A Phase 2, Double-Blind, Placebo-Controlled Trial of Mycophenolate Mofetil Alone or With Voclosporin for Systemic Lupus: Examining Distinct Immunophenotypes to Validate and Enhance Rational Treatment (DIVERT) (ALE10)
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)



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Confidentiality Statement  
The information contained within this document is not to be disclosed in any way without the prior permission of the Protocol 
Chair, or the Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases of the 
National Institutes of Health. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Synopsis 
Title 
A Phase 2, Double-Blind, Placebo-Controlled Trial of Mycophenolate Mofetil 
alone or with Voclosporin for Systemic Lupus: Examining Distinct 
Immunophenotypes to Validate and Enhance Rational Treatment 
Short Title 
The DIVERT trial 
Clinical Phase 
II 
Number of Sites 
Approximately 15 sites in the United States  
Sponsor/IND Number 
The National Institute of Allergy and Infectious Diseases (NIAID)/IND Exempt 
Study Objectives 
Primary Objective  
Assuming that mycophenolate mofetil (MMF) is an effective treatment in some, 
but not all, systemic lupus erythematosus (SLE) patients, the primary objective 
of this study is to evaluate the potential effectiveness of 24 weeks of MMF within 
previously discovered immunologically defined subsets of SLE patients [1].  
This objective will be most effectively supported within the context of a 
successful demonstration of superiority of MMF over placebo, pooled over all 
clusters. To this end, individuals with lupus who are without organ-threatening 
disease will be randomized to 24 weeks of MMF or placebo. The primary 
objective is to compare the cumulative incidence of treatment failure with 24 
weeks of MMF or placebo by treatment arm. Subsequently, treatment effects 
will be evaluated within the individual immunologically-homogenous subsets 
defined at screening. 
Secondary Objectives 
• 
To describe the effects of long-acting corticosteroid injections, MMF, 
MMF plus voclosporin, and placebo on measures of safety and toxicity. 
• 
To describe the effects of MMF, MMF plus voclosporin, and placebo on 
exploratory clinical response measures and disease flare indices. 
• 
To describe the effects of MMF, MMF plus voclosporin, and placebo on 
patient-reported quality of life indices. 
Mechanistic Objectives 
• 
To explore and compare pre-randomization gene expression patterns 
among responders and non-responders to MMF and MMF plus voclosporin.  

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• 
To use comprehensive immunophenotyping to study the immunologic 
changes that accompany treatment-induced disease improvement to 
better understand key checkpoints in SLE pathophysiology. 
• 
To use comprehensive immunophenotyping to better understand 
immunologic changes associated with the loss of clinical response. 
Study Design 
This will be a multicenter, double blind, placebo-controlled Phase 2 trial of 120 
participants with SLE who will enter with significant symptoms, but no organ-
threatening disease. The study will be conducted in 3 stages.  
Stage 1: Treatment Withdrawal: During Stage 1, which may last up to 4 weeks, 
consenting participants will receive an intramuscular (IM) injection of a long-
acting corticosteroid, which may be repeated if needed to achieve amelioration 
of symptoms. A total of 3 corticosteroid injections may be given during Stage 1 
with the first injection given as early as the Screening Visit after the mechanistic 
blood draw is completed and the last injection given as late as the Stage 2 
Randomization Visit after the mechanistic blood draw is completed. Dose will be 
dependent on the available formulation. 
In addition, participants will withdraw from all other treatments for lupus with 
the following exceptions: (i) as needed (PRN) nonsteroidal anti-inflammatory 
treatments may be started or continued, (ii) PRN topicals may be continued, 
(iii) hydroxychloroquine, chloroquine, or quinacrine may be continued at any 
stable dose, and (iv) prednisone, if ≤ 10 mg/day, may be continued at stable 
doses but not started. Participants may screen if taking up to 20 mg/day 
prednisone (or equivalent) but both the participant and the investigator must 
be willing and able to taper to 10 mg/day (under cover of corticosteroid 
injections) by the Stage 2 Randomization Visit. Withdrawal of background lupus 
medications can start any time after the first corticosteroid injection is given 
but must be completed by the Stage 2 Randomization Visit. 
Stage 2: Randomization: One hundred and twenty qualifying participants who 
withdraw from treatment as described in protocol Section 3.1.1, Stage 1: 
Treatment Withdrawal, and meet improvement criteria for randomization as 
outlined in Section 4.2.2, Inclusion criteria required prior to randomization, will 
be randomized (1:1) to receive up to 48 weeks of either MMF or corresponding 
MMF placebo. For the first 2 weeks, a scheduled “taper-up” of MMF will take 
place. Participants will receive 500mg MMF (or corresponding MMF placebo) 
twice a day (BID) for 7 days, followed by 500mg and 1,000mg MMF (or 
corresponding MMF placebo) in divided doses for 7 days. They will then 
continue at a stable dose of 1,000mg MMF (or corresponding MMF placebo) 
BID. Visits to evaluate adverse events (AE), vital signs, hematology and 
chemistry, study medication compliance, medication use, disease status, 
participant reported outcomes, and to obtain biomarker samples will occur 
every 4 weeks after randomization.  

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Participants will be followed for a maximum of 48 weeks on study-provided 
medication in Stage 2. If a participant experiences an increase in SLE symptoms 
at any scheduled or unscheduled visit at or before the Stage 2 Week 24 visit, 
they will proceed in the study as follows: 
• 
If the participant is deemed a Stage 2 treatment failure as defined in 
protocol Section 3.2, Primary Endpoint, and a corticosteroid injection is 
deemed sufficient for treatment without new or increased lupus 
medication, then a blood sample for mechanistic studies will be drawn, 
the injection will be administered, and the participant will immediately 
proceed to Stage 3: Re-randomization. (See Section 3.1.3, Stage 3 Re-
Randomization). 
• 
If the participant is deemed a Stage 2 treatment failure as defined in 
protocol Section 3.2, Primary Endpoint, and a corticosteroid injection 
is deemed sufficient for treatment without new or increased lupus 
medication, but the participant refuses the corticosteroid injection, 
then a blood sample for mechanistic studies will be drawn, and the 
participant will still immediately proceed to Stage 3: Re-randomization 
without the  corticosteroid injection. (See Section 3.1.3, Stage 3 Re-
Randomization). 
• 
If the participant is deemed a Stage 2 treatment failure as defined in 
protocol Section 3.2, Primary Endpoint, and a corticosteroid injection 
is deemed insufficient and a new or increased lupus medication is 
required, then a blood sample for mechanistic studies will be drawn, 
Stage 2 study-provided medication will be stopped, and the new or 
increased lupus medication will be started outside of the study. The 
participant will not be eligible for Stage 3 but will be followed to Stage 
2 Week 24 or 4 weeks ± 10 days after the last dose of study-provided 
medication, whichever is later, before exiting the study. Participants 
who exit the study at Stage 2 Week 24 should complete all End of 
Study/Safety Follow-Up visit assessments at this time. 
Participants who have not failed Stage 2 on or before the Stage 2 Week 24 visit 
will continue on Stage 2 study-provided medication through Stage 2 Week 48 or 
until treatment failure, whichever occurs first.  
• 
If the participant is deemed a Stage 2 treatment failure after Stage 2 
Week 24, then study-provided medication will be stopped. Prior to 
treatment with a corticosteroid injection or a new or increased lupus 
medication outside of the study, a blood sample for mechanistic studies 
will be drawn. The participant  will return for an End of Study/Safety 
Follow-Up Visit 4 weeks ± 10 days after the final dose of study-provided 
medication. 
• 
Participants who have not failed Stage 2 on or before the Stage 2 Week 
48 visit will return for an End of Study/Safety Follow-Up Visit 4 weeks ± 
10 days after the final dose of study-provided medication. 

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Severe lupus manifestations that are life-threatening or organ-threatening should 
prompt consideration for withdrawal from the study in order to enable maximal 
therapy with corticosteroids and other lupus medications. The ultimate decision on 
withdrawal should be left up to the clinical judgment of the investigator. 
Stage 3: Re-Randomization: Participants moving into Stage 3 will be re-
randomized (1:1) to receive up to 24 weeks of either MMF plus voclosporin (23.7 
mg BID) or MMF plus placebo for voclosporin. Individuals who previously received 
MMF placebo in Stage 2 will receive a 2-week taper-up of MMF (see taper details for 
Stage 2, Section 3.1.2, Stage 2: Randomization). During the first 2 weeks of 
treatment, a single IM injection of a long-acting corticosteroid may be 
administered if needed to achieve amelioration of symptoms without meeting the 
definition of treatment failure in Stage 3 and without a requirement to stop Stage 3 
study-provided medication. This single IM corticosteroid injection within the first 2 
weeks of Stage 3 treatment may be administered regardless of whether or not one 
was given at the time of Stage 2 treatment failure for a total of 2 corticosteroid 
injections (dose will be dependent on the available formulation) with the first 
injection given as early as the visit where participants have a Stage 2 treatment 
failure after the mechanistic blood draw and the second injection given as late as 
the Stage 3 Week 2 Visit. Visits to evaluate AEs, vital signs, hematology and 
chemistry, study medication compliance, medication use, disease status, participant 
reported outcomes, and to obtain biomarker samples will occur every 4 weeks 
after re-randomization.  
In Stage 3, participants will be on treatment for a maximum of 24 weeks or until 
treatment failure, whichever occurs first.  
• 
If the participant is deemed a Stage 3 treatment failure, study-provided 
medication will be stopped. Prior to treatment with a corticosteroid 
injection or a new or increased lupus medication outside of the study, a 
blood sample for mechanistic studies will be drawn. The participant  will 
return for an End of Study/Safety Follow-Up Visit 4 weeks ± 10 days after 
the final dose of study-provided medication. 
• 
Participants who have not failed Stage 3 on or before the Stage 3 Week 24 
visit will return for an End of Study/Safety Follow-Up Visit 4 weeks ± 10 days 
after the final dose of study-provided medication. 
 
As in Stage 2, severe lupus manifestations that are life-threatening or organ-
threatening should prompt consideration for withdrawal from the study in order to 
enable maximal therapy with corticosteroids and other lupus medications. The 
ultimate decision on withdrawal should be left up to the clinical judgment of the 
investigator. 
Primary Endpoint 
The primary endpoint is the cumulative incidence of participants who experience a 
Stage 2 treatment failure at or before the Stage 2 Week 24 visit. The criteria for 
treatment failure are defined in Section 3.5.1, Treatment Failure. 

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Secondary Endpoint(s) 
Efficacy 
• 
Clinical response in Stage 2, defined by the BILAG-based combined Lupus 
Assessment (BICLA) (see Section 3.5.3, BILAG-based Combined Lupus 
Assessment (BICLA)) at Stage 2 Week 24. 
• 
The cumulative incidence of participants who experience a Stage 3 
treatment failure, defined as the occurrence of any criteria in Section 3.5.1, 
Treatment Failure after re-randomization and on or before completing Stage 
3. 
• 
Time to treatment failure in Stage 3, defined as the interval from the day of 
Stage 3 randomization until the day of treatment failure.  
• 
Clinical response in Stage 3, defined by the BICLA (see Section 3.5.3, BILAG-
based Combined Lupus Assessment (BICLA)) at Stage 3 Week 24. 
Safety 
The following specific events will be evaluated separately for each stage of the study: 
• 
The incidence of Grade 3 or higher related AEs. 
• 
The incidence of Grade 3 or higher infections. 
• 
The incidence of renal dysfunction, defined as Grade 3 or higher chronic 
kidney disease with estimated glomerular filtration rate (eGFR) < 30 ml/min 
per 1.73 m2. 
• 
The incidence of Grade 3 or higher hypertension (HTN), defined as a systolic 
blood pressure ≥ 160 mm Hg or a diastolic blood pressure of ≥ 100 mm Hg. 
Exploratory Endpoints 
Clinical Endpoints: 
The following will be evaluated in Stage 2 and Stage 3: 
• 
Proportions of participants in each arm who achieve responder status 
as assessed by Systemic Lupus Erythematosus Responder Index (SRI)-4, 
SRI-6, and SRI-7 (as defined in Section 3.5.2, Systemic Lupus 
Erythematosus Responder Index (SRI)) every 4 weeks through Week 24. 
• 
Incidence rates for Mild/Moderate and Severe flares accumulated 
during the treatment period. Three flare assessments will be evaluated 
independently:  
a. Thanou modified Safety of Estrogen in Lupus: National 
Assessment Systemic Lupus Erythematosus Disease Activity 
Index (SELENA-SLEDAI) Flare Index (See Section 19.3.5, Thanou 
Modified SFI) [2]. 
b. BILAG (British Isles Lupus Assessment Group) flare, defined as 
a new A or 2 new Bs. 
c. 
BILAG flare, defined as any item marked new or worse that 
could support a BILAG A (severe flare) or 2 organs with items 
marked new or worse that could support a BILAG B (moderate 
flare). 
• 
Incidence rates for Mild, Moderate and Severe disease activity. 
Assessments across multiple organs/systems are rated using:  

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a. Lupus Foundation of America Rapid Evaluation of Activity in 
Lupus (LFA-REAL) clinician assessment 
b. LFA-REAL participant assessment 
• 
Longitudinal profiles of the Physical Component Summary, Mental 
Component Summary, and individual domains of the SF-36 patient-
reported outcome that are observed over the treatment period. 
Mechanistic Endpoints: 
The following pharmacodynamic markers will be evaluated in Stage 2 and Stage 3: 
• 
Differential expression, at the module or single gene level, between 
participants within immunologically-homogenous clusters who do and 
do not obtain a clinical response. 
• 
Identification of complex immunophenotypes characterizing clinical 
response or non-response to study treatment. 
• 
Longitudinal profiles of Tumor Necrosis Factor-Like Weak Inducer of 
Apoptosis (TWEAK), CR3, FYN, Interleukin-16 (IL16), Interleukin 17 
Receptor A (IL17RA), and Interleukin-2 receptor Subunit Beta (IL2RB) 
over 24-week treatment periods. 
Accrual Objective 
120 randomized (1:1) to MMF or placebo MMF 
Randomization will be stratified by screening gene expression signature: 
• 
Group 1: high interferon and high inflammation 
• 
Group 2: low inflammation and high B Cells (interferon can be high or 
low) 
• 
Group 3: other profiles not included in groups 1 or 2 
• 
Group 4: gene expression signature results unavailable (e.g. due to 
shipping or laboratory error) 
Study Duration 
Participants will be engaged in the study for a maximum of 56 Weeks. We 
anticipate 2.5 years to achieve the target number of randomizations at Stage 2. 
Overall study duration is expected to be 3.5 years. 
Treatment Description  
Stage 1 (Treatment Withdrawal), up to 4 weeks: 
• 
Long-acting corticosteroid IM injection, may be repeated twice for a 
total of 3 corticosteroid injections prior to Stage 2 randomization. Dose 
will be dependent on the available formulation. 
• 
Lupus medications are withdrawn. 
Stage 2 (Randomization):  
• 
After a 2-week taper-up, 1000 mg MMF BID or corresponding MMF 
placebo BID for up to 48 weeks. 
Stage 3 (Re-Randomization):  
• 
Optional long-acting corticosteroid IM injection, one may also be given 
within the first 2 weeks of Stage 3 regardless of whether or not one was 

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given at the time of Stage 2 treatment failure for a total of 2 
corticosteroid injections. Dose will be dependent on the available 
formulation. 
• 
1000 mg MMF BID plus either voclosporin (23.7 mg) or corresponding 
placebo for voclosporin BID for up to 24 weeks. 
o 
Those on MMF placebo during Stage 2 will taper up to the full 
MMF dose over 2 weeks. 
Inclusion Criteria 
Inclusion Criteria  
Participants must meet all of the following criteria to be eligible for 
randomization as study participants.  
1. Aged ≥ 18 and ≤ 60 years at the time of informed consent. 
2. Meets European League Against Rheumatism/American College of 
Rheumatology (EULAR/ACR) 2019 criteria for SLE [3]. 
3. Moderately severe, active, but non-organ threatening disease. 
Specifically, signs or symptoms meeting criteria for a minimum of:  
a. 1 BILAG A (severe) score in the constitutional, musculoskeletal 
or mucocutaneous system at the time of screening. See 
Section 4.3, Exclusion Criteria number 2 for additional detail. 
b. 2 BILAG B (moderate) activity scores in any organ systems; or 
c. 1 BILAG B (moderate) activity score in any organ systems and 
a SELENA-SLEDAI score of ≥ 6.  
• 
If there is only 1 BILAG B score: 
 
If a musculoskeletal BILAG B is scored due to 
moderate arthritis, where some loss off 
functional range of movements was present 
on several days over the last 4 weeks, there 
must also be a minimum of at least 3 joints 
that are both tender and swollen due to 
lupus disease activity in wrists, MCPs or PIPs 
for the participant to qualify.  
 
If a mucocutaneous BILAG B is scored due to 
acute or subacute cutaneous skin eruption, 
the rash must cover at least 4% of the body 
surface area for the participant to qualify. 
Any active discoid lesion or other form of 
chronic cutaneous lupus would be 
qualifying.  
4. Approval, by an adjudication committee, of a brief entry packet 
describing the type, severity and duration of symptoms meeting the 
minimal criteria for entry. The participant will meet this criterion if the 
committee is confident of all of the following:  

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a. Convincing diagnosis of SLE, 
b. Active disease, due to SLE, warranting the potential of dual 
therapy with potent immune modulators, 
c. 
No medical or other condition to contraindicate participation 
in a placebo-controlled, outpatient study of this design. 
5. Women of childbearing potential must have a negative serum 
pregnancy test at screening.  
6. Able or willing to use reliable methods of contraception, as outlined in 
the Mycophenolate Risk Evaluation and Mitigation Strategy (REMS) 
brochure for health care providers, from 4 weeks prior to first 
randomization to 6 weeks after completion of the study. This criterion 
applies to females of reproductive potential. Mycophenolate REMS 
Program acceptable contraceptive methods are outlined in Appendix 1, 
see Section 19.1. 
Inclusion Criteria Required Prior to Randomization 
Participants who meet the following criterion at the Stage 2 Randomization Visit 
may proceed to randomization in Stage 2: 
7. After completion of corticosteroid injection(s) and prior to 
randomization in Stage 2, the participant and his/her physician must 
agree that disease activity has improved sufficiently from screening 
such that randomization is acceptable.  
a. The physician must score the Clinical Global Impression of 
Change [4] (CGI-C) as “moderately better” or “much better” 
prior to randomization. 
• 
The reference value for the CGI-C should be the 
investigator’s determination of the participant’s 
condition at the Screening Visit. 
b. The participant must agree that his/her symptoms have 
improved (yes/no). 
Exclusion Criteria 
Exclusion Criteria 
Participants who meet any of the following criteria are not eligible for 
randomization as study participants:  
1. Inability or unwillingness of a participant to understand and provide 
written informed consent or comply with the study protocol. 
2. BILAG A (severe) disease in the Cardiorespiratory, Neuropsychiatric, 
Gastrointestinal, Ophthalmic, Renal, or Hematological Systems.  
3. Severe or unstable nephritis defined as any of the following: 
a. History of confirmed Class 3-5 nephritis within the last 2 years, 

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b. History of confirmed Class 3-5 nephritis > 2 years ago in the 
absence of documented treatment including both induction and 
maintenance therapy, 
c. 
Urine protein: creatinine ratio (UPCR) > 1 g/g at screening, 
• 
If UPCR is > 0.5 g/g and ≤ 1 g/g at screening, then a 
second assessment must be completed with at least 1 
week between assessments. If the second 
assessment is > 1 g/g or has increased by ≥ 0.3 g/g, 
then the participant is excluded. 
4. Evidence of chronic kidney disease defined as eGFR < 45 mL/min per 
1.73 m2 at screening, where  
175 x (Creatinine/88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 
if of African descent) [5]. 
5. History of cirrhosis or chronic liver disease unrelated to SLE other than 
fatty liver disease.  
6. History, within 1 year of the Screening Visit, of uncontrolled SLE that 
would have warranted a BILAG A (except mucocutaneous, 
constitutional, musculoskeletal) including, but not limited to, hemolytic 
anemia, neuropsychiatric lupus, or interstitial lung disease. 
7. Uncontrolled HTN at the Screening or Randomization Visits defined as 
blood pressure > 150/100 with or without treatment, not to exceed 3 
complementary antihypertensive treatments.  
8. Any of the following laboratory values during screening: 
a.  Hemoglobin (Hg) < 8.0 g/dL,  
b. White blood cell count (WBC) < 2.0 x 109 cells/L,  
c. 
Absolute neutrophil count (ANC) < 1.0 x 109 cells/L, 
d. Platelets < 60 x 109 cells/L at screening,  
• 
If platelets < 70 x 109 cells/L at screening, platelet 
count should be retested 2 weeks later. If platelets 
are < 60 x 109 cells/L at retest, participant will be 
excluded. 
e. Aspartate Aminotransferase (AST) or Alanine 
Aminotransferase (ALT) > 2.5 times the upper limit of normal 
(ULN), 
f. 
Serum IgG levels < 5 g/L 
9. Use of ≥ 40 mg/day of prednisone within 4 weeks prior to the Screening 
Visit, or use of > 20 mg/day of prednisone at screening. 
10. Unwilling or unable to taper to ≤ 10 mg/day of prednisone or equivalent 
by the day of randomization. 

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11. Use of hydroxychloroquine, chloroquine or quinacrine, if taking, at a 
prescribed dose that has not been stable for at least 2 months prior to 
randomization. 
12. Use of MMF within 1 year of randomization. 
13. Use of calcineurin inhibitors (CNI) within 3 months of randomization. 
Topical formulations applied stably for at least one month are allowed.  
14. Use of rituximab, obinutuzumab, ocrelizumab, or long-acting B cell 
depletion agents within 1 year of randomization.  Use of agents ≥ 6 
months and within 1 year of randomization is permitted if there is 
evidence of B cell reconstitution as defined as CD19+ counts of ≥ 50 
cells/µL.  
15. History of intolerance or allergy to MMF, voclosporin or long-acting 
corticosteroid preparations. 
16. Individuals with a known hypersensitivity to Polysorbate 80 (Tween). 
17. A woman who is pregnant, breastfeeding, or planning pregnancy from 
the time of consent until 6 weeks after completion of the study. 
18. Any participant with plans for major surgery during the time of the trial. 
19. Active infections requiring hospitalization or intravenous antibiotics 
within 1 month prior to the Screening Visit. 
20. Any grade 2 infection or higher from 14 days prior to the Screening 
Visit and through the screening period that has not resolved by 
randomization. 
21. Acute herpes zoster within 4 months of the Screening Visit. 
22. Positive results from a SARS-CoV-2 antigen test administered 2 days 
prior to and on the day of first randomization. 
23. Positive Quantiferon Gold (or equivalent) assay. Indeterminate 
Quantiferon Gold (or equivalent) assays must be repeated (with same 
or other interferon gamma release assay per local policy) and shown to 
be negative. Alternatively, if the Quantiferon Gold (or equivalent) assay 
remains indeterminate, a participant must have a negative purified 
protein derivative (PPD). Finally, if the participant has had the Bacille 
Calmette-Guerin (BCG) vaccine or has some other condition 
complicating the interpretation of tuberculosis (TB) testing, 
consultation with infectious disease specialist must be obtained.  

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• 
Participants diagnosed with latent TB are eligible but must have 
received appropriate prophylaxis for 30 days prior to initiation of 
Stage 2 treatment.  
24. Serologic evidence at screening of chronic infections including: 
a. 
Human immunodeficiency virus (HIV) infection.  
b. Hepatitis B as indicated by surface antigen or hepatitis B core 
antibody positivity; if a participant has an isolated positive 
hepatitis B core antibody, they will be eligible to participate in the 
study if they are negative for reflex viral load at Screening. 
c. 
Hepatitis C as indicated by anti-hepatitis C antibody positivity; if a 
participant is Hepatitis C antibody positive, they will be eligible to 
participate in the study if they are negative for viral load at 
Screening. 
25. Current, diagnosed, or self-reported drug or alcohol abuse within the last 
6 months that, in the opinion of the investigator, would interfere with 
the ability to comply with study protocol. 
26. Recipient of live attenuated vaccine(s) within 8 weeks of the Screening 
Visit. 
27. Use of investigational drugs (excluding SARS-CoV-2 vaccinations or SARS-
CoV-2 therapeutics) within 8 weeks of the Screening Visit or 5 half-lives, 
whichever is longer. 
28. Past or current mental or physical problems or findings from physical 
examination or laboratory testing that are not listed above, which, in 
the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s ability to 
comply with study requirements, or may impact the quality or 
interpretation of the data obtained from the study. 
Study Stopping Guidance 
There are no pre-specified criteria that will stop the study, but the Data and 
Safety Monitoring Board (DSMB) will be convened for an ad hoc meeting should 
any of the following events occur: 
• 
Any death that occurs during the study. 
• 
BILAG A flares in Cardiorespiratory, Neuropsychiatric, Gastrointestinal, 
Ophthalmic, Renal, or Hematological Systems occurring in 
o 
3 or more of the first 10 randomized participants or  
o 
30% or more of randomized participants at any time point 
after the 11th participant is randomized. 
• 
Infections requiring hospitalization or > 1 dose of intravenous 
antibiotics occurring in  
o 
3 or more of the first 10 randomized participants or  

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o 
30% or more of randomized participants at any time point 
after the 11th participant is randomized. 

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Table of Contents 
1 
Rationale and Background ........................................................................................................................................ 25 
1.1 
Background and Scientific Rationale ..................................................................................................................... 25 
1.1.1 
Systemic Lupus Erythematosus ..................................................................................................................... 25 
1.1.2 
Current Therapeutic Landscape of SLE ......................................................................................................... 26 
1.1.3 
Unlicensed Drugs .......................................................................................................................................... 26 
1.2 
Rationale for Selection of Study Design ................................................................................................................ 26 
1.2.1 
The BOLD Design ........................................................................................................................................... 26 
1.2.2 
Rationale for Withdrawal of Background Medication .................................................................................. 27 
1.2.3 
Rationale for the Current Two-Part Protocol Design .................................................................................... 27 
1.3 
Rationale for Selection of Investigational Products .............................................................................................. 28 
1.4 
Experience with MMF ........................................................................................................................................... 28 
1.4.1 
Preclinical Experience with MMF .................................................................................................................. 28 
1.4.2 
Clinical Experience with MMF ....................................................................................................................... 29 
1.5 
Experience with Voclosporin................................................................................................................................. 30 
1.5.1 
Preclinical Experience with Voclosporin ....................................................................................................... 30 
1.5.2 
Clinical Studies with Voclosporin .................................................................................................................. 30 
2 
Study Hypotheses/Objectives ................................................................................................................................... 32 
2.1 
Hypotheses and Research Questions .................................................................................................................... 32 
2.1.1 
MMF versus placebo ..................................................................................................................................... 32 
2.1.2 
MMF versus MMF plus Voclosporin ............................................................................................................. 32 
2.2 
Primary Objective .................................................................................................................................................. 32 
2.3 
Secondary Objectives ............................................................................................................................................ 32 
2.4 
Mechanistic Objectives ......................................................................................................................................... 33 
3 
Study Design .............................................................................................................................................................. 33 
3.1 
Description of Study Design .................................................................................................................................. 33 
3.1.1 
Stage 1: Treatment Withdrawal: ................................................................................................................... 33 
3.1.2 
Stage 2: Randomization ................................................................................................................................ 33 
3.1.3 
Stage 3: Re-Randomization ........................................................................................................................... 34 
3.2 
Primary Endpoint .................................................................................................................................................. 38 
3.3 
Secondary Endpoints ............................................................................................................................................ 38 
3.3.1 
Efficacy Endpoints ......................................................................................................................................... 38 

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3.3.2 
Safety Endpoints ........................................................................................................................................... 38 
3.4 
Exploratory Endpoints ........................................................................................................................................... 38 
3.4.1 
Clinical Endpoints .......................................................................................................................................... 38 
3.4.2 
Mechanistic Endpoints .................................................................................................................................. 39 
3.5 
Definitions ............................................................................................................................................................. 39 
3.5.1 
Treatment Failure ......................................................................................................................................... 39 
3.5.2 
Systemic Lupus Erythematosus Responder Index (SRI) ................................................................................ 39 
3.5.3 
BILAG-based Combined Lupus Assessment (BICLA)...................................................................................... 40 
3.6 
Stratification, Randomization, and Blinding ......................................................................................................... 40 
3.6.1 
Procedure for Unblinding .............................................................................................................................. 40 
4 
Selection of Participants ........................................................................................................................................... 41 
4.1 
Rationale for Study Population ............................................................................................................................. 41 
4.2 
Inclusion Criteria ................................................................................................................................................... 41 
4.2.1 
Inclusion Criteria ........................................................................................................................................... 41 
4.2.2 
Inclusion Criteria Required Prior to Randomization ..................................................................................... 42 
4.3 
Exclusion Criteria ................................................................................................................................................... 42 
5 
Known and Potential Risks and Benefits to Participants .......................................................................................... 45 
5.1 
Risks of MMF as cited in the USPI ......................................................................................................................... 45 
5.2 
Risks of voclosporin as cited in the Investigator Brochure and Package Insert .................................................... 46 
5.3 
Risks of long-acting corticosteroid injections ...................................................................................................... 47 
5.4 
Risks of Withdrawal of Lupus Medications ........................................................................................................... 48 
5.5 
Special Considerations for COVID-19 or Other Public Health Emergency ............................................................ 48 
5.6 
Potential Benefits .................................................................................................................................................. 48 
6 
Investigational Agent ................................................................................................................................................ 48 
6.1 
Investigational Agents ........................................................................................................................................... 48 
6.1.1 
MMF and Placebo for MMF .......................................................................................................................... 48 
6.1.2 
Voclosporin and Placebo for Voclosporin ..................................................................................................... 49 
6.2 
Drug Accountability ............................................................................................................................................... 50 
6.3 
Assessment of Participant Compliance with Investigational Agents .................................................................... 51 
6.4 
Toxicity Prevention and Management .................................................................................................................. 51 
6.4.1 
Hypersensitivity ............................................................................................................................................. 51 
6.4.2 
Reproductive Risks ........................................................................................................................................ 51 

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6.4.3 
Malignancy .................................................................................................................................................... 51 
6.4.4 
Infections ....................................................................................................................................................... 51 
6.4.5 
Gastrointestinal Abnormalities ..................................................................................................................... 52 
6.4.6 
Hypertension ................................................................................................................................................. 52 
6.4.7 
Decreases in eGFR ......................................................................................................................................... 52 
6.4.8 
Glucose and Diabetes .................................................................................................................................... 53 
6.4.9 
Hematological Abnormalities ........................................................................................................................ 53 
6.4.10 
Hepatic Abnormalities ................................................................................................................................... 53 
6.5 
Premature Discontinuation of Investigational Agent ........................................................................................... 53 
7 
Other Medications .................................................................................................................................................... 54 
7.1 
Concomitant Medications ..................................................................................................................................... 54 
7.1.1 
Protocol-mandated: Corticosteroid Injections ............................................................................................. 54 
7.1.2 
Permitted Concomitant Medications for SLE ................................................................................................ 55 
7.1.3 
Permitted Concomitant Medications for non-SLE Conditions ...................................................................... 55 
7.2 
Prophylactic Medications ...................................................................................................................................... 56 
7.3 
Prohibited Medications ......................................................................................................................................... 56 
7.3.1 
Live Attenuated Vaccines .............................................................................................................................. 56 
7.3.2 
Immunomodulatory or Immunosuppressive Medications ........................................................................... 56 
7.3.3 
Grapefruit Juice ............................................................................................................................................. 56 
7.3.4 
Strong CYP3A4/5 Inhibitors and Inducers ..................................................................................................... 56 
7.3.5 
Moderate CYP3A4/5 Inhibitors and Inducers ............................................................................................... 56 
7.3.6 
Antacids ......................................................................................................................................................... 56 
8 
Study Procedures ...................................................................................................................................................... 57 
8.1 
Study Visits ............................................................................................................................................................ 57 
8.1.1 
Screening and Enrollment ............................................................................................................................. 57 
8.1.2 
Evaluation of Eligibility and Randomization for Stage 2 ............................................................................... 58 
8.1.3 
Study-Provided Medication for Stage 2 ........................................................................................................ 58 
8.1.4 
Evaluation and Eligibility for Stage 3 ............................................................................................................. 58 
8.1.5 
Study-Provided Medication for Stage 3 ........................................................................................................ 58 
8.1.6 
Unscheduled Visits ........................................................................................................................................ 58 
8.1.7 
Early Termination .......................................................................................................................................... 58 
8.2 
Study Procedures and Assessments ...................................................................................................................... 59 

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8.2.1 
General Assessments .................................................................................................................................... 59 
8.2.2 
Clinical Laboratory Assessments ................................................................................................................... 59 
8.2.3 
Mechanistic Assessments ............................................................................................................................. 60 
8.2.4 
Disease Activity Assessments ........................................................................................................................ 60 
8.2.5 
Other Disease-Specific Assessments ............................................................................................................. 61 
9 
Mechanistic Assays ................................................................................................................................................... 70 
9.1 
Hypothesis-driven assays based on preliminary data ........................................................................................... 70 
9.2 
Exploratory Investigation of Diverse Pathologies with in SLE ............................................................................... 70 
10 
Biospecimen Storage................................................................................................................................................. 70 
11 
Criteria for Participant and Study Completion and Premature Study Termination.................................................. 71 
11.1 
Participant Completion ......................................................................................................................................... 71 
11.2 
Participant Stopping Rules and Early Termination Criteria................................................................................... 71 
11.3 
Participant Replacement ....................................................................................................................................... 71 
11.4 
Early Study Withdrawal ......................................................................................................................................... 71 
11.5 
Study Stopping Rules............................................................................................................................................. 71 
12 
Safety Monitoring and Reporting ............................................................................................................................. 71 
12.1 
Overview ............................................................................................................................................................... 71 
12.2 
Definitions ............................................................................................................................................................. 72 
12.2.1 
Adverse Event (AE) ........................................................................................................................................ 72 
12.2.2 
Suspected Adverse Reaction (SAR) ............................................................................................................... 72 
12.2.3 
Unexpected Adverse Event ........................................................................................................................... 72 
12.2.4 
Serious Adverse Event (SAE) ......................................................................................................................... 72 
12.3 
Grading and Attribution of Adverse Events .......................................................................................................... 73 
12.3.1 
Grading Criteria ............................................................................................................................................. 73 
12.3.2 
Attribution Definitions .................................................................................................................................. 74 
12.4 
Collection and Recording of Adverse Events ........................................................................................................ 74 
12.4.1 
Collection Period ........................................................................................................................................... 74 
12.4.2 
Collecting Adverse Events ............................................................................................................................. 74 
12.4.3 
Recording Adverse Events ............................................................................................................................. 75 
12.5 
Reporting of Serious Adverse Events and Adverse Events ................................................................................... 75 
12.5.1 
Reporting of Adverse Events to DAIT/NIAID ................................................................................................. 75 
12.5.2 
Reporting of Serious Adverse Events to DAIT/NIAID .................................................................................... 75 

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12.5.3 
Reporting of BILAG A Flares to DAIT/NIAID .................................................................................................. 75 
12.5.4 
Reporting to FDA ........................................................................................................................................... 75 
12.5.5 
Reporting of Adverse Events to the IRB ........................................................................................................ 75 
12.6 
Pregnancy Reporting ............................................................................................................................................. 76 
12.6.1 
Mycophenolate REMS Program .................................................................................................................... 76 
12.7 
Reporting of Other Safety Information ................................................................................................................. 76 
12.8 
Review of Safety Information ............................................................................................................................... 76 
12.8.1 
Medical Monitor Review ............................................................................................................................... 76 
12.8.2 
DSMB Review ................................................................................................................................................ 77 
13 
Statistical Considerations and Analytical Plan .......................................................................................................... 78 
13.1 
Overview ............................................................................................................................................................... 78 
13.2 
Endpoints .............................................................................................................................................................. 78 
13.3 
Measures to Minimize Bias ................................................................................................................................... 78 
13.4 
Analysis Plan .......................................................................................................................................................... 78 
13.4.1 
Analysis Populations ..................................................................................................................................... 78 
13.4.2 
Primary Analysis of Primary Endpoint ........................................................................................................... 80 
13.4.3 
Supportive Analyses of the Primary Endpoint .............................................................................................. 80 
13.4.4 
Analyses of Secondary Safety Endpoints ...................................................................................................... 81 
13.4.5 
Analyses of Secondary Efficacy Endpoints .................................................................................................... 81 
13.4.6 
Analyses of Exploratory Endpoints ............................................................................................................... 81 
13.4.7 
Descriptive Analyses ..................................................................................................................................... 82 
13.5 
Interim Analyses .................................................................................................................................................... 82 
13.6 
Statistical Hypotheses ........................................................................................................................................... 82 
13.7 
Sample Size Considerations .................................................................................................................................. 82 
14 
Identification and Access to Source Data ................................................................................................................. 84 
14.1 
Source Data ........................................................................................................................................................... 84 
14.2 
Access to Source Data ........................................................................................................................................... 84 
15 
Quality Assurance and Quality Control ..................................................................................................................... 84 
16 
Protocol Deviations ................................................................................................................................................... 85 
16.1 
Protocol Deviation Definitions .............................................................................................................................. 85 
16.2 
Reporting and Managing Protocol Deviations ...................................................................................................... 85 
17 
Ethical Considerations and Compliance with Good Clinical Practice ........................................................................ 86 

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17.1 
Statement of Compliance ..................................................................................................................................... 86 
17.2 
Informed Consent Process .................................................................................................................................... 86 
17.3 
Privacy and Confidentiality ................................................................................................................................... 86 
18 
Publication Policy ...................................................................................................................................................... 87 
19 
Appendices ................................................................................................................................................................ 88 
19.1 
Appendix 1: Mycophenolate REMS Program Acceptable Methods for Females of Reproductive Potential ....... 88 
19.2 
Appendix 2: Examples of CYP3A4/5 Inhibitors and Inducers ................................................................................ 89 
19.3 
Disease-Specific Assessments ............................................................................................................................... 90 
19.3.1 
EULAR/ACR Classification Criteria for SLE [3]................................................................................................ 90 
19.3.2 
BILAG 2004 .................................................................................................................................................... 92 
19.3.3 
Hybrid SLEDAI ................................................................................................................................................ 93 
19.3.4 
SELENA-SLEDAI Flare Composite ................................................................................................................... 95 
19.3.5 
Thanou Modified SFI ..................................................................................................................................... 96 
19.3.6 
LFA-REAL CLINRO .......................................................................................................................................... 97 
19.3.7 
LFA-REAL PRO ................................................................................................................................................ 99 
19.3.8 
CGI–I (CGI-S, CGI-C) ..................................................................................................................................... 101 
19.3.9 
PGI-I (PGI-S and PGI-C) ................................................................................................................................ 102 
19.3.10 PGA .............................................................................................................................................................. 103 
19.3.11 SF-36 ............................................................................................................................................................ 104 
20 
References .............................................................................................................................................................. 110 
 
 
 
 
 
 
 
 
 

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Glossary of Abbreviations 
AE 
Adverse Event  
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
Anti-dsDNA 
Antibodies to double stranded DNA 
AST 
Aspartate Aminotransferase  
BCG 
Bacille Calmette-Guerin 
BICLA 
BILAG-based Combines Lupus Assessment  
BID 
Twice a day  
BILAG 
British Isles Lupus Assessment Group 
BOLD 
Biomarkers of Lupus Disease 
CGI-C 
Clinical Global Impression of Change 
CGI-I 
Clinical Global Impression of Improvement 
CGI-S 
Clinical Global Impression of Severity 
CFR 
Code of Federal Regulations 
ClinRO 
Clinical Reported Outcome 
CMV 
Cytomegalovirus  
CNI 
Calcineurin Inhibitor  
CNS 
Central Nervous System 
CPC 
Clinical Product Center 
CR3 
Complement receptor 3 
CRR 
Complete Renal Remission 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
Cytochrome P450 3A4 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DDI 
Drug-Drug Interactions  
DSMB 
Data Safety Monitoring Board 
EBV 
Epstein Barr Virus 
eCRF 
Electronic Case Report Form 

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eGFR 
Estimated Glomerular Filtration Rate  
EUA 
Emergency Use Authorization 
EULAR/ACR 
European League Against Rheumatism/American College of Rheumatology 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HTN 
Hypertension 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonisation 
IORA 
Investigator of Record Agreement 
H-SLEDAI 
Hybrid Systemic Lupus Erythematosus Disease Activity Index 
ICF 
Informed Consent Form 
IL16 
Interleukin-16 
IL17RA 
Interleukin 17 Receptor A 
IL2RB 
Interleukin-2 receptor Subunit Beta 
IM 
Intramuscular 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LN 
Lupus Nephritis 
LFA-REAL 
Lupus Foundation of America Rapid Evaluation of Activity in Lupus 
mITT 
Modified Intent-to-Treat Population 
mITT3 
Stage 3 Modified Intent-to-Treat Population 
MMF 
Mycophenolate Mofetil 
MPA 
Mycophenolic Acid 
NIAID 
National Institute of Allergy and Infectious Diseases 
NSAIDS 
Non-steroidal Anti-inflammatory Drugs 
PGA 
Physician Global Assessment  
PGI-C 
Patient Global Impression of Change  
PGI-I 
Patient Global Impression of Improvement 

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PGI-S 
Patient Global Impression of Severity 
PRO 
Patient-Reported Outcome 
P-GP 
Permeability Glycoprotein  
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PPD 
Purified Protein Derivative 
PRCA 
Pure Red Cell Aplasia 
PRN 
As Needed  
PRR 
Partial Renal Response 
PTLD 
Post-Transplant Lymphoproliferative Disorder  
REMS 
Risk Evaluation and Mitigation Strategy 
RR 
Renal Response 
SCCC 
Statistical and Clinical Coordinating Center 
SADR  
Serious Adverse Drug Reactions  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SELENA-SLEDAI 
Safety of Estrogen in Lupus: National Assessment Systemic Lupus 
Erythematosus Disease Activity Index 
SLE 
Systemic Lupus Erythematosus 
SRI 
Systemic Lupus Erythematosus Responder Index 
TB 
Tuberculosis  
TWEAK 
Tumor Necrosis Factor-Like Weak Inducer of Apoptosis 
ULN 
Upper limit of Normal  
UPCR 
Urine Protein: Creatinine Ratio 
USPI 
United States Prescribing Information 
WBC 
White Blood Cell Count 
 
 

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1 Rationale and Background  
1.1 Background and Scientific Rationale 
1.1.1 Systemic Lupus Erythematosus  
Systemic Lupus Erythematosus (SLE or lupus) is a chronic, waxing and waning autoimmune disorder [6] which usually 
affects women in their childbearing years but may arise in people of any age and gender. Clinical manifestations 
range from mild to moderate flares of mucocutaneous and musculoskeletal features to severe manifestations of the 
hematologic, constitutional, renal, cardiopulmonary, neurologic, or central nervous systems (CNS). The onset, timing, 
severity, and type of symptom that a patient can expect to develop is unpredictable. Patients are known to be 
heterogeneous in both clinical manifestations and in their underlying immune abnormalities.  
1.1.1.1 Subsets of Disease 
Clinical manifestations do not predict response to treatment. Most SLE patients share arthritis and 
mucocutaneous involvement [7, 8]. Other clinical signs and symptoms occur sporadically, and do not sort 
patients into stable subsets [6, 7, 9]. Although autoantibody profiles may predict prognosis, they are not helpful 
in choosing treatment. Although antinuclear antibodies are seen in almost all SLE patients, certain patterns of 
less ubiquitous autoantibodies are a long-known way to distinguish subsets at risk for discrete clinical 
manifestations [1]. Antibodies to double stranded DNA (anti dsDNA) are strongly associated with renal 
involvement and risk for other more serious organ disease. Anti-SSA (RO) antibodies correlate with subacute 
cutaneous rashes, lymphopenia, secondary Sjogren’s Syndrome and neonatal lupus symptoms; and 
antiphospholipid antibodies are harbingers for thrombotic complications. Lupus signs and symptoms appear to 
represent an overlapping spectrum disorder and cannot be used to subset patients for optimal treatment.  
Given longstanding confusion of conflicting pathways in SLE immune pathology [10], failure of past subsetting 
methods to improve current treatment choices [11], and disappointing results of 40 investigational agents for 
lupus [12], there is a mandate for better stratification of patients into subsets likely to respond to specific 
treatments. Recently, several investigators have utilized multi-omic approaches to define clusters of SLE patients 
that manifest unique and reproducible patterns of altered gene and protein expression. In a longitudinal cohort 
of pediatric SLE patients, Banchereau and colleagues [13] identified patterns of transcriptional modules that 
change with disease activity and clarified clinically relevant subsets of pediatric patients. A similar approach was 
utilized by Guthridge and colleagues to define 7 clusters of adult lupus patients based on Random Forest 
modeling of gene co-expression pathways [1]. This group also identified cytokines, chemokines, adhesion 
molecules, and soluble receptors associated with risk of disease flare [14, 15].  
These findings demonstrate the value of high-dimensional data for understanding the range of pathogenic 
mechanisms in SLE and suggested a method for more rational testing of targeted treatments. In one study, 
insights into the impact of MMF have been obtained [13] and in an exploratory analysis of a Phase 2 abatacept 
trial, a preliminary identification of responsive immunophenotypes [16] were identified. We used similar 
methodology to study samples from a Phase 2 trial of an agonist to Fc gamma RIIb and identified 2 clusters of 
SLE patients with overlapping immunologic features where the treatment effect was far greater than in the 
overall population [17]. The current project focuses on utilizing these methods for immunophenotying to 
investigate which individuals might benefit from a single agent or combination therapy.   

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1.1.2 Current Therapeutic Landscape of SLE  
1.1.2.1 Licensed Therapies 
A few medications have been approved for the treatment of SLE without undergoing the rigorous approval 
process that is required today, including corticosteroids, hydroxychloroquine, and aspirin. Corticosteroids and 
hydroxychloroquine are staples of care despite their limitations and long-term risks with sustained use. In 2011, 
belimumab was approved for treating the signs and symptoms of general lupus with approval specifically for 
lupus nephritis (LN) in 2020 [18]. This agent has repeatedly been demonstrated to be safe and well tolerated in 
many large studies [19] but it has never been evaluated as a single agent, and is generally used in combination 
with other medications. Efficacy rates have ranged from 35-60% underscoring the unmet need for new 
treatments and/or a better understanding of how we combine different treatments together. Similarly, 
anifrolumab was approved for SLE in 2021 with similar efficacy considerations and unresolved issues about 
optimal use [20]. Voclosporin, a relatively new CNI, was recently approved for LN [21]. In other diseases it has 
been considered safer than other drugs in its class. Data on its efficacy and safety in SLE is discussed below.  
1.1.3 Unlicensed Drugs 
Despite these few recently approved licensed therapies, the standard of care in lupus is to empirically prescribe 
immune modulating treatments marketed for use in other diseases. These most commonly include azathioprine (or 6 
mercapto-purine), methotrexate, MMF (or mycophenolic acid (MPA)), leflunomide, or CNIs such as tacrolimus. The 
efficacy and pharmacodynamics of these medications on heterogeneous SLE populations are not completely 
understood.  
Many novel treatments currently in development are being used (or tested) in the context of “background” therapy, 
with little to no knowledge of whether these combinations are optimal for patients or whether efficacy might vary 
among different pathophysiologic subsets of lupus patients. The combination of MMF and CNI is a recent 
development in the treatment of SLE. This project focuses on addressing several questions: What is the clinical and 
immunologic impact of MMF on different subsets of patients and does this depend on baseline immune phenotype? 
What changes when those who did not respond to MMF receive the addition of a CNI?  
1.2 Rationale for Selection of Study Design 
1.2.1 The BOLD Design 
This protocol design is based on the Biomarkers of Lupus Disease (BOLD) study. The trial is limited to participants 
without organ-threatening disease and mandates withdrawal of all lupus medications except for low dose steroids, 
antimalarials and/or Non-steroidal Anti-inflammatory Drugs (NSAIDs). The BOLD protocol was designed to test the 
hypothesis that if patients with active but not organ threatening SLE are given temporary relief by steroid injections, 
withdrawal of background immunosuppressants can be accomplished safely. Improvement from the initial steroid 
injection will wane, ensuring low response rates in the absence of additional effective treatment. In a clinical trial 
designed on the BOLD principle, participants can be designated as non-responders once steroid response starts to 
wane and then they may be immediately treated with reasonable safety. Furthermore, responses to the test 
medication can be more cleanly evaluated without excessive interaction or interference from other medications. A 
total of 41 participants with moderate disease underwent the BOLD procedure; all but 1 lost their steroid response 
within 6 months. The protocol was safe and well tolerated and all subsequent flares resolved with treatment within 6 
weeks [22].  

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The BOLD design has been employed in the assessment of several investigational agents, including small investigator-
initiated trials of MMF and abatacept, a pilot study of AMG 557, and a Phase 2 study of obexelimab (Xmab5871) [17, 
23-25]. The latter was the most successful in that in a small trial of 102 patients, a subset analysis of patient baseline 
phenotypes identified 2 clusters of lupus patients with overlapping features that exhibited a large treatment effect, 
whereas there was no difference at all between treatment and placebo in all other clusters. No safety concerns were 
identified. The BOLD study approach will be utilized in the current study to lessen placebo response rates so 
differences can be observed in this smaller study, and to better define phenotypic subsets that may benefit from 
MMF alone or MMF combined with voclosporin.  
1.2.2 Rationale for Withdrawal of Background Medication 
Since participants will be receiving a proven effective treatment for their immediate symptoms through steroid 
injections, this mitigates concerns that reduction of background treatments as early as the Screening Visit might 
precipitate a flare. Indeed, since all patients will be entered with active disease, the treatments being withdrawn will 
not be effective at that time point by definition. Safety is improved by allowing a washout of potentially interacting 
immune suppressants prior to starting the investigational treatment. Furthermore, simplification of background 
treatment early in the study will improve interpretability of both clinical and biomarker data, providing a valuable 
clarity for evaluation of the study treatment(s). In particular, the evaluation of MMF as a single agent will be 
facilitated by allowing it to exert its effects as a single agent from the start of administration.  
Substitution of an ineffective treatment with a known, almost universally effective treatment (corticosteroid) is 
consistent with standard of care. The actual withdrawal of background treatment per se begins as a gradual decline in 
steroid levels over time. The earliest flares may start within a month, indicating that sufficient steroid dose was likely 
not given during the withdrawal phase. In the rare situations this does not ameliorate disease activity sufficiently for 
a participant to safely enter the trial, the participant will be taken off study, and they will be treated with whatever is 
appropriate at that time. Most flares in studies of this design occur after 2 or 3 months. This allows time to 
distinguish an effective treatment from placebo. As a flare becomes apparent, the participant becomes a non-
responder in that part of the protocol and will also be immediately treated. Because of this, the trial design is in some 
ways easier to tolerate than some alternative protocols where participants who do not feel well must drop out or 
wait many weeks for treatment. 
1.2.3 Rationale for the Current Two-Part Protocol Design  
The two parts of this protocol are designed to:  
• Test the clinical and immunologic effects of MMF, compared to placebo in phenotypic clusters of 
participants with SLE. This first part of the trial (Stage 2) is expected to identify molecular clusters 
associated with clinical success or failure of MMF treatment. 
• Test the clinical and immunologic effects of adding voclosporin (or not) for those participants who do not 
respond to MMF alone. Compare MMF vs MMF + voclosporin in a subset of non-responders who received 
placebo in the first part (Stage 2) of the trial. If one or more clusters of participants who have not 
responded to MMF alone can be identified by immunophenotypes, either at baseline or after receiving 
MMF, the question of whether all of these or only certain subsets are candidates for voclosporin can be 
addressed in an exploratory way. The study is likely underpowered to fully confirm cluster association 
with response (non-response) in this second part of the trial (Stage 3). The observations obtained may 
provide important hypotheses for further testing.  

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1.3 Rationale for Selection of Investigational Products  
Data from the AURA and AURORA trials [26, 27] suggests a potent additive efficacy for LN when voclosporin is added to 
MMF, which is the most commonly used, first line treatment for nephritis. In 2021, the FDA approved the use of 
voclosporin in combination with MMF for the treatment of LN [28]. Other data have also confirmed a particularly strong 
effect when CNIs are used with MMF. Recently, a 24-week, multicenter randomized trial of induction therapy for LNat 
26 centers in China reported superiority of MMF plus tacrolimus (45.9% complete remission) to cyclophosphamide 
(25.6% complete remission) (p < 0.001) [29]. At least 1 meta-analysis concluded that these agents are effective at about 
the same rates when used singly [30] and an open label, randomized study of 150 LN patients from C.C. Mok’s group in 
Hong Kong prospectively confirmed equal efficacy between tacrolimus and MMF [31]. Taken together, these data 
suggest the possibility of a potential synergy between MMF and T cell modulators such as voclosporin, or at least 
complementary mechanisms. 
A fundamental concept underlying this study is that, in at least some patients, MMF alone is effective. For example, it 
was equally effective as cyclophosphamide or tacrolimus in head to head nephritis studies [30, 31], at least somewhat 
effective as a background treatment in many studies [12, 32-47] superior to azathioprine in a maintenance study [48], 
superior to placebo in a small trial at Oklahoma Medical Research Foundation (OMRF) [49] and superior to other 
standard of care treatments in a summary analysis of several clinical trials [50]. This substantial evidence suggests the 
importance of determining which patients benefit from MMF alone as opposed to those who would require the addition 
of a CNI to obtain clinical improvement and whether identifiable immune phenotypes can help predict response.  
These considerations justify a study to investigate how the effects of MMF, alone and in combination with a CNI, play 
out in identifiable immune phenotypes of lupus. To facilitate the safety and interpretability of such study, the BOLD 
approach will be taken in patients without nephritis or any other organ-threatening disease and background 
medications will be limited. Our work has already demonstrated that patients with non-nephritis fall into the same 
immune-phenotypes as patients with nephritis [1]. Therefore, we hypothesize that the immune components of the 
additive effects of MMF and a CNI are unlikely to differ in non-nephritis lupus [1]. Finally, the controlled circumstance of 
studying patients without organ-threatening disease, which will increase the safety of treatment withdrawal, is unlikely 
to mean that the findings will be completely inapplicable to nephritis patients who share the same phenotypes.  
1.4 Experience with MMF 
One of the investigational products to be studied in this protocol is MMF. MMF is indicated for the prophylaxis of organ rejection 
in recipients of allogenic kidney, heart, or liver transplants and should be used in combination with other immunosuppressants. 
MMF is widely used in clinical practice around the world for SLE [28].  
1.4.1 Preclinical Experience with MMF 
At least two models have confirmed efficacy of MMF in murine nephritis [51-56]. In the (NZB x NZW) F1 model, MMF 
had a dose-dependent effect in autoantibodies [51] and disease severity [51, 52]. In the MRL lpr model, beneficial 
effects on proteinuria, survival and histologic severity of glomerulonephritis have been reported [53], with 
confirmation of efficacy in several other reports [54, 55]. MMF has also been compared to cyclophosphamide in 
murine lupus and found to be more effective than cyclophosphamide in preventing renal fibrosis, associated with 
decreased expression of TGF-β1, fibronectin and collagen I [57]. In a mouse with SLE disease accompanied by 
accelerated atherosclerosis (the gld apoE model), MMF treatment was associated with decreased autoantibodies, 
improved nephritis, and also decreased accumulation of atherosclerotic lesions [58] . In a recent study using the (NZB 

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x NZW) F1 model, MMF treatment was associated with decreased glomerular deposits and proteinuria, and decrease 
of the podocyte urokinase receptor, which conducts signals associated with foot process effacement and proteinuria 
[59]. 
1.4.2 Clinical Experience with MMF 
MMF has been used as a background therapy in many clinical trials of SLE [12, 32-47, 60] . Most of these trials were either 
unable to find differences between treatment and placebo groups (added to standard of care) or, at best, revealed 
disappointing results, with placebo group response rates as high as 35-40%. MMF has performed very well in LN trials when 
it was directly compared to cyclophosphamide [61-64] and with little or no difference in efficacy rates in the induction 
phase, and in general a better safety profile for MMF. Voclosporin has now been tested in combination with MMF in 
two pivotal trials [26, 27] in LN, demonstrating greater efficacy than MMF alone. The summary of clinical trials data 
below focuses mostly on safety. 
The most complete summary of AEs in lupus patients with MMF comes from the international ALMS trial [23] The 
treatments were equally effective. The most common AEs in the MMF group were infections and diarrhea. There 
were more deaths in the MMF group, in contrast to data from previous trials. Most of the participants who died had 
severe renal disease at baseline. Details are shown in the following table: 
Parameter 
MMF 
(N=184) 
n (%) 
CYC 
(N=180) 
N (%) 
Deaths 
9 (4.9) 
5 (2.8) 
Withdrawals as a result of  
24 (13.0) 
13 (7.2) 
All AEs  
177 (96.2) 
171 (95.0) 
Diarrhea 
52 (28.3) 
23 (12.8) 
Headache 
38 (20.7) 
47 (26.1) 
Peripheral 
35 (19.0) 
30 (16.7) 
Arthralgia 
29 (15.8) 
43 (23.9) 
Nausea 
27 (14.7) 
82 (45.6) 
Hypertension 
26 (14.1) 
25 (13.9) 
Nasopharyngitis 
25 (13.6) 
29 (16.1) 
Vomiting 
25 (13.6) 
68 (37.8) 
Cough 
24 (13.0) 
16 (8.9) 
Anemia 
23 (12.5) 
12 (6.7) 
Alopecia 
20 (10.9) 
64 (35.6) 
Abdominal Pain 
19 (10.3) 
16 (8.9) 
Back Pain 
19 (10.3) 
17 (9.4) 
Muscle Spasms 
19 (10.3) 
21 (11.7) 
Urinary Tract 
19 (10.3) 
17 (9.4) 
 
 

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1.5 Experience with Voclosporin 
One of the investigational products to be studied in this protocol is voclosporin, and the preclinical experience and 
clinical studies in LN are reported in the Investigator’s Brochure for voclosporin (version 2.0 dated 15 October 2021) and 
is summarized below [65]. 
1.5.1 Preclinical Experience with Voclosporin 
Preclinical studies suggest CNIs are associated with T cell inhibition. The MRL/lpr model was recently used for a “post-
human” study in mice, reported only after the combination of MMF and tacrolimus were studied in a human trial [66]. 
Mice were treated with prednisone, MMF, or tacrolimus, or with the combination, and renal outcomes were 
significantly improved in the mice that received combination treatment. Transcriptome analysis of kidney samples 
demonstrated that the combination treatment inhibited expression of TLR7, stabilized podocyte actin and suppressed 
the IL-6/Stat3 pathway [66]. In vitro studies of voclosporin using human cells support similar action to other CNIs in T 
cell inhibition [67] but with more potency [68]. In non-human primates, voclosporin prolonged renal graft survival 
[69]. It has also been found to suppress lymphocyte proliferation, and cytokine production more or equally than 
cyclosporine despite lower peak and trough concentrations [70], confirming similar mechanistic impact with a greater 
potency. Calcineurin inhibition at trough blood levels was also found to by higher with the voclosporin construct [69].   
1.5.2 Clinical Studies with Voclosporin 
1.5.2.1 Pharmacokinetic (PK) Studies  
Administration of voclosporin oral solution with meals decreased both the rate and extent of absorption, which 
seemed related to the fat content of the meal. This suggests that the drug should be taken on an empty 
stomach. In in vitro assays, none of the major metabolites seem to cause much calcineurin inhibition. In the 
Phase 1 studies, inhibition of calcineurin by voclosporin appeared to be dose-related up to a maximum of 
approximately 90% after either a 1.5 mg/kg single dose or a 1 mg/kg BIDdose for 10 days. The degree of 
calcineurin inhibition is related to both dose and whole blood concentration of voclosporin. 
1.5.2.2 Drug-Drug Interactions 
Three clinical drug-drug interactions (DDI) studies have confirmed that voclosporin is a substrate for the  
Cytochrome P450 3A4 (CYP3A4)/5, which is primarily responsible for its metabolism. Interaction with other 
substrates of CYP3A4/5 have not been observed. However, use of voclosporin with ketoconazole a strong 
CYP3A4/5 inhibitor or rifampin, an enhancer, will affect voclosporin levels. Voclosporin has also been found to 
be both a substrate for and an inhibitor of P-gp (permeability glycoprotein or multidrug resistance protein 1). 
Verapamil, a known inhibitor of P-gp, was observed to increase voclosporin levels. Concomitant administration 
of voclosporin with digoxin, which is a P-gp substrate, was associated with a 25% increase in digoxin levels and a 
decrease in renal clearance. 
1.5.2.3 Clinical Efficacy and Safety of Voclosporin in Lupus Nephritis 
Voclosporin has been demonstrated to be efficacious in two pivotal LN studies [26, 27, 65]. The AURA-LV study 
tested the novel CNI voclosporin for efficacy and safety in active LN. AURA-LV was a Phase 2, multicenter, randomized, 
double-blind, placebo-controlled trial of two doses of voclosporin (23.7 mg or 39.5 mg, each BID) versus placebo in 
combination with MMF (2 g/d) and rapidly tapered low-dose oral corticosteroids for induction of remission in LN. Two 
hundred sixty-five participants from 79 centers in 20 countries were recruited and randomized to treatment for 48 
weeks. Complete renal remission (CRR) at week 24 was achieved by 29 (32.6%) participants in the low-dose voclosporin 

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group, 24 (27.3%) participants in the high-dose voclosporin group, and 17 (19.3%) participants in the placebo group 
(OR=2.03 for low-dose voclosporin versus placebo). The significantly greater CRR rate in the low-dose voclosporin group 
persisted at 48 weeks, and CRRs were also significantly more common in the high-dose voclosporin group compared to 
placebo at 48 weeks. The overall incidence of AEs and treatment-related AEs appeared to increase with increasing dose 
of voclosporin, with AEs attributed as treatment-related in 17.0% of participants in the placebo group compared to 
50.6% and 62.5% of participants in the low-dose and high-dose voclosporin groups, respectively. The majority of AEs 
were mild or moderate in severity. There were more serious adverse events (SAE) in both voclosporin groups, and 13 
participants died during the study with more deaths observed in the low-dose group compared to placebo and high-
dose voclosporin groups (11.2%, 1.1%, and 2.3%, respectively). These results suggested that the addition of low-dose 
voclosporin to MMF and corticosteroids for induction therapy of active LN results in a superior renal response compared 
to MMF and corticosteroids alone but higher rates of AEs including death were observed in the Phase II study. A 
combined safety analysis of Phase II and III studies will be discussed in more detail below. 
AURORA 1 was a Phase III multicenter, randomized, double-blind, placebo-controlled 52-week study of active LN 
patients. Participants were randomized 1:1 to voclosporin (23.7 mg BID) or placebo in combination with MMF (1 g BID) 
and rapidly tapered oral steroids. Three hundred fifty-seven participants were enrolled, 88% female, median age of 31 
and 33% of Hispanic/Latino ethnicity. Renal response (RR) by intention to treat analysis at 52 weeks was 40.8% for the 
voclosporin arm and 22.5% for the control arm (OR: 2.65; 95% CI: 1.64, 4.27; p< 0.001). Ethnicity subgroup analysis of RR 
at 52 weeks noted benefit of voclosporin in both Hispanic/Latino (voclosporin 38.6% and control 18.6%, p=0.0062, OR 
3.45) and non-Hispanic/Latino participants (voclosporin 41.8% and control 24.6%, p=0.0045, OR 2.29). The benefits of 
voclosporin were also seen for all pre-specified hierarchical secondary endpoints: RR at 24 weeks, partial renal response 
(PRR) at 24 and 52 weeks, time to achieve UPCR ≤ 0.5, and time to 50% reduction in UPCR. Furthermore, all pre-
specified subgroup analyses (age, sex, race, biopsy class, region, and prior MMF use) favored voclosporin. Voclosporin 
was well tolerated with no unexpected safety signals, as summarized below. Participants who completed 52 weeks of 
study treatment (voclosporin or placebo) in the AURORA 1 study were eligible to continue with their randomized 
treatment for up to a further 24 months in the AURORA 2 continuation study. A total of 216 participants entered the 
AURORA 2 study: 116 participants from the voclosporin arm and 100 participants from the placebo arm. The AURORA 2 
study is ongoing with final analyses planned to evaluate long term efficacy, including programmed renal response, PRR 
and changes in UPCR.  
In a combined safety analysis of the three clinical trials (AURORA 1, AURA-LV and AURION) and the ongoing continuation 
study AURORA 2, the most common AEs were in Infections and Infestations, reported by 66% and 59% of participants  
respectively [26, 27, 65], in the voclosporin/MMF and placebo/MMF groups. The majority were mild or moderate. 
Gastrointestinal disorders were also common in both voclosporin/MMF and placebo/MMF groups (49% and 38%, 
respectively), predominantly diarrhea and nausea. The most common individual AEs in voclosporin-treated participants 
were glomerular filtration rate (GFR) decreased (voclosporin: 29%, placebo 11%) and hypertension (voclosporin 21%, 
placebo 11%), both known effects of CNIs. The majority of GFR decreases were of mild to moderate intensity and 
resolved following temporary interruption or modification of dose per protocol guidance based on theeGFR. SAEs 
occurred in a similar proportion of participants in the voclosporin/MMF and placebo/MMF groups (28% and 25%, 
respectively). Infections and infestations were the most common SAEs reported in both groups (12% and 13%, 
respectively). Serious opportunistic infections were uncommon (<1%) in both treatment groups. Seventeen participants 
(2.5%) died due to AEs occurring on or within 30 days of the last dose of study treatment (10 (2.7%) voclosporin/MMF, 7 

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(2.6%) placebo/MMF). None of the AEs leading to death were considered by the investigator, sponsor or the DSMB to 
be related to study treatment. The reasons for death were consistent with the types of comorbid conditions and 
complications that would be expected in a population with LN. 
2 Study Hypotheses/Objectives 
2.1 Hypotheses and Research Questions 
2.1.1 MMF versus placebo 
Hypothesis 1: Long-acting corticosteroid-induced improvement in lupus disease activity achieved prior to 
randomization will be lost more rapidly in the placebo arm compared to the MMF arm. 
Research Question 1: Are there immunologically definable subsets of SLE patients [1] for whom MMF is an effective 
treatment? 
Hypothesis 2: Expression of TWEAK, complement receptor 3 (CR3), FYN, IL16, IL17RA, and/or IL2RB will decline over 
24 weeks for those participants on MMF who do not develop treatment failure compared to those who do fail on or 
prior to week 24. 
2.1.2 MMF versus MMF plus Voclosporin 
Research Question 2: Do baseline gene expression patterns characterizing response (or non-response) to MMF and 
MMF plus voclosporin differ? 
2.2 Primary Objective 
Assuming that MMF is an effective treatment in some, but not all, SLE patients, the primary objective of this study is to 
evaluate the potential effectiveness of 24 weeks of MMF within previously discovered immunologically defined subsets of 
SLE patients [1]. 
This objective will be most effectively supported within the context of a successful demonstration of superiority of MMF 
over placebo, pooled over all clusters. To this end, individuals with lupus who are without organ-threatening disease will 
be randomized to 24 weeks of MMF or placebo. The primary objective is to compare the cumulative incidence of 
treatment failure with 24 weeks of MMF or placebo by treatment arm. Subsequently, treatment effects will be 
evaluated within the individual immunologically-homogenous subsets defined at screening. 
2.3 Secondary Objectives 
• 
To describe the effects of long-acting corticosteroid injections, MMF, MMF plus voclosporin, and placebo on 
measures of safety and toxicity. 
• 
To describe the effects of MMF, MMF plus voclosporin, and placebo on exploratory clinical response 
measures and disease flare indices. 
• 
To describe the effects of MMF, MMF plus voclosporin, and placebo on patient-reported quality of life indices. 
 
 

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2.4 Mechanistic Objectives 
• 
To explore and compare pre-randomization gene expression patterns among responders and non-responders to 
MMF and MMF plus voclosporin.  
• 
To use comprehensive immunophenotyping to study the immunologic changes that accompany treatment- 
induced disease improvement to better understand key checkpoints in SLE pathophysiology. 
• 
To use comprehensive immunophenotyping to better understand immunologic changes associated with the loss of 
clinical response. 
3 Study Design 
3.1 Description of Study Design  
This will be a multicenter, double blind, placebo-controlled Phase 2 trial of 120 participants with SLE who will enter with 
significant symptoms, but no organ-threatening disease. The study will be conducted in 3 stages.  
3.1.1 Stage 1: Treatment Withdrawal: 
During Stage 1, which may last up to 4 weeks, consenting participants will receive an IM injection of a long-acting 
corticosteroid, which may be repeated if needed to achieve amelioration of symptoms. A total of 3 corticosteroid 
injections may be given during Stage 1 with the first injection given as early as the Screening Visit after the 
mechanistic blood draw is completed and the last injection given as late as the Stage 2 Randomization Visit after the 
mechanistic blood draw is completed. Dose will be dependent on the available formulation. 
In addition, participants will withdraw from all other treatments for lupus with the following exceptions: (i) PRN 
nonsteroidal anti-inflammatory treatments may be started or continued, (ii) PRN topicals may be continued, (iii) 
hydroxychloroquine, chloroquine, or quinacrine may be continued at any stable dose, and (iv) prednisone, if ≤ 10 
mg/day, may be continued at stable doses but not started. Participants may screen if taking up to 20 mg/day 
prednisone (or equivalent) but both the participant and the investigator must be willing and able to taper to 10 
mg/day (under cover of long-acting corticosteroids) by the Stage 2 Randomization Visit. Withdrawal of background 
lupus medications can start any time after the first corticosteroid injection is given but must be completed by the 
Stage 2 Randomization Visit. 
3.1.2 Stage 2: Randomization 
One hundred and twenty qualifying participants who withdraw from treatment as described in protocol Section 3.1.1, 
Stage 1: Treatment Withdrawal, and meet improvement criteria for randomization as outlined in Section 4.2.2, 
Inclusion criteria required prior to randomization, will be randomized (1:1) to receive up to 48 weeks of either MMF or 
corresponding MMF placebo. For the first 2 weeks, a scheduled “taper-up” of MMF will take place. Participants will 
receive 500 mg MMF (or corresponding MMF placebo) BID for 7 days, followed by 500mg and 1,000mg MMF (or 
corresponding MMF placebo) in divided doses for 7 days. They will then continue at a stable dose of 1,000mg MMF 
(or corresponding MMF placebo) BID. Visits to evaluate AEs, vital signs, hematology and chemistry, study medication 
compliance, medication use, disease status, participant reported outcomes, and to obtain biomarker samples will 
occur every 4 weeks after randomization.  

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Participants will be followed for a maximum of 48 weeks on study-provided medication in Stage 2. If a participant 
experiences an increase in SLE symptoms at any scheduled or unscheduled visit at or before the Stage 2 Week 24 
visit, they will proceed in the study as follows: 
• 
If the participant is deemed a Stage 2 treatment failure as defined in protocol Section 3.2, Primary 
Endpoint, and a corticosteroid injection is deemed sufficient for treatment without new or increased 
lupus medication, then a blood sample for mechanistic studies will be drawn, the injection will be 
administered, and the participant will immediately proceed to Stage 3: Re-randomization. (See Section 
3.1.3, Stage 3 Re-Randomization).  
• 
If the participant is deemed a Stage 2 treatment failure as defined in protocol Section 3.2, Primary 
Endpoint, and a corticosteroid  injection is deemed sufficient for treatment without new or increased 
lupus medication, but the participant refuses the corticosteroid injection, then a blood sample for 
mechanistic studies will be drawn, and the participant will still immediately proceed to Stage 3: Re-
randomization without the corticosteroid injection. (See Section 3.1.3, Stage 3: Re-Randomization). 
• 
If the participant is deemed a Stage 2 treatment failure as defined in protocol Section 3.2, Primary 
Endpoint, and a corticosteroid injection is deemed insufficient and a new or increased lupus medication 
is required, then a blood sample for mechanistic studies will be drawn, Stage 2 study-provided medication 
will be stopped, and the new or increased lupus medication will be started outside of the study. The 
participant will not be eligible for Stage 3 but will be followed to Stage 2 Week 24 or 4 weeks ± 10 days 
after the last dose of study-provided medication, whichever is later, before exiting the study. Participants 
who exit the study at Stage 2 Week 24 should complete all End of Study/Safety Follow-Up visit 
assessments at this time.  
Participants who have not failed Stage 2 on or before the Stage 2 Week 24 visit will continue on Stage 2 study-
provided medication through Stage 2 Week 48 or until treatment failure, whichever occurs first.  
• 
If the participant is deemed a Stage 2 treatment failure after Stage 2 Week 24, then study-provided 
medication will be stopped. Prior to treatment with a corticosteroid injection or a new or increased lupus 
medication outside of the study, a blood sample for mechanistic studies will be drawn. The participant 
will return for an End of Study/Safety Follow-Up Visit 4 weeks ± 10 days after the final dose of study-
provided medication. 
• 
Participants who have not failed Stage 2 on or before the Stage 2 Week 48 visit will return for an End of 
Study/Safety Follow-Up Visit 4 weeks ± 10 days after the final dose of study-provided medication. 
Severe lupus manifestations that are life-threatening or organ-threatening should prompt consideration for withdrawal from 
the study in order to enable maximal therapy with corticosteroids and other lupus medications. The ultimate decision on 
withdrawal should be left up to the clinical judgment of the investigator. 
3.1.3 Stage 3: Re-Randomization 
Participants moving into Stage 3 will be re-randomized (1:1) to receive up to 24 weeks of either MMF plus 
voclosporin (23.7 mg BID) or MMF plus placebo for voclosporin. Individuals who previously received MMF placebo in 
Stage 2 will receive a 2-week taper-up of MMF (see taper details for Stage 2, Section 3.1.2 Stage 2: 
Randomization).During the first 2 weeks of treatment, a single IM injection of a long-acting corticosteroid may be 
administered if needed to achieve amelioration of symptoms without meeting the definition of treatment failure in 
Stage 3 and without a requirement to stop Stage 3 study-provided medication. This single IM corticosteroid injection 

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within the first 2 weeks of Stage 3 treatment may be administered regardless of whether or not one was given at the 
time of Stage 2 treatment failure for a total of 2 corticosteroid injections (dose will be dependent on the available 
formulation) with the first injection given as early as the visit where participants have a Stage 2 treatment failure after 
the mechanistic blood draw and the second injection given as late as the Stage 3 Week 2 Visit. Visits to evaluate AEs, 
vital signs, hematology and chemistry, study medication compliance, medication use, disease status, participant 
reported outcomes, and to obtain biomarker samples will occur every 4 weeks after re-randomization.  
In Stage 3, participants will be on treatment for a maximum of 24 weeks or until treatment failure, whichever occurs 
first.  
• 
If the participant is deemed a Stage 3 treatment failure, study-provided medication will be stopped. Prior to 
treatment with a corticosteroid injection or a new or increased lupus medication outside of the study, a blood 
sample for mechanistic studies will be drawn. The participant will return for an End of Study/Safety Follow-Up 
Visit 4 weeks ± 10 days after the final dose of study-provided medication. 
• 
Participants who have not failed Stage 3 on or before the Stage 3 Week 24 visit will return for an End of 
Study/Safety Follow-Up Visit 4 weeks ± 10 days after the final dose of study-provided medication. 
As in Stage 2, severe lupus manifestations that are life-threatening or organ-threatening should prompt consideration for 
withdrawal from the study in order to enable maximal therapy with corticosteroids and other lupus medications. The 
ultimate decision on withdrawal should be left up to the clinical judgment of the investigator. 

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Figure 1. Study Flow Diagram
 

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3.2 Primary Endpoint 
The primary endpoint is the cumulative incidence of participants who experience a Stage 2 treatment failure at or before 
the Stage 2 Week 24 visit. The criteria for treatment failure are defined in Section 3.5.1, Treatment Failure. 
3.3 Secondary Endpoints 
3.3.1 Efficacy Endpoints 
• 
Clinical response in Stage 2, defined by the BICLA (see Section 3.5.3, BILAG-based Combined Lupus Assessment 
(BICLA)) at Stage 2 Week 24. 
• 
The cumulative incidence of participants who experience a Stage 3 treatment failure, defined as the occurrence 
of any criteria in Section 3.5.1, Treatment Failure after re-randomization and on or before completing Stage 3. 
• 
Time to treatment failure in Stage 3, defined as the interval from the day of Stage 3 randomization until the day 
of treatment failure.  
• 
Clinical response in Stage 3, defined by the BICLA (see Section 3.5.3, BILAG-based Combined Lupus Assessment 
(BICLA)) at Stage 3 Week 24. 
3.3.2 Safety Endpoints 
The following specific events will be evaluated separately for each stage of the study: 
• 
The incidence of Grade 3 or higher related AEs. 
• 
The incidence of Grade 3 or higher infections. 
• 
The incidence of renal dysfunction, defined as Grade 3 or higher chronic kidney disease with eGFR < 30 ml/min 
per 1.73 m2. 
• 
The incidence of Grade 3 or higher hypertension, defined as a systolic blood pressure ≥ 160 mm Hg or a diastolic 
blood pressure of ≥ 100 mm Hg. 
3.4 Exploratory Endpoints 
3.4.1 Clinical Endpoints 
The following will be evaluated in Stage 2 and Stage 3: 
• 
Proportions of participants in each arm who achieve responder status as assessed by SRI-4, SRI-6, and 
SRI-7 (as defined in Section 3.5.2, Systemic Lupus Erythematosus Responder Index) every 4 weeks through 
Week 24. 
• 
Incidence rates for Mild/Moderate and Severe flares accumulated during the treatment period. Three 
flare assessments will be evaluated independently:  
a. Thanou modified SELENA-SLEDAI Flare Index (see Section 19.3.5, Thanou Modified SFI)[2].  
b. BILAG flare, defined as a new A or 2 new Bs. 
c. BILAG flare, defined as any item marked new or worse that could support a BILAG A (severe flare) 
or 2 organs with items marked new or worse that could support a BILAG B (moderate flare). 
• 
Incidence rates for Mild, Moderate and Severe disease activity. Assessments across multiple 
organ/systems are rated using:  
a. LFA-REAL clinician assessment 
b. LFA-REAL participant assessment 

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• 
Longitudinal profiles of the Physical Component Summary, Mental Component Summary, and individual 
domains of the SF-36 patient-reported outcome (PRO) that are observed over the treatment period. 
3.4.2 Mechanistic Endpoints  
The following pharmacodynamic markers will be evaluated in Stage 2 and Stage 3: 
• 
Differential expression, at the module or single gene level, between participants within immunologically-
homogenous clusters who do and do not obtain a clinical response. 
• 
Identification of complex immunophenotypes characterizing clinical response or non-response to study 
treatment. 
• 
Longitudinal profiles of TWEAK, CR3, FYN, IL16, IL17RA, and IL2RB over 24-week treatment periods. 
3.5 Definitions 
3.5.1 Treatment Failure 
Treatment failure is defined as the first occurrence after randomization (Stage 2) or as the first occurrence after re-
randomization (Stage 3) of any of the following events: 
• 
Corticosteroid injections or treatment with a new or increased lupus medication, except the occasional use of 
corticosteroids for reasons not associated with SLE flare (see Section 7.1.2.2, Prednisone (or equivalent) for 
additional information); or 
• 
BILAG flare, defined as any item marked new or worse that could support a BILAG A (severe flare) or 2 organs 
with items marked new or worse that could support a BILAG B (moderate flare), and if the participant’s 
condition is deemed by the investigator to be “moderately worse” or “much worse” compared to the day of 
randomization, as assessed by the CGI-C; or 
• 
Premature permanent discontinuation of study-assigned treatment for any reason. 
For Stage 2, the reference values for the CGI-C should be the investigators determination of the participant’s condition at the 
Stage 2 Day 0 Randomization Visit. For Stage 3, the reference values for the CGI-C should be the investigator’s determination 
of the participant’s condition at the most recent assessment before the Stage 3 Re-randomization Visit.  
3.5.2 Systemic Lupus Erythematosus Responder Index (SRI) 
• 
For SRI-4, SRI-6, and SRI-7, a decrease in the Hybrid Systemic Lupus Erythematosus Disease Activity Index (H-
SLEDAI) total score of ≥ 4, 6, or 7 points from the reference visit. 
• 
No new BILAG A scores among organs scored as B, C, D, or E at the reference visit, and  
• 
≤ 1 new BILAG B scores among organs scored as C, D, or E at the reference visit, and 
• 
No worsening (≤ 0.3 point increase) in Physician Global Assessment (PGA) compared to the reference visit. 
For Stage 2 and Stage 3, the reference value for SRI-4, SRI-6, and SRI-7 will be the H-SLEDAI total score, BILAG scores, and PGA 
obtained at the Screening Visit. For Stage 3, additional supportive analyses will use the most recent assessment before 
the Stage 3 Re-Randomization Visit as the reference value for the H-SLEDAI total score, BILAG scores, and PGA. 
 
A response for the SRI-4, SRI-6 and SRI-7 is defined as meeting the following four criteria at the time of the SRI 
assessment: 

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3.5.3 BILAG-based Combined Lupus Assessment (BICLA) 
Clinical response at Week 24, defined by the BICLA [71] as follows: 
• 
All BILAG A scores must improve to B, C, or D, and  
• 
All BILAG B scores must improve to C or D, and 
• 
No new BILAG A scores among organs scored as B, C, D, or E, and  
• 
≤ 1 new BILAG B scores among organs scored as C, D, or E , and 
• 
No worsening of H-SLEDAI total score, and 
• 
Less than a 10% increase (worsening) in the Physician’s Global Assessment (visual analogue scale). 
For Stage 2 and Stage 3, the reference values for BILAG, H-SLEDAI total score and PGA are the assessments obtained at the 
Screening Visit. For Stage 3, additional supportive analyses will use the most recent assessment before the Stage 3 Re-
Randomization Visit as the reference value for H-SLEDAI total score, BILAG scores, and PGA. 
3.6 Stratification, Randomization, and Blinding 
For Stage 2 randomization, participants will be stratified by screening gene expression signature: 
• 
Group 1: high interferon and high inflammation 
• 
Group 2: low inflammation and high B Cells (interferon can be high or low) 
• 
Group 3: other profiles not included in groups 1 or 2 
• 
Group 4: gene expression signature results unavailable (e.g. due to shipping or laboratory error) 
 
For Stage 3 re-randomization, participants will be stratified by the Stage 2 treatment assignment: MMF vs Placebo MMF 
along with whether or not a long-acting corticosteroid injection was given at the time of Stage 2 treatment failure.  
 
The randomization will be performed by the Division of Allergy, Immunology, and Transplantation (DAIT) Statistical and 
Clinical Coordinating Center (SCCC). Blinding will be maintained for all study participants and trial personnel throughout 
the study, except for the study site pharmacist. Treatment assignments will be centrally randomized and communicated 
to the unblinded study site pharmacist. The investigators, clinic personnel, and participants will not be informed 
regarding the intervention assignment until the study is unblinded. Laboratories performing assays for this protocol will 
be blinded to the identity and group assignment of biological materials to be studied. 
3.6.1 Procedure for Unblinding 
Unblinding must be approved by the study NIAID Medical Monitor unless an immediate life-threatening condition has 
developed and the Medical Monitor is not accessible. The site investigator will notify the NIAID Medical Monitor, Protocol 
Chair and the SCCC of the unblinding event on the next business day. The emergency unblinding will also be reported to 
the DSMB by the NIAID Medical Monitor.  
A full account of the event will be recorded, including the date and time of the unblinding, the reason for the decision to 
unblind, and the name of the individual who made the decision and the names of the Medical Monitor and others who 
were notified. The reasons for unblinding of a participant’s treatment will be included in the final study report.  
Unblinding the study due to an approved interim analysis, final analysis, or study termination will require written approval 
from NIAID.  
 

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4 Selection of Participants 
4.1 Rationale for Study Population 
SLE affects all races, all genders, and all ages, but is more prevalent in women in their childbearing years who are of African, 
Asian or Native American Ancestry. This will be a trial of individuals between the ages of 18 and 60 with no restrictions for race 
or gender. These criteria are inclusive of most people with SLE, with restrictions for those who are medically vulnerable or 
who cannot complete all of the procedures. Children are not included since they usually have more severe disease, and this is 
unlikely to be a safe protocol for them. The current treatments for SLE are inadequate to prevent recurrent flares, progressive 
disability, and early mortality, often from accelerated atherosclerosis or infection. The population of SLE patients selected for 
this trial is an underserved community with chronic, sometimes life-long symptoms that significantly affect their work 
productivity, family relationships and overall quality of life. However, flares tend to be moderate in severity and primarily 
affect the musculoskeletal and mucocutaneous systems, without life-threatening or organ-threatening components. Our 
qualification criteria, adjudication process, and pre-testing for early flare markers have all evolved from our past experience 
with (and test development from) the BOLD study [22]. 
The BOLD study was conducted safely [22] (clinicaltrials.gov # NCT00987831), as was our past pilot study of MMF 
NCT00594932, which used a BOLD design, and since then two industry-sponsored trials have utilized the same design - 
NCT00774943, NCT02725515 - one of which is completed and recently published[23]. We are also in the process of 
completing three Investigator-initiated trials in Oklahoma using the BOLD design: NCT02270957, NCT03355482, 
NCT02270970. All of the unpublished SLE trials using the BOLD design are a short time from completion and there has been no 
unacceptable safety signal to date. However, selection of the appropriate participant population for a trial of this structure is 
critical, both to its success in obtaining interpretable results and for participant well-being and safety. Our Inclusion and 
Exclusion Criteria address the selection and verification of this very population. 
4.2 Inclusion Criteria 
4.2.1 Inclusion Criteria  
Participants must meet all of the following criteria to be eligible for randomization as study participants.  
1. Aged ≥ 18 and ≤ 60 years at the time of informed consent. 
2. Meets EULAR/ACR 2019 criteria for SLE [3]. 
3. Moderately severe, active, but non-organ threatening disease. Specifically, signs or symptoms meeting 
criteria for a minimum of:  
a. 1 BILAG A (severe) score in the constitutional, musculoskeletal or mucocutaneous system at the 
time of screening. See Section 4.3, Exclusion Criteria number 2 for additional detail. 
b. 2 BILAG B (moderate) activity scores in any organ systems; or 
c. 1 BILAG B (moderate) activity score in any organ systems and a SELENA-SLEDAI score of ≥ 6.  
• 
If there is only 1 BILAG B score: 
 
If a musculoskeletal BILAG B is scored due to moderate arthritis, where some loss 
off functional range of movements was present on several days over the last 4 
weeks, there must also be a minimum of at least 3 joints that are both tender and 

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swollen due to lupus disease activity in wrists, MCPs or PIPs for the participant to 
qualify.  
 
If a mucocutaneous BILAG B is scored due to acute or subacute cutaneous skin 
eruption, the rash must cover at least 4% of the body surface area for the 
participant to qualify. Any active discoid lesion or other form of chronic cutaneous 
lupus would be qualifying.  
4. Approval, by an adjudication committee of a brief entry packet describing the type, severity and duration of 
symptoms meeting the minimal criteria for entry. The participant will meet this criterion if the committee is 
confident of all of the following:  
a. Convincing diagnosis of SLE,  
b. Active disease, due to SLE, warranting the potential of dual therapy with potent immune modulators, 
c. No medical or other condition to contraindicate participation in a placebo-controlled, outpatient 
study of this design. 
5. Women of childbearing potential must have a negative serum pregnancy test at screening.  
6. Able or willing to use reliable methods of contraception, as outlined in the Mycophenolate REMS brochure 
for health care providers, from 4 weeks prior to first randomization to 6 weeks after completion of the 
study. This criterion applies to females of reproductive potential. Mycophenolate REMS Program acceptable 
contraceptive methods are outlined in Appendix 1, see Section 19.1. 
4.2.2 Inclusion Criteria Required Prior to Randomization  
Participants who meet the following criterion at the Stage 2 Randomization Visit may proceed to randomization in 
Stage 2: 
7. After completion of corticosteroid injection(s) and prior to randomization in Stage 2, the participant and 
his/her physician must agree that disease activity has improved sufficiently from screening such that 
randomization is acceptable.  
a. The physician must score the CGI-C [4] as “moderately better” or “much better” prior to randomization. 
• 
The reference value for the CGI-C should be the investigator’s determination of the 
participant’s condition at the Screening Visit. 
b. The participant must agree that his/her symptoms have improved (yes/no). 
4.3 Exclusion Criteria 
Participants who meet any of the following criteria are not eligible for randomization as study participants:  
1. Inability or unwillingness of a participant to understand and provide written informed consent or comply with 
the study protocol. 
2. BILAG A (severe) disease in the Cardiorespiratory, Neuropsychiatric, Gastrointestinal, Ophthalmic, Renal, or 
Hematological Systems.  
3. Severe or unstable nephritis defined as any of the following: 
a. History of confirmed Class 3-5 nephritis within the last 2 years, 

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b. History of confirmed Class 3-5 nephritis > 2 years ago in the absence of documented treatment including 
both induction and maintenance therapy, 
c. UPCR > 1 g/g at screening, 
• 
If UPCR is > 0.5 g/g and ≤ 1 g/g at screening, then a second assessment must be completed with 
at least 1 week between assessments. If the second assessment is > 1 g/g or has increased by ≥ 
0.3 g/g, then the participant is excluded. 
4. Evidence of chronic kidney disease defined as eGFR < 45 mL/min per 1.73 m2 at screening, where   
175 x (Creatinine/88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if of African 
descent) [5]. 
5. History of cirrhosis or chronic liver disease unrelated to SLE other than fatty liver disease.  
6. History, within 1 year of the Screening Visit, of uncontrolled SLE that would have warranted a BILAG A 
(except mucocutaneous, constitutional, musculoskeletal) including, but not limited to, hemolytic anemia, 
neuropsychiatric lupus, or interstitial lung disease. 
7.  Uncontrolled HTN at the Screening or Randomization Visits defined as a blood pressure > 150/100 with or 
without treatment, not to exceed 3 complementary antihypertensive treatments.  
8. Any of the following laboratory values during screening: 
a.  Hemoglobin (Hg) < 8.0 g/dL,  
b. WBC < 2.0 x 109 cells/L,  
c. ANC < 1.0 x 109 cells/L,  
d. Platelets < 60 x 109 cells/L at screening,  
• 
If platelets < 70 x 109 cells/L at screening, platelet count should be retested 2 weeks later. If 
platelets are < 60 x 109 cells/L at retest, participant will be excluded 
e. AST or ALT > 2.5 times the ULN, 
f. Serum IgG levels < 5 g/L 
9. Use of ≥ 40 mg/day of prednisone within 4 weeks prior to the Screening Visit or use of > 20 mg/day of 
prednisone at screening. 
10. Unwilling or unable to taper to ≤ 10 mg/day of prednisone or equivalent by the day of randomization. 
11. Use of hydroxychloroquine, chloroquine, or quinacrine, if taking, at a prescribed dose that has not been 
stable for at least 2 months prior to randomization.  
12. Use of MMF within 1 year of randomization. 
13. Use of CNIs within 3 months of randomization. Topical formulations applied stably for at least one month 
are allowed. 
14. Use of rituximab, obinutuzumab, ocrelizumab, or long-acting B cell depletion agents within 1 year of 
randomization. Use of agents ≥ 6 months and within 1 year of randomization is permitted if there is 
evidence of B cell reconstitution as defined as CD19+ counts of ≥ 50 cells/µL.  

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15. History of intolerance or allergy to MMF, voclosporin, or long-acting corticosteroid preparations. 
16. Individuals with known hypersensitivity to Polysorbate 80 (Tween). 
17. A woman who is pregnant, breastfeeding, or planning pregnancy from the time of consent until 6 weeks 
after completion of the study. 
18. Any participant with plans for major surgery during the time of the trial. 
19. Active infections requiring hospitalization or intravenous antibiotics within 1 month prior to the Screening 
Visit. 
20. Any grade 2 infection or higher from 14 days prior to the Screening Visit and through the screening period 
that has not resolved by randomization. 
21. Acute herpes zoster within 4 months of the Screening Visit. 
22. Positive results from a SARS-CoV-2 antigen test administered 2 days prior to and on the day of first 
randomization.  
23. Positive Quantiferon Gold (or equivalent) assay. Indeterminate Quantiferon Gold (or equivalent) assays must 
be repeated (with same or other interferon gamma release assay per local policy) and shown to be negative. 
Alternatively, if the Quantiferon Gold (or equivalent) assay remains indeterminate, a participant must have a 
negative PPD. Finally, if the participant has had the BCG vaccine or has some other condition complicating 
the interpretation of TB testing, consultation with infection disease specialist must be obtained.  
• 
Participants diagnosed with latent TB are eligible but must have received appropriate prophylaxis 
for 30 days prior to initiation of Stage 2 treatment.  
 
24. Serologic evidence at screening of chronic infections including: 
a. HIV infection.  
b. Hepatitis B as indicated by surface antigen or hepatitis B core antibody positivity; if a participant has an 
isolated positive hepatitis B core antibody, they will be eligible to participate in the study if they are 
negative for reflex viral load at Screening. 
c. Hepatitis C as indicated by anti-hepatitis C antibody positivity; if a participant is Hepatitis C antibody 
positive, they will be eligible to participate in the study if they are negative for viral load at Screening.  
25. Current, diagnosed, or self-reported drug or alcohol abuse within the last 6 months that, in the opinion of the 
investigator, would interfere with the ability to comply with study protocol. 
26. Recipient of live attenuated vaccine(s) within 8 weeks of the Screening Visit. 
27. Use of investigational drugs (excluding SARS-CoV-2 vaccinations or SARS-CoV2 therapeutics) within 8 weeks 
of the Screening Visit or 5 half-lives, whichever is longer. 
28. Past or current mental or physical problems or findings from physical examination or laboratory testing that 
are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in 

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the study, may interfere with the participant’s ability to comply with study requirements, or may impact the 
quality or interpretation of the data obtained from the study. 
5 Known and Potential Risks and Benefits to Participants 
5.1 Risks of MMF as cited in the USPI 
Risks cited below are noted in the United States Prescribing Information (USPI) for MMF updated 2/2019 [28]. 
Contraindications: MMF is contraindicated in patients with a hypersensitivity to MMF, MPA, any component of the drug 
product, and in patients who are allergic to Polysorbate 80 (Tween). 
Embryofetal Toxicity: MMF use has been associated with risk of first trimester pregnancy loss and congenital 
malformations, especially external ear and other facial abnormalities including cleft lip and palate, and, according to the 
package insert, anomalies of the distal limbs, heart, esophagus, kidney and nervous system. Embryofetal Toxicity is listed 
as a boxed warning in the package insert [28]. 
Lymphoma and Other Malignancies: Patients receiving MMF, or immunosuppressants in general, are at increased risk 
of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity 
and duration of immunosuppression rather than to the use of any specific agent. Malignancies are listed as a boxed 
warning in the package insert [28]. 
Post-transplant lymphoproliferative disorder (PTLD) developed in 0.4% to 1% of patients receiving MMF (2 g or 3 g) with 
other immunosuppressive agents in controlled clinical trials of kidney, heart and liver transplant patients. The majority 
of PTLD cases appear to be related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those 
individuals who are EBV seronegative, a population which includes many young children.  
Infections: Patients receiving MMF, or immunosuppressants in general, are at increased risk of developing bacterial, 
fungal, protozoal and new or reactivated viral infections, including opportunistic infections. The risk increases with the 
total immunosuppressive load. These infections may lead to serious outcomes, including hospitalizations and death. 
Serious viral infections reported include: Polyomavirus-associated nephropathy, especially due to BK virus infection; JC 
virus-associated progressive multifocal leukoencephalopathy Cytomegalovirus (CMV) infections, especially for CMV 
seronegative transplant patients who receive an organ from a CMV seropositive donor; and viral reactivation in patients 
infected with Hepatitis B and C. Serious infections are listed as a boxed warning in the package insert [28]. 
Blood Dyscrasias: Neutropenia and Pure Red Cell Aplasia (PRCA): Severe neutropenia [ANC < 0.5 x 103/µL] developed in 
transplant patients receiving MMF 3 g daily, a dose higher than intended for this study. Neutropenia has been observed 
most frequently in the period from 31 to 180 days post-transplant in patients treated for prevention of kidney, heart and 
liver rejection.  
Cases of PRCA have been reported in patients treated with MMF in combination with other immunosuppressive agents.  
GI Disturbances: Diarrhea and vomiting are common. Gastrointestinal bleeding requiring hospitalization, ulceration and 
perforations were observed in clinical trials.  
 

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5.2 Risks of voclosporin as cited in the Investigator Brochure and Package Insert 
Risks cited below are noted in the voclosporin Investigator’s Brochure [65] and Package Insert [21]. 
Contraindications:  
• 
Voclosporin is contraindicated in patients with hypersensitivity or anaphylactic reactions to voclosporin or 
any constituents [65].  
• 
Voclosporin should not be given with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin). Voclosporin exposure was 18-fold higher in the presence of the strong CYP3A4 inhibitor 
(ketoconazole) compared to voclosporin administered alone [65].  
• 
Voclosporin should not be given in patients with hypertensive urgency or BP > 165/105 mmHg [21].  
• 
Voclosporin is not recommended for patients with a baseline eGFR < 45 mL/min per 1.73 m2 unless benefit 
exceeds risks [21].  
Hypertension: Voclosporin can cause or worsen systemic HTN. Mild or moderate HTN is encountered more frequently 
than severe HTN. Serious adverse drug reactions (SADR) classified by the MedDRA preferred term “hypertension” are 
considered “expected” for the purpose of regulatory reporting. Life-threatening or fatal SADRs are “unexpected”. HTN 
may require antihypertensive therapy. 
Decreases in GFR: Voclosporin can cause chronic and/or acute nephrotoxicity. eGFR should be monitored regularly and 
dose adjustments considered for decreases in eGFR. In the first 4 weeks of treatment with voclosporin, hemodynamic 
reductions in eGFR have been observed, which subsequently stabilize. Chronic nephrotoxicity has been observed at 
levels of CNI suppression needed in organ transplantation. The level of CNI suppression of voclosporin in LN is lower 
than that generally required in transplantation induction and maintenance. Renal impairment and acute kidney injury 
occurred more frequently in voclosporin-treated patients than placebo-treated patients. 
Serious Infections: Immunosuppressants, including voclosporin, may increase the risk of developing bacterial, viral, 
fungal, and protozoal infections, including opportunistic infections. These infections may be serious and have fatal 
outcomes. Serious infections are listed as a boxed warning in the package insert [21]. 
Neurotoxicity: Voclosporin, like other CNIs, may cause a spectrum of neurotoxicities, the most severe of which are 
posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma; others include tremors, 
paresthesias, headache, mental status changes, and changes in motor and sensory functions. 
Hyperkalemia: Voclosporin has been reported to cause hyperkalemia which may be exacerbated by use of other agents 
such as potassium-sparing diuretics, ACE inhibitors and angiotensin receptor blockers.  
QTc prolongation: Voclosporin prolongs the QTc interval in a dose-dependent manner after single dose administration at a dose 
higher than the recommended LN therapeutic dose. The use of voclosporin in combination with other drugs that are known to 
prolong QTc may result in clinically significant QT prolongation.  
Pure Red Cell Aplasia: Although not reported with voclosporin, cases of PRCA have been reported in patients treated 
with other CNIs.  
Lymphomas and Other Malignancies: Voclosporin is an immunosuppressant. Long-term treatment with 
immunosuppressants increases the risk of developing lymphomas and other malignancies, particularly of the skin. The 

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risk appears to be related to the intensity and duration of immunosuppression rather than to specific use of a 
medication. Patients should be advised to avoid or limit unprotected exposure to sunlight and UV light. Malignancy is a 
boxed warning in the package insert [21]. 
Other Concerns:  
• 
Voclosporin should be avoided during pregnancy because of the alcohol content of the drug formulation. 
Nonclinical studies with oral voclosporin showed that low levels of voclosporin crossed the placental barrier. 
The available data on the use of voclosporin in pregnant women are insufficient to determine whether there 
is a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. Study 
product will be discontinued in any participant who becomes pregnant, and the pregnancy will be followed 
per Section 12.6, Pregnancy Reporting. 
• 
Limited transfer to breast milk was also demonstrated in rats. No information is available on the presence of 
voclosporin in human milk, the effects of voclosporin on the breastfed infant, or the effects of voclosporin 
on milk production. 
5.3 Risks of long-acting corticosteroid injections  
Corticosteroids rapidly decrease the numbers and function of peripheral lymphocytes and inflammatory cytokines. 
Short term, high dose IM injections are generally well tolerated, but it is important to monitor for HTN, fluid retention 
and common psychiatric side effects including insomnia and agitation. The potential side effects of corticosteroids are 
well documented and familiar to the lupus clinic. Although the temporary use of steroid injections used in this protocol 
is not likely to lead to many side effects, it is important for all study staff to be familiar with them and is good clinical 
practice. Discussions about minimizing steroids will take place with all participants with SLE, who suffer significant 
morbidity over the many years of illness from these extremely useful but chronically toxic medications. 
Potential risk of long term corticosteroid use may result in cardio-renal side effects such as elevation of blood pressure, 
increased excretion of potassium, and increased calcium excretion; endocrine side effects such as hypothalamic-
pituitary adrenal  axis suppression, Cushing’s syndrome, and hyperglycemia; dermatological side effects such as acne, 
striae, thin parchment skin, and easy bruising; ophthalmic side effects such as posterior subcapsular cataracts, 
glaucoma with possible damage to the optic nerves, and enhanced risk of secondary ocular infections; weight gain; 
moon facies; increased susceptibility to infections, and osteoporosis. In addition, glucocorticoids can cause 
dyslipidemia, heart disease, fluid retention, gastrointestinal bleeding and neuropsychiatric effects like mood disorders 
and psychosis. Many of the risks are for corticosteroid use in general and may not be applicable for the short periods 
before randomization and re-randomization for which this treatment will be used.  
Risks of intramuscular administration of methylprednisolone acetate cited below are noted in the United States 
Prescribing Information for DEPO-MEDROL® (methylprednisolone acetate injectable suspension, USP) from 2018.  
Contraindications:  
• 
Methylprednisolone acetate is contraindicated in patients with known hypersensitivity to the product and 
its constituents.  
• 
Methylprednisolone acetate is contraindicated in systemic fungal infections, except when administered as 
an intra-articular injection for localized joint conditions. 
• 
Administration of live or live, attenuated vaccines is contraindicated in patients receiving 
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With the use of triamcinolone acetonide IM, there is a risk of subcutaneous fat atrophy and hypopigmentation which 
can be minimized by intramuscular injection into the gluteal muscle using at least a 1 1/2 inch needle [72]. 
5.4 Risks of Withdrawal of Lupus Medications  
During Stage 1, consenting participants will withdraw from current lupus medications. Withdrawal of lupus medications per 
protocol prior to randomization into Stage 2 could lead to disease exacerbation or flare. After signing of consent, the participant 
will receive a corticosteroid injection, which may be repeated an additional 2 times to achieve amelioration of symptoms. The 
use of corticosteroid injections which naturally wane in their effects gradually is a mitigation strategy for these risks. 
5.5 Special Considerations for COVID-19 or Other Public Health Emergency 
Clinical trial conduct may be impacted by the COVID-19 or other infectious disease public health emergency. Infectious disease 
screening or testing procedures mandated by local health authorities or the health system where the clinical trial is conducted 
may be performed without the need for a protocol amendment. In certain cases, the participants may not be able to come to the 
study site, or local institutional policies or other factors may limit access to the research site. The sponsor, study team, and site 
investigator will determine if alternative methods for conducting assessments and procedures are necessary and feasible, for 
example telemedicine. The safety of participants is paramount. 
Participants will be educated regarding the risk of the infectious disease, and about public health recommendations for 
precautions. 
5.6 Potential Benefits 
For Stage 2 (randomization to MMF or corresponding placebo MMF), one or more baseline immunophenotypes may be 
associated with treatment success (or failure). This knowledge could set the stage for future studies to establish 
biomarkers that inform treatment option decisions. 
Voclosporin, in combination with MMF, has shown benefit in LN. Although it has not been evaluated in SLE without LN, 
participants treated with voclosporin plus MMF in Stage 3 (randomization to voclosporin plus MMF or MMF alone) may 
experience a longer period of symptom relief when compared to participants who receive MMF alone.  
The knowledge gained from this study may advance our understanding of how molecular and gene expression profiles 
relate to treatment success (or failure) and suggest strategies for personalized medicine for future study. 
6 Investigational Agent  
6.1 Investigational Agents 
6.1.1 MMF and Placebo for MMF  
6.1.1.1 Formulation, Packaging, and Labeling 
 MMF is an antimetabolite immunosuppressant [28]. It is the 2-morpholinoethyl ester of MPA, an 
immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor. The chemical name for 
MMF is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-
methyl-4-hexenoate. MMF is a white to almost white crystalline powder. It is slightly soluble in water (43 
mcg/mL at pH 7.4), freely soluble in acetone, soluble in methanol, sparingly soluble in anhydrous ethanol [28].  

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Commercially available MMF (250 mg capsules) manufactured by Sandoz will be purchased by NIAID 
Investigational Product Procurement Center, and overencapsulated, rebottled, blind labeled, packaged, and 
distributed by DAIT/NIAID Clinical Product Center (CPC) to site investigational pharmacies. 
Placebo for MMF will be manufactured by DAIT CPC and will not contain active ingredients. Both MMF and 
placebo for MMF will be overencapsulated to blind MMF/Placebo capsules. 
6.1.1.2 Dosage, Preparation, and Administration 
MMF and matching placebo for MMF will be provided in 250mg overencapsulated gel capsules and will be 
administered orally. The blinded overencapsulated MMF/Placebo capsules should not be opened or crushed. 
Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in blinded 
overencapsulated MMF/Placebo capsules. 
Blinded overencapsulated MMF/Placebo should be stored at 20° to 25°C (68° to 77°F).  
Stage 2 Dosing: 
• 
Week 1: Participants will receive 500mg MMF/Placebo twice daily 
• 
Week 2: Participants will receive 500mg/Placebo in the morning and 1,000mg MMF/Placebo in the 
evening 
• 
Weeks 3-48: Participants will receive 1000mg MMF/Placebo twice daily 
Stage 3 Dosing: (Individuals who received placebo MMF in Stage 2) 
• 
Week 1: Participants will receive 500mg MMF plus matching placebo for MMF (to appear like a 
1000mg dose) twice daily 
• 
Week 2: Participants will receive 500mg plus matching placebo for MMF (to appear like a 1000mg 
dose) and 1000mg in divided doses 
• 
Weeks 3-24: 1000mg MMF twice daily  
Participants who received MMF in Stage 2 
• 
Week 1-24: 1000mg MMF twice daily 
 
6.1.2 Voclosporin and Placebo for Voclosporin  
6.1.2.1 Formulation, Packaging, and Labeling 
Voclosporin is a calcineurin-inhibitor immunosuppressant [21]. Chemically, voclosporin is named: Cyclo{{(6E)-
(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6,8-nonadienoyl}-L-2-aminobutyryl-N-methyl-glycyl-N-methyl-
L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl}. It 
appears as white to off-white solid matter. At ambient temperature, voclosporin is freely soluble in acetone, 
acetonitrile, ethanol, and methanol, and practically insoluble in heptanes (USP). Voclosporin is practically 
insoluble (less than 0.1 g/L at 20ºC) in water and melts above 144ºC with decomposition [21].  
The manufacturer Aurinia Pharmaceuticals will supply LUPKYNISTM (voclosporin) 7.9 mg gel capsules and placebo 
for voclosporin. Placebo capsules do not contain active ingredients.  

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DAIT CPC will label and distribute active voclosporin and placebo for voclosporin to the clinical site pharmacies. 
Clinical site pharmacies will dispense voclosporin/placebo to participants as required per arm of Stage 3.  
6.1.2.2 Dosage, Preparation, and Administration 
Voclosporin will be provided in 7.9 mg gel capsules for oral administration. Placebo for Voclosporin will be 
provided as gel capsules for oral administration. 
 
The rate and extent of voclosporin absorption is decreased on co-administration with food, therefore, to maximize 
absorption it is recommended that voclosporin is administered on an empty stomach.  
Voclosporin should be stored at 20° to 25°C (68° to 77°F).  
Stage 3 Dosing: 
• 
Weeks 1-24: 23.7 mg Voclosporin/Placebo (3 x 7.9 capsules) twice daily 
Voclosporin/Placebo dose may be modified for renal impairment, see Section 6.4.7, Decreases in eGFR. 
• 
Allowed voclosporin/placebo dose reductions include: 15.8 mg or Placebo (2 capsules) orally twice 
daily and 7.9 mg or Placebo (1 capsule) orally twice daily.  
6.2 Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62), the investigator will maintain adequate records of 
the disposition of the investigational agents, including the date and quantity of the product(s) received, to whom the 
product(s) was dispensed (participant-by-participant accounting), and a detailed accounting of any product(s) 
accidentally or deliberately destroyed. Details of investigational product(s) distribution to each participating clinical site 
will be maintained by the DAIT CPC.  The investigator must delegate the drug accountability responsibility to a 
licensed/registered pharmacist at registered investigational pharmacy at the clinical research site. Please refer to the 
DAIT Pharmacy Guidelines (https://www.niaid.nih.gov/sites/default/files/pharmacy.pdf). 
All personnel involved in drug management and preparation must receive proper training based on the DAIT and site 
requirements prior to study initiation. The Pharmacist of Record should be listed on the Delegation of Responsibility Log 
(DoR) and is responsible to ensure that any pharmacy personnel involved in any aspect of the drug management, 
preparation, and dispensing process have completed and documented all DAIT required trainings (Good Clinical Practice 
(GCP)/Human Subject Protection (HSP), protocol/pharmacy manual, DAIT Pharmacy Guidelines). Only individuals listed 
on the DoR log and/or the Investigator of Record Agreement (IORA) may manage drug products for this study. All drug 
disposition and dispensing (receipt, storage, use, return, and disposition) will be maintained by the study site using 
investigation product(s) and/or placebo-accountability and participant-specific dispensing logs that are approved by 
DAIT/NIAID and 21 CFR Part 11 compliant. This log will contain the identification of each participant and the date and 
quantity of investigational product(s) dispensed. 
The study clinical research associate (CRA) will conduct accountability of the drugs by monitoring the main 
Accountability Records and Participant-Specific Accountability logs. The study CRA will also review other pharmacy logs, 
as applicable. All records regarding the disposition of the investigational product(s) will be available for monitoring and 
inspection. At the termination of the study, all unused product(s) (expired or un-expired) will be returned to DAIT CPC. 
For more detailed information on handling of the investigational product(s), please refer to the Pharmacy Manual.  

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6.3 Assessment of Participant Compliance with Investigational Agents 
The number of capsules of study product returned to the site will be counted and recorded at all clinic visits. Participants 
will also be given a diary to record episodes of intolerance or reasons why a pill may not have been taken. 
6.4 Toxicity Prevention and Management 
6.4.1 Hypersensitivity 
Individuals with known hypersensitivity MMF, MPA, any component of MMF, Polysorbate 80 (Tween), long-acting 
corticosteroid preparations or their constituents, or voclosporin or its constituents will be excluded from participation 
in the trial. 
6.4.2 Reproductive Risks 
Women on MMF are at increased risk of first trimester pregnancy loss and congenital malformations in children. Data 
on pregnancy risk is unavailable for voclosporin. Women of childbearing potential will have a pregnancy test at each 
study visit. Should pregnancy occur, study medications will be discontinued immediately, study visits will continue as 
scheduled except for study medication, and the pregnancy will be followed per Section 12.6, Pregnancy Reporting. 
Appropriate referrals should be made for counseling on fetal effects of study medication. The pregnancy should be 
reported to the Mycophenolate Pregnancy Registry, which is a part of the MMF REMS program. Male participants 
and female partners capable of becoming pregnant are encouraged to use a contraceptive barrier method during the 
study. 
6.4.3 Malignancy 
Immunosuppression is associated with increased risk of lymphoma and other malignancies, particularly skin cancers. 
Participants should be advised to avoid or limit unprotected exposure to sunlight and UV light. If evidence of 
lymphoproliferative disease emerges, work up will be guided by the institution’s standard of care requirements. If 
malignancy (other than non-melanoma skin cancer) is diagnosed, study medications will be discontinued, and the 
participant will be treated according to standard of care per institutional requirements. If new non-melanoma skin 
cancer is found and fully treated with local procedures, the participant may continue in the trial as planned based on 
investigator discretion. Participants over the age of 50 should have age-appropriate cancer screenings at the 
investigator’s discretion prior to enrollment and throughout the course of the study. For additional information, 
consult the American Cancer Society (ACS) reference below: 
http://www.cancer.org/healthy/toolsandcalculators/reminders/screening-recommendationsby-age  
6.4.4 Infections 
Immunosuppression is associated with increased risk of infection. Individuals with active or chronic infections are 
excluded from the study. Participants will receive guidance recommending vaccinations be up-to-date according to 
local standards and lymphocyte counts will be monitored through the study. Participants will be followed closely for 
signs of infection at study visits, and between visits if needed. In the setting of infection, study medications may be 
withheld based on institutional practices or investigator judgment, for up to 2 weeks and then resumed at scheduled 
dose. Otherwise, refer to the guidelines in in 6.5, Premature Discontinuation of Investigational Agent in the event of 
toxicity. 
Additionally, low IgG levels are found in less than 10% of patients with SLE and are usually not associated with 
infection [73]. However significant drops in IgG have been seen with various immune-modulating medications and if 

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not carefully monitored may increase risk for serious infections and death [26, 43]. We will employ a safety mitigation 
strategy that was successfully employed in a study of Atacicept, the ADDRESS II trial [74]. At the Screening Visit, 
participants must have serum IgG levels ≥ 5 g/L. Immunoglobulin levels will be checked throughout the course of the 
study per Table 8.1 Schedule of Events. If at any time during the study these levels fall to < 4 g/L, study medication 
will be withheld with a retest at one week. If retest demonstrates recovery to ≥ 4.5 g/L, medication may be restarted. 
If not, another retest may be performed in another week. If IgG does not recover to ≥ 4.5 g/L after the second retest, 
study medication will be permanently withdrawn as per the guidelines in Section 6.5, Premature Discontinuation of 
Investigational Agent. 
6.4.4.1 SARS-CoV-2 Infections 
Participants are encouraged to receive full COVID-19 vaccination per CDC guidelines. Participants will be tested 
for SARS-CoV-2 as part of screening as mandated by the entry criteria and throughout the study as clinically 
indicated. Assessment, prophylaxis, and treatment for infection will be guided by standard of care per 
institutional requirements; however, individuals participating in ALE10 are at high risk for SARS-CoV-2 infection. 
Per standard recommendations, a participant with mild to moderate COVID-19 symptoms should be evaluated 
for treatment with an FDA authorized or approved COVID-19 treatment as soon as possible following 
confirmation of the infection and within 10 days of symptom onset. Additionally, any participant who has close 
contact with a SARS-CoV-2 infected individual should be evaluated as soon as possible after exposure. Additional 
FDA Approvals and EUAs are anticipated for the prevention and treatment of SARS-CoV-2. Site investigators are 
expected to keep abreast of these approvals and authorizations in order to advise ALE10 trial participants about 
optimal prevention and treatment. NIH COVID-19 treatment guidelines can be found here: 
https://www.covid19treatmentguidelines.nih.gov/.  
6.4.5 Gastrointestinal Abnormalities 
Gastrointestinal side effects including nausea and diarrhea are associated with MMF use. If these symptoms 
exacerbate without other likely explanation, study medications may be withheld for up to 2 weeks and resumed at 
the scheduled dose. Otherwise, refer to the guidelines in Section 6.5, Premature Discontinuation of Investigational 
Agent in the event of toxicity. 
6.4.6 Hypertension 
Voclosporin may be associated with increased risk of HTN [75]. Individuals with uncontrolled HTN are excluded from 
participation in the study (See Section 4.3, Exclusion Criteria number 7 for additional detail). During the study, blood 
pressure will be evaluated at each study visit, including once 2 weeks after initiating Stage 3 study therapy. Clinically 
concerning elevated blood pressure should be managed with antihypertensive therapy. In the event of HTN 
associated with a SAE or a Grade 3 or above AE that is possibly or definitely related to study medication, study 
medications may be withheld for up to 2 weeks. If the AE does not resolve down to Grade 2 or below after 2 weeks of 
withholding medication, study medication should be discontinued. If the AE improves to grade 2 or below but 
increases again to grade 3 once study medication is reinstituted then study product should be discontinued 
permanently.  
6.4.7 Decreases in eGFR 
For voclosporin use, regular monitoring of eGFR is recommended per the Investigator Brochure, every 2 weeks for 
first month then every 4 weeks thereafter. Clinically significant decreases have been observed with voclosporin plus 

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MMF as well as for MMF alone. For this study, individuals with eGFR < 45 mL/min per 1.73 m2 at screening are 
excluded. eGFR will be evaluated at each study visit. It will also be assessed at a Stage 3 Week 2 Safety Check Visit 
two weeks after initiating Stage 3 therapy. The most recent assessment of eGFR before the Stage 3 Re-randomization 
Visit should be used as baseline for Stage 3 Week 2 eGFR assessment. 
If eGFR < 60 mL/min per 1.73 m2 and is reduced from Stage 3 baseline by 20-30%, reduce dose by one capsule BID 
(total of 2 capsules BID). Reassess eGFR in 2 weeks, and if it is still reduced by > 20% from baseline, reduce dose to 1 
capsule BID. If eGFR < 60 mL/min per 1.73 m2 and reduced from Stage 3 baseline by > 30%, withhold voclosporin for 2 
weeks, then reassess and consider re-initiating at 1 capsule BID if eGFR is > 80% of baseline.  
6.4.8 Glucose and Diabetes  
The development of new-onset diabetes is in an important, recognized effect of CNI inhibitors. In voclosporin clinical trials, 
the incidence of AEs related to diabetes and glycemic control was low and similar in both treatment groups, indicating that 
there is no increase in these types of events with voclosporin treatment. Uncontrolled diabetes may be excluded from the 
trial per investigator discretion according to the inclusion/exclusion criteria set in Section 4, Selection of Participants. 
6.4.9 Hematological Abnormalities 
Individuals meeting thresholds for exclusionary levels of neutrophils, WBC, platelets, and hemoglobin at screening 
are excluded from the study (See Section 4.3, Exclusion Criteria number 8 for additional detail). To monitor potential 
hematological toxicity, the participants will have a complete blood count at each visit. If any of the following develop 
without explanation and persist after a repeat check in one week, then study medications will be held for one week 
and the test repeated: 
• 
neutropenia (neutrophils < 800/mm3, equivalent to 0.8 x109/L),  
• 
leukopenia (WBC < 1500/mm3, equivalent to 1.5 x109/L),  
• 
thrombocytopenia (platelets < 40,000/mm3, equivalent to 40 x109/L), or  
• 
anemia (hemoglobin < 7.0 g/dL).  
 
Study medication may be held up to 2 weeks while the abnormality is monitored weekly for recovery. If recovery to 
screening value occurs then study medication can be resumed. Otherwise, refer to the guidelines in Section 6.5, 
Premature Discontinuation of Investigational Agent in the event of toxicity. If participants have symptomatic 
complications from the hematological derangements, this should be treated according to standard of care per 
institutional requirements. 
6.4.10 Hepatic Abnormalities 
Individuals with AST or ALT > 2.5x ULN at screening are excluded from the study. Liver function tests will be checked 
every 4 weeks for signs of hepatic toxicity. If transaminases exceed 3x ULN without explanation, then study 
medications will be held for up to 2 weeks, and the abnormality followed weekly for resolution to screening value. 
Should resolution occur within 14 days, the study medication may be resumed. Otherwise, refer to the guidelines in 
6.5, Premature Discontinuation of Investigational Agent in the event of toxicity. 
6.5 Premature Discontinuation of Investigational Agent 
Study participants who discontinue investigational agent prematurely but are willing and able to remain in the study and 
undergo evaluation per protocol will be encouraged to do so. 

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Study therapy may be paused for up to 2 weeks for infections, gastrointestinal abnormalities, HTN, decreased eGFR, 
hematologic abnormalities and hepatic abnormalities as detailed in Section 6.4, Toxicity Prevention and Management.  
Study therapy may be prematurely discontinued for any participant for any of the following reasons: 
1. Participant decision. 
2. Determination of unacceptable toxicity, including but not limited to: 
a. Gastrointestinal abnormalities that do not resolve after study medications are withheld for up to 2 
weeks as outlined in Section 6.4.5, Gastrointestinal abnormalities; 
b. HTN that does not resolve after study medications are withheld for up to 2 weeks as outlined in 
Section 6.4.6, Hypertension; 
c. Decreased eGFR that does not resolve after study medications are withheld for 2 weeks as outlined 
in Section 6.4.7, Decreases in eGFR;  
d. Hematological Abnormalities that do not resolve after study medications are withheld for up to 2 
weeks as outlined in Section 6.4.9, Hematological Abnormalities;  
e. Hepatic Abnormalities that do not resolve after study medications are withheld for up to 2 weeks as 
outline in Section 6.4.10, Hepatic Abnormalities; 
f. Grade 4 Leukopenia (WBC < 1000/mm3, equivalent to 1.0 x109/L); and  
g. Grade 4 Neutropenia (Neutrophils < 500/mm3, equivalent to 0.5 x109/L); 
3. Treating physician determination of any condition that warrants withdrawal of study medication. 
4. Any condition that in the opinion of the DAIT Medical Monitor warrants withdrawal of study medication. 
5. The participant becomes pregnant. 
6. The participant develops a malignancy (other than non-melanoma skin cancer). 
7. Treatment failure, as defined in Section 3.5.1, Clinical Endpoints including corticosteroid injection(s) or 
treatment with a new or increased lupus medication. 
8. Toxicity or Infection (see Section 6.4, Toxicity Prevention and Management): 
a. If study medication is withheld for more than 14 sequential days due to suspected toxicity or 
infection. 
b. Grade 4 infection. 
7 Other Medications 
7.1 Concomitant Medications 
Information about the concomitant medications and treatments will be collected at each visit. All concomitant 
medications given to the participant during the study will be recorded on the electronic case report form (eCRF). 
7.1.1 Protocol-mandated: Corticosteroid Injections 
During Stage 1, at least one IM injection of a long-acting corticosteroid must be given to participants. This may be 
repeated up to 2 additional times as needed to ameliorate symptoms.  
 
Participants may also receive a long-acting corticosteroid IM injection to ameliorate symptoms during the first 24 
weeks of the study due to treatment failure as defined in Section 3.5.1, Treatment Failure. An additional 
corticosteroid injection may be administered during the first 2 weeks of Stage 3 treatment without meeting the 
definition of treatment failure in Stage 3 and without a requirement to stop Stage 3 study-provided medication, for a 

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total of 2 corticosteroid injections from the time of Stage 2 Treatment Failure up and including to the Stage 3 Week 2 
Visit. 
 
Dose will be dependent on the available formulation. Methylprednisolone acetate (80mg) will be used for all 
corticosteroid injections administered during the study. If methylprednisolone acetate (80mg) is not available, 
triamcinolone acetonide (60mg) may be substituted. If triamcinolone acetonide (60mg) is not available, substitution 
of a therapeutically equivalent long-acting corticosteroid injection may be allowed but must be approved by the 
study NIAID Medical Monitor. 
7.1.2 Permitted Concomitant Medications for SLE 
7.1.2.1 Anti-malarial Agents 
Participants can be on concurrent hydroxychloroquine, chloroquine or quinacrine at a prescribed dose that has 
been stable for at least 2 months prior to randomization. Hydroxychloroquine is approved by the FDA for the 
treatment of SLE. Hydroxychloroquine has been shown to help prevent flare in SLE, and to improve skin and 
musculoskeletal activity in particular [76, 77]. Even LN outcomes appear improved on a background of 
hydroxychloroquine therapy [78]. 
7.1.2.2 Prednisone (or equivalent) 
Individuals may screen for the study if taking up to 20 mg/day prednisone (or equivalent) but both the 
participant and the investigator must be willing and able to taper to 10 mg/day (under cover of long-acting 
corticosteroids) by the Stage 2 Randomization Visit. Prednisone (or equivalent) may be continued at a stable 
dose ≤ 10 mg/day once the participant is randomized into the trial. Individuals are not eligible for the study if 
they have taken ≥ 40 mg/day of prednisone within 4 weeks prior to the Screening Visit.  
To accommodate the occasional use of extra corticosteroids for reasons not associated with SLE flares, increases 
of up to 40 mg/day that are decreased back to the baseline dose within 14 days are permitted, but not on more 
than one occasion prior to Week 20 in Stage 2 and one occasion prior to Week 20 in Stage 3.  
7.1.2.3 NSAIDS 
Participants may start or continue NSAIDS PRN during the course of the study. NSAIDs should be held on the 
morning of study visits. 
7.1.2.4 Topical treatments for Lupus 
As needed topical treatments for the treatment of lupus symptoms that are initiated prior to screening may be 
continued. New topical treatments are restricted after screening.  
7.1.3 Permitted Concomitant Medications for non-SLE Conditions 
Concomitant therapies taken for long-term treatment of pre-existing conditions other than SLE should be continued 
during the study, provided that they are in accordance with the exclusion criteria (see Section 4.3, Exclusion criteria). 
It is preferred that these medications be stabilized before entry and continued wherever practical without variation 
of dose or regimen during the study. Participants should also continue to receive SARS-CoV-2 vaccinations per CDC 
and FDA recommendations and other vaccinations as recommended by their treating physician during the course of 
the study. 

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7.2 Prophylactic Medications 
There are no protocol-mandated prophylactic medications. However, non-immunosuppressive treatments for symptom 
control (anti-emetics, antipyretics) in susceptible participants will be allowed as determined appropriate by the local 
investigator. Participants should continue to take their medications for co- morbid conditions, but these should be 
reviewed by the investigator prior to the start of the study in order to ensure no prohibited medications are being taken 
(see Section 7.3, Prohibited Medications). 
7.3 Prohibited Medications 
All participants are to have access to any care deemed medically necessary, but administration of the following 
medications, for the purposes of this study, are prohibited: 
7.3.1 Live Attenuated Vaccines 
Live attenuated vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, 
and TY21a typhoid vaccines) will be prohibited for the course of the study. 
7.3.2 Immunomodulatory or Immunosuppressive Medications 
No new or increased immunomodulatory or immunosuppressive medications may be added while a participant is on 
study drug. Participants who require a new or increased immunomodulatory or immunosuppressive medication will 
be considered as having met primary endpoint (see Section 3.2, Primary Endpoint) and will be required to discontinue 
study drug (see Section 6.5, Premature Discontinuation of Investigational Agent) prior to initiating the new or 
increased lupus therapy. 
7.3.3 Grapefruit Juice 
Grapefruit juice will not be permitted during Stage 3. 
7.3.4 Strong CYP3A4/5 Inhibitors and Inducers 
Strong CYP3A4/5 inhibitors and inducers will be prohibited during Stage 3 of the study. For common examples of 
Strong CYP3A4/5 inhibitors and inducers, please see Appendix 2. Additionally, please reference the tables in the FDA 
guidance regarding CYP3A4 inhibitors and inducers: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers. 
7.3.5 Moderate CYP3A4/5 Inhibitors and Inducers 
Moderate CYP3A4/5 inhibitors and inducers should be avoided during Stage 3 if possible. Voclosporin is a weak 
inhibitor of P-gp and caution is advised for co-administration of voclosporin with the sensitive P-gp substrate, digoxin, 
with appropriate monitoring of digoxin performed as clinically indicated and described in the digoxin product 
labeling. Additionally, please reference the tables in the FDA guidance regarding CYP3A4 inhibitors and inducers: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-
inhibitors-and-inducers. 
7.3.6 Antacids  
Antacids with magnesium or aluminum hydroxide, proton pump inhibitors, drugs that interfere with enterohepatic 
recirculation, telmisartan, and calcium-free phosphate binders should be avoided while a participant is on study 
medication as they may interfere with systemic exposure and reduce MMF efficacy. 

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8 Study Procedures 
8.1 Study Visits 
8.1.1 Screening and Enrollment  
The study will be explained in lay terms to each potential research participant. The potential participant will sign an 
IRB-approved informed consent form (ICF) before undergoing any study procedures. Once the ICF has been signed, 
the participant is considered enrolled in the study and will be assigned a unique participant number. At this time, 
study-specific procedures may be performed. Consented participants will receive an intramuscular injection of a long-
acting corticosteroid at screening which may be repeated if needed to achieve amelioration of symptoms. 
Withdrawal of background lupus medications can start any time after the first corticosteroid injection is given, but 
must be complete by the Stage 2 Randomization Visit. 
 
The purpose of screening, which begins at the time of signed consent, is to confirm eligibility to enter the study. All 
screening procedures, assessments, and laboratory measures to determine participant eligibility will be conducted 
within a 28-day screening window. The assessment of eligibility may take a series of visits that occur on separate 
days. Blood draws for screening should be performed prior to initiation of any change of therapy, including 
corticosteroid injection(s) or withdrawal of background medications. The Screening Visit biomarkers should reflect, as 
much as possible, the biometrics of the participant prior to any study procedures. Participants with abnormal 
laboratory values that prohibit entry may be re-tested once during the screening, which may last up to 28 days. 
Participants who screen fail may be rescreened one time and must repeat all screening assessments. Any further 
rescreening activity requires approval by the medical monitor. 
Participants who withdraw from their lupus medications and then screen fail prior to Stage 2 will have a safety 
follow-up visit 4 weeks ± 10 days after the date of screen fail. Participants will then be treated by their 
rheumatologist per clinical judgment.  
Participants who do not screen fail at screening will undergo review by a committee of at least two adjudicators. The 
committee will include the protocol chair and the NIAID medical monitor. The committee will have access to a secure 
website and will receive an email notification when materials for a potential participant have been uploaded. The 
review packet will contain a paragraph from the investigator, the EULAR/ACR 2019 criteria, SLEDAI, BILAG, and clinical 
notes. The investigator will be required to answer the following questions:  
1. Is active lupus occurring and can it be classified properly? 
2. Is current disease activity sufficient to meet inclusion/exclusion criteria? Here the investigator will justify 
why they scored lupus disease activity the way they did. 
3. Is the participant stable enough to participate in the study? Here the investigator will ensure that the 
participant does not have organ-threatening disease or is too sick to participate in the study. 
The committee will confirm entry criteria. Site investigators will need to be available to answer any questions the 
committee has within 2 business days. 
 
 

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8.1.2 Evaluation of Eligibility and Randomization for Stage 2 
Participants who meet all eligibility criteria and show improvement will proceed with Stage 2 randomization, 
treatment, visits, and assessments according to Table 8.1, Stage 1 & 2 Schedule of Events. See Section 8.2, Study 
Procedures and Assessments for more information on individual clinical and research assessments.  
8.1.3 Study-Provided Medication for Stage 2 
• 
Stage 2 study-provided medication (MMF or corresponding MMF placebo) is dispensed to eligible 
participants at the Stage 2 Randomization Visit after confirmation of participant eligibility and completion 
of all study visit activities, including corticosteroid injection (if applicable). Dosing begins on the day of 
randomization.  
• 
Study medication compliance is evaluated at all follow-up visits.  
• 
Refer to Section 3.1.2, Stage 2 Randomization for additional information. 
8.1.4 Evaluation and Eligibility for Stage 3 
Eligible and consenting participants who have a qualifying Stage 2 treatment failure at or before the Stage 2 Week 24 
Visit will immediately proceed with Stage 3 re-randomization according to Table 8.2, Stage 3 Schedule of Events. If a 
qualifying Stage 2 treatment failure is identified after a visit has taken place due to laboratory values, the participant 
should return for Stage 3 re-randomization within 5 days of discovery of the event. See Section 8.2 Study Procedures 
and Assessments for more information on individual clinical and research assessments. 
8.1.5 Study-Provided Medication for Stage 3 
• 
Stage 3 study-provided medication (MMF/voclosporin or MMF/corresponding placebo for voclosporin) is 
dispensed to eligible participants at the Stage 3 Re-Randomization Visit. Dosing begins on the day after 
re-randomization. 
• 
Study medication compliance is evaluated at all following visits.  
• 
Refer to Section 3.1.3, Stage 3 Re-Randomization for additional information. 
8.1.6 Unscheduled Visits 
The investigator may schedule visits in addition to those listed in Table 8.1, Stage 1 & 2 Schedule of Events and Table 
8.2, Stage 3 Schedule of Events, in order to conduct evaluations or assessments required to protect the well-being of 
the participant. If disease activity increases or other concerns arise between regularly scheduled visits, participants 
will be instructed to contact study personnel and may be asked to return to the study site for an “Unscheduled” visit. 
See Table 8.1, Stage 1 & 2 Schedule of Events and Table 8.2, Stage 3 Schedule of Events, to see what assessments and 
procedures should be obtained for an unscheduled visit. In the event that the unscheduled visit is due to a disease 
flare qualifying as a “treatment failure” (see Section 3.2, Primary Endpoint), see Figure 1, Study Flow Diagram, for 
more information on how the future path of the participant.  
8.1.7 Early Termination 
An Early Termination Visit should be requested for participants who withdraw from the study prior to study 
completion. Assessments to be conducted at an early termination visit can be found in Table 8.1, Stage 1 & 2 
Schedule of Events and Table 8.2, Stage 3 Schedule of Events. 
 

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8.2 Study Procedures and Assessments 
8.2.1 General Assessments 
• 
ICF 
• 
Demographics. Participants should provide demographic information. In particular, race and ethnicity 
should be self-identified. 
• 
Medical History. Medical history will be performed as part of screening activities and standard medical 
care. The medical history assessment will include current illnesses/conditions and past medical history. 
• 
Comprehensive Physical Examination. Physical examinations are to include, at least, the following 
systems: general appearance, skin, head/eyes/ears/nose/neck/throat, respiratory/chest, cardiovascular, 
abdominal, neurological, & musculoskeletal/extremities. Neurological exam may only be performed 
based on participant complaint after the screening and Stage 2 Randomization Visit.  
• 
Vital Signs. Height will only be collected at screening. Weight, temperature, pulse, and blood pressure 
will be collected at each visit. Vital signs should be obtained with the participant in a seated position and 
prior to taking samples for laboratory testing at applicable study visits. 
• 
ECG 
• 
Adverse Event Collection 
• 
Concomitant Medications (including Contraceptives). A current list of prescription and over-the-counter 
medications, supplements, and treatments for SLE will be obtained. Assessment of eligibility should 
include a review of permitted and prohibited medications. The medication, dose, frequency, route, start 
date, stop date, and indication should be captured. 
• 
Treatment Surveys 
8.2.2 Clinical Laboratory Assessments 
Blood and urine for the clinical laboratory assessments listed below will be collected per Table 8.1, Stage 1 & 2 Schedule of 
Events and Table 8.2, Stage 3 Schedule of Events. All laboratory assessments will be collected after the participant sees the 
physician so that appropriate clinical and mechanistic labs can be drawn if the participant is a treatment failure. The results 
will be evaluated for safety by the site investigator. Abnormal tests that meet grading and reporting criteria will be reported 
as AEs (See Section 12.3.1, Grading Criteria). 
• 
Hematology including complete blood count (CBC) with differential. 
• 
Blood Chemistry including complete metabolic panel, eGFR, and creatine kinase PRN. 
• 
Lipids (triglycerides and cholesterol). 
• 
Urinalysis including dipstick, microscopic, and spot protein-creatinine. 
• 
TBNK Trucount 
o For participants who have used B cell depleting therapy within 1 year of screening, CD19+ B Cells will 
also be evaluated at the Screening Visit. 
• 
Anti-dsDNA, C3, C4 
• 
Immunoglobulin G 
• 
Autoantibodies including Antinuclear Antibody (ANA), Extractable Nuclear Antigen Antibodies (ENA) 
Panel (Smith Antibody, anti-RNP, Anti-SSA, Anti-SSB), and anticardiolipin antibodies. 
• 
Infectious Disease Testing (Screening Only) including HIV Testing, Hepatitis B surface antigen and core 
antibody (with viral load if indicated), Hepatitis C antibody (with viral load if indicated), and TB Testing. 

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• 
Pregnancy Testing (Women of Child-Bearing Potential Only). Serum human chorionic gonadotropin 
(HCG) at screening and then urine pregnancy test at all following visits. First date of last menstrual cycle 
should also be collected at each visit.  
• 
SARS-CoV-2 Antigen Testing  
8.2.3 Mechanistic Assessments  
• 
Whole Blood/PBMC/Plasma 
• 
Serum 
• 
RNA Assays 
• 
DxTerity Blood Draw: RNA for Inflammation and Interferon Markers (for Group Stratification)  
• 
Urine 
8.2.4 Disease Activity Assessments 
The original lupus instruments to assess disease flares included an evaluation of proteinuria based on the 
protein:creatinine ratio derived from a 24-hour urine. For this study, the protein:creatinine ratio will typically be 
derived from the spot urine assessment although a 24-hour urine may be used if the investigator believes it is 
indicated. 
All PROs (LFA-REAL PRO, SF-36, and Patient Global Impression of disease activity change and severity (PGI-C and 
PGI-S)) should be completed in a quiet space prior to any other study related assessments. 
8.2.4.1 Hybrid SLEDAI 
The H-SLEDAI is a modification of the SELENA SLEDAI with a simplification of the proteinuria definition [22, 24, 32, 
35]. The H-SLEDAI is a one-page assessment that contains 24 items which are scored as either present or absent. 
The H-SLEDAI captures disease activity within the 28 days prior to the assessment and an item must be 
attributable to SLE to be marked present. Each item is assigned a weighted score. The total score is the sum of the 
weighted scores. 
8.2.4.2 BILAG 2004 
The updated version (BILAG 2004) was published in 2010 and is a validated measure of disease activity [79]. 
BILAG 2004 assesses 97 clinical signs, symptoms and laboratory parameters important in SLE across nine organ 
systems. Each symptom is scored with respect to severity and progress over the previous 28 days (0 = not 
present, 1 = improving, 2 = same, 3 = worse, and 4 = new).  
As above, each item is recorded as 0, 1, 2, 3, or 4. The BILAG 2004 scoring algorithm categorizes disease activity 
into 5 different severity levels from A–E. Grade A represents very active disease likely necessitating 
immunosuppressive drugs and/or a prednisolone (or equivalent) dose of > 20 mg daily or high-dose anti-
coagulation. Grade B represents moderate disease activity prompting consideration of a lower dose of 
corticosteroids, topical steroids, topical immunosuppressive drugs, anti-malarial drugs, or NSAIDS. Grade C 
Planned and potential mechanistic assays for this study are noted below. Blood drawn from participants for 
mechanistic and clinical blood draws may not exceed NIH blood draw limits (550mL over 8 weeks). 
All laboratory assessments will be collected after the participant sees the physician so that appropriate clinical 
and mechanistic labs can be drawn if the participant is a treatment failure. 

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indicates mild stable disease, while grade D implies no disease activity but the system had previously been 
affected. Grade E indicates no current or previous disease activity. 
8.2.4.3 Physician’s Global Assessment 
This instrument has been widely used in SLE trials [80, 81]. This study will implement the PGA as a three inch 
scale with anchors at one inch intervals. The score is determined by asking the investigator to assess the 
participant’s current disease activity over a continuum between anchors of 0 (no disease) to 1 (cutoff for mild 
disease) to 2 (moderate disease) and to 3 (maximally severe disease). This assessment is not made relative to 
the participant’s own most improved or severe state but the most remitted and severe state possible in SLE. The 
scoring procedure requires investigators to compare the current visit to the previous visit in determining the 
score. 
8.2.4.4 LFA REAL 
The LFA-REAL Clinical Reported Outcome (ClinRO) and PRO provide an integrated system that can directly 
compare a patient’s and clinician’s view on individual items that are part of active lupus disease [82, 83] For 
both the patient and clinician components, the instrument is constructed as a series of individual anchored 
visual analogue scales with the ability to assess disease by symptom, by organ or by global total disease. All 
scales default to 0, so it is easy and quick to choose the limited number of symptoms likely to be present at a 
given time and score their severity. 
The patient’s component is complementary but not identical to the clinician’s component [84, 85]. Unlike the 
other PROs to be used in this trial, this is a disease activity assessment by the patients, specific to SLE signs and 
symptoms and it is not a quality of life assessment. Thus, the information it might provide is not redundant to, 
but might be complementary to other PRO measures. 
8.2.4.5 PGI/CGI Anchor Scales 
To provide evidence that may help interpret a meaningful within-patient score change from the point of view of 
both clinicians and patients, simple discontinuous scales will be administered for the CGI-C and Clinical Global 
Impression of Severity (CGI-S) and PGI-C and PGI-S [86-89]. The PGI and CGI-S anchor scales will be administered 
with a recall period of one month. The CGI-C anchor scale will be administered with both a recall period of one 
month and as compared to the start of the current Stage of treatment. 
8.2.5 Other Disease-Specific Assessments 
• 
EULAR/ACR 2019 Classification Criteria (Screening Only) [3]  
• 
SELENA-SLEDAI Flare Index and Thanou Modified Flare Index [4] 
• 
Assessment of Primary Endpoint (Stage 2) and Disease and SLE Treatment Status (Stage 3) 
• 
SF-36 (Patient- Reported) [90] 
• 
Tender and Swollen Joint Count Assessment  
 
 

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K. Physical examinations are to include, at least, the following systems: general appearance, skin, head/eyes/ears/nose/neck/throat, respiratory/chest, cardiovascular, abdominal, neurological, & musculoskeletal/extremities. Neurological exam may only 
be performed based on participant complaint after the screening and Stage 2 Randomization visit. 
L. Participants who withdraw from their lupus medications and then screen fail prior to Stage 2 will have a safety follow-up visit 4 weeks ± 10 days after the date of screen fail.  
M. Local SARS-CoV-2 antigen testing) should be performed if clinically indicated. 
N. MMF/Placebo MMF will not be dispensed if the participant has stopped Stage 2 study-provided medication and has started a new or increased lupus medication due to a treatment failure.  
O. Lab volumes to not exceed 550 cc over 8 weeks.  
P. Participants who exit the study at Stage 2 Week 24 should complete all End of Study/Safety Follow-Up visit assessments at this time. 
Q. Patient-reported outcomes should be completed in a quiet space and prior to any other study assessments.   
R. Local SARS-CoV-2 antigen testing must be completed 2 days before the randomization visit. Participants will be required to self-test 2 days prior to the randomization visit and provide proof of negativity. 
S. For participants who have used B cell depleting therapy within 1 year of screening, CD19+ B Cells will also be evaluated at the Screening Visit. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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D. Pregnancy tests for women of child-bearing potential only. First date of last period will also need to be collected. 
 
 
 
 
 
E. An additional  corticosteroid injection may be given up to 2 weeks after re-randomization whether or not it was given at time of Stage 2 treatment failure as well for a total of  2 corticosteroid injections from the time of Stage 2 Treatment Failure up to 
and including the Stage 3 Week 2 Visit. 
 
 
 
 
 
F. MMF 1000mg BID+Voclosporin (23.7 BID) or MMF 1000mg BID+Placebo voclosporin. Participants who previously received placebo MMF in stage 2 will receive a two-week taper-up of MMF.  
G. Study-provided medication will not be dispensed if participant receives a corticosteroid injection or has started new or increased lupus medications. The participant will stop Stage 3 study drug. 
H. Creatinine for eGFR only 
 
 
 
 
 
 
 
 
 
 
 
I. Physical examinations are to include, at least, the following systems: general appearance, skin, head/eyes/ears/nose/neck/throat, respiratory/chest, cardiovascular, abdominal, neurological, & musculoskeletal/extremities Neurological exam may only 
be performed based on patient complaint. 
J. Local SARS-CoV-2 molecular testing (or alternative viral test per institutional standard) should be performed if clinically indicated. 
K. If not already collected as a part of the Stage 2 Visit.  
L. Lab volumes to not exceed 550 cc over 8 weeks. 
M. Patient-reported outcomes should be completed in a quiet space and prior to any other study assessments.   
N. The re-randomization visit should be completed on the date that treatment failure is identified + 5 days. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9 Mechanistic Assays 
9.1 Hypothesis-driven assays based on preliminary data 
We have recently developed innovative assays that will be applied to the samples in this protocol [1, 14, 15, 91]. Our preliminary 
data indicates that MMF treatment is associated with upregulation of expression of genes for CR3, TWEAK, FYN, IL16, IL17RA, 
and/or IL2RB. We will seek to confirm or refute these findings in the current study and also test for the protein expression. All 
except CR3 are soluble mediators and will be quantified either by a multiplex bead-based assay [14, 15] that we have optimized 
or by ELISA. Expression of CR3 will be measured by flow cytometry in 2 aliquots, one for total CR3 and one for activated CR3. In 
addition, we will use our established multiplex bead based assay for 50 soluble mediators and further characterize this 
population.  
We will examine the early flare phenotype to determine whether this phenotype is altered in those who respond to treatment 
and/or whether this is a population resistant to treatment. We previously characterized this subset of lupus patients most likely 
to flare if treatment is not added, characterized by differential gene expression in monocyte, T cell, interferon, and inflammation 
modules, as well as significantly higher frequencies of activated (aCD11b+) neutrophils and monocytes, and activated (CD86hi) 
naïve B cells [92].  
At the Screening Visit, all participants will be assigned to one of 3 consolidated clusters of phenotypes in SLE, that cover the 7 
overlapping clusters we derived from gene co-expression network analysis (WGCNA) [1, 91]. Later, using more comprehensive, 
immunophenotyping on batched samples, we will determine whether response to MMF or MMF plus voclosporin segregates to 
1 or 2 SLE immunophenotypic clusters, or whether we must look deeper at the individual immune expression modules that 
comprise the clusters or even at the individual gene level to characterize response to these treatments. 
9.2 Exploratory Investigation of Diverse Pathologies with in SLE 
We will use a structured, multi-level evaluation of the phenotypic clusters described above to establish whether the following 
questions can be answered: 
1. Can baseline samples predict the immune factors/patterns of participants more likely to respond to MMF as 
a single agent versus the need to add voclosporin?  
2. If some participants have a phenotype associated with high rates of response, but these individuals do not 
respond as expected, can interrogation of gene and protein expression patterns reveal the reason(s)? For 
example, can we differentiate those for whom the treatment did not meet its intended target from those for 
whom it did, but who may have additional pathways operating to prevent clinical improvement?  
3. Will some of those latter participants have evidence of active pathways that will predict response when 
voclosporin is added to the regimen that would not have been present before MMF was added? 
10 Biospecimen Storage 
With informed consent, laboratory samples will be stored in a biorepository for future studies at OMRF. Stored samples will 
include serum, plasma, urine, RNA, and DNA. 
 
 

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11 Criteria for Participant and Study Completion and Premature Study Termination 
11.1 Participant Completion 
Study completion can occur in either Stage 2 or Stage 3 and the time of completion will depend on study trajectory of 
each participant as described in Figure 1, Study Flow Diagram. Completion of the study in Stage 2 can occur with either a 
Stage 2 Week 24 Visit where all End of Study/Safety Follow-Up assessments are conducted, a Stage 2 End of 
Study/Safety Follow-Up visit or an Early Termination Visit. The final study visit can follow any visit up to the Stage 2 
Week 48 visit.  
Completion of the study in Stage 3 can occur with either a Stage 3 End of Study/Safety Follow-Up Visit or an Early 
Termination Visit. The final study visit can follow any visit up to the Stage 3 Week 24 visit.  
Participants who request early termination will be encouraged to return for the Safety Follow-Up Visit.  
Those who cannot tolerate the study medication or develop an adverse reaction necessitating early discontinuation of the 
study-provided medication will continue in the study (if they agree) without receiving further study-provided medication. 
11.2 Participant Stopping Rules and Early Termination Criteria  
Participants may be prematurely terminated from the study for the following reasons: 
1. The participant elects to withdraw consent from all future study activities, including follow-up. 
2. The participant dies.  
3. The DAIT Medical Monitor no longer believes participation is in the best interest of the participant. 
4. The investigator no longer believes participation is in the best interest of the participant. 
5. The study is stopped. 
6. The participant is “lost to follow-up.” 
11.3 Participant Replacement 
Randomized participants who never initiate Stage 2 study treatment will not count towards the target accrual of 120. 
11.4 Early Study Withdrawal 
If a participant withdraws or is withdrawn from the study for any reason, they will be encouraged to return for the 
safety follow up visit for their final visit. 
11.5 Study Stopping Rules 
See Section 12.8.2.2 Ad Hoc DSMB Meetings and Section 12.8.2.2.1 Temporary Suspension of Randomization and Dosing 
for ad hoc DSMB Safety Review for more information on study stopping rules. 
12 Safety Monitoring and Reporting 
12.1 Overview 
This section defines the types of safety data that will be collected under this protocol and outlines the procedures for 
appropriately collecting, grading, recording, and reporting those data. AEs that are classified as serious according to the 
definition of health authorities must be reported promptly (per Section 12.5, Reporting of Serious Adverse Events and 

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Adverse Events) to the DAIT/NIAID. Appropriate notifications will also be made to site principal investigators (PI) and the 
single IRB of record.  
Information in this section complies with the International Conference on Harmonisation (ICH) Guideline E2A: Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting, ICH Guideline E-6: Guideline for Good 
Clinical Practice, 21CFR Parts 312 and 320, and applies the standards set forth in the National Cancer Institute (NCI), 
Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0: 
https://ctep.cancer.gov/protocoldevelopment/electronic applications/ctc.htm#ctc 60. 
12.2 Definitions 
12.2.1 Adverse Event (AE) 
Any untoward or unfavorable medical occurrence associated with the participant’s participation in the research, 
whether or not considered related to the participant’s participation in the research (modified from the definition of 
adverse events in the 1996 ICHE-6 Guidelines for Good Clinical Practice) (from OHRP "Guidance on Reviewing and 
Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (1/15/07)" 
http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2 )  
12.2.2 Suspected Adverse Reaction (SAR)  
Any AE for which there is a reasonable possibility that the investigational drug [or investigational study therapy 
regimen] caused the AE. For the purposes of safety reporting, ‘reasonable possibility’ means there is evidence to 
suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction (SAR) implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug 
(21 CFR 312.32(a)). 
12.2.3 Unexpected Adverse Event  
An AE or SAR is considered “unexpected” if it is not listed in the Investigator Brochure or package insert or is not 
listed at the specificity, severity or rate of occurrence that has been observed; or is not consistent with the risk 
information described in the general investigational plan. 
12.2.4 Serious Adverse Event (SAE) 
An AE or SAR is considered “serious” if, in the view of either the investigator or DAIT/NIAID, it results in any of the 
following outcomes (21 CFR 312.32(a)): 
a. 
Death. 
b. 
A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of either the investigator 
or DAIT/NIAID, its occurrence places the participant at immediate risk of death. It does not include an AE or 
SAR that, had it occurred in a more severe form, might have caused death. 
c. 
Inpatient hospitalization or prolongation of existing hospitalization. 
d. 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. 
e. 
Congenital anomaly or birth defect.  
f. 
Important medical events that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the participant 
and may require medical or surgical intervention to prevent one of the outcomes listed above. 

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Elective hospitalizations or hospital admissions for the purpose of conduct of protocol mandated procedures are not 
to be reported as an SAE unless hospitalization is prolonged due to complications. 
12.3 Grading and Attribution of Adverse Events 
12.3.1 Grading Criteria 
The study site will grade the severity of AEs experienced by the study participants according to the criteria set forth in 
the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 5.0 other than exceptions 
listed below. This document (referred to herein as the NCI-CTCAE manual) provides a common language to describe 
levels of severity, to analyze and interpret data, and to articulate the clinical significance of all AEs. The NCI-CTCAE 
has been reviewed by the Protocol Chair and has been deemed appropriate for the participant population to be 
studied in this protocol. 
AEs will be graded on a scale from 1 to 5 according to the following standards in the NCI-CTCAE manual: 
Grade 1 = mild adverse event 
Grade 2 = moderate adverse event 
Grade 3 = medically significant adverse event 
Grade 4 = life-threatening or urgent intervention 
indicated adverse event 
Grade 5 = death 
Events grade 2 or higher and all Grade 1 or higher COVID-19 events will be recorded on the appropriate AE eCRF for 
this study. 
For grading an abnormal value or result of a clinical or laboratory evaluation (including, but not limited to, a 
radiograph, an ultrasound, an electrocardiogram etc.), an AE is defined as an increase in grade from screening or 
from the last post-screening value that doesn’t meet grading criteria. If a specific event or result from a given clinical 
or laboratory evaluation is not included in the NCI-CTCAE manual, then an abnormal result would be considered an 
AE if changes in therapy or monitoring are implemented as a result of the event/result. 
Liver function abnormalities will be graded using alternative criteria which are based on CTCAE version 4.0, and are 
defined relative to the ULN as follows: 
• 
Aspartate aminotransferase [AST] increased 
o Grade 1: > ULN - 3.0x ULN 
o Grade 2: > 3.0x ULN - 5.0x ULN 
o Grade 3: > 5.0x ULN - 20.0x ULN  
o Grade 4: > 20.0x ULN 
• 
Alanine aminotransferase [ALT] increased 
o Grade 1: > ULN - 3.0x ULN 
o Grade 2: > 3.0x ULN - 5.0x ULN 
o Grade 3: > 5.0x ULN - 20.0x ULN  
o Grade 4: > 20.0x ULN 

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• 
Alkaline phosphatase [ALP] increased 
o Grade 1: > ULN - 2.5x ULN 
o Grade 2: > 2.5x ULN - 5.0x ULN 
o Grade 3: > 5.0x ULN - 20.0x ULN  
o Grade 4: > 20.0x ULN 
• 
Blood bilirubin increased  
o Grade 1: > ULN - 1.5x ULN 
o Grade 2: > 1.5x ULN - 3.0x ULN 
o Grade 3: > 3.0x ULN - 10.0x ULN  
o Grade 4: > 10.0x ULN  
12.3.2 Attribution Definitions 
The relationship, or attribution, of an AE to the study therapy regimen or study procedure(s) will initially be determined by 
the site investigator and recorded on the appropriate AE eCRF. Final determination of attribution for safety reporting will be 
determined by DAIT/NIAID. The relationship of an AE to study therapy regimen or procedures will be determined using the 
descriptors and definitions provided in Table 12.1.  
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-CTCAE web site: 
http://ctep.cancer.gov/reporting/ctc.html.  
Table 12.1 Attribution of Adverse Events 
Code 
Descriptor 
Relationship (to primary investigational product and/or 
other concurrent mandated study therapy or study 
procedure). 
1 
Unrelated 
The adverse event is clearly not related; there is 
insufficient evidence to suggest a causal relationship. 
2 
Possible 
The adverse event has a reasonable possibility to be 
related; there is evidence to suggest a causal relationship. 
3 
Definite 
The adverse event is clearly related. 
12.4 Collection and Recording of Adverse Events 
12.4.1 Collection Period 
AEs will be collected from the time of consent until a participant completes study participation or until 30 days after he/she 
prematurely withdraws (without withdrawing consent) or is withdrawn from the study. 
12.4.2 Collecting Adverse Events 
AEs (including SAEs) may be discovered through any of these methods: 
• 
Observing the participant  
UNRELATED CATEGORY 
RELATED CATEGORIES 

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• 
Interviewing the participant [e.g. using a checklist, structured questioning, diary etc.]  
• 
Receiving an unsolicited complaint from the participant 
• 
In addition, an abnormal value or result from a clinical or laboratory evaluation can also indicate an AE as 
defined in Section 12.3, Grading and Attribution of Adverse Events. 
12.4.3 Recording Adverse Events 
Throughout the study, the investigator will record AEs and SAEs as described previously (see Section 12.2, Definitions) 
on the appropriate AE eCRF regardless of the relationship to study therapy regimen or study procedure.  
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or until the end of study 
participation, or until 30 days after the participant prematurely withdraws (without withdrawing consent)/or is 
withdrawn from the study, whichever occurs first. For AEs where an abnormal value or result of a clinical or 
laboratory evaluation is observed (see Section 12.3.1, Grading Criteria), resolution is defined as the first value post-
abnormality that is in the normal range (Grade 0). 
12.5 Reporting of Serious Adverse Events and Adverse Events 
12.5.1 Reporting of Adverse Events to DAIT/NIAID 
This section describes the responsibilities of the site investigator to report AEs to DAIT/NIAID reporting of AEs is 
required by 21 CFR and ICH E6 guidelines. Unless otherwise noted below in Section 12.5.2, Reporting of SAEs and 
Section 12.5.3, Reporting of BILAG A Flares to DAIT/NIAID, AEs must be recorded on the AE eCRF within five (5) days 
of discovery of the event. 
12.5.2 Reporting of Serious Adverse Events to DAIT/NIAID 
12.5.3 Reporting of BILAG A Flares to DAIT/NIAID 
This section describes the responsibilities of the site investigator to report BILAG As to DAIT/NIAID via the AE/SAE eCRF. 
Timely reporting of AEs is required by 21 CFR and ICH E6 guidelines. 
Site investigators will report all new BILAG As other than those noted at the screening visit, regardless of relationship or 
expectedness within 24 hours of discovering the event. For BILAG As, all requested information on the AE/SAE eCRF will be 
provided even if the BILAG A is not classified as an SAE. However, unavailable details of the event will not delay submission of 
the known information. As additional details become available, the AE/SAE eCRF will be updated and submitted. 
12.5.4 Reporting to FDA 
This clinical study has been granted exemption from IND regulations by the FDA in accordance with 21 CFR 312.2(b) of the 
regulations, therefore, AEs will not be reported to the FDA by the study sponsor (NIAID).  
12.5.5 Reporting of Adverse Events to the IRB 
All investigators shall report AEs, including expedited reports, in a timely fashion to the single IRB of record in accordance 
with applicable regulations and guidelines.  
Site investigators will report all SAEs (see Section 12.2.4, Serious Adverse Event), regardless of relationship or 
expectedness within 24 hours of discovering the event. For SAEs, all requested information on the AE/SAE eCRF 
will be provided. However, unavailable details of the event will not delay submission of the known information. 
As additional details become available, the AE/SAE eCRF will be updated and submitted. 

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SAEs that are determined by DAIT/NIAID to have potential impact on the safety of all trial participants will be distributed by 
the DAIT/NIAID (or designee) to all participating site investigators and the single IRB of record.  
12.6 Pregnancy Reporting 
The investigator shall be informed immediately of any pregnancy in a study participant. A pregnant participant shall be 
instructed to stop taking investigational study medication. The investigator shall counsel the participant and discuss the risks of 
continuing with the pregnancy and the possible and unknown effects on the fetus. Monitoring of the pregnant participant shall 
continue until the conclusion of the pregnancy.   
The investigator shall report all pregnancies to DAIT/NIAID via the SCCC within 1 business day of becoming aware of the event 
using the Pregnancy eCRF. All pregnancies identified during the study shall be followed to conclusion and the outcome of each 
must be reported. The Pregnancy eCRF shall be updated and submitted to the SCCC when details about the outcome are 
available.  
Information requested about the delivery shall include: 
• 
Gestational age at delivery 
• 
Birth weight, length, and head circumference 
• 
Gender 
• 
Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5 minutes, and 24 hours 
after birth, if available 
• 
Any abnormalities 
All pregnancy complications that result in a congenital abnormality, birth defect, miscarriage, and medically indicated abortion - 
an SAE shall be submitted to the SCCC using the SAE reporting procedures described above (Section 12.5.1, Reporting of Serious 
Adverse Events to DAIT/NIAID).   
If a pregnancy occurs in a partner of a participant, the male participant whose partner gets pregnant will inform the 
investigator of the pregnancy. The participant will be encouraged to use barrier methods for the remainder of the pregnancy. 
The pregnant partner should see their Obstetrician. Data on partner pregnancies will not need to be collected for this study. 
12.6.1 Mycophenolate REMS Program 
ALE10 investigators are required to enroll in the FDA’s Mycophenolate REMS program. An investigator will be required to 
report any pregnancy occurring in an ALE10 female participant while she is taking MMF or within the first 6 weeks following 
discontinuation of MMF treatment to the Mycophenolate Pregnancy Registry, which is part of the MMF REMS program. 
Participants will be required to participate in MMF REMS program as well. 
12.7 Reporting of Other Safety Information 
An investigator shall promptly notify DAIT/NIAID via the SCCC within 24 hours when an “unanticipated problem involving risks to 
participants or others” is identified, which is not otherwise reportable as an AE. 
12.8 Review of Safety Information 
12.8.1 Medical Monitor Review 
The DAIT/NIAID Medical Monitor shall receive monthly reports from the SCCC compiling new and accumulating information 
on AEs, SAEs, and pregnancies recorded by the study sites on appropriate eCRFs. 

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In addition, the Medical Monitor shall review and make decisions on the disposition of the SAE and pregnancy reports 
received by the SCCC (See Sections 12.5.1, Reporting of SAEs to DAIT/NIAID, and 12.6, Pregnancy Reporting). 
12.8.2 DSMB Review  
12.8.2.1 Planned DSMB Reviews  
The DSMB shall review safety data at least yearly during planned DSMB Data Review Meetings. Data for the planned 
safety reviews will include, at a minimum, a listing of all reported AEs and SAEs.  
SAEs that are determined by DAIT/NIAID to have potential impact on the safety of all trial participants will be distributed 
by DAIT/NIAID to the DSMB and all participating site investigators. 
12.8.2.2 Ad hoc DSMB Reviews  
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may be called upon for ad hoc 
reviews. The DSMB will review any event that potentially impacts safety at the request of the Protocol Chair or 
DAIT/NIAID. In addition, the following events will trigger an ad hoc comprehensive DSMB Safety Review:  
• 
Any death that occurs during the study. 
• 
BILAG A flares in Cardiorespiratory, Neuropsychiatric, Gastrointestinal, Ophthalmic, Renal, or 
Hematological Systems occurring in 
o 3 or more of the first 10 randomized participants or  
o 30% or more of randomized participants at any time point after the 11th participant is 
randomized. 
• 
Infections requiring hospitalization or > 1 dose of intravenous antibiotics in 
o 3 or more of the first 10 randomized participants or  
o 30% or more of randomized participants at any time point after the 11th participant is 
randomized. 
After review of the data, the DSMB will make recommendations regarding study conduct and/or continuation. 
12.8.2.2.1 Temporary Suspension of Randomization and Dosing for ad hoc DSMB Safety Review 
If any of the events listed in Section 12.8.2.2, Ad hoc DSMB Reviews, occur, the chair of the DSMB will be 
notified and a review of the safety data will be performed. The DSMB will have the discretion to recommend 
actions regarding study conduct, and will determine if enrollment in the study should be stopped and/or 
administration of study medications should be halted. 
 
If a death occurs during the study, a temporary halt in consenting and screening of new participants as 
well as randomizing participants to Stage 2 will be implemented until after DSMB completes review of 
the safety data. Participants who have been consented and screened but not yet randomized into Stage 
2 will be permitted to withdraw from their lupus medications per protocol during the randomization 
halt. If participants who have withdrawn from their lupus medications exceed their 28 day screening 
window during the ad hoc DSMB review period, an extension will be granted and the participant will be 
allowed to randomize once the ad hoc DSMB allows for resumption of randomization. Participants on 
study can continue with their assigned treatment, and participants deemed as a Stage 2 treatment 
failure at or before the Stage 2 week 24 can move into Stage 3 and be re-randomized. 

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If an ad hoc DSMB is called for excessive BILAG A flares or infections, the study will proceed as planned 
pending DSMB review of the data. However, if 2 weeks have elapsed and the DSMB has not met, then 
no new participants will be consented, screened, or randomized into Stage 2 until after the DSMB 
completes review of the safety data. Participants who have been consented and screened but not yet 
randomized into Stage 2 will be permitted to withdraw from their lupus medications per protocol 
during the randomization halt. If participants who have withdrawn from their lupus medications exceed 
their 28 day screening window during the ad hoc DSMB review period, an extension will be granted and 
the participant will be allowed to randomize once the ad hoc DSMB allows for resumption of 
randomization. Participants on study can continue with their assigned treatment, and participants 
deemed as a Stage 2 treatment failure at or before the Stage 2 week 24 can move into Stage 3 and be 
re-randomized. 
13 Statistical Considerations and Analytical Plan 
13.1 Overview  
This is a multicenter, double blind, placebo-controlled clinical trial of participants with non-organ-threatening SLE. The study will 
be conducted in 3 stages. Stage 1 will be a treatment withdrawal phase where participants must demonstrate adequate 
improvement with long-acting corticosteroids in order to proceed to Stage 2. Stage 2 will be a randomization phase comparing 
MMF versus corresponding MMF placebo. The purpose of Stage 2 is to assess the primary endpoint, which investigates the 
effectiveness of 24 weeks of MMF within previously identified immunologically-homogenous subsets of SLE patients. Stage 3 is a 
re-randomization phase comparing MMF plus voclosporin or MMF plus placebo for voclosporin. Stage 3 is intended to be an 
exploratory investigation of baseline gene expression patterns and their associations with response. 
13.2 Endpoints 
Endpoints are listed in Sections 3.2, Primary Endpoint, 3.3, Secondary Endpoints, and 3.4, Exploratory Endpoints.  
13.3 Measures to Minimize Bias 
The following measures will be employed to minimize bias: 
• 
Randomization to treatment assignment to avoid selection bias. 
• 
Double blind design to avoid ascertainment bias. 
• 
Use of central laboratories for consistency in assay procedures and measurements for clinical and mechanistic 
endpoints. 
13.4 Analysis Plan 
13.4.1 Analysis Populations 
13.4.1.1 Stage 2 Analysis Populations  
Modified Intent to Treat Population: 
The modified Intent-to-Treat population (mITT) will consist of all Stage 2 randomized participants who received 
at least one dose of MMF or MMF placebo. The mITT population will be used for all Stage 2 efficacy analyses and 
will include participants under the treatment to which they were randomized, regardless of compliance with 
assigned treatment. 

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Per Protocol Populations: 
Two per protocol (PP) populations will be defined for Stage 2 analyses.  
The PP1 population will consist of mITT participants who: 
• 
Have either completed the Stage 2 Week 24 visit without experiencing a Stage 2 failure or have 
experienced a treatment failure on or prior to Stage 2 Week 24; 
• 
Have ≥ 80% compliance with MMF or MMF placebo administration from randomization through the 
Stage 2 Week 24 visit or until treatment failure (whichever comes first), where compliance is 
assessed by numbers of capsules of study product returned to the site; 
• 
Have no protocol violations or ineligible entry criteria deemed likely to affect the efficacy outcomes 
of interest either through Week 24 of Stage 2 or treatment failure (whichever comes first). 
 The PP2 population will consist of mITT participants who: 
• 
Have either completed the Stage 2 Week 48 visit without experiencing a Stage 2 failure or have 
experienced a treatment failure on or prior to Stage 2 Week 48; 
• 
Have ≥ 80% compliance with MMF or MMF placebo administration from randomization through the 
Stage 2 Week 48 visit or until treatment failure (whichever comes first), where compliance is 
assessed by numbers of capsules of study product returned to the site; 
• 
Have no protocol violations or ineligible entry criteria deemed likely to affect the efficacy outcomes 
of interest either through Week 48 of Stage 2 or treatment failure. 
A blinded data review panel will evaluate deviations from the protocol including, for example, violations of 
entry criteria, departures from assigned treatment regimen, modifications of concurrent therapy, failure to 
complete study visits, or administration of study procedures outside the specified visit windows to determine if 
occurrence of these deviations should exclude participants from the PP1 or PP2 population. 
The PP1 population will be used for the Stage 2 analysis of the primary endpoint and secondary/exploratory 
endpoints assessed at Stage 2 Week 24, the PP2 population will be used in the analyses of the 
secondary/exploratory Stage 2 efficacy endpoints which are assessed over the entire 48 week treatment period. 
13.4.1.2 Stage 3 Analysis Populations  
Modified Intent to Treat Population: 
The Stage 3 modified Intent-to-Treat population (mITT3) will consist of all Stage 3 randomized participants who 
received at least one dose of MMF plus voclosporin or MMF plus placebo for voclosporin. The mITT3 population 
will be used for all Stage 3 efficacy analyses and will include participants under the treatment to which they 
were randomized, regardless of compliance with assigned treatment. 
Per Protocol Population: 
The Stage 3 PP population (PP3) will consist of mITT3 participants who: 
• 
Have either completed the Stage 3 Week 24 visit without experiencing a Stage 3 failure or have 
experienced a treatment failure on or prior to Stage 3 Week 24; 

A ut oi m m u nity C e nt ers of Exc ell e nc e  
C o nfi d e nti al  
P a g e 8 0  of 1 1 4  
 
AL E 1 0 ( T h e DI V E R T Tri al)  
V 4. 0  
Oct o b er 2 6 , 2 0 2 3  
 
 
 
 
•  
H a v e ≥ 8 0 % c o m pli a nc e wit h M M F  + v ocl os p ori n  or M M F + pl ac e b o  f or v ocl os p ori n  a d mi nistr ati o n  
fr o m r a n d o miz ati o n t hr o u g h t h e St a g e 3 W e e k 2 4  visit or u ntil tr e at m e nt f ail ur e  ( w hic h e v er c o m es 
first), w h er e c o m pli a nc e is ass ess e d by n u m b ers of c a ps ul es of st u dy pr o d uct r et ur n e d t o t h e sit e; 
•  
H a v e n o  pr ot oc ol vi ol ati o ns  or i n eli gi bl e e ntry crit eri a  d e e m e d li k el y t o aff ect t h e effic ac y o utc o m es 
of i nt er est  t hr o u g h o ut t h e e ntir e st u dy. 
A bli n d e d d at a r evi e w p a n el will ev al u at e d evi ati o ns fr o m t h e pr ot oc ol i ncl u di n g, f or ex a m pl e, vi ol ati o ns of 
e ntr y crit eri a, d e p art ur es fr o m assi g n e d tr e at m e nt r e gi m e n, m o dific ati o ns of c o nc urr e nt t h er a py, f ail ur e t o 
c o m pl et e st u dy visits, or a d mi nistr ati o n of st u dy pr oc e d ur es o utsi d e t h e s p ecifi e d visit wi n d o ws t o d et er mi n e if 
occ urr e nc e of t h es e d e vi ati o ns s h o ul d excl u d e p artici p a nts fr o m t h e P P 3 p o p ul ati o n.  
  
Th e P P 3 p o p ul ati o n will b e us e d i n t h e a n alys es of t h e St a g e 3 s ec o n d ar y effic ac y e n d p oi nts.  
1 3. 4. 1. 3  S af et y P o p ul ati o n  
T h e s af et y p o p ul ati o n will i ncl u d e all p artici p a nts w h o r ec eiv e at l e ast o n e I M i nj ecti o n of a l o n g -acti n g 
c ortic ost er oi d or w h o i niti at e wit h dr a w al of l u p us m e dic ati o ns i n St a g e 1. T h e s af et y p o p ul ati o n will b e us e d f or 
all s af ety a n al ys es. A n alysis p erf or m e d o n t h e s af ety p o p ul ati o n will b e acc or di n g t o t h e tr e at m e nt act u all y 
r ec eiv e d i n b ot h St a g e 2 a n d St a g e 3. 
1 3. 4. 2  Pri m ar y A n al ysis of Pri m ar y E n d p oi nt  
T h e pri m ary e n d p oi nt is t h e c u m ul ati v e i nci d e nc e of tr e at m e nt f ail ur e at or b ef or e t h e St a g e 2 W e ek 2 4 visit. Ti m e t o 
tr e at m e nt f ail ur e is d efi n e d as t h e i nt erv al fr o m t h e d a y of St a g e 2 r a n d o miz ati o n u ntil t h e d a y of tr e at m e nt f ail ur e 
(as d efi n e d i n S ecti o n 3. 2, Pri m ar y E n d p oi nt). P artici p a nts w h o wit h dr a w fr o m t h e st u dy e arly wit h o ut e vi d e nc e of 
tr e at m e nt f ail ur e will b e c e ns or e d at d a y of t h e l ast ass ess m e nt t h e y w er e d et er mi n e d t o b e f ail ur e-fr e e. T h e ris k of 
tr e at m e nt f ail ur e o v er t h e p eri o d of St a g e 2 r a n d o miz ati o n t hr o u g h 2 4 w e eks of f oll o w-u p will b e pr es e nt e d 
gr a p hic all y usi n g K a pl a n -M ei er pr o d uct li mit esti m at es of t h e s urvi v al f u ncti o n i n s u b gr o u ps d efi n e d by tr e at m e nt 
ar m a n d by i m m u n ol o gic ally -h o m o g e n o us s u bs ets . T h e K a pl a n-M ei er esti m at es of e v e nt -fr e e s ur viv al a n d 
c o nfi d e nc e i nt erv als usi n g Gr e e n w o o d’s f or m ul a f or st a n d ar d err or will b e r e p ort e d by s u bgr o u p at St a g e 2 W e ek 2 4. 
T h e pri m ar y a n alysis will b e a str atifi e d t w o -s a m pl e t est of t h e c u m ul ati v e i nci d e nc e of tr e at m e nt f ail ur e at St a g e 2 
W e ek 2 4 usi n g a 2 -si d e d = 0. 0 5.  
T h e ulti m at e g o al of St a g e 2 is t o e v al u at e t h e p ot e nti al eff ecti v e n ess of M M F wit hi n t h e 7 pr evi o usly -i d e ntifi e d 
i m m u n ol o gic all y-h o m o g e n e o us cl ust ers f or l u p us. R e g ar dl ess of t h e o utc o m e of t h e str atifi e d t est f or t h e p o ol e d 
a n al ysis, wit hi n -cl ust er l a n d m ar k t w o-s a m pl e t ests will b e p erf or m e d f or c o m p aris o ns of t h e c u m ul ati v e i nci d e nc e of 
tr e at m e nt f ail ur e at St a g e 2 W e e k 2 4 f or e ac h cl ust er. D u e t o t h e li mit e d s a m pl es siz es a ntici p at e d i n e ac h 
i m m u n ol o gic all y-d efi n e d s u b gr o u p, n o c orr ecti o n f or m ulti pl e c o m p aris o ns will b e m a d e, a n d p -v al u es of <  0. 1 0 will 
b e c o nsi d er e d n ot a bl e fi n di n gs  b ut will b e i nt er pr et e d wit h c a uti o n gi v e n t h e hi g h pr o b a bilit y of a f a mil y -wis e err or 
wit h m ulti pl e c o m p aris o ns u n d er a str o n g n ull hy p ot h esis of n o tr e at m e nt b e n efit.  
1 3. 4. 3  S u p p orti v e A n al ys es of t h e Pri m ar y E n d p oi nt  
A s a s u p p ortiv e a n al yse s, t h e ris k of tr e at m e nt f ail ur e ov er t h e e ntir e 4 8 w e e k p eri o d of St a g e 2 will b e s u m m ariz e d 
usi n g K a pl a n -M ei er pr o d uct li mit esti m at es, a n d a str atifi e d l o g-r a n k t est will b e c o n d uct e d wit h c o m pl et e f oll o w -u p 
of p artici p a nts. A d diti o n al c o v ari at es i ncl u di n g p artici p a nt a n d dis e as e c h ar act eristics at st u dy e ntry a n d i n St a g e 1 
tr e at m e nt wit h dr a w al, a n d ti m e-d e p e n d e nt c ov ari at es d uri n g St a g e 2 will b e ex pl or e d i n a m ultiv ari a bl e C ox m o d el s 

A ut oi m m u nity C e nt ers of Exc ell e nc e  
C o nfi d e nti al  
P a g e 8 1  of 1 1 4  
 
AL E 1 0 ( T h e DI V E R T Tri al)  
V 4. 0  
Oct o b er 2 6 , 2 0 2 3  
 
 
 
 
usi n g m ai n eff ects a n d i nt er acti o n t er ms. M ulti v ari a bl e m o d els will b e  f ull y d efi n e d i n t h e st atistic al a n alysis pl a n 
(S A P ). Fi n all y, i n a d diti o n t o c o nsi d eri n g h et er o g e n eity fr o m i m m u n ol o gic ally d efi n e d s u bs ets a n d ot h er o bs er v e d 
f act ors, a s u p p orti v e a n alysis will ex pl or e t h e us e of  fr ailt y m o d els t o c o nsi d er v ari a bilit y fr o m a d diti o n al u n o bs erv e d 
f act ors usi n g r a n d o m eff ects t er ms.   
1 3. 4. 4  A n al ys es of S ec o n d ar y S af et y E n d p oi nt s 
Saf et y a n al ys es will b e p erf or m e d o n t h e s af ety s a m pl e a n d will b e ass ess e d by s u m m arizi n g A Es  s e p ar at ely f or e ac h 
st a g e of t h e st u dy. T h e l e n gt h of ti m e p artici p a nts  ar e f oll o w e d wit hi n e ac h st a g e is v ari a bl e a n d c o ul d d e p e n d o n if a 
p artici p a nt  m e ets tr e at m e nt f ail ur e. T o acc o u nt f or p ot e nti al diff er e nti al d ur ati o n of st u dy p artici p ati o n, A E 
s u m m ari es by tr e at m e nt gr o u p will i ncl u d e t h e n u m b er of e v e nts p er p ers o n-y e ar i n a d diti o n t o t h e n u m b er a n d 
p erc e nt a g e of ev e nts a n d p artici p a nts  ex p eri e nci n g e v e nts. A Es a n d S A Es will b e s u m m ariz e d by s yst e m or g a n cl ass, 
pr ef err e d t er m, a n d s e v erity gr a d e.  
S af et y e n d p oi nts i d e ntifi e d i n S ecti o n 3. 3. 2  S af ety E n d p oi nts, will b e s u m m ariz e d a n d list e d s e p ar at ely f or e ac h st a g e 
of t h e st u dy. F or e ac h s uc h e n d p oi nt, t h e n u m b er of ev e nts p er p ers o n -y e ar as w ell as n u m b ers a n d p erc e nt a g es of 
e v e nts a n d p artici p a nts w h o  ex p eri e nc e t h es e e v e nts will b e s u m m ariz e d o v er all i n St a g e 1 a n d by tr e at m e nt gr o u p 
i n St a g e 2 a n d 3. N o f or m al st atistic al t esti n g will b e p erf or m e d t o c o m p ar e saf ety b et w e e n tr e at m e nt gr o u ps.  
1 3. 4. 5  A n al ys es of S ec o n d ar y Effic ac y E n d p oi nts  
T h e k e y s ec o n d ar y effic acy e n d p oi nt is cli nic al r es p o ns e at St a g e 2 W e e k 2 4, d efi n e d by t h e BI CL A (s e e S ecti o n 3. 3. 1 , 
Effic ac y E n d p oi nts ). A Fis h er’s ex act t est ( 2-si d e d = 0. 0 5) will b e p erf or m e d t o t est t h e hy p ot h esis t h at t h er e is n o 
diff er e nc e i n t h e pr o p orti o n of r es p o n d ers b et w e e n tr e at m e nt gr o u ps.  T his a n alysis will als o b e r e p e at e d at St a g e 3 
W e ek 2 4.  A n a d diti o n al s u p p orti v e St a g e 3 a n al ysis will us e t h e m ost r ec e nt ass ess m e nt b ef or e t h e St a g e 3 D a y 0 
visit as t h e r ef er e nc e (s e e S ecti o n 3. 5. 3 , BIL A G -b as e d C o m bi n e d L u p us Ass ess m e nt ( BI CL A) ). 
F or St a g e 3,  t h e c u m ul ativ e i nci d e nc e of p artici p a nts w h o ex p eri e nc e a tr e at m e nt f ail ur e i n St a g e 3 will b e e v al u at e d. 
T h e pri m ar y a n alysis will b e r e p e at e d c o nsi d eri n g tr e at m e nt f ail ur es occ urri n g d uri n g t h e ti m e p eri o d fr o m St a g e 3 
r e-r a n d o miz ati o n t hr o u g h St a g e 3 We e k 2 4.   
Ti m e t o tr e at m e nt f ail ur e will  als o  b e e v al u at e d  i n St a g e 3, w h er e  t h e K a pl a n-M ei er esti m ati o n a n d l o g -r a nk t ests 
fr o m t h e s u p p ortiv e a n alysis of t h e pri m ar y a n al ysis will b e r e p e at e d f or t h e ti m e p eri o d fr o m St a g e 3 r e-
r a n d o miz ati o n t hr o u g h St a g e 3 W e e k 2 4.  
Giv e n t h e u n k n o w n s a m pl es siz es a n d s u b gr o u ps d efi n e d by St a g e 2 tr e at m e nt assi g n m e nt , a ll i nf er e nti al a n al ys es 
f or St a g e 3 ar e c o nsi d er e d s u p p orti v e; p -v al u es f or t est of diff er e nc es a m o n g gr o u ps will b e pr es e nt e d wit h o ut 
a dj u st m e nt f or m ulti pl e c o m p aris o ns, a n d p-v al u es of <  0. 1 0 will b e c o nsi d er e d n ot a bl e fi n di n gs.  
1 3. 4. 6  A n al ys es of E x pl or at or y E n d p oi nt s 
D et ails of t h e ex pl or at ory a n al ysis of cli nic al e n d p oi nts will b e o utli n e d i n  t h e S A P . F or m ec h a nistic e n d p oi nts, 
ex pl or at ory a n alys es will b e c o n d uct e d s e p ar at ely f or s u b gr o u ps all oc at e d t o e ac h St a g e 2 tr e at m e nt ar m b ec a us e 
p artici p a nts e nt eri n g St a g e 3 fr o m t h e diff er e nt tr e at m e nt ar ms ar e n ot c o m p ar a bl e at t h e p oi nt of r e -
r a n d o miz ati o n. M ec h a nistic pl a ns ar e t o ex pl or e b as eli n e ( pr e -r e-r a n d o miz ati o n) g e n e ex pr essi o n a n d pr ot ei n l e v el 
p att er ns a m o n g t h os e w h o r es p o n d ( or d o n ot r es p o n d) t o M M F a n d M M F pl u s v ocl os p ori n, a n d t o d escri b e 
diff er e nc es b et w e e n t h e 2 ar ms.  R es p o ns e will b e d efi n e d usi n g BI CL A at 2 4 w e eks p ost r e -r a n d o miz ati o n.  

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13.4.7 Descriptive Analyses  
Descriptive analyses will include baseline and demographic characteristics, use of medications, and AEs, with 
separate tables for SAEs, and infections. 
Summary statistics for baseline and demographic characteristics, disposition, and medication use will be provided for 
the mITT and PP populations. These data will be presented in the following manner:  
• 
Continuous data (e.g. age, weight, and height) will be summarized by mean, standard deviation, median, and 
range.  
• 
Categorical data (e.g. sex and race) will be presented as counts and percentages.  
13.5 Interim Analyses  
Interim analyses of data will be reported to the DSMB at planned DSMB meetings and as requested by the DSMB. 
Planned interim analyses for the DSMB will focus on study conduct and participant safety and may include information 
on enrollment, randomization, site activation status, major protocol deviations, participant status and demographics, 
and safety analyses. In addition, the DSMB may review selected disease flare data. 
No other interim analyses for futility or efficacy are planned. 
13.6 Statistical Hypotheses  
The null and alternative hypotheses for the primary analysis of the primary endpoint are defined as follows for the 
cumulative incidence of treatment failure at Stage 2 Week 24 in the i-th arm and j-th immunologically-defined 
subgroup, 1 −𝑆𝑆𝑖𝑖,𝑗𝑗(24), 
 
𝐻𝐻0:  𝑆𝑆𝑀𝑀𝑀𝑀𝑀𝑀,𝑗𝑗(24) = 𝑆𝑆𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃,𝑗𝑗(24) for all 𝑗𝑗= 1 to 7 
𝐻𝐻𝐴𝐴:  𝑆𝑆𝑀𝑀𝑀𝑀𝑀𝑀,𝑗𝑗(24) ≠ 𝑆𝑆𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃,𝑗𝑗(24)  for 𝑗𝑗∈{1, … , 7}   
This hypothesis will be evaluated first for the mITT population pooled over all immunologic cluster. Step-down 
evaluations will then evaluate the cumulative incidence of treatment failure at Stage 2 Week 24 separately for each 
cluster. 
13.7 Sample Size Considerations  
The goal of Stage 2 of the study is to evaluate the potential effectiveness of MMF within previously-identified 
immunologically-homogeneous clusters of lupus patients. To place these cluster comparisons in the context of a 
successful trial, target enrollment is based on power to show superiority of MMF over placebo in a pooled lupus 
population. 
In previous studies using BOLD designs in lupus populations [22, 93, 94] where long-acting corticosteroids were 
administered during the treatment withdrawal stage, survival free-from-failure at 6 months in untreated or placebo-
treated participants ranged from 5-20% [25]. These studies included participants with a range of disease activity, had 
differing rules on implementation of background steroids and different definitions for treatment failure. By limiting 
steroids and carefully adhering to entry criteria to recruit an appropriate population with active lupus disease activity, 
and by defining treatment failure to include individuals who receive rescue medications post-randomization or who 
withdraw from treatment prematurely, a placebo survival at 24 weeks of 15% or less should be achievable. In the MMF 
arm, a minimum clinically meaningful improvement would be 35% survival at 24 weeks.  

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Stage 2 Randomization 
Stage 3 Re-randomization 
MMF 
Placebo MMF 
MMF + voclosporin 
n_MMF_Combo (~18) 
n_placebo_Combo (~24) 
MMF + placebo voclosporin 
n_MMF_MMF (~18) 
n_placebo_MMF (~24) 
 
Stage 3 is intended to explore baseline (pre-re-randomization) gene expression patterns and their associations with 
response (or non-response) to MMF and MMF plus voclosporin, and to describe differences in those associations 
between the 2 arms. Gene expression patterns may include immunologically-homogeneous clusters defined at 
screening, gene expression at the Stage 2 Day 0 Randomization Visit, or differential expression observed during the 
Stage 2 treatment period. Among those randomized to placebo in Stage 2, if we re-randomize 24 to MMF, we anticipate 
8-12 responders (i.e. 35-50% who have not failed by Stage 2 Week 24) and 12-16 non-responders on which to evaluate 
baseline gene expression patterns. In the MMF plus voclosporin arm, the number of responders is expected to be at 
least as high as MMF alone. Stage 3 is exploratory and not powered to test a pre-specified hypothesis.  
14 Identification and Access to Source Data 
14.1 Source Data 
Source documents and source data are considered to be the original documentation where participant information, 
visits consultations, examinations and other information are recorded. Documentation of source data is necessary for 
the reconstruction, evaluation and validation of clinical findings, observations and other activities during a clinical trial.  
14.2 Access to Source Data 
The site investigators and site staff will make all source data available to the DAIT/NIAID, NIAID representatives, agents, 
employees, contractors, and other persons assisting in conducting, monitoring, or analyzing the study, as well as to 
relevant health authorities. Authorized representatives, as noted above, are bound to maintain the strict confidentiality 
of medical and research information that may be linked to identify individuals. 
15 Quality Assurance and Quality Control 
The PI is required to keep accurate records to ensure that the conduct of the study is fully documented. The PI is 
required to ensure that all eCRFs are completed for every participant entered in the trial. The period of record retention 
should be consistent with the record retention policies of the sponsoring agency or applicable regulatory agencies. 
However, in certain instances, documents should be retained for a longer period if required by the applicable regulatory 
agency or by the National Institutes of Health (NIH). 
Data will be obtained from a variety of sources including, but not limited to laboratory notebooks, automated 
instrument output files, and clinical participant charts. Data from these source materials will be transmitted to the DAIT 
data center via one of two mechanisms. Data collected electronically at central laboratories will be transferred 
electronically directly from the laboratory to the DAIT data center using standard secure data transfer procedures. Data 
collected at the clinical site will be transmitted to the DAIT data center using an internet-based remote data entry 
system. Clinical site personnel use an internet browser to key data into eCRFs; each CRF page is submitted to the clinical 

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database electronically as the page is completed. Univariate data validation tests are performed as the data are keyed. 
The clinical database is backed up nightly; backup tapes are saved in a secure, off-site location. At any time, authorized 
site personnel may log in to the remote data entry system, review and correct previously entered data, or key 
additional data. The data will be further validated per the study data validation plan via a series of computerized and 
manual edit checks, and all relevant data queries will be raised and resolved on an ongoing basis. Complete, clean data 
will be frozen to prevent further inadvertent modifications. All discrepancies will be reviewed and any resulting queries 
will be resolved with the investigators and amended in the database. All elements of data entry (i.e., time, date, 
verbatim text, and the person performing the data entry) will be recorded in an electronic audit trail to allow all data 
changes in the database to be monitored and maintained in accordance with federal regulations.  
Monitors are responsible for regular inspection of the conduct of the trial, for verifying adherence to the protocol, and 
for confirming the completeness, consistency, and accuracy of all documented data.  
 Monitors will periodically visit the participating clinical site and audit the source documents in order to validate the 
data in the central database. Data will be provided using the participants screening or enrollment number, the DAIT 
data center will not collect personally identifying information such as the participants name or social security number. 
Participants s will provide demographic information such as race, ethnicity, and birth date. 
Data collected by the DAIT data center will be held in the strictest confidence and are protected from access that could 
reveal personally identifying information about any participant in the trial.  
16 Protocol Deviations 
16.1 Protocol Deviation Definitions 
Protocol Deviation – The investigators and site staff will conduct the study in accordance to the protocol; no deviations 
from the protocol are permitted. Any change, divergence, or departure from the study design or procedures constitutes 
a protocol deviation. As a result of any deviation, corrective actions will be developed by the site and implemented 
promptly as appropriate. 
Major Protocol Deviation (Protocol Violation) - A Protocol Violation is a deviation from the IRB-approved protocol that 
may affect the participant's rights, safety, or well-being and/or the completeness, accuracy and reliability of the study 
data. In addition, protocol violations include willful or knowing breaches of human subject protection regulations, or 
policies, any action that is inconsistent with the NIH Human Research Protection Program’s research, medical, and 
ethical principles, and a serious or continuing noncompliance with federal, state, local or institutional human subject 
protection regulations, policies, or procedures.  
Non-Major Protocol Deviation - A non-major protocol deviation is any change, divergence, or departure from the study 
design or procedures of a research protocol that does not have a major impact on the participant's rights, safety or well-
being, or the completeness, accuracy and reliability of the study data. 
16.2 Reporting and Managing Protocol Deviations 
The study site PI has the responsibility to identify, document and report protocol deviations as directed by DAIT/NIAID. 
However, protocol deviations may also be identified during site monitoring visits or during other forms of study conduct 
review.  

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When a deviation occurs, corrective actions may be necessary depending on the nature of the deviation. Risk 
assessment must occur by the investigator and study sponsor. The investigator should ensure a procedure for the 
timely correction and documentation of problems identified by study personnel, outside monitors or auditors, or other 
parties involved in the conduct of a study. The depth of Corrective Action/Preventive Action (CAPA) required should 
match the risk and impact on safety of participants and/or the quality of the data. 
Upon determination that a protocol deviation has occurred, the investigator/designated study staff will report the 
deviation according to the processes outlined for the study. A major deviation is to be reported within 3 business days 
and reported by the investigator to the IRB per IRB reporting requirements. The study sponsor will determine 
reportability of the deviation to the DSMB as applicable.  
17 Ethical Considerations and Compliance with Good Clinical Practice 
17.1 Statement of Compliance 
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance for Industry: E6 Good 
Clinical Practice Consolidated Guidance, and according to the criteria specified in this study protocol. Before study 
initiation, the protocol and the informed consent documents will be reviewed and approved by the IRB. Any 
amendments to the protocol or to the consent materials will also be approved by the IRB before they are implemented. 
17.2 Informed Consent Process 
The consent process will provide information about the study to a prospective participant and will allow adequate time 
for review and discussion prior to his/her decision. The investigator or designee listed on the IORA will review the 
consent and answer questions. The prospective participant will be told that being in the trial is voluntary and that he or 
she may withdraw from the study at any time, for any reason. All participants (or their legally acceptable 
representative) will read, sign, and date a consent form before undergoing any study procedures. Consent materials will 
be presented in participants’ primary language. A copy of the signed consent form will be given to the participant. 
The consent process will be ongoing. The consent form will be revised when important new safety information is 
available, the protocol is amended, and/or new information becomes available that may affect participation in the 
study. The consent/assent process will be documented in the research or medical records.  
17.3 Privacy and Confidentiality 
A participant’s privacy and confidentiality will be respected throughout the study. Each participant will be assigned a 
unique identification number and these numbers rather than names will be used to collect, store, and report participant 
information. Site personnel will not transmit documents containing personal health identifiers (PHI) to the study 
sponsor or their representatives. 
The study protocol, documentation, data and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without prior written 
approval of the sponsor. 
The study monitor or other authorized representatives of the sponsor may inspect all documents and records required 
to be maintained by the investigator, including but not limited to, medical records (office, clinic or hospital) and 
pharmacy records for the participants in this study. The clinical study sites will permit access to such records. 

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18 Publication Policy 
The Autoimmune Centers of Excellence policy on the publication of study results will apply to this trial. Authorized study 
personnel may find details regarding the policy on the ACE study portal. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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19 Appendices 
19.1 Appendix 1: Mycophenolate REMS Program Acceptable Methods for Females of Reproductive Potential 
Acceptable Contraception Methods for Females of Reproductive Potential* 
Option 1 
Methods to Use Alone 
• 
Intrauterine devices (IUDs) 
• 
Tubal sterilization 
• 
Participant’s partner had a vasectomy 
OR 
Option 2 
 
Choose One Hormone 
Method AND One 
Barrier Method 
Hormone Methods 
choose 1 
 
Barrier Methods 
choose 1 
Estrogen and Progesterone 
• 
Oral contraceptive pill 
• 
Transdermal patch 
• 
Vaginal ring 
 
Progesterone-only 
• 
Injection  
• 
Implant  
AND 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Contraceptive sponge 
• 
Male condom 
• 
Female condom 
OR 
Option 3 
 
Choose One Barrier 
Method from each 
column (must chose 
two methods) 
Barrier Methods 
choose 1 
 
Barrier Methods 
choose 1 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Contraceptive sponge 
 
AND 
• 
Male condom 
• 
Female condom 
* Females of reproductive potential include girls who have entered puberty and all women who have a 
uterus and have not passed through menopause.  
 
 
 
 
 
 
 

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19.2 Appendix 2: Examples of CYP3A4/5 Inhibitors and Inducers 
The table below lists examples of CYP3A4/5 Inhibitors and Inducers. It is not an all-inclusive list.  
CYP3A4 Inducers 
CYP3A4  
Inhibitors 
P-gp 
Inducers 
P-gp Inhibitors 
P-gp 
SUBSTRATES 
carbamazepine 
allopurinol 
aspirin 
amiloride 
dipyridamole 
corticosteroids 
amiodarone 
paclitaxel 
amiodarone 
digoxin 
efavirenz 
amprenavir 
Other CNI 
atorvastin 
diltiazem 
modafinil 
cimetidine 
 
carvedilol 
losartan 
nevirapine 
diltiazem 
 
digoxin 
quinidine 
omeprazole 
erythromycin 
 
diltiazem 
Other CNIs 
phenytoin 
fluconazole 
 
dipyridamole 
 
rifampin 
grapefruit juice 
 
felodipine 
 
St. John’s Wort 
isoniazid 
 
lidocaine 
 
 
ketoconazole 
 
lovastatin 
 
 
nifedipine 
 
nifedipine 
 
 
quinolones 
 
quinidine 
 
 
tamoxifen 
 
simvastatin 
 
 
verapamil 
 
verapamil 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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19.3 Disease-Specific Assessments 
19.3.1 EULAR/ACR Classification Criteria for SLE [3] 
 

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19.3.2 BILAG 2004 
 

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19.3.5 Thanou Modified SFI 
 
 

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19.3.6 LFA-REAL CLINRO 
 
 

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19.3.7 LFA-REAL PRO 
 

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19.3.11 
SF-36 
 
 

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