Phase 2a, Randomized, Double-blind, Placebo-controlled Trial of PRV-3279 EVAluation In Lupus
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Sponsor: Provention Bio, a Sanofi Company

CONFIDENTIAL 
Protocol PREVAIL-2 
Provention Bio, Inc. 
1 
Final 
Internal
Clinical Study Protocol 
Phase 2a, Randomized, Double-blind, Placebo-controlled Trial of PRV-3279 
EVAluation In Lupus (PREVAIL-2) 
Protocol Number: 
PRV-3279-2a 
Compound:   
PRV-3279 
Study Phase:   
2a 
Short Title:   
PRV-3279-2a trial in systemic lupus 
Acronym:  
PREVAIL-2 
Sponsor Name:  
Provention Bio, Inc. 
55 Broad Street, 2nd Floor 
Red Bank, NJ 07701 
Regulatory Agency Identifier Number(s):  IND: 121930 
Version:  
 
2.0 
Approval Date:  
16 Dec 2022 
CONFIDENTIAL 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from Provention Bio, Inc. In the event of any 
actual or suspected breach of this obligation, Provention Bio, Inc., must be promptly notified. 
These restrictions on disclosure will apply equally to all future information supplied to you that 
is indicated as privileged or confidential. 
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NCT: NCT05087628

CONFIDENTIAL 
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Sponsor Signatory: 
Senior Vice President, Clinical Development 
Provention Bio, Inc. 
Date 
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Table of Contents  
Clinical Study Protocol ..................................................................................................................1 
Table of Contents ...........................................................................................................................3 
Summary of Changes .....................................................................................................................7 
1. 
Protocol Summary ........................................................................................................15 
1.1. 
Synopsis ..........................................................................................................................15 
1.2. 
Schematic ........................................................................................................................22 
1.3. 
Schedule of Activities (SoA) ..........................................................................................23 
2. 
Introduction ...................................................................................................................26 
2.1. 
Rationale .........................................................................................................................26 
2.2. 
Background on PRV-3279 ..............................................................................................26 
2.2.1. 
Relevance of the PRV-3279 Mechanism of Action to SLE ...........................................26 
2.3. 
Nonclinical Safety...........................................................................................................27 
2.4. 
Phase 1 Studies of PRV-3279 in Healthy Humans .........................................................28 
2.4.1. 
Single Ascending Dose Study: CP-MGD010-01 ............................................................28 
2.4.1.1. 
Safety Results ..............................................................................................................28 
2.4.1.2. 
Pharmacokinetic Results .............................................................................................29 
2.4.1.3. 
Immunogenicity Results ..............................................................................................29 
2.4.1.4. 
Pharmacodynamic Results ..........................................................................................29 
2.4.2. 
Multiple Ascending Dose Study (PREVAIL-1) .............................................................30 
2.4.2.1. 
Safety Results ..............................................................................................................30 
2.4.2.2. 
Pharmacokinetic Results .............................................................................................30 
2.4.2.3. 
Immunogenicity Results ..............................................................................................31 
2.4.2.4. 
Pharmacodynamic Results ..........................................................................................31 
2.5. 
Risk-Benefit Assessment ................................................................................................32 
3. 
Objectives and Endpoints ............................................................................................34 
4. 
Study Design ..................................................................................................................37 
4.0. 
Design .............................................................................................................................37 
4.1. 
Scientific Rationale for Study Design ............................................................................39 
4.2. 
Justification for Dose ......................................................................................................39 
4.3. 
Definition of End of Study..............................................................................................40 
5. 
Study Population ...........................................................................................................41 
5.1. 
Inclusion Criteria ............................................................................................................41 
5.2. 
Exclusion Criteria ...........................................................................................................42 
5.3. 
Screen Failures ................................................................................................................45 
6. 
Study Treatment ...........................................................................................................46 
6.1. 
Study Drug Administration .............................................................................................46 
6.1.1. 
Monitoring for Infusion or Allergic Reactions ...............................................................46 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................47 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................48 
6.3.1. 
Randomization ................................................................................................................48 
6.3.2. 
Blinding...........................................................................................................................48 
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6.3.3. 
Emergency Unblinding ...................................................................................................48 
6.4. 
Study Treatment Compliance .........................................................................................49 
6.5. 
Dose Modification or Interruption ..................................................................................49 
6.5.1. 
Treatment Modification ..................................................................................................49 
6.5.2. 
Treatment Interruption Rules ..........................................................................................49 
6.6. 
Concomitant Therapy .....................................................................................................49 
6.6.1. 
Prohibited Medications ...................................................................................................50 
6.6.1.1. 
Prohibited Medications (See Exclusion Periods for Investigational and Biological 
Agents) ........................................................................................................................50 
6.6.1.2. 
Prohibited Medications at Any Time During the Study ..............................................50 
6.6.2. 
Permitted SLE Medications ............................................................................................50 
6.6.3. 
SLE Medications to Treat a Flare ...................................................................................51 
7. 
Discontinuation of Study Treatment and Patient Withdrawal ................................52 
7.1. 
Discontinuation of Study Treatment ...............................................................................52 
7.2. 
Patient Withdrawal from the Study ................................................................................52 
7.3. 
Lost to Follow-up............................................................................................................53 
8. 
Study Assessments and Procedures.............................................................................54 
8.1. 
Study Procedures ............................................................................................................54 
8.1.1. 
Screening Procedures ......................................................................................................54 
8.1.2. 
Baseline/Randomization Visit (Week 0, Day 1) .............................................................56 
8.1.3. 
Scheduled Visits from Week 4 through Week 28 ...........................................................56 
8.1.4. 
Unscheduled and “Flare Assessment” Visits ..................................................................57 
8.1.5. 
Efficacy Assessments......................................................................................................57 
8.1.6. 
Disease Measurement Instruments .................................................................................57 
8.1.6.1. 
Hybrid Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI) ............57 
8.1.6.2. 
SELENA-SLEDAI Physicians Global Assessment (ssPGA) .....................................58 
8.1.6.3. 
SELENA-SLEDAI Flare Index (SFI) .........................................................................58 
8.1.6.4. 
Modified SELENA-SLEDAI Flare Index (mSFI) ......................................................59 
8.1.6.5. 
British Isles Lupus Assessment Group (BILAG) Index .............................................59 
8.1.6.6. 
Cutaneous Lupus Erythematous Disease Area and Severity Index (CLASI) .............59 
8.1.6.7. 
Tender and Swollen Joint Counts ...............................................................................59 
8.1.7. 
Patient-Reported Outcomes ............................................................................................60 
8.1.7.1. 
Short Form 36 Health Survey (SF-36) ........................................................................60 
8.1.7.2. 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) ....................61 
8.1.7.3. 
Patient Global Impression Scales (PGIS and PGIC) ...................................................62 
8.1.8. 
Laboratory Tests of Lupus Disease Activity ..................................................................62 
8.2. 
Safety Assessments .........................................................................................................62 
8.2.1. 
Physical Examinations ....................................................................................................63 
8.2.2. 
Vital Signs .......................................................................................................................63 
8.2.3. 
Electrocardiograms .........................................................................................................63 
8.2.4. 
Tuberculosis Screening ...................................................................................................63 
8.2.5. 
Clinical Safety Laboratory Assessments ........................................................................63 
8.2.6. 
Data Review Committees ...............................................................................................64 
8.2.6.1. 
Central Adjudication Committee (CAC) ....................................................................64 
8.2.6.2. 
Independent Data Monitoring Committee (IDMC) ....................................................64 
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8.3. 
Adverse Events (AEs) and Serious Adverse Events (SAEs) ..........................................65 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................65 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................65 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................65 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................65 
8.3.5. 
Pregnancy ........................................................................................................................66 
8.3.6. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as TEAEs ......................................................................................................66 
8.3.7. 
Adverse Events of Special Interest .................................................................................66 
8.3.8. 
Infusion or Allergic Reactions ........................................................................................67 
8.4. 
Overdose .........................................................................................................................67 
8.5. 
Pharmacokinetic Assessments ........................................................................................67 
8.6. 
Immunogenicity Assessments.........................................................................................67 
8.7. 
Pharmacodynamic/Biomarker Assessments ...................................................................67 
9. 
Statistical Considerations .............................................................................................69 
9.1. 
Sample Size Determination ............................................................................................69 
9.2. 
Populations for Analyses ................................................................................................69 
9.3. 
Statistical Analyses .........................................................................................................70 
9.3.1. 
General Considerations ...................................................................................................70 
9.3.1.1. 
Handling of Missing Data ...........................................................................................70 
9.3.2. 
Primary Analysis .............................................................................................................70 
9.3.3. 
Secondary Efficacy Analysis ..........................................................................................71 
9.3.4. 
Exploratory Analyses ......................................................................................................71 
9.3.5. 
Safety Analyses ...............................................................................................................71 
9.3.6. 
Immunogenicity Analyses ..............................................................................................72 
9.3.7. 
Pharmacokinetic ..............................................................................................................72 
9.3.8. 
Pharmacodynamic Analyses ...........................................................................................73 
9.3.9. 
Subgroup Analyses of Primary/Secondary Efficacy Endpoints .....................................73 
9.3.10. Sensitivity Analyses ........................................................................................................73 
9.4. 
Interim Analysis ..............................................................................................................73 
10. 
Supporting Documentation and Operational Considerations ..................................74 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................74 
10.1.1. Regulatory and Ethical Considerations ...........................................................................74 
10.1.2. Financial Disclosure........................................................................................................74 
10.1.3. Informed Consent Process ..............................................................................................74 
10.1.4. Data Protection................................................................................................................75 
10.1.5. Dissemination of Clinical Study Data.............................................................................75 
10.1.6. Data Quality Assurance ..................................................................................................75 
10.1.7. Source Documents ..........................................................................................................76 
10.1.8. Study and Site Start and Closure ....................................................................................76 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................78 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................79 
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10.3.1. Definition of AE .............................................................................................................79 
10.3.2. Definition of SAE ...........................................................................................................80 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................................81 
10.3.4. Reporting of SAEs ..........................................................................................................82 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................84 
10.5. 
Appendix 5: Equivalence of Common Corticosteroid 
Formulations and Permitted Antimalarials .....................................................................87 
10.6. 
Appendix 6: Clinical Endpoints and Disease Activity 
Instruments......................................................................................................................88 
10.6.1. Composite Endpoints Used in this Study........................................................................88 
10.6.1.1. 
SLE Responder Index-4 (SRI-4) .................................................................................88 
10.6.1.2. 
BILAG-based Combined Lupus Assessment (BICLA) ..............................................88 
10.6.2. Clinical Outcome Measures: Glossaries, Scoring Instructions and 
Forms ..............................................................................................................................88 
10.6.2.1. 
Form and Glossary for Hybrid SELENA-SLEDAI ....................................................89 
10.6.2.2. 
SLEDAI Flare Index (SFI) and Modified SFI ............................................................97 
10.6.2.3. 
SELENA-SLEDAI Physician’s Global Assessment (ssPGA) ....................................97 
10.6.2.4. 
Form, Glossary and Scoring Rules for BILAG ...........................................................99 
10.6.2.5. 
Clinicians Global Impression of Change (CGIC) .....................................................127 
10.6.2.6. 
Cutaneous Lupus Erythematosus Diseases Area and Severity Index (CLASI) Form 
with Descriptors ........................................................................................................128 
10.6.2.7. 
Tender and Swollen Joint Count Form .....................................................................129 
10.7. 
Patient-Reported Outcomes ..........................................................................................130 
10.7.1. Medical Outcomes Study Questionnaire Short Form 36 Health 
Survey (SF-36) ..............................................................................................................130 
10.7.2. Patients Global Impression Scales (PGIS and PGIC) ...................................................133 
10.7.3. FACIT-Fatigue Scale ....................................................................................................134 
11. 
Abbreviations ..............................................................................................................135 
12. 
References ....................................................................................................................140 
 
 
 
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Summary of Changes  
Protocol version 1.1 dated 20Aug2021 to 2.0 dated 16Dec2022 
Protocol PRV-3279-2a version 1.1 dated 20Aug2021 has been amended to version 2.0 dated 
16Dec2022. Substantive changes to the previous version of the protocol are listed in the table 
below along with rationales. In addition, minor corrections and administrative/editorial changes 
and clarifications have been made throughout the document. All changes are clearly identified in 
the track-changes version of the amendment. 
 
Section 
Rationale for Change 
Original Text 
Revised Text 
Throughout the 
protocol 
China and the option 
for geographies in 
addition to Hong Kong 
and the US have been 
included in the 
PREVAIL-2 study 
 
 
 
For enhanced safety, 
urinalysis has been 
included in all study 
visits  
 
 
 
The option of a serum 
pregnancy test has 
been added to all 
treatment visits. 
 
 
 
Text clarifying that 
covid tests must 
demonstrate negative 
results prior to 
administering study 
drug has been added 
 
 
 
 
 
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Section 
Rationale for Change 
Original Text 
Revised Text 
Title Page 
The sponsor signatory 
has been changed  
 
 
1.3. Schedule of 
Activities,  
8.5. 
Pharmacokinetic 
Assessments 
Additional PK 
sampling timepoints 
have been reduced for 
patient and site 
convenience and 
windows have been 
added to each 
timepoint 
Additional samples will 
be collected at the Day 
1 and Day 
visits, at 
the following 
timepoints: 
 
Additional samples will 
be collected at the Day 
1 and Day 
 visits, at 
the following 
timepoints: 
. 
1.3. Schedule of 
Activities 
Receptor Occupancy 
sampling timepoints 
have been reduced for 
patient and site 
convenience and 
windows have been 
added to each 
timepoint 
Additional samples will 
be collected at the Day 
1 and Day 
 visits, at 
the following 
timepoints: 
e. 
1.3. Schedule of 
Activities,  
8.1.1. Screening 
Procedures, 
8.2.2. Vital 
Signs 
Appropriate patient 
position and 
assessment window for 
obtaining vital signs 
have been defined 
On dosing days, vital 
signs should be 
performed before the 
study drug infusion and 
approximately 30 
minutes after the end of 
infusion. 
On dosing days, vital 
signs should be 
performed after patient 
is supine for at least 5 
minutes during the 30 
minutes before the 
study drug infusion and 
approximately 30 
minutes after the end of 
infusion. 
2.5. Risk-
Benefit 
Assessment, 
4.1. Design,  
The study population 
will not be restricted to 
these patients, but, 
using a rapid gene 
expression profiling 
system (e.g., DxTerity 
or similar) at Screening, 
a reasonably accurate 
surrogate for the 
presence or absence of 
this, or part of this 
 
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phenotype will be one 
of the stratification 
factors during 
randomization.  
     
4.1 Design 
The option for 
extending the 
screening period by 
two weeks at the 
discretion of the 
Medical Monitor has 
been added to allow 
flexibility for delays 
due to sample analysis 
delays or other delayed 
screening results 
If a patient takes any 
new SLE medications 
(other than NSAIDs), 
increases the dose of 
current SLE 
medications (other than 
NSAIDs), misses 2 
consecutive doses or 3 
or more total doses of 
the study drug, the 
patient should 
permanently 
discontinue study drug 
and continue study 
procedures and 
assessments, but will be 
documented as a 
nonresponder in the 
primary and applicable 
secondary efficacy 
endpoints. 
If a patient takes any 
new SLE medications 
(other than NSAIDs), 
increases the dose of 
current SLE 
medications (other than 
NSAIDs), misses 2 
consecutive doses or 3 
or more total doses of 
the study drug, the site 
should contact the 
Medical Monitor to 
discuss permanent 
discontinuation of the 
study drug. The patient 
will be encouraged to 
continue study 
procedures and 
assessments, but will 
be documented as a 
nonresponder in the 
primary and applicable 
secondary efficacy 
endpoints. 
5.2 Exclusion 
Criteria, 6.6.1.1. 
Prohibited 
Medications at 
Entry 
Clarification for 
exclusion criterion 1 
regarding excluded 
SLE medications at 
randomization has 
been added 
1. Currently receiving 
disease-modifying 
antirheumatic drug 
(DMARD), JAK 
inhibitor, or calcineurin 
inhibitor treatment for 
induction or 
maintenance treatment 
of nephritis or any other 
reason. 
1. Currently receiving 
induction treatment or 
maintenance treatment 
(e.g., mycophenolate 
mofetil, azathioprine, 
JAK inhibitor, 
calcineurin inhibitor, 
others) for lupus 
nephritis. 
5.2 Exclusion 
Criteria 
Clarification of 
eligibility criteria for 
CBC and requirements 
for repeat samples to 
determine eligibility 
7. Complete blood 
count (CBC): 
a. white blood cell 
(WBC) count 
<1.5×109/L;  
7. Complete blood 
count (CBC):  
a. white blood cell 
(WBC) count 
<1.5×109/L;  
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b. lymphocyte count 
<0.3×109/L;  
c. neutrophil count 
<1.0×109/L;  
d. hemoglobin ≤8.0 
g/dL;  
e. platelet count 
<40×109/L. (If the 
platelet count is <70× 
109/L, a repeat 
sample must not 
decrease >5×109 /L 
within the Screening 
period. If lymphocyte 
count is <0.5×109/L, 
a repeat sample must 
not be decreasing.)  
 
b.lymphocyte count 
<0.3×109/L (If 
lymphocyte count is 
<0.5×109/L, a repeat 
sample must be 
collected and 
analyzed and must 
not be decreasing.);  
c. neutrophil count 
<1.0×109/L;  
d.hemoglobin ≤8.0 
g/dL;  
e. platelet count 
<40×109/L (If the 
platelet count is <70× 
109/L, a repeat 
sample must be 
collected and 
analyzed and must 
not decrease >5×109 
/L within the 
Screening period.)  
5.2 Exclusion 
Criteria, 
6.6.1.2. 
Prohibited 
Medications at 
Any Time 
During the 
Study 
Clarification for 
exclusion criterion 13 
regarding vaccinations 
has been added 
13. Received a live 
attenuated vaccine 
within 2 months of 
Screening, received a 
non-live or mRNA 
vaccine within 2 weeks 
of Screening, or 
expecting to receive 
any vaccine during the 
study period. 
13. Received a live 
attenuated vaccine 
within 2 months of 
Screening, or received 
a non-live or mRNA 
vaccine within 2 weeks 
of Screening. Patients 
should be advised to 
delay vaccines until 
after the study 
completion to ensure 
optimal vaccine 
efficacy; however 
receipt of a non-live 
vaccine after 
randomization is not 
exclusionary. 
5.2 Exclusion 
Criteria 
Clarification for 
exclusion criterion 14 
regarding patients with 
positive 
QuantiFERON TB-
QuantiFERON TB-
Gold-positive patients 
are allowed to 
participate in the study 
if chest x-ray confirms 
QuantiFERON TB-
Gold-positive patients 
may be allowed to 
participate in the study 
if all the following are 
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Rationale for Change 
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Gold results has been 
added 
no active disease, and 
one of the following 
conditions is met: 
- Active TB is ruled out 
by a certified TB 
specialist or 
pulmonologist who is 
familiar with 
diagnosing and 
treating TB (as 
acceptable per local 
practice). 
- The patient has 
documented evidence 
of satisfactory 
completion of LTBI-
appropriate 
prophylaxis as per 
WHO or national 
guidelines within the 
last 5 years following 
review by a physician 
specializing in TB. 
- The patient has 
completed at least 4 
weeks of LTBI-
appropriate 
prophylaxis prior to 
randomization with 
agents recommended 
as preventative 
therapy for LTBI 
according to country-
specific/Centers for 
Disease Control and 
Prevention (CDC) 
guidelines and is 
willing to complete 
the entire course of 
recommended LTBI 
therapy. 
true: (a) chest x-ray 
confirms no active 
disease, and (b) the 
patient has completed 
at least 4 weeks of 
LTBI-appropriate 
prophylaxis prior to 
randomization with 
agents recommended as 
preventative therapy 
for LTBI according to 
country-
specific/Centers for 
Disease Control and 
Prevention (CDC) 
guidelines and is 
willing to complete the 
entire course of 
recommended LTBI 
therapy, and (3) the 
CAC confirms the 
patient to be stable for 
inclusion. 
Table 1 
Treatment 
Interruption 
Corrections made to 
levels required at 
screening and for 
No return Screening 
level 
No return to level 
required at Screening 
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Rationale for Change 
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Based on Safety 
Laboratory 
Tests 
treatment 
interruptions; 
conditions for next 
dose suspended 
clarified  
8. Study 
Assessments 
and Procedures 
Corrections and 
clarifications made to 
amount of blood 
collected 
The maximum amount 
of blood collected from 
most patients over the 
duration of the study 
will not exceed 500 
mL. Due to additional 
PK blood sample 
collections (Section 
8.5), the maximum 
blood volume will be 
approximately 550 mL 
in approximately 20 
patients at Hong Kong 
sites (and other select 
patients). 
The maximum amount 
of blood collected from 
most patients over the 
duration of the study 
will not exceed 525 
mL. Due to additional 
PK blood sample 
collections (Section 
8.5) and Receptor 
Occupancy sample 
collections (Section 
8.7), the maximum 
blood volume will be 
approximately 630 mL 
in approximately 30 
patients. 
8.1 Study 
Procedures 
New text added to 
clarify timing of PRO 
questionnaires at study 
visits 
 
Patients will complete 
PRO questionnaires 
prior to any blood 
draws or other 
interventions with the 
study staff.   
8.1.2. Baseline/ 
Randomization 
Visit (Week 0, 
Day 1) 
Additional text added 
to clarify requirements 
and timing for 
confirming patient 
eligibility at 
randomization visit 
Upon arrival at the 
clinic, patients will 
complete the PRO 
questionnaires prior to 
any blood draws or 
other interventions with 
the study staff. Patients 
will then have an 
interim history and a 
brief physical 
examination performed 
(including body 
weight). The 
Investigator must 
confirm that there has 
been “definite 
improvement” or 
Upon arrival at the 
clinic, patients will 
complete the PRO 
questionnaires prior to 
any blood draws or 
other interventions with 
the study staff. Patients 
will then have an 
interim history and a 
brief physical 
examination performed 
(including body 
weight). The 
Investigator will also 
complete the 
hSLEDAI, ssPGA, SFI, 
mSFI, BILAG, CLASI, 
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“major or complete 
improvement” using the 
CGIC. The Investigator 
will also complete the 
hSLEDAI, ssPGA, SFI, 
mSFI, BILAG, CLASI, 
and joint counts. 
A pre-dose urinalysis 
(with reflex 
protein/creatinine ratio 
if dipstick is ≥2+) and 
urine pregnancy test 
(for WOCBP) will be 
obtained.  
Vital signs, ECG, AE, 
and concomitant 
medication assessments 
will be performed.  
Rapid COVID-19 test 
will be performed 
locally.  
 
and joint counts. To 
assess eligibility, the 
Investigator must 
confirm that the patient 
has achieved at least a 
moderate improvement 
in SLE signs and 
symptoms as indicated 
by:  
CGIC score of 
“definite 
improvement” or 
“major or complete 
improvement”  
AND  
≥4-point decrease in 
hSLEDAI score from 
Screening, OR 
improvement by ≥1 
severity grade in at 
least one BILAG 
system that was 
severe (A score) or 
moderate (B score) at 
Screening (i.e., from 
A to B-D or from B 
to C or D).  
A pre-dose urinalysis 
and urine or serum 
pregnancy test (for 
WOCBP) will be 
obtained.  
Vital signs, ECG, AE, 
and concomitant 
medication assessments 
will be performed.  
Rapid COVID-19 test 
will be performed 
locally to confirm 
negative result prior to 
study drug 
administration.  
10.2. Appendix 
2: Clinical 
Corrections made to 
chemistry analysis  
Chemistry: sodium, 
potassium, chloride, 
Chemistry: sodium, 
potassium, chloride, 
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Section 
Rationale for Change 
Original Text 
Revised Text 
Laboratory 
Tests 
calcium, ALP, ALT, 
AST, BUN, creatinine, 
total protein, albumin, 
glucose, phosphorous, 
and bicarbonate 
calcium, ALP, ALT, 
AST, BUN, creatinine, 
CPK, direct and total 
bilirubin, total protein, 
albumin, glucose, 
phosphorous, and 
bicarbonate 
Note that all protocol changes were also reflected in Section 1.1 Synopsis 
 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: Phase 2a, Randomized, Double-blind, Placebo-controlled Trial of PRV-3279 
EVAluation In Lupus (PREVAIL-2) 
Short Title: PRV-3279-2a trial in systemic lupus 
Rationale: PRV-3279 is a humanized dual affinity re-targeting (DART®) protein that binds to 
both CD32B (Fcγ receptor IIb) and CD79B on B cells only. The mechanism of action and early 
clinical data suggest that PRV-3279 may be a safe and effective treatment for chronic systemic 
lupus erythematosus (SLE).  
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary  
To evaluate the ability of PRV-3279 to prevent 
flare, i.e., to maintain the improvement in SLE 
signs and symptoms for 24 weeks, after the 
amelioration of active disease induced by 
corticosteroid treatment before Day 1 with the 
withdrawal of major background medications. 
Proportion of patients who maintain the 
improvement in SLE disease activity from 
Baseline (Day 1) to Week 24, defined as no 
lupus flare during this period.  
A lupus flare is defined as: 
• 
Investigator’s assessment that the SLE 
activity meets the Lupus Foundation of 
America (LFA) international consensus 
definition for a flare1 AND 
• 
A score of “definite worsening” or “severe 
worsening” on Clinician’s Global Impression 
of Change (CGIC), AND  
• 
at least one of the following occurrences:  
o an increase of ≥4 points from baseline 
in the hybrid Safety of Estrogens in 
Lupus Erythematosus National 
Assessment -Systemic Lupus 
Erythematosus Disease Activity Index 
(SELENA-SLEDAI) score 
(hSLEDAI), OR  
o ≥1 organ with an A score (severe) or B 
Score (moderate) item rated new or 
worse on British Isles Lupus 
Assessment Group (BILAG) Index 
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Objectives 
Endpoints 
Secondary 
Efficacy: 
1. To evaluate whether PRV-3279 prolongs the 
duration of disease amelioration induced by 
corticosteroids before Day 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. To determine whether PRV-3279 allows 
patients to achieve and sustain European 
League Against Rheumatism (EULAR)-
recommended treatment goal of low disease. 
 
3. To evaluate the effect of PRV-3279 on patient-
reported physical functioning. 
 
4. To determine whether PRV-3279 can reduce 
one or more signs and symptoms of SLE using 
a stringent definition for improvement in each 
sign or symptom, based on the SLE Responder 
Index-4 (SRI-4) 
 
 
 
 
 
 
 
1. Time to treatment failure. 
Treatment failure is defined compared to 
Baseline (Day 1): 
• 
Occurrence of an SLE flare (as defined 
in the primary endpoint), OR 
• 
Missing 2 consecutive doses or 3 or 
more total doses of the study drug for 
any reason, OR 
• 
Initiation of a new SLE medication, OR 
• 
Increased dose of current SLE 
medication, with the exception of 
nonsteroidal anti-inflammatory drugs 
(NSAIDs), OR 
• 
Patient withdrawal from the study before 
the Week 24 visit 
 
2. Proportion of patients who meet either of the 
following criteria at Week 24: 
• 
hSLEDAI score <3 OR 
• 
All BILAG scores are C or less 
 
3. Change from Screening to Week 24 in the 
Physical Component Score (PCS) score in 
the Short Form 36 Health Survey (SF-36). 
 
4. Proportion of patients who meet the criteria 
for SRI-4 at Week 24 compared to 
Screening.  
SRI-4 is defined as:  
• 
A hSLEDAI score decrease of ≥4 points, 
AND 
• 
No new organs with a BILAG A (severe) 
score, AND  
• 
No more than 1 new organ with a 
BILAG B (moderate) score, AND  
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Objectives 
Endpoints 
5. To determine whether PRV-3279 reduces 
disease activity in all organs that are rated as 
moderately or severely active at Screening 
using the BILAG Index. 
 
 
 
 
• 
No SELENA-SLEDAI Physician’s 
Global Assessment (ssPGA) score 
increase of >0.3 points. 
 
5. Proportion of patients who meet the BILAG-
based Combined Lupus Assessment 
(BICLA) criteria at Week 24 compared to 
Screening:  
• 
Reduction by ≥1 grade in all organs with 
BILAG A or B scores AND 
• 
No worsening of SLEDAI or other 
BILAG organs AND 
• 
No ssPGA score increase of ≥0.3 points.  
Safety: To evaluate the safety and tolerability of 
PRV-3279. 
Frequency of treatment-emergent adverse events 
(TEAEs), serious adverse events (SAEs), TEAEs 
leading to drug withdrawal, adverse events of 
special interest (AESIs), and total serum 
immunoglobulin levels. Frequency of potentially 
clinically important changes in clinical 
laboratory tests, vital signs, electrocardiograms 
(ECGs), and physical examinations.  
PK and Immunogenicity: To evaluate the 
pharmacokinetics (PK) and immunogenicity of 
PRV-3279 in patients with SLE. 
Serum concentrations of PRV-3279.  
Anti-drug antibody (ADA) titers.  
Exploratory 
1
  
1. “A flare is a measurable increase in disease activity in one or more organ systems involving new or worse 
clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by 
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Objectives 
Endpoints 
the assessor, and usually, there would be at least consideration of a change or an increase in treatment.” 
(Ruperto 2011) 
Design 
This is a randomized, double-blind, placebo-controlled study in adult patients with active SLE. 
Approximately 100 eligible patients will be randomized at a 1:1 ratio to receive treatment with 
either 10 mg/kg PRV-3279 or placebo. The study drug, PRV-3279 or placebo, will be given as 
an intravenous (IV) infusion over 2 hours, every 4 weeks from Week 0 through Week 20 for a 
total of 6 doses. Two follow-up visits are planned (Week 24 and Week 28). The EOS visit will 
occur at Week 28. 
During the Screening period, the patient will receive an intramuscular (IM) injection of 
methylprednisolone acetate (Depo-Medrol® or equivalent) at a dose of ≥40 mg to induce 
improvement of SLE signs and symptoms. Repeat injections may be given to further ameliorate 
symptoms, up to a total of 4 injections with a maximum total dose of 320 mg.  
Starting on Day 1 (Baseline/Randomization visit) and continuing throughout the study, the only 
background SLE treatments that may be continued are hydroxychloroquine up to 400 mg per day 
(or other antimalarial [Section 10.5]), up to 10 mg per day prednisone (or equivalent 
corticosteroid [Section 10.5]), and NSAIDs. Patients will be asked to abstain from NSAIDs on 
the mornings of the Randomization visit and all subsequent study visits (NSAIDs can be re-
started after completing all evaluations on the day of each study visit). On other days throughout 
the study, NSAIDs are allowed without restrictions. All other SLE treatments taken at the time of 
Screening will be withdrawn during the Screening period and prior to Randomization. 
Potentially eligible patients will return to the study site to confirm eligibility for randomization on 
Day 1. The Investigator must confirm that the patient has achieved at least a moderate 
improvement in SLE signs and symptoms as indicated by:  
CGIC score of “definite improvement” or “major or complete improvement”  
AND  
≥4-point decrease in hSLEDAI score from Screening, OR improvement by ≥1 severity grade 
in at least one BILAG system that was severe (A score) or moderate (B score) at Screening 
(i.e., from A to B-D or from B to C or D).  
Note: Assessments by hSLEDAI and BILAG Index at the Randomization visit may not follow 
the standard 4-week assessment rules but will be scored by a simple clinical comparison of SLE 
disease activity at Week 0 (Day 1, Randomization Visit) to the Screening Visit.  
If the patient is confirmed eligible, randomization will occur through an interactive voice/web 
response system (IVRS/IWRS) and will be stratified by the presence or absence of serum 
anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibodies. 
 
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At each visit, formal assessments of disease activity and safety will be conducted, and laboratory 
specimens will be collected. Patients will receive IV infusions of the study drug every 4 weeks 
from Week 0 through Week 20, inclusive.  
All efforts should be made to retain all patients in the study, regardless of their compliance with 
study procedures. If a patient takes any new SLE medications (other than NSAIDs), increases the 
dose of current SLE medications (other than NSAIDs), misses 2 consecutive doses or 3 or more 
total doses of the study drug, then the site should contact the Medical Monitor to discuss whether 
permanent discontinuation of the study drug is necessary. Patients who permanently discontinue 
study drug will be encouraged to continue study procedures and assessments, but will be 
documented as a nonresponder in the primary and applicable secondary efficacy endpoints. In 
the case of medications taken briefly and in error, exception may be considered following 
discussion with, and approval of, the Medical Monitor. 
If a lupus flare occurs (as defined in the primary endpoint [Section 1.1 and Section 3]), the 
patient should contact the study site immediately and be seen as soon as possible for a Flare 
Assessment visit, regardless of visit schedule, and should be assessed according to the Schedule 
of Activities (SoA, Section 1.3). SLE medications may be prescribed as warranted to control the 
symptoms and/or signs present at this visit. If confirmed, the patient will discontinue any further 
study drug administration and will be considered a nonresponder in the primary and applicable 
secondary efficacy endpoints. 
Throughout the study, SLE disease activity and patient -reported outcomes (PROs) will be 
assessed using the following instruments:   
• Disease Activity Instruments: 
o The hybrid Safety of Estrogens in Lupus National Assessment Systemic 
Erythematosus Lupus Erythematosus Disease Activity Index [hSLEDAI]  
o The SELENA-SLEDAI Physician’s Global Assessment (ssPGA) 
o SELENA-SLEDAI Flare Index (SFI) 
o Modified SELENA-SLEDAI Flare Index (mSFI)  
o British Isles Lupus Assessment Group (BILAG) Index 
o Clinician’s Global Impression of Change (CGIC) 
o Cutaneous Lupus Erythematous Disease Area and Severity Index (CLASI) 
o Tender and swollen joint counts  
• PROs: 
o Short Form 36 Health Survey (SF-36) 
o Patient Global Impression of Change in Clinical Status (PGIC) 
o Patient Global Impression of Change in Disease Severity (PGIS)  
o Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue Scale) 
Safety assessments will include TEAEs, vital signs, physical examination findings, 12-lead 
ECGs, and clinical laboratory tests (hematology, chemistry, urinalysis, coagulation panel, 
lupus-related serologies, SLE disease activity markers, and T cell, B cell, natural killer cell 
[TBNK] panel). A rapid COVID-19 test will be performed at Screening and must be confirmed 
to be negative prior to each study drug administration. A urine or serum pregnancy test will be 
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performed for women of childbearing potential (WOCBP) onsite prior to each study drug 
administration (serum pregnancy test at Screening). 
PK (serum PRV-3279 concentrations), PD (biomarkers), and immunogenicity assessments will 
also be conducted.  
Disclosure Statement: This is a Phase 2a, double-blind, placebo-controlled trial with 
2 treatment arms (PRV-3279 versus placebo) added to limited background medications for SLE.  
Number of Patients: Approximately 100 patients will be randomized to receive study drug 
treatment. The study will be conducted at approximately 40 sites in countries planned to include, 
but not limited to, United States (US), Hong Kong and China. Approximately 50 patients will be 
assigned to each treatment group (PRV-3279 or placebo). Randomized patients who discontinue 
study drug or withdraw consent for study participation will not be replaced. 
Treatment Groups and Duration: 
Treatment Groups: 
• PRV-3279: 10 mg/kg IV infusion, administered over 2 hours, once every 4 weeks, from 
Week 0 to Week 20 
• Placebo: 0.9% sodium chloride IV infusion, administered over 2 hours, once every 
4 weeks, from Week 0 to Week 20 
Duration of study participation for each patient: up to 34 weeks 
• Screening: up to 6 weeks 
o Note: The Screening period may be increased by 2 weeks, under exceptional 
circumstances such as delayed laboratory results or the impact of COVID-19, and 
upon approval by the Medical Monitor. 
• Study Treatment Period: 20 weeks 
• Follow-up: 8 weeks 
Central Adjudication Committee (CAC): Study integrity will be supported with remote 
oversight by a CAC working in tandem with study clinical and data monitors to confirm entry 
qualification and accuracy of disease activity scoring and to adjudicate flares.  
The CAC will consist of independent medical reviewers with clinical expertise in SLE. The CAC 
responsibilities will include: 
• Confirming patients’ eligibility at Screening to enter the study 
• Adjudicating SLE flare 
• Ensuring the accuracy and consistency of scoring of the disease activity instruments  
The CAC will be blinded to study treatment. Details of the CAC composition, objectives, and 
conduct will be described in the CAC charter. 
Independent Data Monitoring Committee (IDMC): An IDMC consisting of 2 physicians and 
1 statistician will be formed. Additionally, 1 or 2 external nonvoting advisors with experience in 
infectious disease, hematology, and other relevant subspecialties may be added as needed. 
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Throughout the study, the IDMC will continually review unblinded safety data. Meetings will be 
held approximately quarterly. Details of the IDMC composition, objectives, and conduct will be 
described in the IDMC charter. 
Statistical Methods: Details of the statistical methods will be provided in the Statistical 
Analysis Plan (SAP).  
Primary efficacy analysis:  
The proportions of patients who meet the criteria of maintained improvement through Week 24 
will be compared between the PRV-3279 and placebo groups using the Cochran-Mantel-
Haenszel (CMH) test, accounting for randomization stratification factors. The Full Analysis Set 
(FAS) of randomized patients will be used. 
Secondary efficacy analysis:  
1. The time to treatment failure will be summarized by treatment group using Kaplan-Meier 
analysis (median, 95% CI, number of events, number censored, etc.) and Kaplan-Meier 
plots. The stratified log-rank test will be used to test for difference between treatment 
groups. 
2. The proportion of patients who achieve the EULAR-recommended goal of low disease at 
Week 24 will be compared between the groups using the same test as the primary 
efficacy analysis. 
3. The change from Screening to Week 24 in the SF-36 PCS will be analyzed using the 
Mixed Model for Repeated Measurements (MMRM). The model will include treatment, 
visit, randomization stratification factors, baseline score as fixed effects, and the 
treatment by visit as interaction term.  
4. The proportion of patients who achieve SRI-4 at Week 24 will be compared between the 
groups using the same test as the primary efficacy analysis.  
5. The proportions of patients who meet the BICLA criteria at Week 24 will be compared 
between the groups using the same test as the primary efficacy analysis. 
The time to treatment failure in subgroups by stratification will be summarized by treatment 
using the Kaplan-Meier method and compared between treatment groups using the log-rank test. 
Exploratory analysis:  
Details of the exploratory analysis will be provided in the SAP. 
Safety analysis:  
TEAEs, SAEs, TEAEs leading to withdrawal of study drug, adverse events of special interest 
(AESIs), and other safety variables will be analyzed using descriptive statistics. 
Immunogenicity: 
ADAs will be analyzed using descriptive statistics.  
PK, PD, and PK/PD analyses:  
PK and PD data will be summarized. Other exploratory analyses, 
, will 
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be detailed in the SAP. Data from this study may be combined with other PK data for a more 
formal population PK analysis in a separate report. 
Sample Size Determination: The published data from the Phase 2, double-blind, randomized, 
placebo-controlled study of a reversible B cell inhibitor, XmAb®5871, in SLE showed that the 
response rates of the maintenance improvement in SLE signs and symptoms in the intent-to-treat 
(ITT) population were 40.4% vs 23.1% at Day 225 and 57.7% vs 34.6% at Day 169 for the 
active arm and control arm, respectively. 
 
1.2. 
Schematic  
 
*All background SLE treatments are stopped or tapered after the Screening visit (before administration of study 
drug on Day 1), except prednisone up to 10 mg daily (or equivalent corticosteroid), up to 400 mg per day 
hydroxychloroquine [or other antimalarial]), and/or NSAIDs.  
**At the time of a flare, the patient should be seen at the study site, regardless of scheduled visits.  
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1.3. 
Schedule of Activities (SoA)  
Period Screening 
Randomized Treatment Visits 
Follow-up 
Flare 
Assessment 
Visit1 
ET Visit 
Week 
-6 to -1 
0 
4 
8 
12 
16 
20 
24 
28 (EOS) 
Day ≤-42 to -1 
1 
29 
57 
86 
113 
141 
169 
197 
Visit Window (± days) 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
+3 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
Eligibility review 
X 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete medical history review 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Complete physical exam4  
X 
 
 
 
 
 
 
 
 
 
 
Brief physical exam5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test in WOCBP 
X 
 
 
 
 
 
 
 
 
 
 
Urine or serum pregnancy test in 
WOCBP 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
FSH & LH (Females – to confirm 
nonsurgical menopause) 
X 
 
 
 
 
 
 
 
 
 
 
Hematology, chemistry, coagulation, 
urinalysis6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TBNK panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV, HCV, HIV &TB tests7 
X 
 
 
 
 
 
 
 
 
 
 
Rapid COVID-19 test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SLE serology tests8 
X 
 
 
 
X 
 
 
X 
X 
 
X 
SLE disease activity markers9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samples10 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADA samples11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PD samples11,13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Receptor Occupancy12 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Period Screening 
Randomized Treatment Visits 
Follow-up 
Flare 
Assessment 
Visit1 
ET Visit 
Week 
-6 to -1 
0 
4 
8 
12 
16 
20 
24 
28 (EOS) 
Day ≤-42 to -1 
1 
29 
57 
86 
113 
141 
169 
197 
Visit Window (± days) 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
+3 
12-lead ECG (local) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
hSLEDAI, ssPGA, SFI, mSFI, BILAG, 
CLASI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIC 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
28 tender and swollen joint counts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36, FACIT-Fatigue, PGIC/PGIS  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer methylprednisolone acetate 
(Depo-Medrol® or equivalent) 14 
X 
 
 
 
 
 
 
 
 
 
 
Study drug administration15 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Abbreviations: ADA=anti-drug antibodies; ANA=antinuclear antibody; anti-dsDNA=anti-double-stranded deoxyribonucleic acid; BILAG=British Isles Lupus 
Assessment Group; CGIC=Clinician’s Global Impression of Change; CLASI= Cutaneous Lupus Erythematous Disease Area and Severity Index; 
COVID=Corona virus disease 2019; ECG=electrocardiogram; ENA=extractable nuclear antigen antibody; EOS=end of study; ET=early termination; 
FACIT=Functional Assessment of Chronic Illness Therapy; FSH=follicle stimulating hormone; GPI=glycoprotein I, HBcAb=hepatitis B core antibody, 
HbsAb=hepatitis B surface antibody, HbsAg=hepatitis B surface antigen, HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
LH=luteinizing hormone; mRNA=messenger ribonucleic acid; mSFI=modified SFI; PD=pharmacodynamics; PGIC=Patient Global Impression of Change in 
Clinical Status; PGIS=Patient Global Impression of Change in Disease Severity; PK=pharmacokinetics; RNA=ribonucleic acid; SFI=SELENA-SLEDAI Flare 
Index; SF-36=Short Form 36; SLE=systemic lupus erythematosus; hSLEDAI=hybrid Systemic Lupus Erythematosus Disease Activity Index; ssPGA=SELENA-
SLEDAI Physician’s Global Assessment; Sm=Smith; RNP=ribonucleoproteins; SSA=Sjögren Syndrome A; SSB=Sjögren Syndrome B; TB=tuberculosis; 
TBNK=T cell, B cell, natural killer (NK) cell; WOCBP=women of child-bearing potential. 
 
Footnotes: 
1. Flare Assessment visits are conducted when patients experience symptoms that require assessments for a potential flare.  
2. Study personnel will record all concomitant medications taken by patients, including prescription and nonprescription medications and any dietary 
supplements (including vitamins and minerals), nutraceuticals, herbal medicines, traditional Chinese medicines, ayurvedic remedies, and any other products. 
3. Vital signs include temperature, heart rate, respiratory rate, and blood pressure. On dosing days, vital signs should be performed after patient is supine for at 
least 5 minutes during the 30 minutes before the study drug infusion and approximately 30 minutes after the end of infusion. 
4. A complete physical exam includes (at a minimum) assessments of the head, eyes, ears, nose, throat, skin, cardiovascular, mucocutaneous, respiratory, 
musculoskeletal, lymphatic, gastrointestinal, and neurological systems.  
5. A brief physical examination must be complete enough to be suitable for SLE instrument scoring. At a minimum, assessments will include mucocutaneous, 
respiratory, cardiovascular, gastrointestinal, and musculoskeletal. 
6. Refer to Section 10.2 for a list of all clinical hematology, serology, coagulation, and urinalysis parameters.  
7. Including HbsAg, HbsAb, HbcAb (total IgM and IgG; if positive, need HBV DNA performed), HCV RNA, HIV 1&2 (and HIV confirmation, if applicable), 
and QuantiFERON TB test (QuantiFERON may be repeated locally if indeterminant).  
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8. SLE serology tests include ANA, ENA (including antibodies against SSA, SSB, Sm, RNP), anti-cardiolipin antibodies (IgA, IgG, and IgM), anti-beta 2 GPI 
antibodies (IgA, IgG, and IgM), and the lupus anticoagulant. 
9. SLE Disease Activity Markers: serum anti-dsDNA antibodies, complement components C3 and C4, and total serum immunoglobulin profile.  
10. 
11. 
. 
12. 
 
13. PD samples will include peripheral blood mononuclear cells for immunophenotype (flow), mRNA analysis including CD32B polymorphisms, and 
exploratory serum markers.  
 
14. At the end of the Screening visit, if no exclusion criteria are known, a patient will receive one or more intramuscular injections of methylprednisolone 
acetate (Depo-Medrol® or equivalent) at a dose of ≥40 mg (maximum total dose 320 mg, maximum 4 injections). The dose will be determined by the 
Investigator to achieve a clinically significant improvement in SLE signs and symptoms. 
 
 
15. Study drug will be administered by intravenous infusion over 2 hours. Patients will be observed for at least 2 hours after first infusion and at least 30 minutes 
after other infusions.  
 
 
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2. 
Introduction  
2.1. 
Rationale  
Systemic lupus erythematosus (SLE) is a chronic, multi-organ autoimmune disease with 
significant impact on survival, disability, and quality of life (QOL). The disease primarily affects 
women of childbearing age, but all age groups may be affected. According to the Lupus 
Foundation of America (LFA), more than 16,000 new cases of lupus are reported annually across 
the United States (US) with a prevalence of at least 1.5 million in the US and 5 million 
worldwide.  
SLE is highly variable both in clinical presentation and course of the disease (Bartels 2014). 
Comorbidities of the disease and side effects of treatment increase the risk of morbidity and 
mortality in patients with SLE (Bertsias 2008). Despite major advances in understanding the 
pathogenesis and clinical course of lupus and improvements in overall survival, the general 
prognosis for lupus patients remains poor with high direct and indirect costs of the disease.  
2.2. 
Background on PRV-3279  
PRV-3279 is a humanized, Dual Affinity Re-Targeting (DART®) protein with a molecular 
weight of 111.5 kDa. DART proteins are bispecific, antibody-based molecules that can bind two 
distinct antigens simultaneously (Veri 2010). PRV-3279 is designed to target CD32B, 
Fc receptor IIb, and CD79B, the Igbeta protein that is part of the B cell receptor (BCR) complex 
(Veri 2010). PRV-3279 was originally developed by MacroGenics, Inc. 
CD32B is a transmembrane inhibitory Fcγ receptor expressed widely on B cells and other 
immune effector cells. CD79B is expressed exclusively on B cells and is an essential signal 
transduction component of the B cell antigen receptor complex (Verschuren 1993; Dal Porto 
2004). Because of the dual affinity of PRV-3279, effects are directed specifically on CD32B on 
B cells, which intentionally couples the B cell activation signal transduced by CD79B to the 
inhibitory CD32B signal. The net effect of this combined binding is the dampening of the 
activation of all B cell subsets, including both naïve and memory B cells, but without broad 
B cell depletion as measured by fluorescence-activated cell sorting (FACS) (Veri 2010). 
Details can be found in the Investigator’s Brochure (IB).  
2.2.1. 
Relevance of the PRV-3279 Mechanism of Action to SLE  
SLE is characterized by the emergence and persistence of pathogenic subsets of B cells and 
autoantibodies against multiple autoantigens, leading to unpredictable flares of inflammation in 
the skin, joints, and other tissues (Bartels 2014; Cancro 2009). There have been few approved 
treatments developed specifically for lupus, and patients must frequently rely on older, untested, 
untargeted immune modulators with significant safety and tolerability issues to control their 
disease.  
B cell activation is not only prevalent but central to the pathogenesis of SLE (Zhang 2001; Stohl 
2003; Chu 2009), supporting the rationale for down-modulation of B cells as a treatment of this 
disease. Given the need for chronic, sometimes lifelong immunosuppression in lupus, a 
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particularly attractive B cell-targeting therapeutic would be one that can rapidly inhibit all 
subsets of activated B cells but spare resting B cells from depletion. PRV-3279 has been 
designed to achieve this and is supported by pre-clinical data. 
2.3. 
Nonclinical Safety  
The chimpanzee is the only relevant species for nonclinical safety evaluation of PRV-3279. It is 
suitable for this purpose given the 100% homology of the extracellular domains of both 
chimpanzee and human CD32B and CD79B and the ability of PRV-3279 to both bind to and 
functionally inhibit human and chimpanzee B cells in a comparable manner. PRV-3279 does not 
bind to CD32B and CD79B in macaques or rodents, making these unsuitable species for 
nonclinical toxicological evaluations. Thus, the principal toxicology studies evaluating 
PRV-3279 included a non-Good Laboratory Practice (GLP) dose escalation toxicology study 
conducted in a single chimpanzee evaluating 5 doses of PRV-3279 ranging from 0.1 to 10 mg/kg 
followed by a recovery observation period and a GLP tissue cross reactivity study of PRV-3279 
on normal human tissues. A supportive non-GLP, tissue cross reactivity study comparing the 
binding profile of PRV-3279 in select normal tissues from both humans and chimpanzees was 
also performed.  
In the non-GLP toxicology study in the chimpanzee, the highest PRV-3279 dose tested 
(10 mg/kg) was not associated with any adverse effects, while dose-dependent pharmacodynamic 
(PD) outcomes were achieved. The non-GLP toxicology study in the chimpanzee was considered 
adequate to support initiation of a first in human, single dose study in healthy subjects 
(Study CP-MGD010-01). 
As safety studies with PRV-3279 in other non-human primates or lower species are not feasible, 
MacroGenics conducted 2 GLP toxicology studies using a PRV-3279 surrogate bispecific 
molecule in transgenic mice lasting 4 and 13 weeks, respectively. The GLP toxicology studies 
were completed following the initiation of the CP-MGD010-01 study. The PRV-3279 surrogate 
molecule used in these studies was designed to target human CD32B and mouse CD79B in a 
mouse deficient (knock-out) for mouse CD32B and transgenic for human CD32B (hCD32B-Tg). 
In the 4-week GLP study, hCD32B transgenic mice received vehicle or the PRV-3279 surrogate 
molecule at a dose level of 25, 50, or 100 mg/kg/day by intraperitoneal injection daily for 
27 consecutive days. Dose levels were selected to determine levels that support a safety factor 
above the potential target clinical dose (up to 10 mg/kg at weekly or longer intervals). 
While analysis of the terminal necropsy completed on 80 mice (20 in each group) revealed no 
gross pathological findings, routine histopathological evaluation revealed that 2 out of 
20 animals that received the surrogate molecule at 100 mg/kg/day had a right atrial thrombus. 
One of these animals also had a pulmonary thrombus. Evaluation of 48 animals from the 
recovery period (12 at each of the 4 dose levels tested) resulted in a microscopic finding of a 
heart thrombus in a single male that received 100 mg/kg/day. Histologically, this thrombus 
differed in that it appeared more fibrous with recanalization, indicating greater chronicity than 
those observed at the terminal necropsy. However, when considering all 3 thrombi, it is believed 
that they all originated during the dosing phase of the study based on histopathologic data. The 
incidence of thrombi in the high-dose animals of this study was approximately 9% (3 out of 
32 animals) and therefore it could not be ruled out that the thrombi were a PRV-3279 surrogate 
related event. No other PRV-3279 surrogate-related events were identified. 
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Subsequently, further characterization of the transgenic mice and PRV-3279 surrogate revealed 
that transgenic mice have higher expression of hCD32B, specifically in peripheral blood 
leukocytes and cardiac endothelial tissue compared with humans, and the PRV-3279 surrogate 
molecule has an increased presence of dimers with increased binding to leukocyte and cardiac 
tissue at higher concentrations than that observed with PRV-3279. These observations associated 
with PRV-3279 surrogate dimers are plausible factors contributing to the observed 
thromboembolic events in some mice treated daily with the PRV-3279 surrogate molecule at the 
higher dose level of 100 mg/kg. Furthermore, it was concluded that these risks were exaggerated 
in or may be unique to hCD32B-Tg mice and the dosing conditions of the GLP toxicity study 
and likely not applicable for subjects administered PRV-3279, as supported by the lack of 
binding of PRV-3279 to human monocytes and cardiac endothelium.  
In the 13-week GLP toxicology study, hCD32B transgenic mice received vehicle or the 
PRV-3279 surrogate molecule at a dose level of 10 or 50 mg/kg/day for 91 consecutive days. 
Dose levels were selected based on the results of the 4-week GLP toxicology study. 
No effects on body weight, food consumption, or ophthalmology were observed. Although no 
clinical signs of toxicity were noted, treatment-related findings during functional observational 
battery evaluations included decreases in rearing activity, piloerection, and a decrease in body 
temperature in males at 50 mg/kg/day at 1-hour post-dose on Day 1 only. There were no 
treatment-related effects on organ weights, macroscopic observations, or microscopic 
observations. Mild, dose-responsive, non-adverse decreases in total protein were attributable to 
mild decreases in albumin and/or globulin in both sexes at ≥10 mg/kg/day, although only the 
decrease in globulin persisted in females at 50 mg/kg/day following recovery. The PRV-3279 
surrogate molecule was well tolerated clinically when administered intraperitoneally to male and 
female hCD32B-Tg mice once daily for 13 weeks at doses of 10 and 50 mg/kg/day. Therefore, 
50 mg/kg/day was considered the no-observed-adverse-effect level. 
2.4. 
Phase 1 Studies of PRV-3279 in Healthy Humans  
2.4.1. 
Single Ascending Dose Study: CP-MGD010-01  
Study CP-MGD010-01 was a Phase 1, double-blind, placebo-controlled, single ascending dose 
(SAD) study in healthy subjects to evaluate the safety, tolerability, pharmacokinetics (PK), PD, 
and immunogenicity of PRV-3279. This study was divided into two parts, dose escalation and 
dose expansion. Dose escalation was conducted in 6 cohorts of 8 subjects each with doses of 
PRV-3279 increasing from 0.01 mg/kg to 10 mg/kg.  
Following dose escalation, a dose-expansion phase was performed, in which doses of 3 mg/kg 
and 10 mg/kg of PRV-3279 were given prior to administration of the hepatitis A virus (HAV) 
vaccine to assess dose dependency of PRV-3279 immune modulation in the context of HAV 
vaccination.  
2.4.1.1. 
Safety Results  
No dose-limiting toxicities occurred in Study CP-MGD010-01. There were no adverse events 
(AEs) leading to study discontinuation in the dose escalation or dose expansion cohorts and no 
deaths occurred. No thrombotic events occurred and there were no significant laboratory 
abnormalities. 
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In summary, single-dose intravenous (IV) infusions of 0.01 to 10 mg/kg PRV-3279 were well 
tolerated. Review of the clinical laboratory data did not reveal any direct laboratory toxicity 
related to PRV-3279 administration. Laboratory abnormalities were not clinically significant, 
dose dependent, or reported as AEs. 
2.4.1.2. 
Pharmacokinetic Results  
In the dose escalation phase of CP-MGD010-01, PRV-3279 exhibited nonlinear PK over the 
single IV dose range of 0.01 to 10 mg/kg in healthy subjects. Exposure, in terms of area under the 
concentration-time curve (AUC), increased in a more than dose-proportional manner with 
increasing dose. Clearance (CL) and volume of distribution decreased with increasing dose. 
There was low variability in exposure parameters (%CV < 27%). The mean CL, volume of 
distribution (Vd), and half-life (t½) of PRV-3279 were approximately 0.35 mL/h/kg, 68 mL/kg, 
and 191 h (~8 days), respectively, for the 10 mg/kg single dose. In the dose escalation phase, 
maximum serum concentration (Cmax) of PRV-3279 and overall exposure (AUC) increased in a 
dose-related manner, with median time to Cmax (Tmax) ranging from 1.98 to 6.00 h between 
0.01 and 10 mg/kg.  
2.4.1.3. 
Immunogenicity Results  
Single doses of PRV-3279 were immunogenic in healthy subjects. The first appearance of 
anti-drug antibodies (ADAs) occurred on Day 15 or later. No placebo-treated subject had 
ADA-positive samples either pre-dose or post-dose. There was an apparent decrease in ADA 
incidence and titers with increasing dose of PRV-3279. The presence of ADA to PRV-3279 had 
no detrimental effect on single-dose PK, as assessed by comparing the PK parameters of 
ADA-positive and negative subjects. Immunogenicity of PRV-3279 had no detrimental effect on 
single-dose PK.  
2.4.1.4. 
Pharmacodynamic Results  
PRV-3279 displayed dose-dependent target B cell binding in the periphery. Following infusion 
of ≥0.1 mg/kg, PRV-3279 binding to B cells was at least 50% of its maximal level with durations 
ranging from 7 to 56 days, again depending on dose. Previous in vitro studies have demonstrated 
that PRV-3279-mediated inhibitory function of B cells reaches optimal effect when >50% of 
maximal PRV-3279 binding to human B cells is achieved.  
Peripheral B cells collected from subjects following a single administration of PRV-3279 at 
≥1 mg/kg displayed inhibited ex vivo response to B cell activation as measured by the calcium 
flux response, with the extent and duration of inhibition correlating with PRV-3279 dose. 
PRV-3279 was not associated with B cell depletion as measured by FACS but B cells exhibited 
dose-dependent down-modulation of surface BCR and the co-stimulation molecule CD40. 
In the dose expansion phase, the effect of PRV-3279 on humoral responses to HAV vaccination 
was investigated. Seroconversion rates and mean serum titers of HAV-IgG were reduced at both 
the 3 mg/kg and 10 mg/kg doses, as compared to placebo. Delayed HAV-IgG seroconversion 
was also observed in the 10 mg/kg PRV-3279 dose group.  
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PRV-3279 did not result in B cell activation, B cell depletion, or systemic cytokine release, at 
any dose. Taken together, these results demonstrate that administration of PRV-3279 inhibits 
B cell activation and function, consistent with its designed mechanism of activation. 
2.4.2. 
Multiple Ascending Dose Study (PREVAIL-1)  
The multiple ascending dose (MAD) study (PREVAIL-1) was designed to assess the safety and 
tolerability of PRV-3279 given as three infusions at two dose levels (3 and 10 mg/kg). Secondary 
objectives were to characterize the multidose PK and the immunogenicity of PRV-3279. 
Exploratory objectives included exploration of the effects of PRV-3279 on potential biomarkers 
for target engagement and B cell function.  
Sixteen healthy subjects were enrolled. Each cohort of 8 subjects received PRV-3279 or placebo 
at a ratio of 3:1 (n=6 for PRV-3279 and n=2 for placebo). Fourteen subjects received all planned 
treatments per protocol and completed the study.  
2.4.2.1. 
Safety Results  
PRV-3279 was well tolerated. There were no AEs of special interest (AESIs), serious adverse 
events (SAEs), or treatment-emergent adverse events (TEAEs) leading to death. One (16.7%) 
subject who received PRV-3279 10 mg/kg had 4 mild TEAEs considered by the Investigator to 
be related to the study drug (abdominal pain, feeling hot, cold sweat, and hyperhidrosis), and the 
subject withdrew from the study due to these TEAEs. A total of 34 TEAEs were reported in 9 
(56.3%) subjects. The most frequently reported TEAEs excluding catheter or venipuncture site 
AEs were feeling hot (3 TEAEs) and cold sweat (2 TEAEs each). All other TEAEs were 
reported once each. Two TEAEs were moderate in severity, and the remainder were mild. All 
out-of-range clinical laboratory values, vital signs measurements, electrocardiogram (ECG) 
results, and physical examination findings were evaluated as not related to the study drug and not 
clinically significant; none were reported as TEAEs. 
2.4.2.2. 
Pharmacokinetic Results  
The t1/2 on Day 29 was 157 h (6.54 days) and 185 h (7.71 days) for the 3 mg/kg and 10 mg/kg 
dose levels, respectively. The volume of distribution at steady state (Vss) was comparable for the 
3 mg/kg and 10 mg/kg doses (618 mL/kg and 576 mL/kg). CL on Day 29 was slightly lower for 
the 10 mg/kg dose (1.63 mL/h/kg) than for the 3 mg/kg dose (2.71 mL/h/kg).  
After multiple dosing to Day 29, there was minimum accumulation of PRV-3279 as shown by 
accumulation ratios based on Cmax (RacCmax) and AUC (RacAUC0-336) values for the 3 and 
10 mg/kg doses of 1.08 and 1.25 and 1.33 and 1.49 levels, respectively. The geometric mean 
(GM) Vss on Day 29 was comparable for the 3 mg/kg and 10 mg/kg dose levels (61.8 mL/kg and 
57.6 mL/kg). The GM CL on Day 29 was lower for the 10 mg/kg dose (0.163 mL/h/kg) 
compared to the 3 mg/kg dose (0.271 mL/h/kg). The Vss and CL on Day 29 in this study compare 
favorably to the corresponding values observed in the dose escalation phase of the SAD study 
(63.0 and 67.6 mL/kg and 0.39 and 0.35 mL/h/kg, for the 3 and 10 mg/kg dose levels, 
respectively).  
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2.4.2.3. 
Immunogenicity Results  
Consistent with the mechanism of action and ability of PRV-3279 to inhibit its own 
immunogenicity, incidence of ADA was higher at 3 mg/kg (6 out of 6) compared to 10 mg/kg 
(4 out of 6) at the end of the study. The assay used was validated and drug tolerant (not affected 
by the presence of PRV-3279). The ADA titers were generally low. Although the numbers of 
subjects per cohort provide a small sample size, there was no apparent effect of ADA on PK 
variables. Evaluation of the mean serum concentrations of PRV-3279 by ADA results shows a 
trend for slightly higher concentrations up to about Day 43 at the 3 mg/kg dose when ADA are 
positive. No trend can be identified for the 10 mg/kg dose due to limited data. The number of 
ADA-positive subjects increased over time. At the 3 mg/kg dose level, the first subject with a 
positive result was on Day 15. All 6 subjects of this dose level tested positive on Day 85. At the 
10 mg/kg dose level, the first subject who tested ADA positive was on Day 36. On Day 85, 4 of 
the 6 subjects were ADA positive. 
2.4.2.4. 
Pharmacodynamic Results  
After initial dosing with 3 and 10 mg/kg PRV-3279, >85% total number of available CD19+ 
peripheral blood B cells were bound. The binding pattern was similar for memory B cells 
(CD19+/CD27+) and naïve B cells (CD19+/CD27-). Binding intensity to B cells by PRV-3279 
did not differ in different B cell subpopulations and was slightly higher for 10 mg/kg than 
3 mg/kg, At the 10 mg/kg dose, levels of >50% receptor occupancy, which is considered the 
minimum level of binding required for optimal B cell modulation, were detected for up to 28 
days after the final dose. Both groups declined to approximately baseline levels at Day 85. Due 
to sample instability, these percent binding values were likely underestimated. 
PRV-3279 treatment was associated with a decrease in IgM production by -35% to -44%, which 
persisted until the end of the study. There was a dose-response trend, with the 10 mg/kg 
achieving greater reductions in IgM and also showing a reduction in IgE. No drug effect was 
observed on IgG levels. This was expected given that there was no concurrent antigen stimulus 
and IgG t½ is longer than the other classes. Peripheral B cell counts showed short-term 
(<24 hours) reduction of <50%, and no abnormalities were seen in other immune cell types. No 
cytokine release was measurable after dosing with PRV-3279. 
Taken together with the PK/PD effects and safety observed in CP-MGD010-01, these results are 
consistent with the hypothesis that repeat administration of PRV-3279 can safely and durably 
inhibit B cell function and humoral immune responses without depletion of B cells in the 
peripheral blood, and support further evaluation of PRV-3279 for modulating autoantibody 
production by B cells in an autoimmune disease setting such as SLE.  
Circulating immunoglobulin levels were also measured. IgM levels steadily decreased 
throughout the dosing period in both the 3 and 10 mg/kg dose groups and remained decreased at 
the last measurement on Day 85. Decreases were dose dependent, with the greatest mean 
percentage change from baseline being -34.5% for 3 mg/kg and -43.9% for 10 mg/kg at Day 85, 
compared to -1.3% in placebo-treated subjects. IgG levels were not affected by dosing with 
PRV-3279.  
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In summary, repeat dosing of PRV-3279 demonstrated a profound and durable modulation of 
B cells in this study, affecting humoral immunity without B cell depletion or cytokine 
stimulation, supporting and further extending the PD observations made in the SAD study.  
2.5. 
Risk-Benefit Assessment  
The PREVAIL (PRV-3279 EVAluation In Lupus) program is designed to evaluate PRV-3279 
for treatment of patients with SLE. Non-human GLP toxicology studies support the predicted 
mechanism and its potential as a treatment for SLE. Specifically, per feedback from the US Food 
and Drug Administration (FDA), 4- and 13-week intraperitoneal toxicology studies with a 
PRV-3279 surrogate molecule provide adequate characterization (hazard identification) with 
respect to potential toxicities of PRV-3279 in human subjects and offer sufficient nonclinical 
support for longer clinical trials. 
An initial SAD study of PRV-3279 in healthy subjects (CP-MGD010-01) demonstrated good 
safety and tolerability of PRV-3279 given IV from 0.1 to 10 mg/kg, along with favorable PK and 
PD characteristics. Proof of mechanism (B cell inhibition) was demonstrated in a dose-expansion 
cohort, in which doses of 3 and 10 mg/kg were given before HAV vaccine. PRV-3279 reduced 
HAV seroconversion and specific antibody titers. In this study, high levels of immunogenicity to 
PRV-3279 were observed as measured by ADA levels. The ADA levels were inversely 
proportional to dose, suggesting PRV-3279 may inhibit its own immunogenicity.  
In the PREVAIL-1 MAD study, the safety, tolerability, and immunogenicity of PRV-3279 were 
evaluated in healthy subjects at dose levels projected to provide sustained high-level receptor 
coverage. Healthy subjects were chosen to avoid confounding effects of background disease and 
concomitant medications. At both 3 and 10 mg/kg, PRV-3279 was well tolerated and bound 
>85% total B cells, including both memory B cells and naïve B cells. At the 10 mg/kg dose, 
levels of >50% receptor occupancy consistent with optimal B cell modulation, were detected for 
up to 28 days after the final dose. Expected reductions of IgM but not IgG levels were observed. 
Immunogenicity (ADA) was again observed to be less common at the higher dose. PRV-3279 
was well tolerated. There were no SAEs, and only one subject had TEAEs leading to withdrawal 
of study drug (abdominal pain, feeling hot, cold sweat, and hyperhidrosis).  
The current PREVAIL-2 study is designed to ensure that SLE patients with active symptoms can 
be assessed for both safety and potential efficacy with PRV-3279. Significant disease activity is 
required at Screening, but subjects with organ-threatening disease will be excluded so that 
background medications can be significantly restricted to better evaluate safety, PK/PD, and 
efficacy of PRV-3279. The restriction on background SLE medications can also minimize 
placebo-response rates, increasing the power and interpretability with a smaller trial and 
minimizing potential drug-drug interactions or additive immunosuppressive effects. This smaller 
trial design reduces the number of subjects exposed to PRV-3279 in early development when any 
potential benefit is uncertain.  
In this study, PRV-3279 will be administered at a dose of 10 mg/kg once every 4 weeks in SLE 
patients, which is based upon supportive PK and PD data from PREVAIL-1. Initial observations 
found 10 mg/kg to be well tolerated and less immunogenic than lower doses of PRV-3279. The 
safety data from the short-term SAD and MAD PK studies in healthy volunteers is reassuring but 
long-term effects of prolonged dosing on immunoglobulins and other immune factors are 
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currently unknown. A risk mitigation strategy that has been successful in other trials of B cell 
modulators will be put into place, which includes ensuring locally appropriate vaccinations are 
up to date prior to study entry, detailed safety monitoring, as well as early recognition and 
treatment for infections. 
A key aspect of this Phase 2a study will be to study the immunologic mechanisms of PRV-3279 
in SLE and to develop an understanding of potential patient subsets for whom the drug might be 
more or less effective. As well as monitoring for the effect of CD32B polymorphisms, PD data 
recently released to the public domain on obexelimab (XmAb®5871), a different biologic agonist 
of FcRIIb (Merrill 2020), provide a unique opportunity to test a pre-specified, evidence-based 
PD hypothesis in this early phase trial. Specifically, we will assess whether the greatest treatment 
effect will be found in a subset of patients with a phenotype characterized by low expression of 
gene signatures associated with inflammation, coupled to elevated expression of B cell signature 
pathways. The study population will not be restricted to these patients, but for patients in 
geographic regions with access to a rapid gene expression profiling system at Screening, the 
presence or absence of elevated expression of B cell signature pathways will be one of the 
stratification factors during randomization.  
The risk-benefit assessment can be summarized as follows: 
1. Favorable safety profile with short-term use in healthy subjects 
2. Risk mitigation strategy to address unexpected risks of longer treatment 
3. Existing evidence that the treatment achieves its targeted mechanism 
4. Sound rationale to test this mechanism in SLE 
5. A trial design that minimizes background medications in order to: 
a. Restrict study entry to patients with non-organ-threatening disease and provide 
immediate flare assessment and treatment by a Central Adjudication Committee 
(CAC) 
b. Support an interpretable small trial, which exposes fewer patients to an early 
phase investigational drug 
c. Achieve clarity in PD assessments 
d. Reduce the risk for infections and toxicities due to drug combinations 
6. An independent Data Monitoring Committee (IDMC) to monitor safety throughout the 
study. 
 
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3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary  
To evaluate the ability of PRV-3279 to prevent 
flare, i.e., to maintain the improvement in SLE 
signs and symptoms for 24 weeks, after the 
amelioration of active disease induced by 
corticosteroid treatment before Day 1 with the 
withdrawal of major background medications. 
Proportion of patients who maintain the 
improvement in SLE disease activity from 
Baseline (Day 1) to Week 24, defined as no 
lupus flare during this period.  
A lupus flare is defined as: 
• Investigator’s assessment that the SLE 
activity meets the LFA international 
consensus definition for a flare1 AND 
• A score of “definite worsening” or 
“severe worsening” on Clinician’s 
Global Impression of Change (CGIC), 
AND  
• at least one of the following occurrences 
o an increase of ≥4 points from 
baseline in the hybrid Safety of 
Estrogens in Lupus Erythematosus 
National Assessment -Systemic 
Lupus Erythematosus Disease 
Activity Index (SELENA-SLEDAI) 
score (hSLEDAI), OR  
o ≥1 organ with an A score (severe) 
or B Score (moderate) item rated 
new or worse on British Isles Lupus 
Assessment Group (BILAG) Index 
Secondary 
Efficacy: 
1. To evaluate whether PRV-3279 prolongs 
the duration of disease amelioration 
induced by corticosteroids before Day 1. 
 
 
 
 
 
 
 
1. Time to treatment failure. 
Treatment failure is defined compared to 
Baseline (Day 1): 
• Occurrence of an SLE flare (as 
defined in the primary endpoint), OR 
• Missing 2 consecutive doses or 3 or 
more total doses of the study drug for 
any reason, OR 
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Objectives 
Endpoints 
 
 
 
 
 
 
 
 
2. To determine whether PRV-3279 allows 
patients to achieve and sustain European 
League Against Rheumatism (EULAR)-
recommended treatment goal of low 
disease. 
 
3. To evaluate the effect of PRV-3279 on 
patient-reported physical functioning. 
 
4. To determine whether PRV-3279 can 
reduce one or more signs and symptoms of 
SLE using a stringent definition for 
improvement in each sign or symptom, 
based on the SLE Responder Index-4 
(SRI-4) 
 
 
 
 
 
 
5. To determine whether PRV-3279 reduces 
disease activity in all organs that are rated 
as moderately or severely active at 
Screening using the BILAG Index. 
 
 
 
• Initiation of a new SLE medication, 
OR 
• Increased dose of current SLE 
medication, with the exception of 
nonsteroidal anti-inflammatory drugs 
(NSAIDs), OR 
• Patient withdrawal from the study 
before the Week 24 visit 
2. Proportion of patients who meet either of 
the following criteria at Week 24: 
• Hybrid SELENA-SLEDAI 
(hSLEDAI) score <3 OR 
• All BILAG scores are C or less 
3. Change from Screening to Week 24 in the 
Physical Component Score (PCS) in the 
Short Form 36 Health Survey (SF-36).  
4. Proportion of patients who meet the 
criteria for SRI-4 at Week 24 compared 
to Screening.  
SRI-4 is defined as:  
• A hSLEDAI score decrease of 
≥4 points, AND 
• No new organs with a BILAG A 
(severe) score, AND  
• No more than 1 new organ with a 
BILAG B (moderate) score, AND  
• No SELENA-SLEDAI Physician’s 
Global Assessment (ssPGA) score 
increase of >0.3 points. 
5. Proportion of patients who meet the 
BILAG-based Combined Lupus 
Assessment (BICLA) criteria at Week 24 
compared to Screening:  
• Reduction by ≥1 grade in all organs 
with BILAG A or B scores AND 
• No worsening of SLEDAI or other 
BILAG organs AND 
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Objectives 
Endpoints 
 
• No ssPGA score increase of ≥0.3 
points.  
Safety: To evaluate the safety and tolerability 
of PRV-3279. 
Frequency of TEAEs, SAEs, TEAEs leading 
to drug withdrawal, AESIs, and total serum 
immunoglobulin levels. Frequency of 
potentially clinically important changes in 
clinical laboratory tests, vital signs, ECGs, 
and physical examinations.  
PK and Immunogenicity: To evaluate the PK 
and immunogenicity of PRV-3279 in patients 
with SLE. 
Serum concentrations of PRV-3279. ADA 
titers.  
Exploratory 
 
1. “A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical 
signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor, 
and usually, there would be at least consideration of a change or an increase in treatment.” (Ruperto 2011) 
 
 
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4. Study Design  
4.0. 
Design  
This is a randomized, double-blind, placebo-controlled study in adult patients with active SLE. 
Approximately 100 eligible patients will be randomized at a 1:1 ratio to receive treatment with 
either 10 mg/kg PRV-3279 or placebo. The study drug, PRV-3279 or placebo, will be given as 
an IV infusion over 2 hours, every 4 weeks from Week 0 through Week 20, inclusive, for a total 
of 6 doses. Two follow-up visits are planned (Week 24 and Week 28). The end of study (EOS) 
visit will occur at Week 28. 
Study integrity will be supported with remote oversight by a CAC working in tandem with study 
clinical and data monitors to confirm entry qualification and accuracy of disease activity scoring 
and to adjudicate flares (see Section 8.2.6.1). The CAC members will be blinded to study 
treatment assignment. Details are provided in the CAC charter.  
During the Screening period, the patient will receive an intramuscular (IM) injection of 
methylprednisolone acetate (Depo-Medrol® or equivalent) at a dose of ≥40 mg to induce 
improvement of SLE signs and symptoms. Repeat injections may be given to further ameliorate 
symptoms, up to a total of 4 injections with a maximum total dose of 320 mg.  
Starting on Day 1 (Baseline/Randomization visit) and continuing throughout the study the only 
background SLE treatments that may be continued are hydroxychloroquine up to 400 mg per day 
(or other antimalarial [Section 10.5]), up to 10 mg per day prednisone (or equivalent 
corticosteroid [Section 10.5]), and NSAIDs. Patients will be asked to abstain from NSAIDs on 
the mornings of the Randomization visit and all subsequent visits (NSAIDs can be re-started 
after completing all evaluations on the day of each study visit). On other days throughout the 
study, NSAIDs are allowed without restrictions. All other SLE treatments taken at the time of 
Screening will be withdrawn during the Screening period and prior to Randomization. 
Potentially eligible patients will return to the study site to confirm eligibility for randomization 
on Day 1. The Investigator must confirm that the patient has achieved at least a moderate 
improvement in SLE signs and symptoms as indicated by: 
CGIC score of “definite improvement” or “major or complete improvement”  
AND  
 
≥4-point decrease in hSLEDAI score from Screening, OR improvement by ≥1 severity grade 
in at least one BILAG system that was severe (A score) or moderate (B score) at Screening 
(i.e., from A to B-D or from B to C or D).  
Note: Assessments by hSLEDAI and BILAG Index at the Randomization visit may not follow 
the standard 4-week assessment rules but will be scored by a simple clinical comparison of SLE 
disease activity at Week 0 (Day 1, Randomization Visit) and the Screening Visit.  
If the patient is confirmed eligible, randomization will occur through an interactive voice/web 
response system (IVRS/IWRS). 
  
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At each visit, formal assessments of disease activity and safety will be conducted, and laboratory 
specimens will be collected. Patients will receive IV infusions of the study drug every 4 weeks 
from Week 0 through Week 20, inclusive.  
All efforts should be made to retain all patients in the study, regardless of their compliance with 
study procedures. If a patient takes any new SLE medications (other than NSAIDs), increases the 
dose of current SLE medications (other than NSAIDs), misses 2 consecutive doses or 3 or more 
total doses of the study drug, the site should contact the Medical Monitor to discuss permanent 
discontinuation of the study drug. The patient will be encouraged to continue study procedures 
and assessments, but will be documented as a nonresponder in the primary and applicable 
secondary efficacy endpoints. 
If a lupus flare occurs (as defined in the primary endpoint [Section 1.1 and Section 3]), the 
patient should contact the study site immediately and be seen as soon as possible for a Flare 
Assessment visit, regardless of visit schedule, and should be assessed according to the Schedule 
of Activities (SoA) (Section 1.3). SLE medications may be prescribed as warranted to control the 
symptoms and/or signs present at this visit (Section 6.6.3). If confirmed, the patient will 
discontinue any further study drug administration and will be considered a nonresponder in the 
primary and applicable secondary efficacy endpoints. 
Throughout the study, SLE disease activity and patient -reported outcomes (PROs) will be 
assessed using the following instruments:   
• Disease Activity Instruments: 
o The hybrid Safety of Estrogens in Lupus Erythematosus National Assessment 
Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI)  
o The SELENA-SLEDAI Physician’s Global Assessment (ssPGA) 
o SELENA-SLEDAI Flare Index (SFI) 
o Modified SELENA-SLEDAI Flare Index (mSFI)  
o British Isles Lupus Assessment Group (BILAG) Index 
o Clinician’s Global Impression of Change (CGIC) 
o Cutaneous Lupus Erythematous Disease Area and Severity Index (CLASI) 
o Tender and swollen joint counts 
• PROs: 
o 
Short Form 36 Health Survey (SF-36) 
o 
Patient Global Impression of Change in Clinical Status (PGIC) 
o 
Patient Global Impression of Change in Disease Severity (PGIS)  
o 
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue Scale) 
Safety assessments will include TEAEs, vital signs, physical examination findings, 12-lead 
ECGs, and clinical laboratory tests (hematology, chemistry, urinalysis, coagulation panel, 
lupus-related serologies, SLE disease activity markers, and T cell, B cell, natural killer cell 
[TBNK] panel). A urine or serum pregnancy test will be performed for women of childbearing 
potential (WOCBP) onsite prior to each study drug administration (serum pregnancy test at 
Screening). 
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PK (serum PRV-3279 concentrations), PD (biomarkers) and immunogenicity assessments will 
also be conducted.  
Disclosure Statement: This is a Phase 2a, double-blind, placebo-controlled trial with 
2 treatment arms (PRV-3279 versus placebo) added to limited background medications for SLE.  
Number of Patients: Approximately 100 patients will be randomized to receive study drug 
treatment. The study will be conducted at approximately 40 sites in countries planned to include, 
but not limited to, US, Hong Kong, and China. Approximately 50 patients will be assigned to 
each treatment group (PRV-3279 or placebo). Randomized patients who discontinue study drug 
or withdraw consent for study participation will not be replaced. 
Treatment Groups and Duration: 
Treatment Groups: 
• PRV-3279: 10 mg/kg IV infusion, administered over 2 hours, once every 4 weeks from 
Week 0 through Week 20, inclusive 
• Placebo: 0.9% sodium chloride IV infusion, administered over 2 hours, once every 
4 weeks, from Week 0 through Week 20, inclusive 
Duration of study participation for each patient: up to 34 weeks 
• Screening: up to 6 weeks 
o Note: The Screening period may be increased by 2 weeks, under exceptional 
circumstances such as delayed laboratory results or the impact of COVID-19, and 
upon approval by the Medical Monitor. 
• Study Treatment Period: 20 weeks 
• Follow-up: 8 weeks 
4.1. 
Scientific Rationale for Study Design  
This double-blind, placebo-controlled study will randomize approximately 100 patients with 
moderate to severe, but non-organ-threatening SLE disease activity. To qualify, patients must 
demonstrate protocol-specified disease improvement after injection of methylprednisolone 
acetate (Depo-Medrol® or equivalent) and withdrawal of all pre-screening SLE treatments except 
up to 400 mg per day for hydroxychloroquine (or other  antimalarial [Section 10.5]), NSAIDs, 
and/or up to 10 mg prednisone (or equivalent corticosteroid [Section 10.5]). Patients will be 
randomized to receive 10 mg/kg PRV-3279 or placebo for 20 weeks to determine which group 
has a greater proportion of responders, defined as reaching Week 24 with no lupus flare activity 
while continuing study treatment and without receiving any SLE medications to treat a flare (as 
defined in Section 6.6.3).  
This study was designed to utilize several innovations in previous SLE clinical trial designs 
(Merrill 2018a), such as the use of corticosteroid injection during Screening to provide 
temporary relief of symptoms in all patients before withdrawing background medications and 
initiating study treatment as well as a CAC committee.  
4.2. 
Justification for Dose  
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4.3. 
Definition of End of Study  
The end of the study is defined as the last patient has completed the last visit in the study.  
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5. 
Study Population  
Eligibility must be confirmed by the CAC (Section 8.2.6.1), which will review each patient’s 
Screening information provided by the Investigator. Details are provided in the CAC Charter.  
5.1. 
Inclusion Criteria  
Patients must meet all of the following criteria for study inclusion: 
1. Able to understand and willing to sign the informed consent form (ICF), which is written 
in a language in which the patient is fluent.  
2. Ages 18 to 70 years, inclusive, at Screening.  
3. Have had a diagnosis of SLE for at least 6 months prior to the Screening visit.  
4. Meet the 2019 European League Against Rheumatism/American College of 
Rheumatology (EULAR/ACR) criteria for SLE at Screening. 
5. Have moderate to severe disease activity despite stable standard-of-care medication, 
defined as:  
a. At Screening: hSLEDAI score ≥6 (≥4 points of which must come from 
non-serological finding), OR at least one BILAG A or one B score. Additionally, in 
the opinion of the Investigator and the CAC, the patient has adequate active reversible 
disease to warrant participation in a clinical trial of an investigational biologic and 
adequate stability to tolerate a protocol in which immunosuppressives are withdrawn.  
b. At Randomization: Patients meet the following definition for improvement: 
1) ≥4-point drop in hSLEDAI, OR one BILAG letter grade improvement in at least 
one A or B score present at Screening, AND  
2) Investigator rates the CGIC as “definite improvement” or “major or complete 
improvement.” 
6. Documented history of positive antinuclear antibody (ANA) and at least one of the 
following serologic parameters within the Screening period:  
a. Positive ANA ≥1/160  
b. ≥1 positive anti-extractable nuclear antigen antibody (ENA) test (Ro, La, Sm, RNP) 
c. Positive serum anti-dsDNA antibodies elevated to above normal (borderline results 
are not accepted)  
d. Complement components C3 or C4 below cutoff value attributed to lupus activity. 
7. Able and willing to receive methylprednisolone acetate (Depo-Medrol® or equivalent) 
injection(s) ≥40 mg during the Screening period sufficient to cause clinically significant 
disease improvement. 
8. Able and willing to stop all lupus treatments except for the following: up to 400 mg per 
day hydroxychloroquine (or other antimalarial [Section 10.5]) if these have been taken 
for at least 2 months prior to Screening at stable dose and well tolerated and/or up to 
10 mg per day prednisone (or equivalent corticosteroid [Section 10.5]) if these have been 
taken for at least two weeks prior to Screening. Stable doses of prednisone of up to 15 mg 
at Screening are permitted if they can be tapered to 10 mg or less during the Screening 
period after given the methylprednisolone acetate (Depo-Medrol® or equivalent) 
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injection(s) and prior to randomization. NSAIDs may be continued or may be initiated or 
taken as needed at any time during the study, but must be withheld on the morning prior 
to Day 1 and subsequent visits.  
9. A female patient is eligible to participate if she is not pregnant, is not breastfeeding, is not 
planning to become pregnant during the study; and at least one of the following 
conditions must apply: 
- Not a WOCBP (Section 10.4), or 
- A WOCBP who agrees to follow the contraceptive guidance (Section 10.4) during 
the entire study through at least 8 weeks after the last dose of the study drug. 
10. WOCBP must have a negative serum pregnancy test at the Screening visit and must have 
a negative urine or serum pregnancy test at the Randomization visit prior to the first dose 
of study drug. Note: Patients with borderline serum pregnancy tests at Screening must 
have a serum pregnancy test ≥3 days later to document a negative result.  
11. Sexually active men with heterosexual partners who are WOCBP must agree to adhere to 
the same effective birth control methods as defined in Section 10.4, and must not plan to 
start a family during the study.  
12. Both men and women must agree to abstain from donating blood, sperm, or eggs during 
the study through at least 8 weeks after the last dose of study drug. 
13. Patient is not incarcerated and is not compelled to participate in the study. 
14. After evaluation of screening data by the CAC, the patient is deemed to have a 
convincing diagnosis of SLE, have adequate active disease to justify potential treatment 
with an investigational biologic, and is medically stable enough to participate in the 
protocol. 
5.2. 
Exclusion Criteria  
Patients must not meet any of the following criteria to be eligible:  
1. Currently receiving induction treatment or maintenance treatment (e.g. mycophenolate 
mofetil, azathioprine, JAK inhibitor, calcineurin inhibitor, others)for lupus nephritis. 
2. Have active lupus nephritis defined as urinary protein >1 g per 24 hours, or new onset 
proteinuria >500 mg per 24 hours without a diagnostic workup to rule out nephritis. 
NOTE: Protein/creatinine ratio may be used as an approximate surrogate for a 24-hour 
urine collection, and 500 mg/g or 56.6 mg/mmol is considered equivalent to 500 mg/day. 
3. Have active central nervous system (CNS) manifestations of SLE, including seizure, 
psychosis, encephalopathy, cerebrovascular accident, or any evidence of active CNS 
vasculitis within 4 months of the Screening visit and up to and including the 
Randomization visit. 
4. Have other inflammatory or autoimmune diseases that, in the opinion of the Investigator 
or CAC, may confound efficacy evaluations. These might include but should not be 
limited to psoriatic arthritis, Lyme disease, or other infectious arthritis, multiple sclerosis, 
or scleroderma. 
5. Common variable immunodeficiency syndrome or any other clinically significant 
immunodeficiency (per Investigator or CAC judgment). 
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6. Liver function: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
≥2.5 times the upper limit of normal (ULN). 
7. Complete blood count (CBC):  
a. white blood cell (WBC) count <1.5×109/L;  
b. lymphocyte count <0.3×109/L (If lymphocyte count is <0.5×109/L, a repeat 
sample must be collected and analyzed and must not be decreasing.);  
c. neutrophil count <1.0×109/L;  
d. hemoglobin ≤8.0 g/dL;  
e. platelet count <40×109/L (If the platelet count is <70× 109/L, a repeat sample 
must be collected and analyzed and must not decrease >5×109 /L within the 
Screening period.)  
8. Renal function: serum creatinine >2 mg/mL. 
Note: Abnormal laboratory tests meeting exclusion criteria may be repeated once during 
Screening. 
9. Hepatitis B virus (HBV):  
a. Hepatitis B surface antigen (HBsAg) positive; or  
b. Total hepatitis B core antibody (HbcAb) positive (IgM and IgG) and HBV DNA 
positive. (HBV DNA will be used as a reflex test if total HbcAb is positive. Those 
with negative HBV DNA may be included in the study.) 
Note: Hepatitis B surface antibody (HbsAb) will also be performed at Screening to 
confirm presence of prior infection or vaccination but is not exclusionary.  
10. Hepatitis C virus (HCV): Patients with positive HCV RNA. 
11. Known COVID-19 infection in the 4 weeks before Screening or positive SARS-CoV-2 
test (any matrix) during Screening. 
12. History of allergic reaction to any human-derived biological product.  
13. Received a live attenuated vaccine within 2 months of Screening, or received a non-live 
or mRNA vaccine within 2 weeks of Screening. Patients should be advised to delay 
vaccines until after the study completion to ensure optimal vaccine efficacy; however, 
receipt of a non-live vaccine after randomization is not exclusionary.  
14. Participated in any interventional clinical trial within 42 days prior to Screening or within 
five half-lives of the investigational product, whichever is longer.  
15. Received rituximab or equivalent treatment that depletes B cells within 6 months of 
Screening unless return of B cells to pre-treatment value or normal range can be 
demonstrated.  
16. Received tumor necrosis factor inhibitors, interleukin antagonists, or other biologics, 
including belimumab, within 42 days or five half-lives of the agent, whichever is longer.  
17. Received IV immunoglobulin (IVIG) or IV cyclophosphamide within 2 months, 
prednisone ≥ 100 mg/day for more than 30 days within 2 months, or plasmapheresis 
within two months of the Screening visit.  
18. Any episode of herpes zoster virus (HZV) infection within 2 months or >2 episodes 
within the past 2 years unless the patient has been vaccinated for HZV.  
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19. Any recent infection requiring antibiotics within two weeks of Screening or any recent 
infection requiring IV antibiotics or hospitalization within 1 month of Screening.  
20. Previous close contact with a person with active tuberculosis (TB) without receiving 
satisfactory anti-TB treatment as per World Health Organization (WHO) or national 
guidelines or history, or current diagnosis, of active TB, or untreated latent TB infection 
(LTBI), defined by a positive QuantiFERON TB-Gold test at the Screening visit.  
A. Indeterminate QuantiFERON TB-Gold may be repeated once (repeat testing may be 
performed locally). If the second test is negative, the patient will be considered 
negative.  If the second test is also indeterminate, the patients may be allowed to 
participate in the study if chest x-ray confirms no active disease, and one of the 
following conditions is met: 
i. 
Active TB is ruled out by a specialist or pulmonologist who is familiar with 
diagnosing and treating TB (as acceptable per local practice).  
ii. 
The patient has documented evidence of satisfactory completion of LTBI-
appropriate prophylaxis as per WHO or national guidelines within the last 5 
years following review by a physician specializing in TB.  
iii. 
The patient has completed at least 4 weeks of LTBI-appropriate prophylaxis 
prior to randomization with agents recommended as preventative therapy for 
LTBI according to country-specific/CDC guidelines and is willing to 
complete the entire course of recommended LTBI therapy.  
B. QuantiFERON TB-Gold-positive patients may be allowed to participate in the study 
if all the following are true:  
i. 
Chest x-ray confirms no active disease,  
ii. 
The patient has completed at least 4 weeks of LTBI-appropriate prophylaxis 
prior to randomization with agents recommended as preventative therapy for 
LTBI according to country-specific/Centers for Disease Control and 
Prevention (CDC) guidelines and is willing to complete the entire course of 
recommended LTBI therapy, and 
iii. 
The CAC confirms the patient to be stable for inclusion.  
21. Non-TB mycobacteria, opportunistic infections (e.g., cytomegalovirus, pneumocystis 
pneumonia, aspergillus, histoplasma, coccidioidomycosis) within 6 months prior to 
Screening.  
22. History of or treatment for any malignancy within the past 5 years, except non-melanoma 
skin cancers.  
23. Known human immunodeficiency virus (HIV) infection or history of clinically 
significant immunodeficiency.  
24. History of solid organ transplant or bone marrow transplant. 
25. Active substance abuse in the past year in the opinion of the Investigator. 
26. Any condition for which, in the opinion of the Investigator or CAC, participation in the 
study would not be in the best interest of the patient (e.g., compromise their well-being) 
or that could prevent, limit, or confound the protocol-specified assessments. 
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5.3. 
Screen Failures  
Screen failures are defined as patients who consent to participate in the study but are not 
subsequently randomly assigned to study treatment. Minimal information required for 
documentation includes demography, screen failure details, eligibility criteria, and any SAEs. 
Patients with screening laboratory tests that are out of the eligibility ranges may be re-tested once 
during screening.  
If re-screening is appropriate, the Investigator must contact the Medical Monitor to discuss the 
reason for screen failure and eligibility for re-screening. 
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6. 
Study Treatment  
In this protocol, the investigational products, i.e., study drugs, are PRV-3279 and placebo 
(0.9% sodium chloride).  
6.1. 
Study Drug Administration  
The PRV-3279 drug product is a sterile, preservative-free solution for IV administration supplied 
at a protein concentration of 4 mg/mL in a single-dose vial containing 20 mg/5 mL (extractable 
content). PRV-3279 10 mg/kg will be administered by IV infusion over 2 hours ± 15 minutes. 
Placebo is commercially available 0.9% sodium chloride sterile solution for injection. An 
equivalent volume (based on the volume required to give 10 mg/kg of PRV-3279) will be 
administered by IV infusion over 2 hours.  
Body weight at time of randomization will be used for calculation of dose throughout the study.   
Details of study drug administration will be provided in the pharmacy manual. 
6.1.1. 
Monitoring for Infusion or Allergic Reactions  
Infusion reactions or allergic reactions have been observed with administration of biologic 
therapies. Note that per Exclusion 12, study drug must not be administered to individuals with a 
known or suspected intolerance or hypersensitivity to any biologic medication or known allergies 
or clinically significant reactions to human proteins, to monoclonal antibodies or antibody 
fragments, or to any components of the PRV-3279 formulation used in this study. 
Serious allergic reactions (e.g., anaphylaxis) may occur at any time during the administration of 
study drug. Serum sickness-like reactions (also known as delayed hypersensitivity reactions) 
have been observed 1 to 14 days after study drug administration. Symptoms associated with 
these reactions include fever, rash, headache, sore throat, myalgia, polyarthralgia, hand and facial 
edema, and/or dysphagia.  
Examples of severe infusion reactions include symptomatic hypotension, symptomatic 
hypertension, bronchoconstriction/vasospasm, bronchospasm with wheezing, laryngeal/tracheal 
edema, laryngospasm, congestive heart failure, circulatory failure/cardiogenic shock, 
angioedema, urticaria (e.g., lip edema with associated bronchospasm), acute respiratory distress 
syndrome (e.g., new and rapid onset hypoxia, pulmonary infiltrates/edema on radiography, 
dyspnea requiring ventilator support), or symptomatic brady- or tachyarrhythmias. 
Examples of non-severe reactions include asymptomatic hypotension, shortness of breath, rash, 
urticaria, flushing, chest pain, fever, back pain, peripheral edema of extremities, vasovagal 
reactions, chills/rigors, nausea/emesis, headache, diaphoresis, lightheadedness, somnolence, or 
myalgia. 
A physician must be immediately available at the site at all times during the administration of 
study drug. All patients must be observed carefully for symptoms of an infusion reaction during 
the infusion and for 2 hours after the first IV infusion of study drug and at least 30 minutes at 
other visits. The Investigator should use clinical judgment in assessing the intensity of any 
infusion reactions. The examples given above are for guidance only. Infusion reactions may be 
considered either severe or non-severe depending on the clinical circumstance.  
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If a mild infusion reaction is observed, the Investigator should consider whether treatment such 
as oral paracetamol/acetaminophen and/or oral antihistamine should be given. In addition, the 
Investigator may elect to provide premedication for patients at subsequent visits, so long as no 
other contraindications are present.  
The following precautions should be applied on dosing days: 
• Before an infusion is started, the appropriate personnel, medications (e.g., epinephrine, 
inhaled β-agonists, antihistamines [may include H1 and/or H2 histamine receptor 
antagonists]), and corticosteroids), and other requirements to treat allergic reactions, 
including anaphylaxis, must be available. Clinical sites must have immediate access to a 
crash cart and electrical defibrillator. 
• If a patient has a severe infusion reaction, the infusion should be stopped immediately, 
and the patient should be treated according to institutional guidelines. If a severe infusion 
reaction occurs, the patient should receive no further infusions of study drug 
(Section 7.1). 
• Any adverse reaction during the infusion of study drug should be noted. 
6.2. 
Preparation/Handling/Storage/Accountability  
A Pharmacy Manual will be provided with complete details of preparation, handling, storage, 
and accountability. An overview is provided in this section. 
PRV-3279 will be supplied by the Sponsor for use in this study.  PRV-3279 will be shipped 
under cold-chain management to the study site and stored at 2-8ºC in light-proof containers. 
Under these conditions, the shelf life of PRV-3279 is 3 years.  
Placebo (0.9% saline) will be supplied by the study sites.  
Unblinded pharmacy personnel at each site will be responsible for drug storage, preparation, and 
dispensing according to the Pharmacy Manual. Unblinded pharmacy personnel will not be 
involved in any other aspect of the study and will not communicate study drug details to other 
blinded study personnel. Study drug will be prepared in a nature to ensure the blind is not 
broken. Timing of preparation and dispensing must be the same for both PRV-3279 and 
0.9% saline (placebo should not be released until an equivalent time has passed for preparation 
of PRV-3279). 
Proper aseptic techniques must be used when preparing and administering sterile parenteral 
products such as PRV-3279 and 0.9% sodium chloride. The study drug should be inspected 
visually for particulate matter prior to administration. If concerns regarding the quality or 
appearance of the investigational product arise, it must not be dispensed, and the Sponsor must 
be contacted immediately. 
Study personnel should record and maintain shipping and receiving records of the study drug, 
and report to the Sponsor immediately any defect or issues with quality, quantity, or cold-chain 
shipping. The site will maintain accurate dosage preparation records and should ensure that all 
pertinent information on the preparation and dose administration is captured in source 
documents. Such information should be made available to the Sponsor’s site monitoring 
representative(s) during monitoring visits. 
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Upon termination of the study, or at the request of the Sponsor, pharmacy personnel must return 
the remaining study drug to Sponsor, unless it is destroyed at the site as agreed upon by both the 
Sponsor and the site. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
6.3.1. 
Randomization  
Enrolled patients meeting the eligibility criteria will be randomized in a 1:1 ratio to the PRV-
3279 or placebo group. Randomization will be stratified by presence or absence of serum anti-
dsDNA antibodies and, as available in certain geographies, the presence or absence of elevated  
 Stratified randomization will be generated electronically and transmitted to 
the site via an IVRS/IWRS. 
Enrolled patients meeting the eligibility criteria will be assigned a unique screening number and 
randomization number to be used throughout the study.  
6.3.2. 
Blinding  
This study has a double-blind design. Treatment assignment records will be maintained by 
unblinded pharmacy personnel who must have no interactions with study patients and avoid 
disclosing treatment assignment to blinded personnel involved in the study conduct. In addition, 
some contract research organization (CRO) and Sponsor personnel and the IDMC members may 
be unblinded to provide necessary oversight. 
All other study site staff, Medical Monitors, the CAC members, and Sponsor staff who interact 
with sites will be blinded to treatment assignment until the database lock.  
Certain laboratory results will not be reported to Investigators or any other blinded study 
personnel during the study. These results may include serum total immunoglobulin levels, 
B lymphocyte stimulator (BLyS) levels, peripheral blood B cell levels, and B cell subsets (Stohl 
2012b; Merrill 2018b; Merrill 2020).  
Some markers that are known to be frequently and nonspecifically affected by improvement in 
SLE from any cause and/or by ongoing use of background treatments will not affect blinding and 
therefore will be reported to the site. Although differences in frequency of improvement may be 
discerned in treatment versus placebo groups, improvement often occurs and persists in 
placebo-treated patients or worsens in treatment groups in lupus trials, thus such patterns in an 
individual patient should not affect blinding. Such markers include results of hematologic and 
renal function tests and complement and anti-dsDNA antibody levels (Stohl 2012a; Merrill 
2018b; Merrill 2019; Manzi 2012; Khamashta 2016), and other tests. Data from past trials 
confirm that these markers might change in both placebo and PRV-3279 treatment groups and 
may serve as a part of the disease activity assessments and as common warning signals of 
impending major organ flare. Thus, these test results can be disclosed to the Investigator during 
the study and may be useful for patient safety. 
6.3.3. 
Emergency Unblinding  
Blinding is critical to the integrity of this study. Every effort must be made to maintain the 
double-blind nature of the study. Therefore, emergency unblinding must only be done in the 
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event of a medical emergency or pregnancy, for which knowledge of the investigational product 
is deemed critical to the patient's management. If emergency unblinding is deemed critical to the 
patient’s immediate management, a formal process is undertaken, and additional Sponsor and 
CRO personnel must be informed as soon as possible. 
6.4. 
Study Treatment Compliance  
Study drug will be administered on site by qualified personnel. If the full dose is not 
administered, this must be documented along with an explanation.  
6.5. 
Dose Modification or Interruption  
6.5.1. 
Treatment Modification  
Treatment modifications (ie. change in study drug dose) are not permitted.  
6.5.2. 
Treatment Interruption Rules  
Study drug administration should be interrupted if any of the abnormal laboratory tests in  
Table 1 are reported. The patient should return for a repeat test as soon as possible. If the repeat 
test does not return to approximately the level at Screening and/or within normal reference limits 
before the next scheduled dose, the next dose should not be given.  
Exceptions can be made at the Investigator’s discretion, upon the approval of the Medical 
Monitor. 
Table 1 
Treatment Interruption Based on Safety Laboratory Tests  
Variable 
Level required 
at Screening 
Level requiring 
treatment interruption 
Next dose suspended 
WBC 
≥1.5 x 109/L 
<1.0 x 109/L 
No return to level required at Screening 
Lymphocytes 
≥0.3 x 109/L 
<0.2 x 109/L 
No return to level required at Screening 
Neutrophils 
≥1.0 x 109/L 
<0.7 x 109/L 
No return to level required at Screening 
Platelets 
≥40 x 109/L 
≤30 x 109/L  
No return to level required at Screening 
Hemoglobin 
>8.0 g/dL 
<7.0 g/dL 
No return to level required at Screening 
ALT/AST 
<2.5 x ULN 
>3 x ULN 
No return to level required at Screening 
Serum creatinine 
≤2 mg/dL 
>2.5 mg/dL 
No return to level required at Screening 
6.6. 
Concomitant Therapy  
The study personnel should record all dietary supplements (including vitamins and minerals), 
nutraceuticals, herbal medicines, traditional Chinese medicines, ayurvedic remedies, and any 
other prescription or nonprescription products taken by the patient from 3 months before 
Screening through the end of the study. The intake of such products must remain unchanged 
(except for permitted SLE medications [Section 6.6.2]) during the study unless a potential 
adverse reaction necessitates their discontinuation. Discontinuation of a concomitant medication 
must be discussed with the Investigator and the reason must be recorded. 
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6.6.1. 
Prohibited Medications  
6.6.1.1. 
Prohibited Medications (See Exclusion Periods for Investigational and Biological 
Agents)  
Use of any of the following medications or procedures are prohibited at entry:  
• Plasmapheresis or plasma exchange 
• Cyclophosphamide 
• Investigational medications 
• Any immunoglobulin therapies 
• Biological immunomodulators, such as rituximab, belimumab 
Mycophenolate mofetil, mycophenolic acid, JAK inhibitor, calcineurin inhibitors, azathioprine, 
and other oral DMARDs not specifically excluded prior to Screening, are permitted at Screening 
but must be discontinued prior to administration of study drug on Day 1.  
6.6.1.2. 
Prohibited Medications at Any Time During the Study  
Use of the medications listed below are prohibited at any time during the study (from study entry 
through the EOS visit).  
Patients who receive the following medications will discontinue study drug but will be 
encouraged to remain in the study and continue all remaining assessments and procedures 
(Section 7.1): 
• Plasmapheresis or plasma exchange 
• Any immunoglobulin therapies 
• Biological immunomodulators (rituximab and belimumab) 
• Live vaccines 
Patients will be permanently withdrawn from participation in the study (Section 7.2) if they 
receive an investigational medication. 
6.6.2. 
Permitted SLE Medications  
During the study period, hydroxychloroquine up to 400 mg per day (or other antimalarial 
[Section 10.5]) and/or prednisone up to 10 mg per day (or equivalent corticosteroid 
[Section 10.5]) may be continued. There are no restrictions on the use of NSAIDs or 
acetaminophen/paracetamol during the study except that on the morning of each visit, NSAIDs, 
acetaminophen/paracetamol, or any other analgesics should be avoided to allow proper 
evaluation of the patient’s condition. The patient may re-start the NSAID or other analgesic after 
the study visit.      
All other SLE treatments taken at the time of Screening will be withdrawn during the Screening 
period and prior to Randomization. (Refer to the exclusion criteria [Section 5.2] for restrictions 
to pre-screening treatment for SLE.)  
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6.6.3. 
SLE Medications to Treat a Flare  
Treatment of a flare is not considered a protocol deviation. During the course of the study, when 
a patient meets the definition of a lupus flare (as defined in Section 1.1 and Section 3), the 
Investigator may prescribe any SLE medications, including increased doses of the permitted SLE 
medications (Section 6.6.2)..  
If the patient initiates use of any SLE medications to treat a flare (or increases dose of the 
permitted SLE medications), the patient will discontinue study drug but will be encouraged to 
remain in the study and continue all remaining assessments and procedures (Section 7.1).  
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7. 
Discontinuation of Study Treatment and Patient Withdrawal  
7.1. 
Discontinuation of Study Treatment  
Every effort will be made to retain patients who permanently discontinue study drug during the 
study. All subsequent assessments should be performed as indicated in the SoA (Section 1.3).  
Patients must discontinue the study drug for any of the following reasons: 
1. A patient misses 2 consecutive doses or 3 or more total doses of the study drug for any 
reason. 
2. Opportunistic systemic infection, or any infection which, in the opinion of the 
Investigator, puts patient at clinically significant risk from continued treatment with the 
study drug. 
3. A severe allergic reaction or serum sickness that is considered to be related to the study 
drug. 
4. A severe laboratory abnormality or severe TEAE or SAE that does not resolve before 
2 consecutive doses or 3 or more total doses of the study drug are missed (see 
Section 6.5.2). 
5. Use of SLE medication to treat a flare (Section 6.6.3) or use of prohibited medication 
(Section 6.6.1.2).   
6. The decision of the Investigator, Medical Monitor, or Sponsor.  
7.2. 
Patient Withdrawal from the Study  
A patient will be withdrawn from study participation if any of the following conditions occur:  
1. The patient withdraws consent.  
2. The patient is unable to continue to provide consent. 
3. The patient becomes pregnant.  
4. The Investigator withdraws the patient from study participation. 
5. The patient initiates use of an investigational medication other than PRV-3279 or 
placebo. 
All patients who withdraw from study participation for any reason will be scheduled for an Early 
Termination visit (Section 1.3). If a patient withdraws the consent for the Early Termination visit 
or loses the ability to consent freely, no further treatment or assessments will be performed. A 
patient who withdraws due to pregnancy will be followed for the outcome of the pregnancy.  
The reason for withdrawal must be documented in the case report form (CRF). Patients who 
withdraw prior to completing the Week 24 visit will be considered nonresponders in the primary 
and applicable secondary efficacy endpoints. 
If a patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
 
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7.3. 
Lost to Follow-up  
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unreachable by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
1. The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible. The site must counsel the patient on the importance of maintaining the assigned 
visit schedule and ascertain whether the patient wishes to and/or should continue in the 
study. 
2. Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record. 
3. Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study. A certified letter will be sent to the patient’s last known 
address to notify the patient of his or her termination from the study.  
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8. 
Study Assessments and Procedures  
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers or 
exemptions will not be allowed. Adherence to the study design requirements, including those 
specified in the SoA, is essential and required for study conduct. Safety concerns should be 
discussed with the Sponsor immediately upon occurrence or awareness to determine if the 
patient should continue or discontinue study intervention. 
The maximum amount of blood collected from most patients over the duration of the study will 
not exceed 525 mL. Due to additional PK blood sample collections (Section 8.5) and Receptor 
Occupancy sample collections (Section 8.7), the maximum blood volume will be approximately 
630 mL in approximately 30 patients. 
8.1. 
Study Procedures  
8.1.1. 
Screening Procedures  
Screening evaluations must be completed and reviewed by the CAC to confirm that each patient 
meets all eligibility criteria. The Investigator will maintain a Screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Details of communication between the CAC and site Investigator are provided in the CAC 
charter.  
At the Screening visit, SLE patients who present with active, moderate to severe symptoms will 
be invited to undertake screening procedures unless one or more exclusionary criteria are already 
identified.  
Study-specific screening procedures will begin only after a properly conducted informed consent 
process. The following procedures will be completed during Screening:  
• Patients will complete PRO questionnaires prior to any blood draws or other 
interventions with the study staff.   
• A complete medical history will be obtained with a full review of systems. To the extent 
that a medical history was already obtained that day as a part of regular medical care, it 
need not be repeated. 
• A complete physical examination will be performed (including weight and height). To 
the extent that a physical examination has already been performed on the same day by the 
study personnel as a part of regular medical care, aspects of the examination already 
performed need not be repeated. 
• A preliminary review of inclusion and exclusion criteria based on available data. Pending 
data will be noted. Documented prior history of positive ANA must be obtained. 
• Clinical disease activity measures will be completed by the Investigator. These will 
include the hSLEDAI (Furie 2011; Navarra 2011; Thanou 2014b) with SFI (Buyon 2005; 
Petri 2005), mSFI (Thanou 2014a), and ssPGA (Buyon 2005; Petri 2005), BILAG 
(Yee 2010), CLASI (Bonilla-Martinez 2008; Klein 2011), and tender and swollen joint 
counts (Sokka 2005).  
• Screening blood tests will be drawn including hematology, serum chemistry, and 
coagulation panels, SLE serology tests, complement components C3 and C4, total serum 
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immunoglobulin levels, serum anti-dsDNA antibodies, HBV, HCV, and HIV serology, 
and PD markers. Samples for urinalysis and for serum pregnancy test (WOCBP) will also 
be obtained. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) will be 
performed to confirm non-surgical menopause.  
• An ECG must be completed and evaluated prior to randomization.  
• Vital sign assessments after patient supine for at least 5 minutes. 
• Record all dietary supplements (including vitamins and minerals), nutraceuticals, herbal 
medicines, traditional Chinese medicines, ayurvedic remedies, and any other 
nonprescription or prescription products taken by the patient within 3 months prior to 
Screening. (The list of such products should be reviewed by the Investigator before 
Randomization.)  
• At the end of the Screening visit, if no exclusion criteria are known: 
o A patient will receive one or more IM injections of methylprednisolone acetate 
(Depo-Medrol® or equivalent) at a dose of ≥40 mg (maximum total dose 320 mg, 
maximum 4 injections). The dose will be determined by the Investigator to achieve a 
clinically significant improvement in SLE signs and symptoms that satisfy 
Inclusion 5b.  
o During the Screening period and prior to Randomization, patients must withdraw 
from all background treatments for SLE except the following medications:  
- Up to 10 mg prednisone (or equivalent corticosteroid [Section 10.5]) if taken for 
at least two weeks prior to Screening. Stable doses of prednisone of up to 15 mg 
may be tapered to 10 mg during the Screening period after giving the 
Depo Medrol injection(s).  
- Optional continuation of hydroxychloroquine up to 400 mg per day (or other 
antimalarial [Section 10.5]) that has been stable and well tolerated for a minimum 
of 2 months. 
- NSAIDs of any type, whether taken in regular doses or as needed (prior to the 
Randomization visit and any subsequent visits, patients will be reminded not to 
take NSAIDs on the day of all visits until the study procedures have been 
completed).  
CAC Adjudication: During the Screening period, a history BILAG (list of all BILAG 
descriptors ever active in the patient), non-lupus medical history, age, weight, disease activity, 
along with a brief narrative written by the Investigator to summarize the patient’s history of SLE 
features and current disease activity. This narrative should include past lupus manifestations, 
comorbid conditions, and a concise but clear description of the signs and symptoms that justify 
the disease activity scores. Information should be provided to convince the CAC that the patient 
is correctly diagnosed with SLE, has active features due to SLE that are significant enough to 
meet the study entry criteria, that the patient is stable enough to tolerate a withdrawal of 
background treatments while disease is ameliorated with temporary steroids, and there are 
limited or controlled co-morbidities, to suggest low risk of serious or opportunistic infections.  
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Once a patient has been deemed eligible to participate in the study, as adjudicated by the CAC, 
he/she may be scheduled for their Randomization visit. Prior to the Randomization visit (i.e., 
Day 1), all eligibility criteria must be confirmed by an Investigator.  
8.1.2. 
Baseline/Randomization Visit (Week 0, Day 1)  
Upon arrival at the clinic, patients will complete the PRO questionnaires prior to any blood draws 
or other interventions with the study staff. Patients will then have an interim history and a brief 
physical examination performed (including body weight). The Investigator will also complete the 
hSLEDAI, ssPGA, SFI, mSFI, BILAG, CLASI, and joint counts. To assess eligibility, the 
Investigator must confirm that the patient has achieved at least a moderate improvement in SLE 
signs and symptoms as indicated by:  
CGIC score of “definite improvement” or “major or complete improvement”  
AND  
≥4-point decrease in hSLEDAI score from Screening, OR improvement by ≥1 severity grade 
in at least one BILAG system that was severe (A score) or moderate (B score) at Screening 
(i.e., from A to B-D or from B to C or D).  
A pre-dose urinalysis and urine or serum pregnancy test (for WOCBP) will be obtained.  
Vital signs, ECG, AE, and concomitant medication assessments will be performed.  
Rapid COVID-19 test will be performed locally to confirm negative result prior to study drug 
administration.  
Blood samples will be drawn for the following assessments at the time points specified in the 
SoA (Section 1.3): PK, PD and ADA, hematology, serum chemistry, and coagulation panels, 
total serum immunoglobulin levels, serum anti-dsDNA antibodies, complement components C3 
and C4.  
After confirmation of the eligibility criteria, patients will be randomly assigned 1:1 to treatment 
with either 10 mg/kg PRV-3279 or placebo via an IVRS/IWRS system.  
The study drug will be administered at the study site. Patients will be observed for a minimum of 
2 hours after end of the first infusion. 
8.1.3. 
Scheduled Visits from Week 4 through Week 28  
Study drug administration will take place at the study site every 4 weeks through Week 20 and 
study procedures performed as outlined in the SoA (Section 1.3). Patients will be observed for a 
minimum of 30 minutes after the end of each infusion.  
At each visit, patients will also complete PRO questionnaires prior to any blood draws or other 
interventions with the study staff. 
Rapid COVID-19 test will be performed locally to confirm negative result prior to study drug 
administration or other study assessments.  
Patients will also undergo AE, concomitant medication, vital signs, ECG, and brief physical 
examination assessments (including body weight).  
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The Investigator will complete the hSLEDAI, ssPGA, SFI, mSFI, BILAG, CLASI, CGIC, and 
joint counts.  
A pre-dose urinalysis dipstick and urine or serum pregnancy test (for WOCBP) will be obtained 
and resulted prior to study drug administration. Urine will also be sent to the central laboratory 
for urinalysis. 
Blood samples will be drawn for the following assessments at the time points specified in the 
SoA (Section 1.3): PK, PD and ADA, hematology, serum chemistry, and coagulation panels, 
total serum immunoglobulin levels, serum anti-dsDNA antibodies, and complement components 
C3 and C4. (SLE serology test samples will be collected at Week 12 and Week 24 only.)  
Patients will return at Week 28 for additional follow-up assessments per the SoA (Section 1.3) 
and to capture any potentially delayed AEs.  
8.1.4. 
Unscheduled and “Flare Assessment” Visits  
Patients should return to the study site for unscheduled visits if there are missed or repeated 
laboratory tests or AEs that require evaluation and/or treatment.  
Patients should return for a Flare Assessment visit if they experience a known or suspected flare. 
The procedures for a Flare Assessment visit are listed in the SoA (Section 1.3). 
The LFA international consensus definition of flare is as follows: “A flare is a measurable 
increase in disease activity in one or more organ systems involving new or worse clinical signs 
and symptoms and/or laboratory measurements. It must be considered clinically significant by 
the assessor and usually there would be at least consideration of change or an increase in 
treatment” (Ruperto 2011). The criteria of a flare, as defined in this study, are given in 
Section 1.1 and Section 3.  
If a flare occurs, the patient may be treated as outlined in Section 6.6.3, and the patient will be 
considered a nonresponder in the primary and applicable secondary efficacy endpoints. 
8.1.5. 
Efficacy Assessments  
During the study per the SOA (Section 1.3), the disease activity of SLE and PROs will be 
evaluated using the following instruments:  
Disease Activity Instruments: hSLEDAI, ssPGA, SFI, mSFI, BILAG Index, CGIC, CLASI, and 
tender and swollen joint count. 
PROs: SF-36, FACIT--Fatigue scale, and PGIC and PGIS scales. 
8.1.6. 
Disease Measurement Instruments                                                   
8.1.6.1. 
Hybrid Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI)  
The version to be used in this study will be the hSLEDAI which was employed to validate the 
SRI-4 outcome measure (Furie 2009). This is also the SLEDAI utilized in the successful Phase 3 
trials for belimumab (Navarra 2011; Furie 2011; Stohl 2017; Zhang 2018; Tanaka 2019). The 
advantages of the hSLEDAI over other versions of the SLEDAI have been reviewed (Thanou 
2014b; Merrill 2019). Although the differences are minor, the hSLEDAI corrected a major 
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inconsistency in the proteinuria definition of the original SLEDAI, as did the SLEDAI 2K 
(Gladman 2000). However, the SLEDAI 2K has a very low threshold for scoring arthritis, 
allowing patients with minimal disease to score 4 points, which can impair interpretation of both 
entry disease level and the improvement threshold (Merrill 2019). The hSLEDAI is therefore the 
preferred instrument both in terms of clinical face validity and in the interpretability of data from 
trials that have employed it.  
The hSLEDAI is scored for disease activity present within the last 28 days, using history, 
physical examination and results of CBC, urinalysis, complement tests, and anti-dsDNA 
antibody testing (or additional confirmatory testing when scoring certain items as positive). The 
hSLEDAI scoring does not reflect symptom severity. One score is given for each sign or 
symptom that meets minimal criteria for the descriptor regardless of the degree of the 
manifestation. The numerical value of the score is based on the frequency and “usual severity” of 
each descriptor, which was derived through consensus of clinicians at the time the instrument 
was developed. As a result, the hSLEDAI is not very useful for comparing one patient to another 
and changes in mean/median hSLEDAI scores are not only difficult to interpret, as they may be 
misleading. However, because one or more symptoms must virtually disappear prior to any 
decrease in the score, the hSLEDAI has emerged as a relatively stringent and discriminatory 
endpoint for SLE trials when score decrease is incorporated as a dichotomous feature of 
endpoints. See Section 10.6.2.1 for the hSLEDAI form and glossary.  
8.1.6.2. 
SELENA-SLEDAI Physicians Global Assessment (ssPGA)  
This measure has the base of a visual analogue scale (VAS), but is anchored with cutoffs for 
mild, moderate and severe disease. The very far left end reflects complete remission. The very 
far right end indicates ‘the most severe disease possible.’ This does not mean only the most 
severe disease seen in a particular patient, but the most severe disease ever seen in all SLE 
patients. When scoring the ssPGA, the assessor should always consider the score from the 
previous visit, so that transitional scoring from month to month is consistent with changes in the 
patient’s condition (Buyon 2005; Petri 2005). In the past the ssPGA has produced confusing 
results. This could be, in part, because the instructions for how to use the cutoffs were 
inconsistently taught by CROs. The Investigators be instructed in the correct and consistent use 
of the anchors in scoring this measurement, (e.g., mild disease will be scored between 0 and 1, 
moderate disease will be scored between 1 and 2 and severe disease will be scored between 2 
and 3). Also, the original ssPGA instructions from the SELENA-SLEDAI group will be used in 
training as archived online in the LFA Professional Online Instrument Training site 
(https://www.LFA-POINT.org). See Section 10.6.2.3 for an example of the ssPGA VAS.  
8.1.6.3. 
SELENA-SLEDAI Flare Index (SFI)  
This index is used with all versions of the SLEDAI and incorporates changes in scoring of the 
main SLEDAI form, changes in ssPGA scoring, medication changes, and assessment of new or 
worsening descriptive features of active SLE. Flares are designated as either mild/moderate or 
severe based on a combination of these factors (Buyon 2005; Petri 2005). We will collect 
information using this original, widely used SFI for the main analyses, but we will also collect 
data in an exploratory endpoint from a modified version (mSFI, see below).  
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8.1.6.4. 
Modified SELENA-SLEDAI Flare Index (mSFI)  
This modified version of the SFI removes the restrictive and outdated medication rules and one 
extra data point is collected by asking the Investigator to distinguish (by clinical opinion) 
between mild and moderate flares. The mSFI was shown to better approximate the clinician’s 
opinion on whether or not there is a flare (Thanou 2014a), and it was found that many features 
that meet criteria for mild/moderate flare are determined by physicians to be clinically 
insignificant. The mSFI will be evaluated in this trial as an exploratory evaluation to enable an 
assessment of only moderate and severe flares, which is expected to be more discriminatory 
between an effective treatment and placebo than when mild, clinically insignificant flares are 
included. This possibility will be examined by direct comparison to the original SFI, and BILAG 
Flare definitions. The mSFI requires no extra data collection other than for the Investigator to 
provide a simple distinction between mild and moderate flares by checking a box to distinguish 
the severity.  
8.1.6.5. 
British Isles Lupus Assessment Group (BILAG) Index  
This instrument is scored for disease activity present within the last month using history, 
physical examination and results of CBC, general chemistry panel, and urinalysis. Additional 
testing is required for scoring certain items, but only if clinically warranted. The BILAG is a 
transitional index, thus clinical progress between visits is an integral part of the scoring 
algorithm. The instrument consists of 97 descriptors for signs and symptoms of lupus divided 
into 9 organ systems (see Section 10.6.2.4 for forms, glossary and scoring rules). At consecutive 
visits, each organ system receives a rating of A (severe disease activity), B (moderate disease 
activity), C (mild disease activity), D (no disease activity in an organ previously affected) or E 
(organ inactive and never previously active). These ratings are derived from assessments made 
on each descriptor within each organ and the determination of whether activity is not present, 
improving, same, worsening or new/recurrent when comparing the degree of disease during the 
past month to the previous month (Yee 2010).  
8.1.6.6. 
Cutaneous Lupus Erythematous Disease Area and Severity Index (CLASI)  
This evaluation is scored predominantly with objective findings observed in the mucocutaneous 
system on the day of the visit. Disease areas are defined (and to some extent weighted) by the 
most characteristic locations of lupus rash. In each area the most severe lesion is rated for color 
and associated features of severity such as scaling and hypertrophy. Because of this, most active, 
discoid lesions are likely to receive a higher score than subacute or acute cutaneous lupus that 
might cover an equivalent area, which is appropriate (Bonilla-Martinez 2008; Klein 2011). See 
Section 10.6.2.6 for the form and CLASI form. 
8.1.6.7. 
Tender and Swollen Joint Counts  
This will be performed by accepted methods employed in studies of rheumatoid arthritis (Sokka 
2005). Using the identical techniques, tender and swollen joint counts have been successful at 
discriminating treatment from placebo in several lupus studies as well (Furie 2017; Merrill 2017; 
Khamashta 2016). For this study, the 28-joint count will be used. The site staff member assigned 
to perform these counts will receive training in joint assessment prior to the study. See 
Section 10.6.2.7 for the tender and swollen joint counts form. 
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8.1.7. 
Patient-Reported Outcomes  
Multiple semi-structured interviews were conducted with 10 SLE patients (Askanase 2019a) in 
order to better understand the kinds of lupus symptoms experienced from the patients’ point of 
view, and the impact of lupus features on daily function and quality of life. Symptoms that were 
of most concern to the patients were arthritis (reported spontaneously by 100%), and fatigue 
(also reported by 100%, half spontaneously and have elicited). The following were noted by at 
least 50% of the patients: swelling (90%), weakness (90%), difficulty breathing/shortness of 
breath (80%), skin problems (80%), chest pain (70%), hair loss (60%), muscle pain, aching, or 
stiffness (50%), and fever (50%).  
Problems that lupus patients experience extend beyond their physical well-being, as found in a 
different qualitative research report (Leung 2019). Patients reported a burden of ambiguity, 
inconsistency, and lack of symptom predictability, poor communication with 
family/friends/partners, and health care providers and lack of external validation for patients' 
experiences (appraisal support). During structured interviews and a focus group, these social 
themes were expanded, finding a significant impact of SLE on interpersonal, familial and 
romantic relationships. The unpredictability of symptoms was highlighted along with lack of 
empathy by physicians and clinic staff and this was thought to affect correct diagnosis and 
appropriate follow-up care. Fatigue was reported as a major clinical feature in these interviews 
and the presence of pain was stressed, along with difficulties in communicating the pain to 
healthcare providers and others.  
The extensive paperwork involved in trial participation is considered a significant burden to 
patients who have experienced trial participation (Arriens 2020). Nevertheless, lupus patients 
have a good knowledge base and strong interest in participation in trials for reasons that include 
altruism and the potential for personal benefit. Consistent with the reports above, other burdens 
of trial participation were the uncertainties, potential disappointments and the difficulties 
maintaining life-health balance. The PROs intended for the current study will all have a one-
month recall period and are likely to require less than 30 minutes each month from a patient. At 
the end of the trial, patients will be given a questionnaire to determine how burdensome this was 
perceived to be and whether certain PROs (or sections of PROs) were perceived to be more or 
less relevant to their experience.  
The SF-36 measures QOL and physical function and symptoms. The FACIT-Fatigue scale 
focuses more in depth on fatigue and the different contexts in which it occurs, resulting in more 
contextual information about this singular major disabling feature of SLE than the SF-36 can 
provide. The PGIS and PGIC are simple, rapid anchoring assessments that are very user friendly 
and can help to verify the findings of how disease severity and disease change may be affecting 
various items on the QOL and PRO disease activity measures. They are different from each other 
because one measures severity and the other change from the last visit. 
8.1.7.1. 
Short Form 36 Health Survey (SF-36)  
The Short Form 36 (SF-36) Health Survey (Ware 1992) is one of the most widely used PROs 
currently used in SLE (Bangert 2019) Within a limited number of questions, it captures eight 
domains relevant to QOL: (physical functioning, general health, mental health, vitality, role 
physical, role emotional, bodily pain, and social functioning) and provides two summary scores 
(PCS and mental component score [MCS]. Scoring can range from 0 to 100 with higher scores 
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designating better health. The psychometric measurement properties of this instrument have been 
extensively studied and applied for lupus across multiple cultures and languages. Reliability, 
including internal consistency and test-retest reliability; validity; and responsiveness of SF-36 
have been confirmed for SLE (Baba 2018; Devilliers 2015; Garcia-Carrasco 2012; Nantes 2018; 
Strand 2003; Strand 2014; Strand 2020; Thumboo 2000; Touma 2011; Yilmaz-Oner 2016). See 
Section 10.7.1 for an example of the SF-36. 
The potential importance of obtaining patient reports using the SF-36 is underscored by the 
findings of one study that both the SF-36 physical component subscale score and self-rated 
health were associated with mortality (Azizoddin 2019). However, when considering the use of 
PROs in time-limited interventional trials, the concept of Minimally Clinically Important 
Differences (MCIDs) is central to the interpretation of these instruments (Rai 2015). A clinical 
intervention can be interpreted as clinically meaningful if the score change that occurs when it is 
tested exceeds the validated MCID for that disease (Rai 2015). MCIDs have been established for 
the SF-36 in SLE (Strand 2003; Strand 2014). For PCS and MCS, ≥2.5 point increases in the 
score meet the MCID for improvement and ≥-0.8 decreases meet the threshold for clinically 
significant worsening. For individual domain scores, ≥5.0 point increases indicate clinically 
significant improvement and ≥–2.5 decreases reach MCID for worsening. These MCID values 
were used to evaluate SF-36 results in a combined analysis of two phase 3 trials of belimumab in 
SLE (Furie 2014). At Week 52 mean improvements in SF-36 PCS were greater in SRI-4 
responders when compared to nonresponders and exceeded the MCID. Not all SF-36 individual 
domains gave consistent results between the two belimumab trials, suggesting the importance of 
exploring the aspects of disease that do or do not improve from the patients’ point of view (Furie 
2014; Strand 2019). It is possible that the SF-36 may lack key domains that are particularly 
relevant to a population with SLE, including fatigue (Moses 2005). PGIC and PGIS will also be 
used to assess MCIDs in the efficacy instruments. 
8.1.7.2. 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)  
Fatigue is reported by most patients with SLE and is one of its most disabling symptoms (Lateef 
2012; Fonseca 2014; Gordon 2013; Holloway 2014; Elefante 2020) and although it is known to 
be multifactorial it cannot be completely explained by depression or other mood disorders 
(Fonseca 2014). In an online survey of 21,101 patients with self-reported lupus, fatigue, pain, 
and joint pain were rated as moderate or severe by at least 80% of patients who reported these 
symptoms (Nyman 2020). Although cross sectional comparisons of fatigue to disease activity 
have not shown a reliable relationship, it has been found that as patients objective disease 
activity improves and remains stable over time, fatigue has been documented to improve as well 
(Strand 2019), making a thorough understanding of types of fatigue in SLE important to measure 
in clinical trials. A dedicated instrument to sort out the components and elements of fatigue is of 
value in clinical trials.  
The FACIT-Fatigue Scale (Cella 2002) is a questionnaire that evaluates both physical and mental 
fatigue and how fatigue affects function and activities of daily life. Thirteen items are each 
scored on a four-point scale with lower scores reflecting more fatigue. The FACIT-F was first 
validated for rheumatic diseases in 1997 (Yellen 1997) and has since been applied in several 
SLE studies (Furie 2014; Strand 2019; Elefante 2020). Psychometric properties have been 
established, including content validity (Kosinski 2013), reliability (Lai 2011), validity (Goligher 
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2008; Lai 2011), and responsiveness (Furie 2014). In the SLE population, the instrument’s 
ability to detect change over time has been critically reviewed (Kwan 2017) and found to be 
meaningful. The median FACIT-F score in a lupus population has been reported to be lower than 
that of healthy controls and not influenced by age, SLE disease duration, cross-sectional disease 
activity scores or accumulated organ damage (Elefante 2020). FACIT-F scores demonstrated a 
significant correlation with other PROs including the SF-36 but may be confounded by the 
presence of fibromyalgia (Elefante 2020). Fatigue is very likely multifactorial in lupus patients 
but the FACIT-Fatigue score has been demonstrated to improve along with treatment that was 
determined to be clinically efficacious for SLE disease activity by physician outcome 
assessments (Stohl 2017; Furie 2014). See Section 10.7.3 for an example of the FACIT-F. 
In a combined analysis of two Phase 3 trials of belimumab in SLE, SRI-4 responders had higher 
mean improvements in FACIT-Fatigue scores compared to nonresponders and only the 
responders met the MCID cutoff (Furie 2014), suggesting that this patient-reported endpoint has 
at least the potential to show consistency with physician-recorded disease improvement. Both 
belimumab treatment dosing groups had significant improvements in FACIT-Fatigue by Week 
52 compared to placebo. Improvements were observed after 8 weeks of treatment and persisted 
throughout the trial. In a different belimumab trial in lupus patients (Stohl 2017) improvement in 
FACIT-Fatigue was only found in a post-hoc subgroup analyses in Hispanic or Latino patients. 
Long term improvement in fatigue, however, was reported in a 6-year follow-up study of 
belimumab in SLE (Strand 2019).  
8.1.7.3. 
Patient Global Impression Scales (PGIS and PGIC)  
The SF-36 and FACIT-Fatigue Scales have established MCID but the other exploratory 
endpoints to be studied in this trial do not. To provide evidence that may help interpret a 
meaningful within-patient score change in these newer instruments, simple discontinuous scales 
will be administered for PGIS and PGIC. These have evolved as the PRO counterpart to the 
Clinical Global Impressions scale (CGI), which was developed in 1976 by the National Institute 
of Mental Health (US) and are widely accepted in clinical studies of a wide variety of disorders 
and have been translated into many languages (Kroenke 2019; Le Gal 2010). These anchor 
scales will be administered such that, like all of the other PROs used in this study, they have a 
recall period of one month and will be completed after, the other PRO instruments. Please see 
Section 10.7.2 for examples of these anchor scales.  
8.1.8. 
Laboratory Tests of Lupus Disease Activity  
The activities of SLE will also be assessed by analyzing the levels of serum anti-dsDNA 
antibodies, complement components C3 and C4, and total serum immunoglobulin levels (IgG, 
IgM, IgA, IgE) in blood samples obtained at the visits outlined in the SoA (Section 1.3). 
Additional autoantibodies to be analyzed include Sm, RNP, anti-cardiolipin antibodies (IgA, 
IgG, IgM), anti-beta 2 glycoprotein (GPI) antibodies (IgA, IgG, IgM), and the lupus 
anticoagulant. 
8.2. 
Safety Assessments  
Safety assessments to be conducted at each monthly visit are listed in the SoA (Section 1.3).  
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If an unscheduled visit occurs, safety assessments should be conducted in the same way as a 
scheduled visit.  
8.2.1. 
Physical Examinations  
A complete physical examination will be performed at Screening and includes, at a minimum, 
assessments of the head, eyes, ears, nose, throat, skin, cardiovascular, respiratory, 
mucocutaneous, musculoskeletal, lymphatic, gastrointestinal, and neurological systems. 
Gynecologic, breast, and rectal examinations are not routinely required except to address a 
specific medical issue. 
A brief physical examination will be performed at time points noted in the SoA (Section 1.3). 
The brief physical examination will include, at a minimum, assessments of the mucocutaneous, 
respiratory, cardiovascular, gastrointestinal, and musculoskeletal as well as any other 
organ/system suggested by the interim history. 
Height will be measured recorded at Screening, and weight will be measured and recorded at 
each visit. 
8.2.2. 
Vital Signs  
Vital signs will be obtained at time points noted in the SoA (Section 1.3). Vital signs should be 
assessed after the patient has been supine for at least 5 minutes and will include body 
temperature, heart rate, respiratory rate, and blood pressure. On dosing days, vital signs should 
be performed once during the 30 minutes before the study drug infusion and again approximately 
30 minutes after the end of infusion. Abnormal and clinically significant vital signs should be 
noted as AEs by the Investigator.  
8.2.3. 
Electrocardiograms  
A 12-lead ECG will be obtained at time points noted in the SoA (Section 1.3), using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT interval 
corrected for heart rate using Friderica’s cubed root formula (QTcF) intervals. Additional ECGs 
may be performed as needed. The Investigator should report one of the following: normal, 
abnormal not clinically significant, abnormal clinically significant.  
8.2.4. 
Tuberculosis Screening  
See Exclusion 20 for eligibility criteria regarding TB Screening. Indeterminate tests should be 
repeated. If the repeat test is positive or still indeterminant, the patient is excluded (repeat 
QuantiFERON tests may be performed locally). 
8.2.5. 
Clinical Safety Laboratory Assessments  
Clinical safety laboratory tests are listed in Section 10.2 and will be performed at time points 
outlined in the SoA (Section 1.3).  
Hematology includes CBC will differential: hematocrit, hemoglobin, red blood cell (RBC) count, 
red blood cell distribution width (RDW), mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelets, absolute 
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reticulocyte count, WBC count with absolute counts of neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils.  
Serum chemistry includes sodium, potassium, chloride, alkaline phosphatase (ALP), ALT, AST, 
blood urea nitrogen (BUN), creatinine, CPK total protein, albumin, glucose, calcium, 
phosphorous, and bicarbonate.  
Coagulation panel: prothrombin time (PT), international normalized ratio (INR), activated partial 
thromboplastin time (aPTT), and fibrinogen. 
TBNK panel is a quantitative lymphocyte panel that includes the assessment of CD4+ T cells, 
CD8+ T cells, B cells, and natural killer (NK) cells.  
Serum pregnancy test will be performed during Screening for WOCBP. FSH and LH will be 
performed during Screening to confirm non-surgical menopause. A urine or serum pregnancy 
test will be performed before each dose of study drug for WOCBP. 
A negative rapid COVID-19 test is required before administering each dose of study drug. 
A urinalysis will be performed at all study visits.  
Out of range laboratory tests are not necessarily an AE.  The following laboratory abnormalities 
should be documented and reported as AEs:  
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
• Any laboratory abnormality that required the patient to have study drug discontinued or 
interrupted. 
• Any laboratory abnormality that required the patient to receive specific corrective 
therapy. 
• If the laboratory test is indicative of a disease or infection, the disease TEAE term should 
be used.  
8.2.6. 
Data Review Committees  
8.2.6.1. 
Central Adjudication Committee (CAC)  
The CAC responsibilities include: 
• Confirm patients’ eligibility to enter the study  
• Adjudicate SLE flare 
• Ensure the accuracy and consistency of scoring on the disease activity instruments  
The CAC will be blinded to the study treatment. Details will be provided in the CAC charter.  
8.2.6.2. 
Independent Data Monitoring Committee (IDMC)  
An independent external committee consisting of 2 physicians and one statistician will be 
formed. Additionally, 1 to 2 external non-voting advisors with experience in rheumatology, 
infectious disease, cardiology and/or hematology may be added as needed. Meetings will be held 
approximately quarterly and as needed to review unblinded safety and other relevant data. After 
each meeting, the IDMC will make recommendations regarding study conduct. The IDMC may 
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recommend the continuation of the study with or without modifications, suspension, or 
termination. 
Details will be provided in the IDMC charter. 
8.3. 
Adverse Events (AEs) and Serious Adverse Events (SAEs)  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. Details are provided below as well as 
in Section 10.3.  
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information  
All SAEs will be collected from the time of the signing of the ICF through the EOS at the time 
points specified in the SoA (Section 1.3). 
TEAEs and treatment-emergent SAEs are defined as events that occur after the start of the study 
treatment. TEAEs and AEs occurring before the start of the study treatment will be reported 
separately.  
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours from the time the site becomes aware of it. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (see Section 7.3). Further information on 
follow-up procedures is provided in Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs  
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that ethical 
responsibilities towards the safety of patients and the safety of a study intervention under clinical 
investigation and legal obligations and are met. 
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The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
it along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5. 
Pregnancy  
Details of all pregnancies in female patients and female partners of male patients will be 
collected from the start of study treatment through the safety follow-up visit. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
TEAEs  
Disease flares of lupus will not be captured as AEs since they are an endpoint of the study. 
However, if they meet the criteria for an SAE such as a particularly severe flare, a life-
threatening event or require hospitalization, it will be captured as an SAE regardless of causality. 
8.3.7. 
Adverse Events of Special Interest  
Adverse events of special interests (AESIs) are TEAEs, including SAEs, that are of scientific and 
medical concern specific to PRV-3279, for which ongoing monitoring and rapid communication 
by the Investigator to the Sponsor is considered appropriate.  
The following AEs are considered AESIs:  
• severe infections requiring IV antibiotics/antifungal/antiviral and/or hospitalization 
• opportunistic infections related to immune suppression (e.g. pneumocystis carinii etc.) 
• herpes zoster  
• moderate or severe infusion site reactions  
• anaphylaxis or severe hypersensitivity reaction 
• new malignancy 
• thrombosis 
• MACE (Major Adverse Cardiovascular Events), defined as the composite of total death; 
myocardial infarction; stroke, hospitalization because of heart failure; and 
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revascularization, including percutaneous coronary intervention, and coronary artery 
bypass graft. 
8.3.8. 
Infusion or Allergic Reactions  
Please refer to Section 6.1.1.  
8.4. 
Overdose  
An overdose is defined as the accidental or intentional administration of any dose of the study 
drug that is considered both excessive and medically important. All occurrences of overdose 
must be reported to pharmacovigilance as an Other Reportable Event. 
8.5. 
Pharmacokinetic Assessments  
At all sites, PK samples will be collected at each visit within 30 minutes pre-dose and within 
5 minutes after the end of infusion, any Flare Assessment visit due to immune-related AEs and at 
the follow-up visit. For approximately 30 patients, additional PK samples may be collected on 
Day 1 and Day 141 at 24 ± 4 hours, 48 ± 4 hours, 72± 4 hours, 168 ± 48 hours and 336 ± 48 
hours post-dose. Detailed instructions on the collection, handling, and shipment of biological 
samples will be provided in the Laboratory Manual. 
Serum samples will be analyzed to determine concentrations of PRV-3279 using a validated, 
specific, and sensitive immunoassay method. 
8.6. 
Immunogenicity Assessments  
Blood samples for ADA titers will be collected pre-dose on Day 1 as a control for natural ADAs 
in SLE, so that placebo patients with positive reactivity can be interpreted. ADA samples will 
also be collected at visits outlined in the SoA (Section 1.3) and at any Flare Assessment visit 
triggered by suspected immunologically related AEs. Detailed instructions on the collection, 
handling, and shipment of biological samples will be provided in the Laboratory Manual. 
Titers of anti-PRV-3279 ADA will be analyzed using a validated immunoassay method. 
8.7. 
Pharmacodynamic/Biomarker Assessments  
Blood samples for PD markers will be collected at the visits outlined in the SoA (Section 1.3). 
(Note that for receptor occupancy assays (if performed), blood collections will only be conducted 
in select patients.)  Blood samples will also be collected at any Flare Assessment visit allow the 
assessment of immunologic consequences of any suspected immunologically related AEs or 
flare. Detailed instructions on the collection, handling, and shipment of biological samples will 
be provided in the Laboratory Manual. 
Analyses may include but are not limited to 
, B cell immunophenotyping, 
 assays, mRNA analysis including CD32B polymorphisms, 
and other exploratory serum markers. Phenotypic patterns may be evaluated by upregulated or 
downregulated cytokines and/or gene expression modules, as defined by the NIAID Human 
Immune Phenotyping Consortium to enable designation of each patient to one of seven known 
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SLE immunophenotype clusters derived from Random Forest Modeling of gene and cluster 
expression patterns (Guthridge 2020; Banchereau 2016).  
Additionally, the underlying variables that may affect the impact of PRV-3279 on B cells will be 
explored. These will be compared between patients on PRV-3279 and placebo and between 
responders and nonresponders. 
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9. 
Statistical Considerations  
9.1. 
Sample Size Determination  
The published data from the Phase 2, double-blind, randomized, placebo-controlled study of a 
reversible B cell inhibitor, XmAb®5871, in SLE showed that the response rates of the 
maintenance improvement in SLE signs and symptoms in the intent-to-treat (ITT) population 
were 40.4% vs 23.1% at Day 225 and 57.7% vs 34.6% at Day 169 for the active arm and control 
arm, respectively (Merrill 2018d).
  
9.2. 
Populations for Analyses  
The analysis sets are defined as follows:  
1. All Screened (ALL) analysis set 
 
The ALL analysis set consists of all Screened patients. 
2. Full analysis set (FAS) 
The FAS analysis set includes all randomized patients who received at least 1 dose of 
study drug. Patients will be analyzed according to the randomized treatment. The analysis 
of efficacy endpoints will be performed in the FAS.  
3. Per-Protocol (PP) analysis set 
The PP analysis set includes all FAS patients except those who have met the major 
protocol deviation criteria that are considered likely to affect the evaluation of the 
efficacy endpoints. These criteria will be defined, and the patients excluded from the PP 
analysis set will be identified and documented prior to unblinding of the study. The 
analysis of the primary efficacy endpoint will be performed in the PP set, if the PP 
analysis set differs substantially from the FAS. 
4. Safety analysis set 
The safety analysis set includes all patients who take at least 1 dose of the study drug 
post-randomization. Patients will be analyzed according to the treatment actually 
received. 
5. PK analysis set 
The PK analysis set includes all randomized patients who received at least 1 dose of the 
study drug and have at least 1 post-dose evaluable PK assessment. 
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6. Immunogenicity (IMG) analysis set 
The IMG analysis set includes all randomized patients who received at least 1 dose of the 
study drug and have at least 1 post-dose evaluable IMG assessment. 
7. PD analysis set 
The PD analysis set includes all randomized patients who received at least 1 dose of the 
study drug and have at least 1 post-dose evaluable PD assessment.  
9.3. 
Statistical Analyses  
A detailed description of the statistical analyses, data derivation rules and handling of missing 
data, if any, will be provided in the Statistical Analysis Plan (SAP). The SAP will be finalized 
prior to database lock and unblinding. This section briefly outlines the planned statistical 
analyses of the efficacy, safety, immunogenicity, PK, and PD. 
9.3.1. 
General Considerations  
All continuous endpoints and respective changes from baseline (absolute and percent) will be 
summarized (N, mean, median, standard deviation [SD], minimum and maximum). Rates or 
proportions will be tabulated by frequency of occurrence (count) and percent. All summaries will 
be by treatment and collection time.  
Baseline values will be derived from observations collected prior to study drug administration. 
All the statistical analyses for the clinical efficacy and safety assessments will be performed 
using SAS version 9.4 or above. 
9.3.1.1. 
Handling of Missing Data  
The rules for handling missing data will be provided in detail in the SAP. 
9.3.2. 
Primary Analysis  
The primary endpoint is proportion of patients who maintain the improvement in SLE disease 
activity from Baseline (Day 1) to Week 24, defined as no lupus flare during this period, who 
have not missed 2 consecutive doses or 3 or more total doses of the study drug for any reason, 
who have not taken a new SLE medication, and whose dose of SLE medication has not been 
increased. 
The null hypothesis is that the proportion of patients who maintain improvement through Week 
24 (i.e., responders) in the PRV-3279 group is the same as that in the placebo group. The 
alternative hypothesis is that the proportion of patients who maintain improvement through 
Week 24 in PRV-3279 group is different from that in the placebo group. 
The difference in the proportion of patients who maintain improvement between the PRV-3279 
and the placebo arms will be tested using the Cochran-Mantel-Haenszel (CMH) test, accounting 
for randomization stratification factors. This will be tested at two-sided 0.20 level of 
significance. If the data is sparse that the asymptotic statistical test is inappropriate, the Fisher’s 
Exact test will be used instead. The numbers and percentages of responders and the associated 
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80% confidence interval (CI), and the proportion difference and the associated 80% CI between 
treatment groups will be tabulated by the treatment group. 
The primary analysis will be conducted on the FAS population. Analysis of the primary endpoint 
will also be conducted on the PP populations if PP population differs substantially from the FAS 
population. 
9.3.3. 
Secondary Efficacy Analysis  
All secondary efficacy analyses will be conducted on the FAS and summarized. The statistical 
testing on the secondary endpoints will not be adjusted for multiplicity and will be considered 
descriptive and non-inferential. The secondary efficacy analyses are: 
1. The time to treatment failure will be summarized by treatment group using Kaplan-Meier 
analysis (median, 95% CI, number of events, number censored, etc.) and Kaplan-Meier 
plots. The stratified log-rank test will be used to test for difference between treatment 
groups. 
2. The proportion of patients who achieve the EULAR-recommended goal of low disease at 
Week 24 will be compared between the groups using the same test as the primary 
efficacy analysis. 
3. The change from Screening to Week 24 in the SF-36 PCS will be analyzed using the 
Mixed Model for Repeated Measurements (MMRM). The model will include treatment, 
visit, randomization stratification factors, baseline score as fixed effects, and the 
treatment by visit as interaction term.  
4. The proportion of patients who achieve SRI-4 at Week 24 will be compared between the 
groups using the same test as the primary efficacy analysis.  
5. The proportions of patients who meet the BICLA criteria at Week 24 will be compared 
between the groups using the same test as the primary efficacy analysis. 
The time to treatment failure in subgroups by stratification will be summarized by treatment 
using the Kaplan-Meier method and compared between treatment groups using the log-rank test.  
9.3.4. 
Exploratory Analyses  
Details of the exploratory analyses will be provided in the SAP.  
9.3.5. 
Safety Analyses  
All safety analyses will be conducted on the Safety analysis set. 
The safety variables, including AEs (coded using the Medical Dictionary for Regulatory 
Activities [MedDRA]) will be tabulated by actual treatment received. TEAEs, TEAEs leading to 
withdrawal, treatment-emergent SAEs, and AESIs will be tabulated by MedDRA system organ 
class and preferred term and treatment group. Potentially clinically important (PCI) laboratory 
tests and abnormal and clinically significant vital signs will be tabulated and listed by visit and 
treatment group. Similarly, abnormal and clinically significant ECG findings will be listed by 
visit and treatment group and tabulated by treatment group.  
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9.3.6. 
Immunogenicity Analyses  
The incidence and titers of positive ADAs will be tabulated. The potential association of 
immunogenicity with safety, PK, and PD results will be explored graphically. The PK, PD, and 
immunogenicity populations will be used for these assessments. 
9.3.7. 
Pharmacokinetic  
In all patients, PRV-3279 serum concentration collected at pre-dose and post-end of infusion on 
Weeks 0, 4, 8, 12, 16, 20, 24 and 28 will be tabulated by time point using descriptive statistics 
and listed. 
Individual PRV-3279 concentrations will be listed and summarized and graphically presented by 
scheduled time point. The following descriptive statistics will be presented for serum 
concentrations obtained at each nominal time point: n, mean, SD, percent coefficient of variation 
(CV%), GM, geometric CV% (gCV%), median, minimum, and maximum values. 
For all patients, PRV-3279 serum concentration will be collected within 30 minutes pre-dose and 
within 5 minutes after the end of infusion in order to determine the accumulation of multiple 
infusions and steady-state serum concentration.  
For approximately 30 patients, extensive PK sampling may be conducted on Day 1 and Day 141. 
The PK parameters listed in Table 2 will be calculated based on actual sampling times using 
noncompartmental analysis methods. Summary statistics will be tabulated for serum PK 
parameters by Day. Descriptive statistics for calculated PK parameters include n, arithmetic 
mean, SD, CV%, GM, gCV%, median, minimum, and maximum values. For Tmax, only median, 
minimum, and maximum values will be presented.  
Table 2  
Pharmacokinetic Parameter Definitions 
Parameter 
Definition 
Time Point 
Cmax 
Maximum serum concentration determined directly from the 
concentration-time profile 
Day 1, Day
Ctrough 
Serum concentration at pre-dose 
Day 1, Day
Tmax 
Time of maximum serum concentration determined directly from the 
concentration-time profile 
Day 1, Day
 
Day 1, Day
AUC0-t 
Area under the concentration-time curve from pre-dose  
(time 0) to the time of the last quantifiable concentration (tlast) 
Day 1, Day
 
-
l
  
Day 1 
t1/2 
Terminal elimination half-life calculated as: ln2/λz 
Day 1, Day
CL 
Clearance 
Day 1, Day
Vd 
Volume of distribution in terminal phase 
Day 1, Day
Vss 
Volume of distribution at steady state 
Day 1, Day
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Parameter 
Definition 
Time Point 
MRT 
Mean Residence Time 
Day 1,
RacCmax 
Accumulation ratio, Cmax on Day
/Cmax on Day 1 
N/A 
RacAUC 
Accumulation ratio, AUC0-
 on Day 
/AUC
 on Day 1 
N/A 
9.3.8. 
Pharmacodynamic Analyses  
Changes in individual biomarkers from baseline to the selected posttreatment time points will be 
summarized. Associations between baseline levels and changes from baseline in select 
biomarkers and clinical response will be explored. The biomarker analysis will characterize the 
response of patients to PRV-3279 and loss of response, to determine if response to PRV-3279 
can be predicted and to further our understanding of lupus.  
The relationship between serum concentrations of PRV-3279 and PD and/or clinical endpoints 
will be graphically explored and if warranted further elucidated with appropriate modeling 
techniques. 
9.3.9. 
Subgroup Analyses of Primary/Secondary Efficacy Endpoints  
Subgroup analysis may be conducted on the primary endpoint for each level of randomization 
stratification factors and relevant demographic and baseline characteristics, such as age group, 
race, baseline disease status, etc. The details of the subgroup analyses will be provided in the 
SAP. 
9.3.10. 
Sensitivity Analyses  
Sensitivity analysis may be conducted on primary endpoint if intercurrent events are identified 
during the course of treatment. Probable intercurrent events and sensitivity analyses will be 
provided in detail in the SAP. 
9.4. 
Interim Analysis  
No interim analysis is planned. 
 
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., advertisements) 
must be submitted to an IRB/IEC by the Investigator and reviewed and approved by the IRB/IEC 
before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process  
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Patients or their legally authorized 
representative will be required to sign a statement of informed consent that meets the 
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requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The Investigator or authorized designee will explain to each 
patient the objectives of the exploratory research. Patients will be told that they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the storage 
period. A separate signature will be required to document a patient's agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate in 
this optional research will not provide this separate signature. 
10.1.4. 
Data Protection  
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient who will be required to give consent for their data to be used as described in the ICF. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Dissemination of Clinical Study Data  
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the Investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the institution and the Sponsor or their designee. 
10.1.6. 
Data Quality Assurance  
All relevant patient data relating to the study will be recorded on the CRF and/or handheld 
devices unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by signing the 
CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
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The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies), methods, responsibilities and requirements, 
including handling of noncompliance issues and monitoring techniques (central, remote, or on-
site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations). 
Study monitors will perform ongoing source data verification to confirm that data collected 
and/or entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of patients are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
10.1.7. 
Source Documents  
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF or entered in the CRF that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The Investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
10.1.8. 
Study and Site Start and Closure  
The study start date is the date on which the clinical study will be open for recruitment of 
patients. 
The first act of recruitment is the first patient Screened and will be the study start date. 
The Sponsor or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of patients by the Investigator 
• 
Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the patient and should assure appropriate patient therapy 
and/or follow-up. 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests  
Except where noted, safety laboratory tests will be performed by central laboratories. Procedures 
for collecting, processing, and shipping blood samples will be detailed in the Laboratory Manual. 
The following clinical laboratory tests conducted at Screening only:  
• Serum pregnancy test for WOCBP  
• Serum FSH and LH to confirm non-surgical menopause  
• HBsAg, HBsAb, total HBcAb (IgM and IgG), HBV DNA (if HBcAb is positive), HCV 
RNA  
• HIV 1 &2 (and HIV confirmation, if applicable)  
• QuantiFERON Gold TB test (local testing may be allowed in a case-by-case basis such as 
to repeat an indeterminate initial test result) 
The following clinical laboratory tests will be performed at the time points outlined in the SoA 
(Section 1.3). 
• Hematology: hematocrit, hemoglobin, RBC, RDW, MCV, MCH, MCHC, platelets, 
absolute reticulocyte count, WBC with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils) including absolute neutrophils, lymphocytes, and 
eosinophil count.  
• Chemistry: sodium, potassium, chloride, calcium, ALP, ALT, AST, BUN, creatinine, 
CPK, direct and total bilirubin, total protein, albumin, glucose, phosphorous, and 
bicarbonate.  
• Coagulation Panel: PT/INR, aPTT and fibrinogen 
• Urinalysis  
• SLE Serology: ANA, ENA (including anti-SSA, anti-SSB, anti-Sm, anti-RNP), 
anti-cardiolipin antibodies, anti-beta 2 GPI antibodies, and the lupus anticoagulant  
• SLE Disease Activity Markers: serum anti-dsDNA antibodies, complement components 
C3 and C4, and total serum immunoglobulin profile including IgG, IgA, IgM, and IgE  
• TBNK panel: CD4+ T cells, CD8+ T cells, B cells, NK cells (Quantitative Lymphocyte 
Subset Panel) 
A urine or serum pregnancy test for WOCBP will be performed before each dose by the local 
laboratories.   
Rapid tests for SARS-CoV-2 (COVID-19) will be performed locally during Screening and 
confirmed negative before each dose. 
Additional blood samples for PK, immunogenicity, and PD will be collected as outlined in 
Section 8.5, Section 8.6, and Section 8.7, respectively.  
Note that some parameters will not be reported to study sites during the study to maintain the 
double-blind nature of the study (Section 6.3.2). 
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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting  
10.3.1. 
Definition of AE  
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study patient, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the Investigator (i.e., not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the patient’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s 
condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
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10.3.2. 
Definition of SAE  
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term “life-threatening” in the definition refers to an event in which the patient was at risk 
of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the patient has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
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• 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE  
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the patient’s medical 
records to the Sponsor and/or CRO in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested 
by the Sponsor and/or CRO. In this case, all patient identifiers, except the patient 
number, will be redacted on the copies of the medical records before submission. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:  
• Mild: An event that is easily tolerated by the patient, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
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• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or 
causality of the AE or SAE as fully as possible. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
• If a patient dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor and/or CRO with a copy of any 
post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor and/or CRO within 
24 hours of receipt of the information. 
10.3.4. 
Reporting of SAEs  
SAE Reporting  
Within 24 hours of identifying an SAE, the Investigator must collect and report the SAE to the 
designated Pharmacovigilance contact. The SAE reporting must contain all information 
required for CIOMS reporting. It should contain a place to indicate whether this is an initial or 
follow-up report. 
Minimum information to be documented for the SAE: 
• Protocol number 
• Name and contact phone number of the Principal Investigator 
• Patient number and year of birth 
• SAE (preliminary diagnosis and SAE criterion), date of event onset, date of last study 
drug administration, brief narrative including current status of patient 
• Investigator causality assessment MUST be provided 
• Concomitant medication information and treatments provided, if applicable 
• Relevant laboratory/diagnostic test results and other relevant information 
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Follow-up information should be provided with the same form with the Follow-up indicated. 
After reporting the SAE to Pharmacovigilance, the CRF should be completed for the SAE. 
This should be updated as the SAE is updated. 
 
 
 
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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information  
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a 
menstrual cycle cannot be confirmed before first dose of study intervention, additional 
evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
• Premenarchal 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s review of the patient’s medical records, 
medical examination, or medical history interview. 
Postmenopausal Female 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause or has had a hysterectomy and/or oophorectomy (surgical menopause). 
A FSH level and LH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with more 
than one FSH measurement (>40 IU/L or mIU/mL) is required.  
Females on HRT and whose menopausal status is in doubt will be required to use one of the non-
estrogen hormonal highly effective contraception methods if they wish to continue their HRT 
during the study and undergo pregnancy testing. 
Contraception Guidance 
All WOBCP and men with partners who are WOBCP must commit to one of the following 
effective methods of birth control: 
• Combined (estrogen and progestogen containing) hormonal contraception (oral, 
intravaginal, transdermal, injectable) associated with the inhibition of ovulation, initiated 
at least 30 days prior to Study Day 1. 
• Progestogen-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation, initiated at least 1 month prior to Study Day 1. 
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• Bilateral tubal occlusion/ligation.  
• Vasectomized partner, provided the vasectomized partner has received medical 
confirmation of surgical success, and is the sole heterosexual partner of the WOCBP trial 
patient. 
• Intrauterine device (IUD). 
• Intrauterine hormone-releasing system (IUS). 
• Practice true abstinence (if acceptable per local requirements): Refraining from 
heterosexual intercourse. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods, and withdrawal) is not acceptable. 
If required by local practices, WOCBP must commit to using 2 methods of contraception.  
If during the course of the study a woman becomes surgically sterile or post-menopausal 
(defined above) and complete documentation is available, contraceptive measures as defined 
above are no longer required. 
It is important to note that the contraception requirements described above are specifically 
intended to prevent pregnancy during exposure to the investigational therapies. For concomitant 
immunosuppressive agent(s) (e.g., methotrexate, azathioprine, mycophenolate mofetil, 
mycophenolic acid, leflunomide, etc.) that have been prescribed per standard of care prior to 
study entry and are allowed to be continued during the study, contraception should continue 
while the patient is on the concomitant immunosuppressive agent(s). The duration of 
contraception after discontinuation of these immunosuppressive agent(s) should be based on the 
local product labelling. Urine or serum pregnancy testing shall be performed prior to dosing at 
monthly intervals per the SoA (Section 1.3). 
Additional local requirements may apply and should be followed accordingly. 
Collection of Pregnancy Information 
Male Patients with Partners Who Become Pregnant 
The Investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this study.  
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the Investigator will record pregnancy information on the appropriate form and submit it to the 
Sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will also be 
followed to determine the outcome of the pregnancy (until delivery of the fetus or termination of 
pregnancy). Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.  
Female Patients Who Become Pregnant 
The Investigator will collect pregnancy information on any female patient who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a patient's 
pregnancy.  
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The patient will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on the patient and the neonate and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE.  
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at >22 
weeks gestational age) is always considered to be an SAE and will be reported as such.  
Any post-study pregnancy related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study patients, he or she 
may learn of an SAE through spontaneous reporting. 
Any female patient who becomes pregnant while participating in the study will discontinue study 
treatment immediately but will be followed for all subsequent visits.  
 
 
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10.5. 
Appendix 5: Equivalence of Common Corticosteroid Formulations 
and Permitted Antimalarials  
 
Medication 
Maximum Daily Dose  
Prednisone 
10 mg 
Cortisone 
50 mg 
Hydrocortisone 
40 mg 
Prednisolone 
10 mg 
Methylprednisolone 
8 mg 
Triamcinolone 
8 mg 
Budesonide 
2 mg 
Dexamethasone 
1.5 mg 
Betamethasone 
1 to 2 mg 
 
Medication 
Maximum Daily Dose 
Hydroxychloroquine 
400 mg 
Chloroquine 
250 mg twice daily  
(but not to exceed 5 mg/kg per day) 
Quinacrine 
100 mg 
 
 
 
 
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10.6. 
Appendix 6: Clinical Endpoints and Disease Activity Instruments  
10.6.1. 
Composite Endpoints Used in this Study  
10.6.1.1. SLE Responder Index-4 (SRI-4)  
 
SRI-4 (incorporates data from SLEDAI, BILAG and ssPGA) 
 
At the visit being measured, compared to Screening there must be: 
 
A 4 Point drop in SLEDAI 
 
No 2 new B scores or 1 new A score on BILAG 
 
No increase in Physician’s Global Assessment of more than 3 points (10% of the scale) 
 
When used in an endpoint, the requirement for also not stopping study drug or increasing 
background treatments beyond protocol allowed limits is classically added on which is also the 
case in this trial.  
10.6.1.2. BILAG-based Combined Lupus Assessment (BICLA)  
 
BICLA (incorporates data from BILAG, hSLEDAI, and ssPGA) 
 
At the visit being measured, compared to Screening there must be: 
 
All A scores present at Baseline must drop to B, C or D and B scores to C or D 
 
No worsening in other BILAG organs or the SLEDAI score 
 
No increase in Physician’s Global Assessment of 3 or more points (10% of the scale) 
 
No use of off protocol medications or withdrawal from study drug 
10.6.2. 
Clinical Outcome Measures: Glossaries, Scoring Instructions and Forms  
Below, we include detailed CRFs, glossaries and scoring algorithms for the main disease scoring 
instrument to be used in this study. Each of these instruments has been described in 
Section 8.1.6, in terms of how they are useful, what some of their pitfalls are and how they are 
integrated into composite endpoints of SRI-4 and BICLA (primary and secondary endpoints) was 
also reviewed.  
 
 
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10.6.2.1. Form and Glossary for Hybrid SELENA-SLEDAI  
10.6.2.1.1. Form  
(Circle in SLEDAI score column if descriptor is present at the time of the visit or in the 
preceding 4 weeks.)    
Item 
no. 
SLEDAI 
score 
Descriptor 
Definition 
1 
8 
Seizure 
Recent onset, exclude metabolic, infectious or drug causes 
2 
8 
Psychosis 
Altered ability to function in normal activity due to severe 
disturbance in the perception of reality. Include hallucinations, 
incoherence, marked loose associations, impoverished thought 
content, marked illogical thinking, bizarre, disorganised, or 
catatonic behaviour. Exclude uraemia and drug causes 
3 
8 
Organic brain 
syndrome 
Altered mental function with impaired orientation, memory, or 
other intellectual function, with rapid onset and fluctuating 
clinical features, inability to sustain attention to environment, 
plus at least 2 of the following: perceptual disturbance, 
incoherent speech, insomnia or daytime drowsiness, or 
increased or decreased psychomotor activity. Exclude 
metabolic, infectious or drug causes 
4 
8 
Visual 
disturbance 
Retinal changes of SLE. Include cytoid bodies, retinal 
hemorrhages, serous exudates or hemorrhages in the choroid, or 
optic neuritis, scleritis or episcleritis. Exclude hypertension, 
infection, or drug causes 
5 
8 
Cranial nerve 
disorder 
New onset of sensory or motor neuropathy involving cranial 
nerves 
6 
8 
Lupus 
headache 
Severe, persistent headache; may be migrainous, but must be 
non-responsive to narcotic analgesia. THIS WOULD RARELY 
BE ATTRIBUTED TO SLE ALMOST NEVER SCORED 
7 
8 
CVA 
New onset Cerebrovascular accident(s). Exclude 
arteriosclerosis 
8 
8 
Vasculitis 
Ulceration, gangrene, tender finger nodules, periungual 
infarction, splinter hemorrhages or biopsy or angiogram proof 
of vasculitis 
9 
4 
Arthritis 
> 2 joints with pain and signs of inflammation (i.e. tenderness 
with swelling or effusion) 
10 
4 
Myositis 
Proximal muscle aching/weakness, associated with elevated 
creatinine phosphokinase (CK)/aldolase, or EMG changes or a 
biopsy showing myositis 
11 
4 
Urinary casts 
Heme-granular or RBC casts 
12 
4 
Hematuria 
> 5 RBC/high power field. Exclude stone, infection or other 
cause 
13 
4 
Proteinuria 
> 0.5 gram/24 hours 
14 
4 
Pyuria 
> 5 WBC/high power field. Exclude infection 
15 
2 
Rash 
Inflammatory type rash 
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Item 
no. 
SLEDAI 
score 
Descriptor 
Definition 
16 
2 
Alopecia 
Abnormal, patchy or diffuse loss of hair 
17 
2 
Mucosal ulcers 
Oral or nasal ulcerations 
18 
2 
Pleurisy 
Pleuritic chest pain or pleural rub or effusion, or pleural 
thickening (does not require an objective component if 
medically convincing) 
19 
2 
Pericarditis 
Classic pericardial pain and/or rub, effusion or ECG or 
echocardiogram confirmation (does not require an objective 
component if medically convincing) 
20 
2 
Low 
complement 
Decrease in CH50, C3 or C4 below lower limit of normal  
21 
2 
Increased DNA 
binding 
Increased DNA binding above normal range for testing 
laboratory 
22 
1 
Fever 
> 38ºC. Exclude infectious cause 
23 
1 
Thrombocytop
enia 
< 100 × 109 platelets/L, exclude drug causes 
24 
1 
Leukopenia 
< 3 × 109 WBC/L, exclude drug causes 
Total Score: __________________ 
 
10.6.2.1.2. Hybrid SELENA-SLEDAI Glossary  
GUIDELINES FOR USE OF HYBRID SELENA-SLEDAI MODIFIED FOR ASSESSMENT 
OVER 28 DAYS TO ASSESS DISEASE ACTIVITY  
The hSLEDAI includes the definitions of proteinuria used in the SLEDAI 2K and is otherwise 
identical to the hSLEDAI.  
• 
The main principle to keep in mind is that this instrument is intended to evaluate current 
lupus activity and not chronic damage, severity is accounted for in part by the 
"weightedness" of the scale.  
• 
Points are given exactly as defined. 
• 
A descriptor is either scored the exact points allotted or not scored, i.e. given a zero. 
Descriptors are scored only if they are present at the time of the physician encounter or in 
the preceding 28 days. Windows acceptable in a clinical trial are acceptable in scoring the 
SLEDAI. However, it is never acceptable to fill in gaps which cover activity over 2-3 
months or more. The reason for this is that disease activity at the visit might have 
changed several times in such intervals and the recording of distant activity becomes 
meaningless.  
Please note that in the original SLEDAI the disease activity being scored was meant to 
cover only a ten day period, the modification to 28 days is a more useful assessment for 
use in clinical trials, in order to capture disease activity between monthly visits. 
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• 
The descriptor must be documented by the notes written in the physician encounter form 
and generally applies to the clinical data and not to the laboratory data. The laboratory 
data is strictly defined as per cutoffs and documentation is provided by the reports from 
the commercial laboratory.  
• 
Descriptors do not have to be new but can be. They can be ongoing, recurrent, or initial 
events. Each would be scored the same way. An example would be a malar rash or 
mucosal ulcer. In these situations a malar rash observed at the initial visit but which 
remains unchanged for the next six months, irrespective of any treatment, is scored 2 
points each time the SLEDAI is completed. Since the nature of lupus is that 
manifestations are not usually fleeting it would be rare for descriptors to be present 10 
days before and not at the time of the encounter. This is discussed in more detail for each 
descriptor but is especially relevant for the neurologic, pulmonary, and cutaneous 
manifestations.  
• 
In some descriptors the exclusions written may not be exhaustive. The intent of the 
SLEDAI is that the descriptor be attributed to SLE. If the physician does not attribute the 
descriptor to SLE it should not be scored, but full documentation must be provided. 
Written in italics is the definition for each descriptor precisely provided in the SLEDAI SCORE  
SEIZURE 
Definition: Recent onset (last 28 days). Exclude metabolic, infectious or drug cause, or seizure 
due to past irreversible CNS damage. 
This descriptor is scored if the patient has had a witnessed seizure or convincing description 
(such as tongue biting or incontinence) within 30 days of the current encounter. The patient need 
not have a positive EEG, CT scan, PET scan, QEEG, or MRI. The CSF may be totally normal. 
A seizure is also not counted: 
1. If a metabolic cause is determined. 
2. In the presence of a proven infectious meningitis, brain abscess, or fungal foci. 
3. If there is a history of recent head trauma. 
4. In the presence of an offending drug. 
5. In the presence of severe hyperthermia or hypothermia. 
6. If the patient has stopped taking anticonvulsant medication. 
7. If the patient has a documented sub-therapeutic anticonvulsant drug level. 
PSYCHOSIS 
Definition: Altered ability to function in normal activity due to severe disturbance in the 
perception of reality. Include hallucinations, incoherence, marked loose associations, 
impoverished thought content, marked illogical thinking, bizarre, disorganized, or catatonic 
behavior. Exclude uremia and drug causes. 
This descriptor is scored if any of the criteria above are met. 
 
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With regard to drug causes the most problematic situation is glucocorticoids. If the treating 
physician attributes the psychosis to glucocorticoids this descriptor should not be counted. 
 
ORGANIC BRAIN SYNDROME  
Definition: Altered mental function with impaired orientation, memory or other intellectual 
function, with rapid onset and fluctuating clinical features. Include clouding of consciousness 
with reduced capacity to focus, and inability to sustain attention to environment, plus at least 
two of the following: perceptual disturbance, incoherent speech, insomnia, daytime drowsiness, 
or increased or decreased psychomotor activity. Exclude metabolic, infectious or drug causes. 
a. reduced capacity to focus as exemplified by new inability to perform everyday 
mathematical computations or disorientation to person, place, time, or purpose 
OR inability to carry on a conversation 
OR reduction in short term memory 
PLUS: Documented abnormality on neuropsychiatric testing  
 
Neuropsychiatric testing may take the form of a "mini-mental-status exam" or a formal 
neuropsychiatric examination. The important aspect for scoring OBS is that it be reversible. 
Consideration should be given to the improvement of OBS after institution of glucocorticoids. 
This descriptor is not scored in the presence of a metabolic, infectious, or drug cause. If the 
problem is chronic this descriptor is not scored in SLEDAI but is scored on the damage index.  
VISUAL DISTURBANCE 
Definition: Retinal and eye changes of SLE. Include cytoid bodies, retinal hemorrhages, serous 
exudate or hemorrhages in the choroid, optic neuritis, scleritis or episcleritis. Exclude 
hypertension, infection or drug causes. 
This is scored exactly as defined with the understanding that it must be supported by objective 
evidence. 
CRANIAL NERVE DISORDER 
Definition: New onset of sensory or motor neuropathy involving cranial nerves. Include vertigo 
due to lupus. 
This is scored exactly as defined and must be supported by objective evidence. However, it 
should be noted that hydroxychloroquine can affect the eighth cranial nerve. 
LUPUS HEADACHE  
Definition: Severe persistent headache: may be migrainous, but must be non-responsive to 
narcotic analgesia. 
For this descriptor to be counted, the headache must be present for greater than 24 hours and 
must not be responsive to narcotic analgesia. Objective documentation need not be present 
although it is expected that such a complaint, given the severity, would prompt formal testing 
such as MRI, CT, LP, etc. Furthermore, the headache should be of sufficient severity to warrant 
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the initiation of glucocorticoids or additional immunosuppressive agents. Scoring of this 
descriptor means attribution of the headache to CNS lupus. 
Most headaches, including most severe and/or migrainous headaches are not attributable to lupus 
and this descriptor should only be scored very rarely. 
CVA 
Definition: New onset of cerebrovascular accident (s). Exclude arteriosclerosis or hypertensive 
causes. 
This descriptor is scored if the patient has had a CVA within 28 days of the current encounter. A 
patient recovering from a CVA that was documented more than 28 days prior to the current 
encounter is not given points for this descriptor. A patient may have had a previous CVA but to 
be scored the current CVA must be new. 
This descriptor is scored in the presence or absence of anti-phospholipid antibodies, i.e., the 
precise pathophysiologic mechanism need not be known. 
The CVA is scored even in the presence of a normal CT or MRI. A TIA is also scored if the 
patient gives a convincing history. To exclude atherosclerosis the patient has to have a normal 
carotid and/or vertebral Doppler and cannot have uncontrolled hypertension. 
VASCULITIS 
Definition: Ulceration, gangrene, tender finger nodules, periungual infarction, splinter 
hemorrhages, or biopsy or angiogram proof of vasculitis. 
To score this descriptor the above definitions must be present. For example, erythematous 
lesions on the hands or feet which may be characteristically considered "leukocytoclastic 
vasculitis" but do not fulfill at least one of the above definitions and if not biopsied, are not 
counted.  
Similarly, livedo reticularis is not counted. Healed ulcers with residual scar are not to be counted, 
but be sure to count these in the damage index.  
A lesion consistent with erythema nodosum should be counted regardless of whether it is 
biopsied or not. Purpura in the presence of a normal platelet count should be counted regardless 
of whether it has been biopsied or not. 
ARTHRITIS  
Definition: More than two joints with pain and signs of inflammation, i.e., tenderness, swelling, 
or effusion.  
Arthritis is scored if it is ongoing; it need not be new or recurrent. 
Arthritis is scored only if more than two joints manifest signs of inflammation. For example if 
only the right second and left third PIPs are involved or only both wrists, points for this 
descriptor are not given. 
Inflammation is strictly defined in this activity index as the presence of tenderness (the patient 
complains of pain on palpating the joint or upon going through range of motion) PLUS any one 
of the following: 
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1. swelling  
2. effusion 
3. warmth 
4. erythema, but must exclude overlying cellulitis 
The presence of tenderness alone is not sufficient. A patient's complaints of pain in specific 
joints without objective findings is not sufficient. An exception would be arthritis of the hip in 
which case pain in the groin on range of motion accompanied by decreased range of motion in 
the absence of swelling, warmth, or erythema would be counted. 
Inflammation of the tendons, ligaments, bursae, and other periarticular structures are not scored. 
For example, subacromial bursitis and trochanteric bursitis are not scored. If further evaluation 
reveals osteonecrosis or osteoarthritis, this descriptor is not counted.  
MYOSITIS 
Definition: Proximal muscle aching/weakness, associated with elevated creatine 
phosphokinase/aldolase or electromyogram changes or a biopsy showing myositis. 
The patient complains of muscle aching and/or weakness in the proximal muscles PLUS one of 
the following must be present: 
1. elevated serum creatine phosphokinase and/or aldolase 
2. abnormalities on electromyogram consistent with myositis 
3. biopsy-proven myositis 
URINARY CASTS 
Definition: Heme-granular or red blood cell casts. 
This is scored if red blood cell casts are seen, even if it is only one. Pigmented casts are counted 
but non-pigmented granular casts, hyaline or waxy casts are not counted. 
HEMATURIA 
Definition: >5 red blood cells/high power field. Exclude stone, infection or other cause. 
With regard to this descriptor, every attempt should be made to see patients when they are not 
menstruating. If this is not possible the urinalysis should be deferred until the next visit. 
This descriptor is not scored if there is documented renal calculi or infection. The latter must be 
confirmed by a positive urinary culture. However, it is acknowledged that associated conditions 
such as chlamydia or urethral irritation may result in mild hematuria and the physician's best 
judgment is warranted. The important point is attribution: there must be other evidence of 
nephritis and other causes of hematuria must be excluded.  
In the complete absence of proteinuria, attribution of hematuria to active nephritis would be very 
unlikely unless pathology is limited to the mesangium. 
PROTEINURIA 
Definition: proteinuria of more than 0.5 g/24 hours. 
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Must be attributed to active lupus nephritis. 
PYURIA 
Definition: >5 white blood cells/high power field. Exclude infection. 
This descriptor is not scored if there is evidence of vaginal contamination (presence of any 
squamous epithelial cells) or a documented infection. The latter must be confirmed by a positive 
urinary culture. However, it is acknowledged that associated conditions such as chlamydia, 
trichomonas or urethral irritation may result in mild pyuria and the physician's best judgment is 
warranted. The important point is attribution; there must be other evidence of nephritis, 
and other causes of pyuria should be excluded. In the complete absence of proteinuria, 
attribution of hematuria to active nephritis would be very unlikely  
RASH 
Definition: Ongoing inflammatory lupus rash. 
A rash is scored if it is ongoing, new or recurrent. Even if it is identical in terms of distribution 
and character to that observed on the last visit and the intensity is improved, it is counted. 
Therefore, despite improvement in a rash, if it is still ongoing it represents disease activity. The 
rash must be attributable to SLE. A description of the rash must appear in the physical exam and 
should include distribution, characteristics such as macular or papular, and size.  
The following should not be scored: 
1. Chronic scarred discoid plaques in any location. 
2. Transient malar flush, i.e., it is not raised and is evanescent 
A common problem one may encounter is the differentiation between scoring a lesion as "rash" 
and/or "vasculitis". If a lesion meets the descriptive criteria of the latter it should not also be 
counted as rash, i.e., the score would be 8 points not 10 points. If a separate rash characteristic of 
SLE is present only then would "rash" also be scored. 
ALOPECIA 
Definition: Ongoing abnormal, patchy or diffuse loss of hair due to active lupus. 
This should be scored if any of the following conditions are present: 
1. There is temporal thinning which is newly present for less than six months (if temporal 
alopecia is present for more than six months with no change it should not be counted)  
2. Areas of scalp with total bald spots if present for less than six months (does not need to 
have accompanying discoid lesion or follicular plugging) 
3. The presence of "lupus frizz" i.e., short of strands of unruly hair in the frontal or temporal 
area 
If a patient complains of hair loss and there is nothing apparent on exam this descriptor is not 
scored. 
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MUCOSAL ULCERS 
Definition: Ongoing oral or nasal ulcerations due to active lupus. 
An ulcer is scored if it is ongoing, it need not be new or recurrent. Ulcers can be present in either 
the nose or oral cavity. Erythema alone without frank ulceration is not sufficient to be scored, 
even if the erythema is present on the upper palate. Ulcers on the buccal mucosa and tongue are 
counted. 
Mucosal ulcers are not counted as vasculitis. 
PLEURISY 
Definition: Classic and severe pleuritic chest pain or pleural rub or effusion or new pleural 
thickening due to lupus. 
This descriptor is scored if the patient complains of pleuritic chest pain lasting greater than 12 
hours. The pain should be classic, i.e., exacerbated by inspiration, to help distinguish it from 
musculoskeletal conditions such as costochondritis, which could be confused with pleurisy. 
  
The symptom does not have to be accompanied by any objective findings. The presence of 
objective findings such as pleural rub or pleural effusions (in the absence of infection, congestive 
heart failure, malignancy, or nephrosis) is counted, even if not accompanied by symptoms. New 
pleural thickening should be counted only if other causes as described above are absent. 
PERICARDITIS 
Definition: Classic and severe pericardial pain or rub or effusion, or electrocardiogram 
confirmation. 
The symptom does not have to be accompanied by objective findings.  
LOW COMPLEMENT 
Definition: Decrease in CH50, C3 or C4 below the lower limit of normal for testing laboratory. 
Exclude a low C4 or CH50 in patients with known inherited deficiency of C4. 
INCREASED DNA BINDING 
Definition: >25% binding by Farr assay or above normal range for testing laboratory. 
FEVER 
Definition: >38°C. Exclude infectious cause. 
This would be scored if one of the following conditions are present: 
1. A documented temperature elevation >100.4°F or >38°C at the time of the visit. 
2. A convincing history from the patient that she/he has been febrile within the preceding 10 
days prior to the visit without any signs or symptoms suggestive of infection. Febrile is 
defined as above and not simply that the patient felt feverish. In this case the patient need 
not be febrile at the time of the visit for a score of 2 to be given. 
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10.6.2.4. Form, Glossary and Scoring Rules for BILAG  
10.6.2.4.1. BILAG Form  
 
 
 
 
 
 Scoring:    ND    Not Done 
  
    1      Improving 
 
    2      Same 
 
    3      Worse 
 
    4      New 
 
   Yes/No OR Value   (where indicated) 
 
   ❑     indicate if  not due to SLE activity 
   (default is 0 = not present) 
 
CONSTITUTIONAL 
1. Pyrexia - documented > 37.5ºC 
   
    ( 
    ) 
2. Weight loss - unintentional > 5% 
 
    ( 
    ) 
3. Lymphadenopathy/splenomegaly 
 
    ( 
    ) 
4. Anorexia 
 
 
 
    ( 
    ) 
 
MUCOCUTANEOUS 
5. Skin eruption - severe 
 
 
    ( 
    ) 
6. Skin eruption - mild 
 
 
    ( 
    ) 
7. Angio-oedema - severe 
 
 
    ( 
    ) 
8. Angio-oedema - mild 
 
 
    ( 
    ) 
9. Mucosal ulceration - severe 
 
    ( 
    ) 
10. Mucosal ulceration - mild  
 
    ( 
    ) 
11. Panniculitis/Bullous lupus - severe  
    ( 
    ) 
12. Panniculitis/Bullous lupus - mild 
 
    ( 
    ) 
13. Major cutaneous vasculitis/thrombosis 
    ( 
    ) 
14. Digital infarcts or nodular vasculitis 
    ( 
    ) 
15. Alopecia - severe 
 
 
    ( 
    ) 
16. Alopecia - mild  
 
 
    ( 
    ) 
17. Peri-ungual erythema/chilblains 
 
    ( 
    ) 
18. Splinter haemorrhages 
 
 
    ( 
    ) 
 
NEUROPSYCHIATRIC 
19. Aseptic meningitis 
 
 
    ( 
    ) 
20. Cerebral vasculitis 
 
 
    ( 
    ) 
21. Demyelinating syndrome  
 
    ( 
    ) 
22. Myelopathy 
 
 
 
    ( 
    ) 
23. Acute confusional state 
 
 
    ( 
    ) 
24. Psychosis 
 
 
 
    ( 
    ) 
25. Acute inflammatory demyelinating  
    ( 
    ) 
       polyradiculoneuropathy 
26. Mononeuropathy (single/multiplex)  
    ( 
    ) 
27. Cranial neuropathy 
 
 
    ( 
    ) 
28. Plexopathy 
 
 
 
    ( 
    ) 
29. Polyneuropathy  
 
 
    ( 
    ) 
30. Seizure disorder 
 
 
    ( 
    ) 
31. Status epilepticus 
 
 
    ( 
    ) 
32. Cerebrovascular disease (not due to vasculitis)    ( 
    )  
33. Cognitive dysfunction 
 
 
    ( 
    ) 
34. Movement disorder 
 
 
    ( 
    ) 
35. Autonomic disorder 
 
 
    ( 
    ) 
36. Cerebellar ataxia (isolated) 
 
    ( 
    ) 
37. Lupus headache - severe unremitting  
    ( 
    ) 
38. Headache from IC hypertension 
 
    ( 
    ) 
 
MUSCULOSKELETAL 
39. Myositis - severe 
 
 
    ( 
    ) 
40. Myositis - mild  
 
 
    ( 
    ) 
41. Arthritis ( severe) 
 
 
    ( 
    ) 
42. Arthritis (moderate)/Tendonitis/Tenosynovitis    ( 
    ) 
43. Arthritis (mild)/Arthralgia/Myalgia  
    ( 
    ) 
 
 
 
 
 
 
 
 
 
CARDIORESPIRATORY 
44. Myocarditis - mild 
 
 
( 
) 
45. Myocarditis/Endocarditis + Cardiac failure 
( 
) 
46. Arrhythmia 
 
 
 
( 
) 
47. New valvular dysfunction  
 
( 
) 
48. Pleurisy/Pericarditis 
 
 
( 
) 
49. Cardiac tamponade 
 
 
( 
) 
50. Pleural effusion with dyspnoea 
 
( 
) 
51. Pulmonary haemorrhage/vasculitis  
( 
) 
52. Interstitial alveolitis/pneumonitis 
 
( 
) 
53. Shrinking lung syndrome  
 
( 
) 
54. Aortitis 
 
 
 
( 
) 
55. Coronary vasculitis 
 
 
( 
) 
 
GASTROINTESTINAL 
56. Lupus peritonitis 
 
 
( 
) 
57. Abdominal serositis or ascites 
 
( 
) 
58. Lupus enteritis/colitis 
 
 
( 
) 
59. Malabsorption  
 
 
( 
) 
60. Protein losing enteropathy 
 
( 
) 
61. Intestinal pseudo-obstruction 
 
( 
) 
62. Lupus hepatitis  
 
 
( 
) 
63. Acute lupus cholecystitis  
 
( 
) 
64. Acute lupus pancreatitis  
 
( 
) 
 
OPHTHALMIC 
65. Orbital inflammation/myositis/proptosis 
( 
) 
66. Keratitis - severe 
 
 
( 
) 
67. Keratitis - mild  
 
 
( 
) 
68. Anterior uveitis  
 
 
( 
) 
69. Posterior uveitis/retinal vasculitis - severe 
( 
) 
70. Posterior uveitis/retinal vasculitis - mild 
( 
) 
71. Episcleritis 
 
 
 
( 
) 
72. Scleritis - severe 
 
 
( 
) 
73. Scleritis - mild  
 
 
( 
) 
74. Retinal/choroidal vaso-occlusive disease 
( 
) 
75. Isolated cotton-wool spots (cytoid bodies) 
( 
) 
76. Optic neuritis  
 
 
( 
) 
77. Anterior ischaemic optic neuropathy 
( 
) 
 
RENAL  
78. Systolic blood pressure (mm Hg) 
  value 
( 
)  ❑ 
79. Diastolic blood pressure (mm Hg)   value 
( 
)  ❑ 
80. Accelerated hypertension                   Yes/No ( 
)   
81. Urine dipstick protein    (+=1, ++=2, +++=3) ( 
)  ❑ 
82. Urine albumin-creatinine ratio         mg/mmol ( 
)  ❑ 
83. Urine protein-creatinine ratio           mg/mmol ( 
)  ❑ 
84. 24 hour urine protein (g)  
  value 
( 
)  ❑ 
85. Nephrotic syndrome  
 
  Yes/No ( 
)   
86. Creatinine (plasma/serum) 
  mol/l ( 
)  ❑ 
87. GFR (calculated)                     ml/min/1.73 m2 ( 
)  ❑ 
88. Active urinary sediment                     Yes/No ( 
)   
89. Active nephritis  
 
  Yes/No ( 
)   
 
HAEMATOLOGICAL 
90. Haemoglobin (g/dl) 
 
  value 
( 
)  ❑ 
91. Total white cell count (x 109/l) 
  value 
( 
)  ❑ 
92. Neutrophils (x 109/l) 
 
  value 
( 
)  ❑ 
93. Lymphocytes (x 109/l) 
 
  value 
( 
)  ❑ 
94. Platelets (x 109/l) 
 
  value 
( 
)  ❑ 
95. TTP  
 
 
   
( 
) 
96. Evidence of active haemolysis          Yes/No ( 
) 
97. Coombs’ test positive (isolated) 
 Yes/No ( 
) 
Only record items due to SLE Disease Activity & assessment refers to manifestations occurring in the last 4 
weeks (compared with the previous 4 weeks).                         TO BE USED WITH THE GLOSSARY  
Weight (kg): 
 
  Serum urea (mmol/l): 
African ancestry:  Yes/No      Serum albumin (g/l): 
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10.6.2.4.2. BILAG-2004 Index Glossary  
Instructions 
• 
Only record features that are attributable to SLE disease activity and not due to damage, 
infection, thrombosis (in absence of inflammatory process) or other conditions 
• 
Assessment refers to manifestations occurring in the last 4 weeks compared with the 
previous 4 weeks 
• 
Activity refers to disease process which is reversible while damage refers to permanent 
process/scarring (irreversible) 
• 
Damage due to SLE should be considered as a cause of features that are fixed/persistent 
(SLICC/ACR damage index uses persistence  6 months to define damage) 
• 
In some manifestations, it may be difficult to differentiate SLE from other conditions as 
there may not be any specific test and the decision would then lie with the physician’s 
judgement on the balance of probabilities 
• 
Ophthalmic manifestations usually need to be assessed by an ophthalmologist and these 
items would need to be recorded after receiving the response from the ophthalmologist 
• 
Guidance for scoring: 
(4) New 
o Manifestations are recorded as new when it is a new episode occurring in the last 
4 weeks (compared to the previous 4 weeks) that has not improved and this 
includes new episodes (recurrence) of old manifestations  
o New episode occurring in the last 4 weeks but also satisfying the criteria for 
improvement (below) would be classified as improving instead of new 
(3) Worse 
o This refers to manifestations that have deteriorated in the last 4 weeks compared 
to the previous 4 weeks 
(2) Same 
o This refers to manifestations that have been present for the last 4 weeks and the 
previous 4 weeks without significant improvement or deterioration (from the 
previous 4 weeks) 
o This also applies to manifestations that have improved over the last 4 weeks 
compared to the previous 4 weeks but do not meet the criteria for improvement 
(1) Improving 
o Definition of improvement:  
(a) The amount of improvement is sufficient for consideration of reduction in 
therapy and would not justify escalation in therapy 
AND 
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(b) Improvement must be present currently and for at least 2 weeks out of the last 
4 weeks 
OR 
Manifestation that has completely resolved and remained absent over the whole of 
last 1 week 
(0) Not present 
(ND) NOT DONE 
o It is important to indicate if a test has not been performed (particularly laboratory 
investigations) so that this will be recorded as such in the database & not as 
normal or absent (which is the default) 
❑ Indicate (Tick) if not due to SLE Activity 
o For descriptors that are based on measurements (in renal and haematology 
systems), it is important to indicate if these are not due to lupus disease activity 
(for consideration of scoring) as they are usually recorded routinely into a 
Database 
10.6.2.4.3. Change in Severity Category  
• 
There are several items in the index which have been divided into categories of mild and 
severe (depending on definition). It is essential to record mild and severe items 
appropriately if the manifestations fulfil both criteria during the last 4 weeks 
• 
If a mild item deteriorated to the extent that it fulfilled the definition of severe category 
(ie changed into severe category) within the last 4 weeks: 
Severe item scored as new (4)  
AND   
Mild item scored as worsening (3) 
• 
If a severe item improved (fulfilling the improvement criteria) to the extent that it no 
longer fulfilled the definition of severe category (i.e., changed into mild category) within 
the last 4 weeks: 
Severe item scored as not present (0) if criteria for severe category has not been met over 
last 4 weeks or as improving (1) if criteria for severe category has been met at some point 
over last 4 weeks 
AND   
  
Mild item scored as improving (1) if it is improving over last 4 weeks or as the same (2) 
if it has remained stable over last 4 weeks 
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Constitutional 
1. Pyrexia 
temperature > 37.5˚C documented 
2. Unintentional weight loss > 5% 
3. Lymphadenopathy 
lymph node more than 1 cm diameter 
exclude infection 
4. Anorexia 
Mucocutaneous 
5. Severe eruption 
• 
18% body surface area  
• 
any lupus rash except panniculitis, bullous lesion & angio-oedema  
• 
body surface area (BSA) is estimated using the rules of nines (used to assess extent of 
burns) as follows:  
o palm(excluding fingers) = 1% BSA  
o each lower limb = 18% BSA  
o each upper limb = 9% BSA  
o torso (front) = 18% BSA  
o torso (back) = 18% BSA  
o head = 9% BSA  
o genital (male) = 1% BSA 
6. Mild eruption 
• 
≤ 18% body surface area  
• 
any lupus rash except panniculitis, bullous lesion & angio-oedema  
• 
malar rash must have been observed by a physician and has to be present continuously 
(persistent) for at least 1 week to be considered significant (to be recorded) 
7. Severe angio-oedema 
• 
potentially life-threatening eg: stridor  
• 
angio-oedema is a variant form of urticaria which affects the subcutaneous, submucosal 
and deep dermal tissues 
8. Mild angio-oedema 
• 
not life threatening 
9. Severe mucosal ulceration 
• 
disabling (significantly interfering with oral intake), extensive & deep ulceration 
• 
must have been observed by a physician 
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10. Mild mucosal ulceration 
• 
localised &/or non-disabling ulceration 
11. Severe panniculitis or bullous lupus 
• 
any one:  
o > 9% body surface area  
o facial panniculitis  
o panniculitis that is beginning to ulcerate panniculitis that threatens integrity of 
subcutaneous tissue (beginning to cause surface depression) on > 9% body surface 
area 
• 
panniculitis presents as a palpable and tender subcutaneous induration/nodule 
• 
note that established surface depression and atrophy alone is likely to be due to damage 
12. Mild panniculitis or bullous lupus 
• 
≤ 9% body surface area does not fulfil any criteria for severe panniculitis (for 
panniculitis) 
13. Major cutaneous vasculitis/thrombosis 
• 
resulting in extensive gangrene or ulceration or skin infarction 
14. Digital infarct or nodular vasculitis 
• 
localised single or multiple infarct(s) over digit(s) or tender erythematous nodule(s) 
15. Severe alopecia 
• 
clinically detectable (diffuse or patchy) hair loss with scalp inflammation (redness over 
scalp) 
16. Mild alopecia 
• 
diffuse or patchy hair loss without scalp inflammation (clinically detectable or by history) 
17. Peri-ungual erythema or chilblains 
• 
chilblains are localised inflammatory lesions (may ulcerate) which are precipitated by 
exposure to cold 
18. Splinter haemorrhages 
Neuropsychiatric 
19. Aseptic meningitis 
• 
criteria (all):  
o acute/subacute onset  
o headache  
o fever  
o abnormal CSF (raised protein &/or  
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o lymphocyte predominance) but negative  
o cultures 
• 
preferably photophobia, neck stiffness and meningeal irritation should be present as well 
but are not essential for diagnosis  
• 
exclude CNS/meningeal infection, intracranial haemorrhage 
20. Cerebral vasculitis 
• 
should be present with features of vasculitis in another system  
• 
supportive imaging &/or biopsy findings 
21. Demyelinating syndrome 
• 
discrete white matter lesion with associated neurological deficit not recorded elsewhere  
• 
ideally there should have been at least one previously recorded event  
• 
supportive imaging required  
• 
exclude multiple sclerosis 
22. Myelopathy 
• 
acute onset of rapidly evolving paraparesis or quadriparesis and/or sensory level  
• 
exclude intramedullary and extramedullary space occupying lesion 
23. Acute confusional state 
• 
acute disturbance of consciousness or level of arousal with reduced ability to focus, 
maintain or Shift attention  
• 
includes hypo- and hyperaroused states and encompasses the spectrum from delirium to 
coma 
24. Psychosis 
• 
delusion or hallucinations 
• 
does not occur exclusively during course of a delirium  
• 
exclude drugs, substance abuse, primary psychotic disorder 
25. Acute inflammatory demyelinating polyradiculoneuropathy 
 
 
• 
criteria: 
o progressive polyradiculoneuropathy 
o loss of reflexes 
o symmetrical involvement 
o increased CSF protein without pleocytosis 
o supportive electrophysiology study 
26. Mononeuropathy (single/multiplex) 
 
 
• 
supportive electrophysiology study required 
27. Cranial neuropathy 
 
 
 
 
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• 
except optic neuropathy which is classified under ophthalmic system 
28. Plexopathy 
 
 
 
 
• 
disorder of brachial or lumbosacral plexus resulting in neurological deficit not 
corresponding to territory of single root or nerve 
• 
supportive electrophysiology study required 
29. Polyneuropathy 
 
 
 
 
• 
acute symmetrical distal sensory and/or motor deficit 
• 
supportive electrophysiology study required 
30. Seizure disorder 
 
• 
independent description of seizure by reliable witness 
31. Status epilepticus  
 
 
 
• 
a seizure or series of seizures lasting ≥ 30 minutes without full recovery to baseline 
32. Cerebrovascular disease (not due to vasculitis)  
 
 
• 
any one with supporting imaging: 
o stroke syndrome 
o transient ischaemic attack 
o intracranial haemorrhage 
• 
exclude hypoglycaemia, cerebral sinus thrombosis, vascular malformation, tumour, 
abscess 
• 
cerebral sinus thrombosis not included as definite thrombosis not considered part of lupus 
activity 
33. Cognitive dysfunction 
 
 
 
 
• 
significant deficits in any cognitive functions: 
o simple attention (ability to register & maintain information) 
o complex attention memory (ability to register, recall & recognise information eg 
learning, recall) 
o visual-spatial processing (ability to analyse, synthesise & manipulate visual-spatial 
information) 
o language (ability to comprehend, repeat & produce oral/written material eg verbal 
fluency, naming) 
o reasoning/problem solving (ability to reason & abstract) 
o psychomotor speed 
o executive functions (eg planning, organising, sequencing) 
• 
in absence of disturbance of consciousness or level of arousal 
• 
sufficiently severe to interfere with daily activities 
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• 
neuropsychological testing should be done or corroborating history from third party if 
possible  
• 
exclude substance abuse 
34. Movement disorder 
 
 
 
 
• 
exclude drugs 
35. Autonomic disorder 
 
 
 
 
• 
any one: 
o fall in blood pressure to standing > 30/15 mm Hg (systolic/diastolic) 
o increase in heart rate to standing ≥ 30 bpm 
o loss of heart rate variation with respiration (max – min < 15 bpm, 
expiration:inspiration ratio < 1.2, Valsalva ratio < 1.4) 
o loss of sweating over body and limbs (anhidrosis) by sweat test 
• 
exclude drugs and diabetes mellitus 
36. Cerebellar ataxia 
 
• 
cerebellar ataxia in isolation of other CNS features 
• 
usually subacute presentation 
37. Severe lupus headache (unremitting) 
 
• 
disabling headache unresponsive to narcotic analgesia & lasting ≥ 3 days 
• 
exclude intracranial space occupying lesion and CNS infection 
38. Headache from IC hypertension  
 
 
• 
exclude cerebral sinus thrombosis 
Musculoskeletal 
39. Severe myositis 
 
 
 
 
• 
significantly elevated serum muscle enzymes with significant muscle weakness 
• 
exclude endocrine causes and drug-induced myopathy 
• 
electromyography and muscle biopsy are used for diagnostic purpose and are not required 
to determine level of activity 
40. Mild myositis 
 
 
 
 
 
• 
significantly elevated serum muscle enzymes with myalgia but without significant muscle 
weakness 
• 
asymptomatic elevated serum muscle enzymes not included 
• 
exclude endocrine causes and drug-induced myopathy 
• 
electromyography and muscle biopsy are used for diagnostic purpose and are not required 
to determine level of activity 
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41. Severe arthritis 
 
 
 
 
• 
observed active synovitis ≥ 2 joints with marked loss of functional range of movements 
and significant impairment of activities of daily living, that has been present on several 
days (cumulatively) over the last 4 weeks 
42. Moderate arthritis or Tendonitis or Tenosynovitis 
• 
tendonitis/tenosynovitis or active synovitis ≥ 1 joint (observed or through history) with 
some loss of functional range of movements, that has been present on several days over 
the last 4 weeks 
43. Mild arthritis or Arthralgia or Myalgia 
 
• 
inflammatory type of pain (worse in the morning with stiffness, usually improves with 
activity & not brought on by activity) over joints/muscle  
• 
inflammatory arthritis which does not fulfil the above criteria for moderate or severe 
arthritis 
Cardiorespiratory 
44. Mild myocarditis  
 
 
 
• 
inflammation of myocardium with raised cardiac enzymes &/or ECG changes and 
without resulting cardiac failure, arrhythmia or valvular dysfunction 
45. Cardiac failure 
 
• 
cardiac failure due to myocarditis or non-infective inflammation of endocardium or 
cardiac valves (endocarditis) 
• 
cardiac failure due to myocarditis is defined by left ventricular ejection fraction ≤ 40% & 
pulmonary oedema or peripheral oedema 
• 
cardiac failure due to acute valvular regurgitation (from endocarditis) can be associated 
with normal left ventricular ejection fraction 
• 
diastolic heart failure is not included 
46. Arrhythmia 
 
• 
arrhythmia (except sinus tachycardia) due to myocarditis or non-infective inflammation 
of endocardium or cardiac valves (endocarditis) 
• 
confirmation by electrocardiogram required (history of palpitations alone inadequate) 
47. New valvular dysfunction 
 
• 
new cardiac valvular dysfunction due to myocarditis or non-infective inflammation of 
endocardium or cardiac valves (endocarditis) 
• 
supportive imaging required 
48. Pleurisy/Pericarditis 
 
• 
convincing history &/or physical findings that you would consider treating 
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• 
in absence of cardiac tamponade or pleural effusion with dyspnoea 
• 
do not score if you are unsure whether or not it is pleurisy/pericarditis 
49. Cardiac tamponade 
 
 
 
 
• 
supportive imaging required 
50. Pleural effusion with dyspnoea 
 
 
 
• 
supportive imaging required 
51. Pulmonary haemorrhage/vasculitis 
 
 
• 
inflammation of pulmonary vasculature with haemoptysis &/or dyspnoea &/or 
pulmonary hypertension 
• 
supportive imaging &/or histological diagnosis required 
52. Interstitial alveolitis/pneumonitis  
 
• 
radiological features of alveolar infiltration not due to infection or haemorrhage required 
for diagnosis 
• 
corrected gas transfer Kco reduced to < 70% normal or fall of > 20% if previously 
abnormal 
• 
on-going activity would be determined by clinical findings and lung function tests, and 
repeated imaging may be required in those with deterioration (clinically or lung function 
tests) or failure to respond to therapy 
53. Shrinking lung syndrome  
 
 
• 
acute reduction (> 20% if previous measurement available) in lung volumes (to < 70% 
predicted) in the presence of normal corrected gas transfer (Kco) & dysfunctional 
diaphragmatic movements 
54. Aortitis 
 
 
 
 
 
• 
inflammation of aorta (with or without dissection) with supportive imaging abnormalities  
• 
accompanied by > 10 mm Hg difference in BP between arms &/or claudication of 
extremities &/or vascular bruits 
• 
repeated imaging would be required to determine  
• 
on-going activity in those with clinical deterioration or failure to respond to therapy 
55. Coronary vasculitis 
 
 
 
 
• 
inflammation of coronary vessels with radiographic evidence of non-atheromatous 
narrowing, obstruction or aneurysmal changes 
Gastrointestinal 
56. Lupus peritonitis  
 
 
 
• 
serositis presenting as acute abdomen with rebound/guarding 
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57. Serositis 
 
 
 
 
 
• 
not presenting as acute abdomen 
58. Lupus enteritis or colitis 
 
• 
vasculitis or inflammation of small or large bowel with supportive imaging &/or biopsy 
findings 
59. Malabsorption 
 
 
 
 
• 
diarrhoea with abnormal D- xylose absorption test or increased faecal fat excretion after 
exclusion of coeliac’s disease (poor response to gluten-free diet) and gut vasculitis 
60. Protein-losing enteropathy 
 
 
 
• 
diarrhoea with hypoalbuminaemia or increased faecal excretion of iv radiolabeled 
albumin after exclusion of gut vasculitis and malabsorption 
61. Intestinal pseudo-obstruction 
 
 
 
• 
subacute intestinal obstruction due to intestinal hypomotility 
62. Lupus hepatitis 
 
 
 
 
• 
raised transaminases  
• 
absence of autoantibodies specific to autoimmune hepatitis (eg: anti-smooth muscle, anti-
liver cytosol 1) &/or biopsy appearance of chronic active hepatitis 
• 
hepatitis typically lobular with no piecemeal necrosis 
• 
exclude drug-induced and viral hepatitis 
63. Acute lupus cholecystitis  
 
 
• 
after exclusion of gallstones and infection 
64. Acute lupus pancreatitis  
 
 
• 
usually associated multisystem involvement 
Ophthalmic 
65. Orbital inflammation 
 
 
 
 
• 
orbital inflammation with myositis &/or extra-ocular muscle swelling &/or proptosis 
• 
supportive imaging required 
66. Severe keratitis  
 
 
 
 
• 
sight threatening 
• 
includes:  
o corneal melt 
o peripheral ulcerative keratitis 
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67. Mild keratitis 
 
 
 
 
 
• 
not sight threatening 
68. Anterior uveitis 
69. Severe posterior uveitis &/or retinal vasculitis 
 
 
 
• 
sight-threatening &/or retinal vasculitis not due to vaso-occlusive disease 
70. Mild posterior uveitis &/or retinal vasculitis 
 
 
• 
not sight-threatening 
• 
not due to vaso-occlusive disease 
71. Episcleritis 
72. Severe scleritis 
 
 
 
 
• 
necrotising anterior scleritis 
• 
anterior &/or posterior scleritis requiring systemic steroids/immunosuppression &/or not 
responding to NSAIDs 
73. Mild scleritis 
 
• 
anterior &/or posterior scleritis not requiring systemic steroids 
• 
excludes necrotising anterior scleritis 
74. Retinal/choroidal vaso-occlusive disease  
 
 
• 
includes:  
o retinal arterial & venous occlusion 
o serous retinal &/or retinal pigment  
o epithelial detachments secondary to choroidal vasculopathy 
75. Isolated cotton-wool spots 
 
 
 
• 
also known as cytoid bodies  
 
76. Optic neuritis 
 
 
 
 
 
• 
excludes anterior ischaemic optic neuropathy 
77. Anterior ischaemic optic neuropathy 
 
• 
visual loss with pale swollen optic disc due to occlusion of posterior ciliary arteries 
Renal 
78. Systolic blood pressure 
79. Diastolic blood pressure 
80. Accelerated hypertension  
 
 
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• 
blood pressure rising to > 170/110 mm Hg within 1 month with grade 3 or 4 Keith-
Wagener-Barker retinal changes (flame-shaped haemorrhages or cotton-wool spots or 
papilloedema) 
81. Urine dipstick 
82. Urine albumin-creatinine ratio 
 
 
 
• 
on freshly voided urine sample 
• 
conversion: 1 mg/mg = 113 mg/mmol it is important to exclude other causes (especially 
infection) when proteinuria is present 
83. Urine protein-creatinine ratio 
 
 
 
• 
on freshly voided urine sample 
• 
conversion: 1 mg/mg = 113 mg/mmol 
• 
it is important to exclude other causes (especially infection) when proteinuria is present 
84. 24-hour urine protein 
 
 
 
 
• 
it is important to exclude other causes (especially infection) when proteinuria is present 
85. Nephrotic syndrome 
 
 
 
 
• 
criteria: 
o heavy proteinuria (  3.5 g/day or protein- creatinine ratio  350 mg/mmol or 
albumin-creatinine ratio  350 mg/mmol) 
o hypo-albuminaemia  
o oedema 
86. Plasma/Serum creatinine  
 
 
• 
exclude other causes for increase in creatinine (especially drugs) 
87. Glomerular Filtration Rate (GFR)  
 
 
 
 
 
• 
Modification of Diet in Renal Disease (MDRD) formula: 
GFR = 170 × [serum creatinine (mg/dl)]-0.999 × [age]-0.176 × [serum urea (mg/dl]-0.17 × 
[serum albumin (g/dl)]0.318 × [0.762 if female] × [1.180 if African ancestry] 
units = ml/min per 1.73 m2 
normal: male = 130 ± 40 
female = 120 ± 40 
conversion: 
serum creatinine - mg/dl = (mol/l)/88.5 
serum urea - mg/dl = (mmol/l) × 2.8 
serum albumin - g/dl = (g/l)/10 
• 
creatinine clearance not recommended as it is not reliable 
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• 
exclude other causes for decrease in GFR (especially drugs) 
88. Active urinary sediment  
 
 
• 
pyuria (> 5 WCC/hpf or > 10 WCC/mm3 (l))  
OR 
• 
haematuria (> 5 RBC/hpf or > 10 RBC/mm3 (l)) 
OR 
• 
red cell casts  
OR 
• 
white cell casts 
• 
exclude other causes (especially infection, vaginal bleed, calculi) 
89. Histology of active nephritis 
 
• 
WHO Classification (1995): (any one)  
o Class III – (a) or (b) subtypes 
o Class IV – (a), (b) or (c) subtypes 
o Class V – (a), (b), (c) or (d) subtypes 
o Vasculitis 
OR 
• 
ISN/RPS Classification (2003): (any one) 
o Class III – (A) or (A/C) subtypes 
o Class IV – (A) or (A/C) subtypes 
o Class V 
o Vasculitis 
• 
within last 3 months 
• 
glomerular sclerosis without inflammation not included 
Haematological 
90. Haemoglobin 
 
 
 
 
 
• 
exclude dietary deficiency & GI blood loss 
91. White cell count  
 
 
 
• 
exclude drug-induced cause 
92. Neutrophil count  
 
 
 
• 
exclude drug-induced cause 
93. Lymphocyte count 
94. Platelet count 
 
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• 
exclude drug-induced cause 
95. TTP 
 
 
• 
thrombotic thrombocytopaenic purpura 
• 
clinical syndrome of micro-angiopathic haemolytic anaemia and thrombocytopenia in 
absence of any other identifiable cause 
96. Evidence of active haemolysis 
 
• 
positive Coomb’s test & evidence of haemolysis (raised bilirubin or raised reticulocyte 
count or reduced haptoglobulins) 
97. Isolated positive Coomb’s test 
Additional Items 
These items are required mainly for calculation of GFR  
i. Weight  
ii. African ancestry  
iii. Serum urea  
iv. Serum albumin  
 
10.6.2.4.4. BILAG-2004 Index Scoring Rules  
Scoring based on the principle of physician’s intention to treat. 
Category 
Definition 
A 
Severe disease activity requiring any of the following treatment: 
1. systemic high dose oral glucocorticoids (equivalent to prednisolone > 20 mg/day) 
2. intravenous pulse glucocorticoids (equivalent to pulse methylprednisolone ≥ 500 mg) 
3. systemic immunomodulators (include biologicals, immunoglobulins and plasmapheresis) 
4. therapeutic high dose anticoagulation in the presence of high dose steroids or immunomodulators 
eg: warfarin with target INR 3-4 
B 
 
Moderate disease activity requiring any of the following treatment: 
1. systemic low dose oral glucocorticoids (equivalent to prednisolone ≤ 20 mg/day) 
2. intramuscular or intra-articular or soft tissue glucocorticoids injection (equivalent to 
methylprednisolone < 500mg) 
3. topical glucocorticoids 
4. topical immunomodulators 
5. antimalarials or thalidomide or prasterone or acitretin 
6. symptomatic therapy eg: NSAIDs for inflammatory arthritis 
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Category 
Definition 
C 
Mild disease 
D 
Inactive disease but previously affected 
E 
System never involved 
 
Constitutional 
Category A 
Pyrexia recorded as 2 (same), 3 (worse) or 4 (new) AND  
Any 2 or more of the following recorded as 2 (same), 3 (worse) or 4 (new): 
Weight loss 
Lymphadenopathy/splenomegaly 
Anorexia 
 
Category B 
Pyrexia recorded as 2 (same), 3 (worse) or 4 (new) OR  
Any 2 or more of the following recorded as 2 (same), 3 (worse) or 4 (new): 
Weight loss 
Lymphadenopathy/splenomegaly 
Anorexia 
BUT do not fulfil criteria for Category A 
 
Category C 
Pyrexia recorded as 1 (improving) OR 
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One or more of the following recorded as > 0:  
Weight loss 
Lymphadenopathy/Splenomegaly 
Anorexia 
BUT does not fulfil criteria for category A or B 
 
Category D 
Previous involvement 
 
Category E 
No previous involvement 
 
Mucocutaneous 
Category A 
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
Skin eruption - severe  
Angio-oedema - severe 
Mucosal ulceration - severe 
Panniculitis/Bullous lupus - severe 
Major cutaneous vasculitis/thrombosis 
 
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Category B 
Any Category A features recorded as 1 (improving) OR  
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
Skin eruption - mild 
Panniculitis/Bullous lupus - mild 
Digital infarcts or nodular vasculitis 
Alopecia – severe 
 
Category C 
Any Category B features recorded as 1 (improving) OR 
Any of the following recorded as > 0: 
Angio-oedema - mild 
Mucosal ulceration - mild 
Alopecia - mild 
Periungual erythema/chilblains 
Splinter haemorrhages 
 
Category D 
Previous involvement 
 
Category E 
No previous involvement 
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Neuropsychiatric 
Category A  
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
Aseptic meningitis 
Cerebral vasculitis 
Demyelinating syndrome 
Myelopathy 
Acute confusional state 
Psychosis 
Acute inflammatory demyelinating polyradiculoneuropathy 
Mononeuropathy (single/multiplex) 
Cranial neuropathy 
Plexopathy 
Polyneuropathy 
Status epilepticus 
Cerebellar ataxia 
 
Category B  
Any Category A features recorded as 1 (improving) OR Any of the following recorded as 2 
(same), 3 (worse) or 4 (new): 
Seizure disorder  
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Cerebrovascular disease (not due to vasculitis) 
Cognitive dysfunction 
Movement disorder 
Autonomic disorder  
Lupus headache - severe unremitting 
Headache due to raised intracranial hypertension 
 
Category C 
Any Category B features recorded as 1 (improving) 
 
Category D  
Previous involvement 
 
Category E  
No previous involvement 
 
Musculoskeletal 
Category A  
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
Severe Myositis 
Severe Arthritis 
 
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Category B  
Any Category A features recorded as 1 (improving) OR Any of the following recorded as 2 
(same), 3 (worse) or 4 (new): 
Mild Myositis 
Moderate Arthritis/Tendonitis/Tenosynovitis 
 
Category C  
Any Category B features recorded as 1 (improving) OR Any of the following recorded as > 0: 
Mild Arthritis/Arthralgia/Myalgia 
 
 
Category D 
Previous involvement 
 
Category E 
No previous involvement 
 
Cardiorespiratory 
Category A  
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
Myocarditis/Endocarditis + Cardiac failure 
Arrhythmia 
New valvular dysfunction 
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Cardiac tamponade 
Pleural effusion with dyspnoea 
Pulmonary haemorrhage/vasculitis 
 
Interstitial alveolitis/pneumonitis  
Shrinking lung syndrome 
Aortitis 
Coronary vasculitis 
 
Category B 
Any Category A features recorded as 1 (improving) OR Any of the following recorded as 2 
(same), 3 (worse) or 4 (new): 
Pleurisy/Pericarditis 
Myocarditis - mild 
 
Category C 
Any Category B features recorded as 1 (improving) 
 
Category D 
Previous involvement 
 
Category E 
No previous involvement 
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Gastrointestinal 
Category A  
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
Peritonitis 
Lupus enteritis/colitis 
Intestinal pseudo-obstruction  
Acute lupus cholecystitis 
Acute lupus pancreatitis 
 
Category B  
Any category a feature recorded as 1 (improving) or any of the following recorded as 2 same), 3 
(worse) or 4 (new): 
Abdominal serositis and/or ascites  
Malabsorption 
Protein losing enteropathy 
Lupus hepatitis 
 
Category C  
Any Category B features recorded as 1 (improving)  
 
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Category D  
Previous involvement 
 
Category E  
No previous involvement 
 
Ophthalmic 
Category A 
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
Orbital inflammation/myositis/proptosis 
Keratitis - severe 
Posterior uveitis/retinal vasculitis - severe 
Scleritis - severe 
Retinal/choroidal vaso-occlusive disease 
Optic neuritis 
Anterior ischaemic optic neuropathy  
 
Category B 
Any Category A features recorded as 1 (improving) OR  
Any of the following recorded as 2 (same), 3 (worse) or 4 (new): 
Keratitis - mild 
Anterior uveitis 
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Posterior uveitis/retinal vasculitis - mild 
Scleritis – mild 
 
Category C 
Any Category B features recorded as 1 (improving) OR Any of the following recorded as > 0: 
Episcleritis 
Isolated cotton-wool spots (cytoid bodies) 
 
Category D 
Previous involvement 
 
Category E 
No previous involvement 
RENAL 
Category A  
Two or more of the following providing 1, 4 or 5 is included: 
1. Deteriorating proteinuria (severe) defined as  
 (a) urine dipstick increased by ≥ 2 levels (used only if other methods of urine protein estimation 
not available); or  
 (b) 24 24-hour urine protein > 1 g that has not decreased (improved) by  25%; or 
 (c) urine protein-creatinine ratio > 100 mg/mmol not decreased (improved) by  25%; or 
 (d) urine albumin-creatinine ratio > 100 mg/mmol not decreased (improved) by  25% 
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2. Accelerated hypertension  
3. Deteriorating renal function (severe) defined as  
 (a) plasma creatinine > 130 mol/l and having risen to > 130% of previous value; or  
 (b) GFR < 80 ml/min per 1.73 m2 and having fallen to < 67% of previous value; or  
 (c) GFR < 50 ml/min per 1.73 m2, and last time was > 50 ml/min per 1.73 m2 or not done 
4. Active urinary sediment 
5. Histological evidence of active nephritis within last 3 months  
6. Nephrotic syndrome 
 
Category B 
One of the following: 
1. One of the Category A features 
2. Proteinuria (that has not fulfilled Category A criteria) 
 (a) urine dipstick which has risen by 1 level to at least 2+ (used only if other methods of urine 
protein estimation not available); or 
 (b) 24-hour urine protein ≥ 0.5 g that has not decreased (improved) by  25%; or 
 (c) urine protein-creatinine ratio ≥ 50 mg/mmol not decreased (improved) by  25%; or 
 (d) urine albumin-creatinine ratio ≥ 50 mg/mmol not decreased (improved) by  25% 
3. Plasma creatinine > 130 mol/l and having risen to ≥ 115% but ≤ 130% of previous value 
 
Category C 
One of the following: 
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1. Mild/Stable proteinuria defined as  
 
 (a) urine dipstick ≥ 1+ but has not fulfilled criteria for Category A & B (used only if other 
methods of urine protein estimation not available); or 
 (b) 24-hour urine protein > 0.25 g but has not fulfilled criteria for Category A & B; or 
 (c) urine prot-creat ratio > 25 mg/mmol but has not fulfilled criteria for Category A & B; or  
 (d) urine albumin-creatinine ratio > 25 mg/mmol not fulfilled criteria for Category A & B 
2. Rising blood pressure (providing the recorded values are > 140/90 mm Hg) which has not 
fulfilled criteria for Category A & B, defined as  
 (a) systolic rise of ≥ 30 mm Hg; and (b) diastolic rise of ≥ 15mm Hg  
 
Category D 
Previous involvement 
 
Category E 
No previous involvement 
 
HAEMATOLOGICAL  
Category A 
TTP recorded as 2 (same), 3 (worse) or 4 (new) OR Any of the following:  
 
 
Haemoglobin < 8 g/dl 
 
White cell count < 1.0 × 109/l 
 
Neutrophil count < 0.5 × 109/l 
 
 
Platelet count < 25 × 109/l 
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Category B  
TTP recorded as 1 (improving) OR Any of the following:  
 
Haemoglobin 8-8.9 g/dl 
 
White cell count 1-1.9 × 109/l 
 
Neutrophil count 0.5-0.9 × 109/l 
 
Platelet count 25-49 × 109/l 
 
Evidence of active haemolysis 
 
Category C 
Any of the following: 
 
Haemoglobin 9-10.9 g/dl  
 
White cell count 2-3.9 × 109/l 
 
Neutrophil count 1-1.9 × 109/l 
 
Lymphocyte count < 1.0 × 109/L 
 
Platelet count 50-149 × 109/l 
 
Isolated Coombs’ test positive  
 
Category D  
Previous involvement  
Category E 
No Previous involvement respectively 
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10.6.2.6. Cutaneous Lupus Erythematosus Diseases Area and Severity Index (CLASI) 
Form with Descriptors  
 
 
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10.6.2.7. Tender and Swollen Joint Count Form  
 
 
 
 
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10.7. 
Patient-Reported Outcomes  
10.7.1. 
Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36)  
This survey asks for your views about your health. This information will help keep track of how 
you feel and how well you are able to do your usual activities. Thank you for completing this 
survey! For each of the following questions, please circle the number that best describes your 
answer. 
1. In general, would you say your health is: 
 
Excellent 
1 
Very good 
2 
Good 
3 
Fair 
4 
Poor 
5 
2. Compared to one year ago, 
Much better now than one year ago 
1 
Somewhat better now than one year ago 
2 
About the same 
3 
Somewhat worse now than one year ago 
4 
Much worse now than one year ago 
5 
 
(Circle One Number on Each Line) 
2. The following items are about activities you might do 
during a typical day. Does your health now limit you in 
these activities? If so, how much? 
Yes, 
Limited a 
Lot (1) 
Yes, 
Limited a 
Little (2) 
No, Not 
Limited at 
All (3) 
a. Vigorous activities, such as running, lifting heavy 
objects, participating in strenuous sports 
1 
2 
3 
b. Moderate activities, such as moving a table, 
pushing a vacuum cleaner, bowling, or playing golf 
1 
2 
3 
c. Lifting or carrying groceries 
1 
2 
3 
d. Climbing several flights of stairs 
1 
2 
3 
e. Climbing one flight of stairs 
1 
2 
3 
f. Bending, kneeling, or stooping 
1 
2 
3 
g. Walking more than a mile 
1 
2 
3 
h. Walking several blocks 
1 
2 
3 
i. Walking one block 
1 
2 
3 
j. Bathing or dressing yourself 
1 
2 
3 
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(Circle One Number on Each Line) 
3. During the past 4 weeks, have you had any of the following problems with 
your work or other regular daily activities as a result of your physical health? 
Yes 
(1) 
No 
(2) 
a. Cut down the amount of time you spent on work or other activities 
1 
2 
b. Accomplished less than you would like 
1 
2 
c. Were limited in the kind of work or other activities 
1 
2 
d. Had difficulty performing the work or other activities (for example, it 
took extra effort) 
1 
2 
 
(Circle One Number on Each Line) 
4. During the past 4 weeks, have you had any of the following problems with 
your work or other regular daily activities as a result of any emotional problems 
(such as feeling depressed or anxious)? 
Yes 
No 
a. Cut down the amount of time you spent on work or other activities 
1 
2 
b. Accomplished less than you would like 
1 
2 
c. Didn't do work or other activities as carefully as usual 
1 
2 
 
5. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups? 
Not at all 
1 
Slightly 
2 
Moderately 
3 
Quite a bit 
4 
Extremely 
5 
 
6. How much bodily pain have you had during the past 4 weeks? 
None 
1 
Very mild 
2 
Mild 
3 
Moderate 
4 
Severe 
5 
Very severe 
6 
 
 
 
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7. During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
Not at all 
1 
A little bit 
2 
Moderately 
3 
Quite a bit 
4 
Extremely 
5 
 
These questions are about how you feel and how things have been with you during the past 4 
weeks. For each question, please give the one answer that comes closest to the way you have 
been feeling. (Circle One Number on Each Line) 
 
8. How much of the time during 
the past 4 weeks 
All of 
the 
Time 
Most 
of the 
Time 
A Good 
Bit of the 
Time 
Some 
of the 
Time 
A 
Little 
of the 
Ti
None 
of the 
Time 
a. Did you feel full of pep? 
1 
2 
3 
4 
5 
6 
b. Have you been a very 
nervous person? 
1 
2 
3 
4 
5 
6 
c. Have you felt so down in the 
dumps that nothing could 
cheer you up? 
1 
2 
3 
4 
5 
6 
d. Have you felt calm and 
peaceful? 
1 
2 
3 
4 
5 
6 
e. Did you have a lot of 
energy? 
1 
2 
3 
4 
5 
6 
f. Have you felt 
downhearted and blue? 
1 
2 
3 
4 
5 
6 
g. Did you feel worn out? 
1 
2 
3 
4 
5 
6 
h. Have you been a happy 
person? 
1 
2 
3 
4 
5 
6 
i. Did you feel tired? 
1 
2 
3 
4 
5 
6 
 
 
 
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10.7.3. 
FACIT-Fatigue Scale  
 
 
 
 
 
 
 
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11. 
Abbreviations  
ACR 
American College of Rheumatology 
ADA 
anti-drug antibody(ies) 
AE 
adverse event 
AESI 
adverse event of special interest 
ALL 
all Screened analysis set 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibody 
anti-dsDNA 
anti-double-stranded deoxyribonucleic acid 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BCR 
B cell receptor 
BICLA 
BILAG-based Combined Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BLyS 
B lymphocyte stimulator 
BUN 
blood urea nitrogen  
CBC 
complete blood count 
CDC 
Centers for Disease Control and Prevention 
CGIC 
Clinician’s Global Impression of Change 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
clearance 
CLASI 
Cutaneous Lupus Erythematous Disease Area and Severity Index 
Cmax 
maximum serum concentration 
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CMH 
Cochran-Mantel-Haenszel 
CNS 
central nervous system 
CRF 
case report form 
CRO 
contract research organization 
Ctrough 
trough concentration 
CV% 
percent coefficient of variation 
DART® 
dual affinity re-targeting (protein) 
DMARD 
disease-modifying antirheumatic drug 
ECG 
electrocardiogram 
ENA 
extractable nuclear antigen antibody 
EOS 
end of study 
EULAR 
European League Against Rheumatism 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FACS 
fluorescence-activated cell sorting 
FAS 
Full Analysis Set 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
gCV% 
geometric percent coefficient of variation 
GFR 
glomerular filtration rate 
GLP 
Good Laboratory Practice 
GM 
geometric mean 
GPI 
glycoprotein 
HAV 
hepatitis A virus 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
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HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
HZV 
herpes zoster virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgA, IgG, IgM 
Immunoglobulin A, G, or M 
IM 
intramuscular 
IMG 
immunogenicity analysis set 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
IVIG 
intravenous immunoglobulin 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LFA 
Lupus Foundation of America 
LH 
luteinizing hormone 
LTBI 
latent tuberculosis infection 
MAD 
multiple ascending dose 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCID 
Minimally Clinically Important Difference 
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MCS 
Mental Component Score 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measurements 
MRT 
mean residence time 
mSFI 
modified SELENA-SLEDAI Flare Index 
NK 
natural killer 
NSAID 
nonsteroidal anti-inflammatory drug 
PCS 
Physical Component Score 
PD 
pharmacodynamic(s) 
PGIC 
Patient’s Global Impression of Change 
PGIS 
Patient’s Global Impression of Severity 
PK 
pharmacokinetic(s) 
PP 
per-protocol 
PRO 
patient-reported outcome 
PT 
prothrombin time 
QOL 
quality of life 
QTcF 
QT interval corrected for heart rate using Friderica’s cubed root 
formula 
RBC 
red blood cell 
RDW 
RBC distribution width 
RNP 
Ribonucleoproteins 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
standard deviation 
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SELENA 
Safety of Estrogens in Lupus Erythematosus National Assessment 
SF-36 
Short Form 36 
SFI 
SELENA-SLEDAI Flare Index 
SLE 
systemic lupus erythematosus 
SLEDAI 
Systemic Lupus Erythematosus Disease Activity Index 
Sm 
Smith protein 
SoA 
Schedule of Activities 
SRI-4 
Systemic Lupus Erythematosus Responder Index-4 
SSA or SSB 
Sjögren’s A or B 
ssPGA 
SELENA-SLEDAI Physician’s Global Assessment 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
half-life 
TB 
tuberculosis 
TBNK 
T cell, B cell, natural killer cell 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum serum concentration 
ULN 
upper limit of normal 
UPCR 
urine protein to creatinine ratio 
VAS 
visual analogue scale 
Vd 
volume of distribution 
Vss 
volume of distribution at steady state 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
 
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12. 
References  
Arriens C, Aberle T, Carthen F, et al. Lupus patient decisions about clinical trial participation: a 
qualitative evaluation of perceptions, facilitators and barriers. Lupus Sci Med. 
2020;15;7(1):e000360.  
Askanase AD, Daly RP, Okado M, et al. Development and content validity of the Lupus 
Foundation of America rapid evaluation of activity in lupus (LFA-REAL™): a patient-reported 
outcome measure for lupus disease activity. Health Qual Life Outcomes. 2019a Jun 7;17(1):99. 
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