; complete physical 
examination; medical history (including FSGS history); vital signs measurements, including 
weight and height; 12-lead ECG; blood and urine sample collection for central laboratory 
assessments, urinalysis, and urine microscopy; FMV urine collection (for determination of 
UPCR); a serum pregnancy test (for women of childbearing potential); and review of prior and 
concomitant medications and entry criteria. Following these assessments and if clinically 
indicated, subjects receiving steroids may start reducing their steroid dose as described in the 
corticosteroid dosing guidelines (see Section 7.1.2.2, Corticosteroids). Any AEs which occur 
after informed consent will be recorded.  
Stability assessments will occur at 14-day intervals (±3 days) with the first assessment 
approximately 2 weeks after the initial screening assessment visit. Stability assessments 1 and 
2 are mandatory; assessments 3 and 4 are optional if additional time is required for the subject’s 
clinical status to stabilize. These stability assessment visits will include BP determination; 
blood sample collection for central laboratory assessments; FMV urine collection (for 
determination of UPCR); a serum pregnancy test (for women of childbearing potential); review 
of any AEs; and review of concomitant medications and entry criteria.  
These renal disease stability assessments will be evaluated to ensure eligibility with respect to 
entry criteria for UPCR and eGFR. 
Note that the laboratory assessments and FMV results of the last stability assessment will be 
used as the qualifying values for eligibility.  
FMV urine samples (for determination of UPCR) will be collected at all visits during the 
screening period and must be returned and the results evaluated prior to Baseline/Day 1. If the 
FMV is for some reason not available at Day 1, Week 12 or Week 24, 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 samples will be drawn according to Table 1. 
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. 
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Women of childbearing potential must have a negative serum pregnancy test result before 
baseline.  
If a subject has not met the requirements in Inclusion Criteria #3 due to not having renal biopsy 
result within the required time frame, a renal biopsy can be performed as per local procedures, 
after signing the study consent, provided the results can be obtained and reviewed prior to 
baseline. 
9.2.2 Treatment Procedures 
Only subjects who meet all of the inclusion and none of the exclusion criteria will be eligible 
for study treatment.  
Study medication will be dispensed per the Schedule of Events, beginning on Day 1. Subjects 
will take their first dose of study medication on Day 2. Women of childbearing potential must 
have a negative serum pregnancy test during Screening and a negative urine pregnancy test 
result on Day 1 prior to dispensing of study treatment.  
Subjects in Cohort 1, will be contacted by telephone at the end of Week 1 as a reminder to 
increase their dose to 2 capsules (15.8 mg) BID for 1 week, starting at Week 2. Subjects will 
be contacted again by telephone at the end of Week 2 as a reminder to increase their dose to 3 
capsules (23.7 mg) BID, starting at Week 3, for the remainder of the treatment period (see 
Section 7.1.2.1, Voclosporin Study Treatment).  
Subjects in Cohort 2, will also be contacted by telephone at the end of each week, as required 
up to the end of Week 3, as a reminder to increase their dose of study medication to the 
maximum dose selected for the second cohort. 
Subjects will complete all assessments per the Schedule of Events at Day 1 and at Weeks 2, 4, 
8, 12 and 18.  
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: 
• PROMIS and KDQOL-SFTM QoL questionnaires will be answered by the subject, as 
first study procedure, at Day 1/Baseline. 
• Abbreviated physical examination at Day 1. 
• Vital signs including weight. 
• Standard 12-lead ECG at Day 1. 
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• Blood and urine sample collection for analysis at central laboratory. 
• FMV urine sample collection. 
• Urine pregnancy testing at Day 1 (before dispensing study treatment)  
• AEs. 
• Concomitant medication. 
• Returned capsule count and drug accountability (except Day 1). 
9.2.3 End of Study (or Early Termination) Procedures 
On completion of treatment at Week 24 or earlier if subject is withdrawn, all assessments for 
Visit 8 (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: 
• PROMIS and KDQOL-SFTM QoL  
• Abbreviated physical examination  
• Vital signs including weight 
• Standard 12-lead ECG 
• Blood and urine sample collection for analysis at central laboratory 
• FMV urine sample collection 
• Serum pregnancy testing 
• Pharmacokinetic and biomarker sampling 
• AEs 
• Concomitant medication 
• Returned capsule count and drug accountability 
• Repeat renal biopsy may be performed on a subset of patients 
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• Confirmation of completion/discontinuation 
9.2.4 Follow-up Procedures 
All subjects who complete the study or withdraw before Week 24 will be followed up at 1 
week (±3 days) and 2 weeks (±3 days) after their last study treatment dose to collect any new 
AEs and concomitant medications. These 2 visits (Visit 9 and Visit 10) will be conducted as 
in-clinic visits. 
Assessments for the follow-up visit are as follows: 
• PROMIS and KDQOL-SFTM QoL 
• Vital signs including weight 
• Blood and urine sample collection for analysis at central laboratory  
• FMV urine sample collection 
• Concomitant medication 
• AEs 
• Confirmation of completed follow-up visit 
9.2.5 Unscheduled Visit 
Unscheduled visits may be performed during the course of the study for safety reasons. . Only 
the data relevant to the purpose of the visit will be collected in the source documents and eCRF. 
Additionally, unscheduled visits will be registered in the electronic data capture (EDC) system.  
An unscheduled visit is requested in the following cases: 
• After dose reduction at any time during the study (unscheduled visit within 2 weeks)  
• QTcF value exceeding 500 msec, or an increase >60 msec from baseline, where the 
ECG will be repeated (confirmed) at an unscheduled visit within 24 hours  
• Decrease in eGFR >30% compared to baseline (unscheduled visit within 48 hours), or 
a decrease in eGFR >20-30% compared to baseline (unscheduled visit within 
approximately 2 weeks) 
• Symptomatic hypertension: Systolic BP is ≥165 mmHg or diastolic BP is ≥105 mmHg 
with symptoms of hypertension, see Section 7.7, Increased Blood Pressure 
(unscheduled visit within 48 hours)  
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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 
one 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 
events will also usually be considered serious.    
Hospitalizations that have been scheduled prior to the subject signing the informed consent 
form (ICF), although not recorded as SAEs, must be documented in the subject’s source 
documents. A renal biopsy performed as part of the study to verify eligibility will not be 
considered an SAE. Any complication experienced during a renal 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 ability to function. 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. 
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 
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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 treatment 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 treatment 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. 
10.2.4 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. 
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If the Investigator considers such an AE as serious it must be reported as an SAE. 
10.2.5 Abuse, Misuse, Overdose and Medication Error 
All AEs of special interest such as study drug 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 observed from time of signing of the ICF will be recorded in the subject's source 
documentation. This applies to all AEs regardless of presumed relationship to the study drug. 
For screen failure subjects, any AEs and SAEs occurring during the screening period (after 
informed consent) will be recorded in the subject’s source documentation only and will not be 
collected on the eCRF. Adverse events leading to discontinuation of study drug must be 
collected. 
If any AE is reported, the date of onset, relationship to study treatment, relationship to disease 
under study, 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 one 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 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. Note that for screen 
failure subjects, any AEs and SAEs occurring during the screening period will be recorded in 
the subject’s source documentation only. For enrolled subjects (i.e., those who successfully 
complete screening), the AE reporting period ends at the second Safety Follow-up visit 
(Visit 10). 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. 
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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 
For screen failure subjects, any SAEs occurring during the screening period (after informed 
consent) will be recorded in the subject’s source documentation only and will not be collected 
on the eCRF. 
For enrolled subjects (i.e., those who successfully complete screening), 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 drug or 
relationship to disease under study. For enrolled subjects, all SAEs will be recorded in the AE 
section of the subject’s eCRF and source documentation. 
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: 
 
If notification is made via email or fax, site staff must enter the SAE information into the 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, whichever is 
longer. No formal study visit is required but Investigators must report any SAEs that occur 
during this 30-day period using the SAE reporting form provided; these will be entered into 
the safety database only. 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 or relationship to disease 
under study, 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. 
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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 9) 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 drug-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 Institutional Review Board (IRB)/Ethics Committee 
(EC)/Independent Ethics Committee (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. 
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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.  
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 
Not applicable. 
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12. DATA AND SAFETY MONITORING BOARD PROCEDURES 
Not applicable. 
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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 approximately 20 subjects, 10 subjects in each of 2 cohorts.  
As this is an exploratory study, sample size calculations are not required. Descriptive statistics 
will be used and the results will only be hypothesis-generating. 
13.3 Populations 
13.3.1 Intent-to-Treat Set 
The intent-to-treat (ITT) set will consist of all enrolled subjects (non-screening failures) and 
will be used for all efficacy analyses. 
13.3.2 Safety Set 
The safety set will consist of all subjects who have taken at least 1 dose of study treatment.  
13.3.3 Per-protocol Set 
The per-protocol set (PPS) will consist of all subjects eligible from the ITT set who do not 
have any major protocol violations. Major protocol violations will be defined in the SAP. 
13.4 Datasets 
Assessments taken at each visit will be analyzed using 2 different datasets. The first will be 
the observed cases dataset whereby all values collected will contribute to the dataset. A second 
dataset will be used for summaries and analyses incorporating data carried forward from a 
subject’s last known value. This dataset will be referred to as the last observation carried 
forward dataset and as such, all subjects with any post-baseline efficacy assessment will 
contribute to the Week 24 analyses. 
13.5 Background and Demographic Characteristics 
Demographic and clinical disease characteristics will be summarized.  
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13.6 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, SD, median, minimum, 
and maximum) and frequency tables.  
13.7 Concomitant Therapy 
All concomitant medications will be coded by the World Health Organization Anatomical 
Therapeutic Chemical (ATC) Drug Reference List classification. The version used will be 
provided in the clinical study report. 
13.8 Efficacy Evaluations 
Primary and secondary endpoints will be assessed overall and for each individual cohort. 
13.8.1 Primary Endpoint 
The primary endpoint is the proportion of subjects with remission of proteinuria at Week 24 
based on the following parameters: 
• Complete remission: UPCR of <0.3 mg/mg 
OR 
• Partial remission: UPCR ≥0.3 mg/mg and <3.0 mg/mg with >50% reduction in UPCR 
from baseline 
13.8.2 Secondary Endpoints 
The following are defined as secondary endpoints: 
• Proportion of subjects with complete remission or partial remission of proteinuria at Weeks 
8 and 12 
• Proportion of subjects with complete remission of proteinuria at Weeks 8, 12, and 24 
• Proportion of subjects with UPCR <0.5 mg/mg at Weeks 8, 12, and 24 
• Proportion of subjects with partial remission of proteinuria at Weeks 8, 12, and 24 
• Time to first occurrence of complete or partial remission of proteinuria 
• Time to first occurrence of complete remission of proteinuria 
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• Time to first occurrence of partial remission of proteinuria 
• Time to first occurrence of 50% reduction in UPCR from baseline 
• Duration of UPCR <0.3 mg/mg 
• Change from baseline in UPCR at each time point 
• Proportion of subjects with a confirmed >30% decrease from baseline in eGFR (utilizing 
the CKD-EPI formula) at each time point (Baseline eGFR is defined as the last assessment 
prior to first dose of study treatment)  
• Proportion of subjects with a confirmed >30% increase in eGFR from the final visit (Week 
24 or last on-treatment visit, for subjects who discontinue prematurely) to the second Safety 
Follow-up visit (Visit 10) 
• Change in UPCR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10)  
• Change in eGFR from the final visit (Week 24 or last on-treatment visit, for subjects who 
discontinue prematurely) to the second Safety Follow-up visit (Visit 10) 
• Change from baseline in serum creatinine, serum albumin, and eGFR at each time point 
• QoL assessments 
− 
Mean change in PROMIS measures at Week 24 
− 
Change from baseline in KDQOL-SFTM score at Week 24 
• Safety and tolerability over 24 weeks 
• Renal biopsy: descriptive analyses of changes in histopathology will be evaluated in post-
treatment (24 weeks) renal biopsies in a subset of patients 
• Change from baseline to Week 4 and 24 in the following biomarkers:  
− 
Urine nephrin 
− 
Urine synaptopodin 
− 
Serum TGF-β 
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13.9 Statistical and Analytical Methods 
All statistical analyses relating to the primary and secondary objectives will be undertaken at 
study closure and will incorporate all available data. 
In order to aid dose decisions for cohort 2, an analysis of the first 6 subjects in cohort 1 will be 
undertaken once the 6th subject reaches week 12. 
Given the small sample size, all analyses will be descriptive in nature.  
Binary remission endpoints will be summarized using counts and proportions while continuous 
data will be summarized using means, SDs, medians, minimums and maximums. Kaplan-
Meier methodology will be used for the analysis of time-to endpoints. Confidence intervals for 
proportions may be calculated but it is recognized that such intervals, being based on 20 
patients, will be very wide. As an example, the 95% Clopper-Pearson CI for a proportion of 
30% based on 20 patients is (11.9%, 54.3%). 
The analysis of the primary endpoint, complete or partial remission of proteinuria at Week 24, 
will be conducted on the ITT set and confirmed with the PPS (if applicable). Remission of 
proteinuria will be summarized and an exact 2-sided 95% CI for the remission rate will be 
calculated. 
The analyses of the secondary endpoints will incorporate the use of 2-sided 95% CIs and are 
described below:  
• Binary endpoints will be summarized using counts and proportions along with exact 
2-sided 95% CIs.  
• Endpoints measured as a time-to-event will be displayed using Kaplan-Meier methodology. 
Median time-to-event along with 2-sided 95% CIs will be displayed.  
• Other endpoints will be summarized by visit. Absolute values and differences between 
baseline and each time point up to and including Week 24 will be summarized using means 
and 2-sided 95% CIs. Changes between last on treatment value and post treatment follow-
up will also be summarized.   
Given the nature of the study, additional exploratory analysis will be undertaken as appropriate. 
This may include the reporting of individual case studies. 
13.10 Safety Evaluations 
Specific safety endpoints are as follows: 
• Biochemical (including liver function tests) and hematological laboratory tests 
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• 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 visit, and as change from baseline. 
Adverse events and diseases 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 and up until 14 
days after last dose will be considered TEAEs, though all AEs after informed consent will be 
recorded. SAEs occurring at any time after informed consent and prior to first study medication 
will be listed.  
All prior and concomitant medications will be summarized using preferred terms and ATC 
Level 2. 
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. 
13.11 Interim Analyses 
There will be no full interim analysis. 
13.12 Other Evaluations 
13.12.1 Pharmacokinetics 
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. 
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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 [28] and the ICH guidelines for GCP [29]. 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 IRB/EC/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. These 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 
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 
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verify the entries on the eCRF. The Investigator (or his/her deputy) must agree 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 termination 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. 
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 [31]. 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 [32] 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 
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Duncan N, Dhaygude A, Owen J, Cairns TD, Griffith M, McLean AG, et al. Treatment 
of focal and segmental glomerulosclerosis in adults with tacrolimus monotherapy. 
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26. 
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29. 
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research involving human subjects. 2013 Oct. 
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ICH Harmonised Tripartite Guideline.: Guideline for good clinical practice. E6 (R1) 
1996 Jun 10. 
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Pharmaceutical Research and Manufacturers of America [Internet]. PhRMA principles 
and guidelines: public disclosure of clinical trial results. 2009. Available from: 
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conduct-of-clinical-trials. 
32. 
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. 
33. 
Reiser J, Fervenza FC, Sethi S. Epidemiology, classification, and pathogenesis of focal 
segmental glomeruloschlerosis. UpToDate.com [Internet]. 2017 Jul 6 [cited 2018 Feb 
12]. Available from: https://www.uptodate.com. 
 
 
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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 
after the screening period (including stabilization visits) in this trial (see Section 7.6.1, 
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 
Classification of FSGS 
The epidemiology, classification and pathogenesis of FSGS has been reviewed by Reiser et al, 
2017 [33]. 
According to this review, FSGS “is a histologic lesion, rather than a specific disease entity, 
that is commonly found to underlie the nephrotic syndrome in adults and children, particularly 
in the United States, Brazil, and many other countries. FSGS is characterized by the presence 
of sclerosis in parts (segmental) of some (focal) glomeruli on light microscopic examination 
of a kidney biopsy specimen.”  
According to this review, FSGS can be classified into the following etiologies, based upon the 
known and/or postulated causes of this histologic pattern: 
• “Primary or idiopathic FSGS, which most often presents with the nephrotic syndrome.”  
• “Secondary FSGS, which most often presents with non-nephrotic proteinuria and, 
commonly, some degree of renal insufficiency. This category most commonly refers to 
FSGS that develops as an adaptive response to glomerular hypertrophy or hyperfiltration. 
This includes disorders associated with a reduced renal mass and/or renal vasodilation, 
such as unilateral renal agenesis. In addition, a nonspecific pattern of secondary FSGS can 
result from scarring produced by a previous injury (due to a variety of conditions, including 
active IgA nephropathy, vasculitis, and LN). Other secondary causes of FSGS include 
drugs and toxins (including heroin, interferon, and pamidronate) and viral infections 
(particularly HIV).” 
• “Genetic causes of FSGS, which may present early in childhood with massive proteinuria 
and nephrotic syndrome or in adolescence or adulthood with less massive proteinuria.”  
Biopsy and diagnosis: According to Reiser et al, “precise quantification of sclerotic glomeruli 
requires three-dimensional morphometric analysis of entire glomeruli and the examination of 
sufficient glomeruli to ensure that the biopsy specimen is representative of glomeruli in the 
whole kidney. Kidney biopsies with few glomeruli (i.e., fewer than 15) cannot confidently 
exclude the diagnosis of FSGS, and, due to sampling error, some cases will be misclassified 
as minimal change disease.” 
“In patients who are found to have a FSGS lesion by light microscopy, the following approach 
can be used to distinguish between those with primary and secondary FSGS: 
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• Patients who present with nephrotic syndrome (ie, urine protein excretion >3.5 g/day and 
hypoalbuminemia), who exhibit extensive foot process effacement (≥80 percent) on EM 
[electron microscopic] examination, and who have no identifiable risk factors associated 
with secondary FSGS (eg, viral infection, drugs) most likely have primary FSGS, although 
genetic forms of FSGS lesions cannot always be excluded with confidence. Thus, primary 
FSGS is always a diagnosis of exclusion. 
• Patients who present with subnephrotic (ie, <3.5 g/day in an adult) or nephrotic-range 
proteinuria and a normal serum albumin concentration (ie, without nephrotic syndrome) 
and segmental foot process effacement (<80 percent) on EM [electron microscopic] 
examination most likely have secondary FSGS.” 
 
 
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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 
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. 
• At the discretion of the Investigator, subjects with hyperlipidemia may be treated with 
lipid lowering agents (e.g., statins) in accordance with standard clinical practice. Doses 
must be stable in the 2 weeks prior to baseline. 
• Subjects with nephrotic edema may be treated with diuretics during the screening 
period. Volume status should be optimized based on the clinical judgment of the 
Investigator and the doses of diuretics must be stable in the 2 weeks prior to baseline. 
• ACEIs, ARBs, and aliskerin and other therapies are recommended, as per standard 
guidelines, but if used their dose must be stable throughout the study. Subjects 
receiving ACEIs or ARBs must be on a stable dose for at least 2 weeks prior to baseline.  
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• In the case of uncontrolled hypertension (systolic BP >165 mmHg or 
diastolic >105 mmHg on two successive measurements), the addition of a diuretic or 
calcium channel blocker only are permitted, together with dose decreases or 
interruption of study treatment per the instructions in Section 7.7, Increased Blood 
Pressure.  
 
 
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Appendix 6 
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 voclosporin 
metabolism 
ACEIs and ARBs 
Stable dose for at least 2 
weeks prior to baseline 
Change or 
commencement 
prohibited 
Interfere with 
primary endpoint 
assessment 
Foods 
Grapefruit and grapefruit 
juice 
 
24 hours 
 
Prohibited 
 
May affect the 
metabolism of 
voclosporin 
Notes:  ACEI=Angiotensin converting enzyme inhibitor; ARB=Angiotensin receptor blocker; NSAID=Non-steroidal anti-inflammatory 
drug; P-gp=P-glycoprotein. 
 
 
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Appendix 7 
PROMIS QoL Assessment 
The PROMIS QoL assessment includes three questionnaires: 
• Physical Function – Short Form 10a (PROMIS® Item Bank v2.0) 
• Fatigue – Short Form 8a (PROMIS® Item Bank v1.0) 
• Pain Interference – Short Form 8a (PROMIS® Item Bank v1.0)  
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Appendix 8 
KDQOL-SFTM QoL Assessment Version 1.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Kidney Disease and Quality of Life™ Short Form  (KDQOL-SF™)
English Version 1.3
Copyright © 1993, 1994, 1995 by RAND and the University of Arizona
Your Health
– and –
Well-Being
Kidney Disease and Quality of Life (KDQOL-SF™ 1.3)
This survey asks for your views about your health. This information
will help keep track of how you feel and how well you are able to do
your usual activities.
Thank you for completing these questions!
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Study of Quality of Life
For Patients on Dialysis
What is the purpose of the study?
This study is being carried out in cooperation with physicians and their patients.  The
purpose is to assess the quality of life of patients with kidney disease.
What will I be asked to do?
For this study, we want you to complete a survey today about your health, how you
feel and your background.
Confidentiality of information?
We do not ask for your name.  Your answers will be combined with those of other
participants in reporting the findings of the study.  Any information that would permit
identification of you will be regarded as strictly confidential.  In addition, all
information collected will be used only for purposes of the study, and will not be
disclosed or released for any other purpose without your prior consent.
How will participation benefit me?
The information you provide will tell us how you feel about your care and further
understanding about the effects of medical care on the health of patients.  This
information will help to evaluate the care delivered.
Do I have to take part?
You do not have to fill out the survey and you can refuse to answer any question.
Your decision to participate will not affect your opportunity to receive care.
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Page 1
Your Health
This survey includes a wide variety of questions about your health and
your life.  We are interested in how you feel about each of these issues.
1. In general, would you say your health is:  [Mark an 
 in the one box
that best describes your answer.]
Excellent
Very good
Good
Fair
Poor
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
2. Compared to one year ago, how would you rate your health in
general now?
Much better
now than
one year
ago
Somewhat
better now
than one
year ago
About the
same as
one year
ago
Somewhat
worse now
than one
year ago
Much
worse now
than one
year ago
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
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Page 2
3. The following items are about activities you might do during a
typical day.  Does your health now limit you in these activities?  If so,
how much?  [Mark an 
 in a box on each line.]
Yes,
limited a
lot
Yes,
limited a
little
No, not
limited
at all
a
Vigorous activities, such as running, lifting
heavy objects, participating in strenuous
sports ............................................................
M
M
M
 1.........
 2 ........
 3
b
Moderate activities, such as moving a table,
pushing a vacuum cleaner, bowling, or
playing golf ....................................................
 1.........
 2 ........
 3
c
Lifting or carrying groceries ............................
 1.........
 2 ........
 3
d
Climbing several flights of stairs ......................
 1.........
 2 ........
 3
e
Climbing one flight of stairs.............................
 1.........
 2 ........
 3
f
Bending, kneeling, or stooping ........................
 1.........
 2 ........
 3
g
Walking more than a mile
 1.........
 2 ........
 3
h
Walking several blocks ...................................
 1.........
 2 ........
 3
i
Walking one block..........................................
 1.........
 2 ........
 3
j
Bathing or dressing yourself............................
 1.........
 2 ........
 3
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Page 3
4. During the past 4 weeks, have you had any of the following problems
with your work or other regular daily activities as a result of your
physical health?
Yes
No
M
M
a
Cut down the amount of time you spent on work
or other activities ................................................
 1.........
 2
b
Accomplished less than you would like................
 1.........
 2
c
Were limited in the kind of work or other
activities.............................................................
 1.........
 2
d
Had difficulty performing the work or other
activities (for example, it took extra effort)...........
 1.........
 2
5. During the past 4 weeks, have you had any of the following problems
with your work or other regular daily activities as a result of any
emotional problems (such as feeling depressed or anxious)?
Yes
No
M
M
a
Cut down the amount of time you spent on work
or other activities ................................................
 1.........
 2
b
Accomplished less than you would like................
 1.........
 2
c
Didn’t do work or other activities as carefully as
usual..................................................................
 1.........
 2
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Page 4
6. During the past 4 weeks, to what extent has your physical health or
emotional problems interfered with your normal social activities with
family, friends, neighbors, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
7. How much bodily pain have you had during the past 4 weeks?
None
Very
mild
Mild
Moderate
Severe
Very
severe
M
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
  
 6
8. During the past 4 weeks, how much did pain interfere with your
normal work (including both work outside the home and
housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
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Page 5
9.
These questions are about how you feel and how things have been
with you during the past 4 weeks.  For each question, please give
the one answer that comes closest to the way you have been feeling.
How much of the time during the past 4 weeks…
All
 of the
time
Most
of the
time
A good
bit
 of the
time
Some
of the
time
A little
of the
time
None
of the
time
M
M
M
M
M
M
a
Did you feel full of
pep?.............................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
b
Have you been a very
nervous person? ...........
 1........
 2 .......
 3........
 4 .......
 5.......
 6
c
Have you felt so down
in the dumps that
nothing could cheer
you up?........................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
d
Have you felt calm and
peaceful?......................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
e
Did you have a lot of
energy? ........................
 1........
 2 .......
 3........
 4 .......
 5.......
 6
f
Have you felt
downhearted and blue? .
 1........
 2 .......
 3........
 4 .......
 5.......
 6
g
Did you feel worn out?..
 1........
 2 .......
 3........
 4 .......
 5.......
 6
h
Have you been a
happy person?..............
 1........
 2 .......
 3........
 4 .......
 5.......
 6
i
Did you feel tired?........
 1........
 2 .......
 3........
 4 .......
 5.......
 6
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Page 6
10. During the past 4 weeks, how much of the time has your physical
health or emotional problems interfered with your social activities
(like visiting with friends, relatives, etc.)?
All
of the time
Most
of the time
Some
of the time
A little
of the time
None
of the time
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
11. Please choose the answer that best describes how true or false each
of the following statements is for you.
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false
a 
I seem to get sick
a little easier than
other people ..........
M
M
M
M
M
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
b
I am as healthy as
anybody I know ....
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
c
I expect my health
to get worse ..........
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
d
My health is
excellent................
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
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Page 7
Your Kidney Disease
12. How true or false is each of the following statements for you?
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false
a 
My kidney
disease interferes
too much with my
life ........................
M
M
M
M
M
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
b
Too much of my
time is spent
dealing with my
kidney disease.......
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
c
I feel frustrated
dealing with my
kidney disease.......
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
d
I feel like a burden
on my family .........
 1 ...........
 2 ...........
 3 ...........
 4 ...........
 5
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Page 8
13. These questions are about how you feel and how things have been
going during the past 4 weeks.  For each question, please give the
one answer that comes closest to the way you have been feeling.
How much of the time during the past 4 weeks…
None
of the
time
A little
of the
time
Some
of the
time
A good
bit of
the
time
Most
of the
time
All of
the
time
a
Did you isolate your-
self from people
around you?.................
M
M
M
M
M
M
 1 .......
 2.......
 3........
 4 .......
 5........
 6
b
Did you react slowly
to things that were said
or done?.......................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
c
Did you act irritable
toward those around
you?.............................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
d
Did you have difficulty
concentrating or
thinking?.......................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
e
Did you get along well
with other people? ........
 1 .......
 2.......
 3........
 4 .......
 5........
 6
f
Did you become
confused? ....................
 1 .......
 2.......
 3........
 4 .......
 5........
 6
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Page 9
14. During the past 4 weeks, to what extent were you bothered by each
of the following?
Not at all
bothered
Somewhat
bothered
Moderately
bothered
Very much
bothered
Extremely
bothered
M
M
M
M
M
a
Soreness in your
muscles?...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
b
Chest pain? ...........
 1 ............
 2 ...........
 3 ............
 4...........
 5
c
Cramps? ...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
d
Itchy skin?.............
 1 ............
 2 ...........
 3 ............
 4...........
 5
e
Dry skin?...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
f
Shortness of
breath?..................
 1 ............
 2 ...........
 3 ............
 4...........
 5
g
Faintness or
dizziness?..............
 1 ............
 2 ...........
 3 ............
 4...........
 5
h
Lack of appetite?...
 1 ............
 2 ...........
 3 ............
 4...........
 5
i
Washed out or
drained?................
 1 ............
 2 ...........
 3 ............
 4...........
 5
j
Numbness in
hands or feet?........
 1 ............
 2 ...........
 3 ............
 4...........
 5
k
Nausea or upset
stomach?...............
 1 ............
 2 ...........
 3 ............
 4...........
 5
l
(Hemodialysis patient only)
Problems with
your access site? ...
 1 ............
 2 ...........
 3 ............
 4...........
 5
m
(Peritoneal dialysis patient only)
Problems with
your catheter site?..
 1 ............
 2 ...........
 3 ............
 4...........
 5
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Page 10
Effects of Kidney Disease on Your Daily Life
15. Some people are bothered by the effects of kidney disease on their
daily life, while others are not.  How much does kidney disease
bother you in each of the following areas?
Not at all
bothered
Somewhat
bothered
Moderately
bothered
Very much
bothered
Extremely
bothered
M
M
M
M
M
a
Fluid restriction?....
 1 ............
 2 ...........
 3 ............
 4...........
 5
b
Dietary restriction?.
 1 ............
 2 ...........
 3 ............
 4...........
 5
c
Your ability to
work around the
house? ..................
 1 ............
 2 ...........
 3 ............
 4...........
 5
d
Your ability to
travel? ...................
 1 ............
 2 ...........
 3 ............
 4...........
 5
e
Being dependent
on doctors and
other medical
staff?.....................
 1 ............
 2 ...........
 3 ............
 4...........
 5
f
Stress or worries
caused by kidney
disease? ................
 1 ............
 2 ...........
 3 ............
 4...........
 5
g
Your sex life?........
 1 ............
 2 ...........
 3 ............
 4...........
 5
h
Your personal
appearance? ..........
 1 ............
 2 ...........
 3 ............
 4...........
 5
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


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Page 12
17. For the following question, please rate your sleep using a scale
ranging from 0 representing “very bad” to 10 representing “very
good.”
If you think your sleep is half-way between “very bad” and “very
good,” please mark the box under the number 5.  If you think you
sleep is one level better than 5, mark the box under 6.  If you think
your sleep is one level worse than 5, mark the box under 4 (and so
on).
On a scale from 0 to 10, how would you rate your sleep overall?
[Mark an 
 in one box.]
Very bad
Very good
M
M
0
1
2
3
4
5
6
7
8
9
10
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


Page 13
18. How often during the past 4 weeks did you...
None
of the
time
A little
of the
time
Some
of the
time
A good
bit of
the
time
Most
of the
time
All of
the
time
a
Awaken during the
night and have trouble
falling asleep again?.......
M
M
M
M
M
M
 1 .......
 2.......
 3........
 4 ......
 5.......
 6
b
Get the amount of
sleep you need?............
 1 .......
 2.......
 3........
 4 ......
 5.......
 6
c
Have trouble staying
awake during the day?...
 1 .......
 2.......
 3........
 4 ......
 5.......
 6
19. Concerning your family and friends, how satisfied are you with...
Very
dissatisfied
Somewhat
dissatisfied
Somewhat
satisfied
Very
satisfied
a
The amount of time
you are able to spend
with your family and
friends?........................
M
M
M
M
 1...............
 2 ..............
 3...............
 4
b
The support you
receive from your
family and friends?........
 1...............
 2 ..............
 3...............
 4
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


Page 14
20. During the past 4 weeks, did you work at a paying job?
Yes
No
M
M
  
 1
  
 2
21. Does your health keep you from working at a paying job?
Yes
No
M
M
  
 1
  
 2
22. Overall, how would you rate your health?
Worst possible
(as bad or worse
 than being dead)
Half-way
between worst
and best
Best
possible
M
M
M
0
1
2
3
4
5
6
7
8
9
10
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4


Page 15
Satisfaction With Care
23. Think about the care you receive for kidney dialysis.  In terms of
your satisfaction, how would you rate the friendliness and interest
shown in you as a person?
Very
poor
Poor
Fair
Good
Very
good
Excellent
The Best
M
M
M
M
M
M
M
  
 1
  
 2
  
 3
  
 4
  
 5
  
 6
  
 7
24. How true or false is each of the following statements?
Definitely
true
Mostly
true
Don’t
know
Mostly
false
Definitely
false
a 
Dialysis staff
encourage me to
be as independent
as possible ............
M
M
M
M
M
 1 ...........
 2 ...........
 3 ...........
 4 ............
 5
b
Dialysis staff
support me in
coping with my
kidney disease.......
 1 ...........
 2 ...........
 3 ...........
 4 ............
 5
Thank you for completing these questions!
DocuSign Envelope ID: D58F9680-4921-4EA6-B299-FE545376CCB4