Clinical trial NCT01946880
Conditions: Systemic Lupus Erythematosus SLE
Keywords: Systemic Lupus Erythematosus Mycophenolate Mofetil (MMF)
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2013-11-20; Completion date: 2019-07-03
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial seeks to describe the effect of withdrawal from mycophenolate mofetil (MMF) on risk of clinically significant disease reactivation in quiescent SLE patients who have been on long-term MMF therapy.

Detailed description:
Participants who have had inactive disease for at least 24 weeks will be enrolled. Half the subjects will continue on MMF and half the subjects will be tapered off their MMF within 12 weeks. All subjects will continue hydroxychloroquine and small doses of prednisone as needed. Subject visits to assess endpoints will occur every 4 weeks from Day 0 through Week 24 and then at Weeks 32, 40, 48, and 60.

Arms: arm 1: These subjects will taper off MMF per the protocol-specified schedule over 12 weeks and remain off MMF for the rest of their study participation (up to Week 60 or until the primary endpoint of disease reactivation is met, whichever comes first). arm 2: These subjects will continue MMF treatment (1000-3000 mg/day) for the rest of their study participation (up to Week 60).
Interventions: intervention 1: Mycophenolate Mofetil intervention 2: Hydroxychloroquine or Chloroquine intervention 3: Prednisone
Intervention descriptions: intervention 1: Subjects will enter the trial on 1000-3000 mg/day of MMF and will be randomized to remain on MMF treatment or to be tapered off MMF within 12 weeks. intervention 2: Subjects will be on concurrent anti-malarial agents (hydroxychloroquine or chloroquine). Hydroxychloroquine is approved by the FDA for the treatment of SLE. Hydroxychloroquine has been shown to help prevent flare in SLE, and to improve skin and musculoskeletal activity in particular.Even lupus nephritis outcomes appear improved on a background of hydroxychloroquine therapy intervention 3: Once the subject is randomized into the trial, the prednisone (or other corticosteroid) dose must be stable through Week 36 (24 weeks following protocol taper of MMF), in the absence of flares as described in Section 3.2 of the study protocol, Description of Primary Endpoint. Further taper of prednisone after that point is by the investigator's discretion based on the subject's clinical status.

Protocol documents:
Prot_001.pdf: 
 
 
 
C O N F I D E N T I A L 
 
 
 
Autoimmunity Centers of Excellence 
 
 
 
Protocol # ALE06 
 
 
An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of 
Mycophenolate Mofetil (MMF) in Patients with Stable, Quiescent Systemic 
Lupus Erythematosus (SLE) 
 
Short Title: Randomized MMF Withdrawal in SLE 
 
 
 
non-IND 
 
Version 2.0, 07 April 2015 
  
 
 
 
Sponsor:  
Division of Allergy, Immunology, and Transplantation (DAIT) 
 
National Institute of Allergy and Infectious Diseases (NIAID) 
 
National Institutes of Health (NIH) 
 
 
 
 
Confidentiality Statement 
The information contained within this document is not to be disclosed in any way without the prior permission of 
the Protocol Chair(s), or the Division of Allergy, Immunology and Transplantation; the National Institute of 
Allergy and Infectious Diseases; and the National Institutes of Health. 
 
 


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Protocol Chair: 
 
 
 
Tammy Utset, MD, MPH 
Associate Professor of Medicine 
University of Chicago 
5841 S. Maryland Ave, MC 0930 
Chicago, IL  60637 
Phone: 773-834-1584 
Fax: 
773-702-8702 
E-mail: tutset@medicine.bsd.uchicago.edu 
 
 
 
Protocol Co-Chair:  
 
 
 
Eliza Chakravarty, MD 
Associate Member 
Arthritis and Clinical Immunology 
Oklahoma Medical Research Foundation 
825 NE 13th Street 
Oklahoma City, OK 73104 
Phone: 405-271-6245 
Fax: 
405-271-2319 
E-mail: Eliza-Chakravarty@omrf.org  
 
 
 
Mechanistic Protocol Co-Chair: 
 
 
 
Judith A. James, MD, PhD 
Professor, Department of Medicine 
Chair, Arthritis and Clinical Immunology Program 
Oklahoma Medical Research Foundation 
825 N. E. 13th Street 
Oklahoma City, OK 73104 
Phone:  405-271-4987 
Fax:  
405-271-7063 
E-mail:  jamesj@omrf.org 
 
 
 
 
 
 


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DAIT, NIAID, NIH 
 
 
 
Medical Monitor: 
Ellen Goldmuntz, MD, PhD 
Division of Allergy, Immunology, and 
Transplantation 
National Institute of Allergy and Infectious 
Diseases 
National Institutes of Health 
5601 Fishers Lane, Room #7D50 
Rockville, MD  20852- 
Phone:  240-627-3502 
E-mail:  egoldmuntz@niaid.nih.gov 
Regulatory Officer: 
Maria-Concetta Veri, PhD 
Division of Allergy, Immunology, and 
Transplantation  
National Institute of Allergy and Infectious 
Diseases 
National Institutes of Health  
5601 Fishers Lane, Room #7B48 
Rockville, MD  20852- 
Phone: 240-627-3572 
E-mail: maria.veri@nih.gov 
 
 
Project Manager: 
Jessica Springer, BSN, MPH/MPA 
Division of Allergy, Immunology, and 
Transplantation   
National Institute of Allergy and Infectious 
Diseases 
National Institutes of Health   
5601 Fishers Lane, Room #7D34 
Rockville, MD  20852 
Phone:  240-627-3474 
E-mail:  springerj@mail.nih.gov 
 
 
 
SACCC – RhoFED, Inc. 
 
 
 
Principal Investigator: 
Lynette Keyes-Elstein, DrPH 
Rho Federal Systems Division, Inc. 
6330 Quadrangle Drive 
Rho Building 
Chapel Hill, NC  27517 
Phone:  919-408-8000 x6410 
Fax:  
919-287-3039 
E-mail:  lynette_keyes-
elstein@rhoworld.com  
Study Coordinator: 
Elizabeth Monson 
Rho Federal Systems Division, Inc. 
6330 Quadrangle Drive 
Rho Building 
Chapel Hill, NC  27517 
Phone: 919-408-8000 x6598 
Fax:  
919-287-3039 
E-mail: elizabeth_monson@rhoworld.com 


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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title:    
An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of 
Mycophenolate Mofetil (MMF) in Patients with Stable, Quiescent 
Systemic Lupus Erythematosus (SLE) 
 
Protocol Number:   ALE06 
 
Protocol Version:   Version 2.0,  07 April 2015 
 
Study Sponsor: 
Division of Allergy, Immunology, and Transplantation (DAIT) 
 
 
 
National Institute of Allergy Infectious Diseases 
 
 
 
5601 Fishers Lane 
 
 
 
Rockville, MD 20852 
Please print, sign, and date at the indicated location below. A copy should be kept for your 
records and the original signature page sent to the SACCC. 
I confirm that I have read the above protocol in the latest version. I understand it, and I will 
work according to the principles of Good Clinical Practice (GCP) as described in the United 
States Code of Federal Regulations (CFR) – 21 CFR Parts 45, 50, 56, and 312, and the 
International Conference on Harmonization (ICH) document “Guidance for Industry: E6 
Good Clinical Practice: Consolidated Guidance” dated April 1996. Further, I will conduct the 
study in keeping with local, legal, and regulatory requirements. 
As a Principal Investigator on this protocol, I agree to conduct “An Investigator-Initiated, 
Phase II, Randomized, Withdrawal Study of Mycophenolate Mofetil (MMF) in Patients with 
Stable, Quiescent Systemic Lupus Erythematosus (SLE).” I agree to carry out the study by 
the criteria written in the protocol and understand that no changes can be made to this 
protocol without written permission of the NIAID. 
 
 
 
 
 
Principal Investigator (Print)  
Principal Investigator Signature 
 
 
Date 
 


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PROTOCOL SYNOPSIS 
Title of the Protocol: An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of Mycophenolate 
Mofetil (MMF) in Patients with Stable, Quiescent Systemic Lupus Erythematosus (SLE) 
ACE Protocol Number: ALE06 
Protocol Chair(s): Tammy Utset, MD, MPH and Eliza Chakravarty, MD 
Sponsor: DAIT/NIAID, NIH 
Primary Objective:  To describe the effect of withdrawal from MMF on risk of clinically significant disease 
reactivation in quiescent SLE patients who have been on long-term MMF therapy 
Study Arms: 
 
MMF maintenance arm: These subjects will continue MMF treatment (1000-3000 mg/day) for the rest 
of their study participation (up to Week 60).  
 
MMF withdrawal arm: These subjects will taper off MMF per the protocol-specified schedule over 12 
weeks and remain off MMF for the rest of their study participation (up to Week 60 or until the 
primary endpoint of disease reactivation is met, whichever comes first).  
Study Design: One hundred twenty eligible subjects will be randomized in a 1:1 ratio to one of the two study 
treatment arms – continuing MMF treatment for 60 weeks or tapering off MMF within 12 weeks. All subjects 
will continue on their anti-malarials and may continue the use of their corticosteroids. 
Subject visits to assess endpoints will occur every 4 weeks from Day 0 through Week 24 and then at Weeks 32, 
40, 48, and 60. As disease flares occur, subjects will be brought in for urgent, flare or endpoint visits to 
document symptoms, collect biological samples, and determine whether primary endpoint has been met. 
Endpoints: 
Primary Endpoint 
The primary endpoint is the probability in each arm of experiencing clinically significant disease reactivation 
by 60 weeks after randomization. Clinically significant SLE reactivation requires both:  
1) A SELENA-SLEDAI*-defined mild/moderate or severe flare and 
2) Increased immunosuppressive therapy on a sustained basis as defined by one of the following criteria:
a. 
Sustained activity: Subject has significant prolonged SLE flare requiring steroid 
increase/burst to ≥ 15 mg/day prednisone (or its equivalent) for more than four weeks. 
b. Frequent relapsing/remitting:  
i. Subject flares requiring an increase/burst of steroids and is successfully tapered to < 
15 mg/day within four weeks, but this occurs on two or more occasions, or  
ii. Intra-articular, intra-muscular or IV steroids, on more than one occasion. 
c. 
Clinical activity of sufficient severity to warrant resumption of or an increased dose of 
MMF or addition of other major immunosuppressive including azathioprine or 
methotrexate. Regardless of steroid use, if the investigator observes disease activity of 
sufficient severity to warrant resumption, addition or increase in dosage of major 
immunosuppressant in the setting of a SELENA-SLEDAI*-defined flare, subject has 
met the primary endpoint. 
Secondary Disease Activity Endpoints 
 
Time from Day 0 to clinically significant disease reactivation (as defined in Section 3.2, Description 
of Primary Endpoint). The time of clinically significant disease reactivation is defined as the date of 
the first SELENA-SLEDAI* assessment that meets (or goes on to meet) the criteria in Section 3.2, 
Description of Primary Endpoint. 
 
The probability of experiencing any SELENA-SLEDAI* flare and the probability of experiencing any 
severe SELENA-SLEDAI* flare by Week 60, in aggregate and within subgroups defined by disease 
manifestation (renal disease / extra-renal disease) and by baseline MMF dosing group (<2000 mg per 
day / ≥ 2000 mg per day). 
 
Time from initiation of withdrawal to first SELENA-SLEDAI* flare and time to first severe 
SELENA-SLEDAI* flare. 
 
The probability of experiencing any BILAG* A flare by Week 60.  
 
Proportion of subjects in the renal subgroup with BILAG* Renal A flare by Week 60  


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Title of the Protocol: An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of Mycophenolate 
Mofetil (MMF) in Patients with Stable, Quiescent Systemic Lupus Erythematosus (SLE) 
 
Change in SLICC/DI from baseline to Weeks 24, 48, and 60. 
 
The probability of adding aggressive adjunctive therapy to MMF (including  IV immunoglobulin or 
rituximab) or change in MMF therapy to cytotoxic drug (e.g., cyclophosphamide) due to flare. 
 
Cumulative systemic steroid dose (PO, IV, IM) at Week 60.  
 
Change in FACIT fatigue score from baseline to Weeks 24, 48, and 60. 
 
Change in SF-36® PF and PCS domains from baseline to Weeks 24, 48, and 60. 
 
Change in Lupus QoL-US© from baseline to Weeks 24, 48, and 60. 
 
The following endpoints will be assessed to describe the ability of subjects to recover from clinically 
significant disease reactivation:  
o 
Time from clinically significant disease reactivation to improvement in BILAG* from 
maximum level during flare; 
o 
Time from clinically significant disease reactivation to recovery to baseline BILAG* scores 
or BILAG* C, whichever is worse; 
o 
Cumulative excess systemic steroid dose from time of clinically significant disease 
reactivation to return to pre-flare dose or end of trial participation; 
o 
Time from clinically significant disease reactivation to return to pre-flare steroid dose. 
Secondary Safety Endpoints 
 
All Grade 3-5 adverse events, as defined by the National Cancer Institute (NCI) – Common 
Terminology Criteria for Adverse Events (CTCAE) system, which are defined as possibly, probably, 
or definitely related to SLE. 
 
All Grade 3-5 adverse events, as defined by the NCI-CTCAE system, which are defined as possibly, 
probably, or definitely related to MMF. 
 
All NCI-CTCAE Grade 3-5 adverse events. 
 
All serious adverse events. 
 
All infection related events. 
 
All malignancies. 
 
All NCI-CTCAE Grade 3-5 hematological events. 
 
Mortality possibly, probably, or definitely related to SLE. 
 
All-cause mortality, defined as any death occurring at any time after randomization 
Secondary Mechanistic Assessments  
 
Levels of C3, C4, and anti-dsDNA at Baseline, Week 20, at the time of first flare, and immediately 
prior to first flare. 
 
Changes in levels of C3, C4, and anti-dsDNA from Baseline to Week 20, from Baseline to the time of 
first flare, and from Baseline to the time point immediately prior to first flare. 
 
Levels of antibodies to Sm, ribonucleoprotein (RNP), SSA/Ro, and SSB/La at Baseline 
 
Changes in levels of antibodies to Sm, RNP, SSA/Ro, and SSB/La from Baseline to Week 60 
 
Levels of interferon-regulated chemokines at Baseline, Week 20, at the time of first flare, and time 
points immediately prior to and after first flare. 
 
Changes in levels of interferon-regulated chemokines from Baseline to Week 20, from Baseline to the 
time of first flare, and from Baseline to the time points immediately prior to and after first flare. 
 
Levels of inflammatory and other cytokines at Baseline, Week 20, at the time of first flare and at time 
points immediately prior to and after first flare. 
 
Changes in levels of inflammatory and other cytokines at Baseline, Week 20, at the time of first flare 
and at time points immediately prior to and after first flare. 
 
Presence/Absence of gene expression patterns (e.g. fingerprint or signature) at Baseline, Week 20, at 
time of first flare, and timepoints immediately prior to and after first flare. 
 
Change in gene expression patterns from Baseline to Week 20, from Baseline to the time of first flare, 
and from Baseline to the time points immediately prior to and after first flare. 
Sample Size: 120 eligible subjects will be randomized within 24 months and each will be followed for up to 
Week 60, for a total study duration of 3 ¼ years. 


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Title of the Protocol: An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of Mycophenolate 
Mofetil (MMF) in Patients with Stable, Quiescent Systemic Lupus Erythematosus (SLE) 
Data Analyses: 
For the primary analysis, the risk difference in disease reactivation by Week 60 will be estimated and 95% 
score confidence intervals calculated, where the risk difference is defined as the difference in the probability of 
disease reactivation by Week 60 between the treatment groups. The observed risk estimates will be used to 
compute the “% Confidence that the true increase is ≤ a” as a function of values for the “Acceptable increase 
in risk with withdrawal of MMF (a)”.  The primary endpoint analysis will be based on the ITT population. 
All secondary analyses will be conducted in an exploratory fashion with p-values and confidence intervals 
presented as descriptive statistics with no adjustments for multiple comparisons. As part of secondary analyses, 
appropriate contrasts will be constructed using model-based approaches. Analyses will be conducted on the 
ITT population and the per protocol population. 
 
Lay Summary: 
 
One hundred twenty eligible subjects who have been on long term MMF for SLE and who 
have had inactive disease for at least 24 weeks will be enrolled. Half the subjects will 
continue on MMF and half the subjects will be tapered off their MMF within 12 weeks. All 
subjects will continue hydroxychloroquine and small doses of prednisone as needed. Subject 
visits to assess endpoints will occur every 4 weeks from Day 0 through Week 24 and then at 
Weeks 32, 40, 48, and 60.


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FLOW DIAGRAM OF PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flare Visit 
To occur whenever a subject experiences a flare. 
May coincide with a regularly scheduled study visit. 
 
Subjects will then continue protocol visits as scheduled. 
Endpoint Visit 
To occur whenever a subject meets primary endpoint. 
May coincide with a regularly scheduled study visit.  
 
Subjects will then continue protocol visits as scheduled. 
Week 12 
Continue on MMF  
Week 12 
Completes the MMF taper. No further study 
drug will be provided to subjects. 
Monthly Study Visits at  
Weeks 4 & 8 
Monthly Study Visits at  
Weeks 4 & 8 
Monthly Study Visits at Weeks 16, 20, 24,  
And Study Visits at Weeks 32, 40, 48 
Monthly Study Visits at Weeks 16, 20, 24,  
And Study Visits at Weeks 32, 40, 48  
Week 60  
Final assessments for efficacy, safety, and 
mechanistic endpoints 
Week 60 
Final assessments for efficacy, safety, and 
mechanistic endpoints 
Pre-screening/Screening Period 
Obtain consent and evaluate eligibility.
Randomization / Baseline / Day 0 
Randomize 120 eligible subjects with clinically 
stable/quiescent SLE in a 1:1 ratio 
MMF Maintenance Arm: 
Continue on MMF   
for up to 60 weeks 
MMF Withdrawal Arm: 
Begin a protocol-defined MMF taper  
(based on baseline MMF dose)  
60 
60 


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ABBREVIATIONS 
 
Ab 
Antibody (antibodies) 
ACE 
Autoimmunity Centers of Excellence 
AE 
Adverse event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
APGAR 
Appearance, pulse, grimace, activity, and respiration 
AST 
Aspartate Transaminase 
AZA 
Azathioprine 
BID 
Twice a day 
BILAG* 
British Isles Lupus Assessment Group 
Note: ALE06 will typically use a spot urine protein:creatinine 
ratio rather than a 24-hour urine assessment. 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DHHS 
Department of Health and Human Services 
DNA 
Deoxyribonucleic Acid 
dsDNA 
Double-stranded Deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FACS 
Fluorescence-Activated Cell Sorting 
FDA 
Food and Drug Administration 
FD&C 
Federal Food, Drug, and Cosmetic Act 
GCP 
Good Clinical Practice 
HCQ 
Hydroxychloroquine 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
IgG 
Immunoglobulin G 
IgM(s) 
Immunoglobulin M 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intention-to-Treat or Intent-to-Treat 
IV 
Intravenous 
MCV 
Mean corpuscular volume 


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mITT 
Modified Intention-to-Treat or Intent-to-Treat 
MMF 
Mycophenolate Mofetil 
m-SLEDAI 
Modified SLEDAI 
MTX 
Methotrexate 
NCI 
National Cancer Institute 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NS 
Not significant 
NSAID(s) 
Nonsteroidal Anti-Inflammatory Drug(s) 
OHRP 
Office of Human Research Protection 
PBMC(s) 
Peripheral Blood Mononuclear Cell(s) 
PCR 
Polymerase Chain Reaction 
PCS 
Physical Component Summary 
PO 
Per os (by mouth) 
PI 
Principal Investigator 
PF 
Physical Functioning 
PP 
Per Protocol 
PPD 
Purified Protein Derivative 
QD 
Once a day 
QFT-G-IT 
QuantiFERON®-TB Gold In-Tube Test 
QoL 
Quality of Life 
qPCR 
Quantitative Polymerase Chain Reaction 
RDW 
Red Cell Distribution Width 
REMS 
Risk Evaluation and Mitigation Strategy 
RhoFED 
Rho Federal Systems Division, Inc. 
RNA 
Ribonucleic Acid 
RNP 
Ribonucleoprotein 
SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious Adverse Event 
SAM 
Significance Analysis of Microarrays 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SDI 
SLICC/ACR Damage Index 
SELENA-SLEDAI* 
Safety of Estrogens in Lupus Erythematosus National Assessment 
- Systemic Lupus Erythematosus-Disease Activity Index 
Note: ALE06 will typically use a spot urine protein creatinine 
ratio rather than a 24-hour urine assessment. 
SF-36® 
Short Form Health Survey 
SLE 
Systemic Lupus Erythematosus 
SLICC/DI* 
Systemic Lupus International Collaborating Clinics/American 
College of Rheumatology Disease Damage Index for Systemic 
Lupus Erythematosus 
Note: ALE06 will typically use a spot urine protein:creatinine 
ratio rather than a 24-hour urine assessment. 


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SSA/Ro 
Sjogren’s Syndrome A / Rogers 
SSB/La 
Sjogren’s Syndrome B / Lane 
SP 
Safety Population 
Tfh  
Follicular T helper cells 
Tregs  
T regulatory cells 
ULN 
Upper limit of normal 
WBC 
White blood cell count 


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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE................................................................................4 
1  BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....................16 
1.1  DISEASE BACKGROUND ............................................................................................16 
1.1.1 
Description and Epidemiology of Disease .................................................16 
1.1.2 
Current Treatment for Disease ..................................................................16 
1.2  SUMMARY OF PRE-CLINICAL AND CLINICAL STUDIES ..............................................17 
1.2.1 
Pre-Clinical Studies ...................................................................................17 
1.2.2 
Clinical Studies ..........................................................................................17 
1.3  STUDY PRODUCT BACKGROUND ...............................................................................18 
1.3.1 
Current Licensing of Product ....................................................................18 
1.3.2 
Other Diseases in Which Product Use Has Been Described .....................18 
1.4  KNOWN AND POTENTIAL RISKS AND BENEFITS OF STUDY PARTICIPATION ...............18 
1.5  RATIONALE FOR STUDY ............................................................................................20 
1.5.1 
Rationale for the Inclusion Criteria ...........................................................21 
1.5.2 
Rationale for the Exclusion Criteria ..........................................................22 
1.5.3 
Rationale for the MMF Withdrawal Arm ...................................................23 
1.5.4 
Rationale for the Continued MMF Treatment Arm ...................................23 
1.5.5 
Rationale for Mechanistic Studies .............................................................24 
2  STUDY OBJECTIVES AND PURPOSE ......................................................................24 
2.1  PRIMARY OBJECTIVE ................................................................................................24 
2.2  SECONDARY OBJECTIVES ..........................................................................................24 
2.2.1 
Secondary Disease Activity Objectives ......................................................24 
2.2.2 
Secondary Safety Objectives ......................................................................24 
2.2.3 
Secondary Mechanistic Objectives ............................................................24 
3  STUDY DESIGN ..............................................................................................................25 
3.1  DESCRIPTION OF STUDY DESIGN ...............................................................................25 
3.1.1 
Stratification, Randomization, and Blinding .............................................27 
3.2  DESCRIPTION OF PRIMARY ENDPOINT .......................................................................27 
3.3  DESCRIPTION OF SECONDARY ENDPOINTS ................................................................28 
3.3.1 
Secondary Disease Activity Endpoints .......................................................28 
3.3.2 
Secondary Safety Endpoints .......................................................................29 
3.3.3 
Secondary Mechanistic Assessments .........................................................29 
4  SELECTION OF SUBJECTS ........................................................................................30 
4.1  INCLUSION CRITERIA ................................................................................................30 
4.2  EXCLUSION CRITERIA ...............................................................................................31 
4.2.1 
Co-enrollment Guidelines ..........................................................................32 
4.3  STRATEGIES FOR RECRUITMENT AND RETENTION ....................................................32 
5  TREATMENT OF SUBJECTS ......................................................................................32 


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5.1  DESCRIPTION OF STUDY PRODUCT ............................................................................32 
5.1.1 
Product Description ...................................................................................32 
5.1.2 
Packaging and Labeling of Study Product ................................................33 
5.1.3 
Storage and Handling of Study Product ....................................................33 
5.2  DOSAGE REGIMEN ....................................................................................................33 
5.3  ADMINISTRATION OF STUDY PRODUCT .....................................................................33 
5.3.1 
Administration of Study Product in Response to SLE Reactivation ..........34 
5.4  PREVENTION AND MANAGEMENT OF TOXICITY FOR MMF .......................................34 
5.4.1 
Malignancy ................................................................................................34 
5.4.2 
Hematological Abnormalities ....................................................................35 
5.4.3 
Hepatic Abnormalities ...............................................................................35 
5.4.4 
Infections ....................................................................................................35 
5.4.5 
Gastrointestinal Abnormalities ..................................................................35 
5.4.6 
Reproductive Risks .....................................................................................35 
5.5  CONCURRENT MEDICATIONS ....................................................................................36 
5.5.1 
Anti-malarial Agents ..................................................................................36 
5.5.2 
Prednisone (or Equivalent) ........................................................................36 
5.6  PROHIBITED MEDICATIONS .......................................................................................36 
5.7  TOXICITY MANAGEMENT PLAN FOR CONCURRENT THERAPY: 
HYDROXYCHLOROQUINE OR CHLOROQUINE ........................................................37 
5.8  OTHER STANDARD OF CARE RECOMMENDATIONS ....................................................37 
5.9  PROCEDURES FOR MONITORING SUBJECT COMPLIANCE ...........................................38 
5.10  TREATMENT DISCONTINUATION AND SUBJECT WITHDRAWAL .................................38 
5.10.1  Study Treatment Discontinuation ..............................................................38 
5.10.2  Subject Withdrawal from the Study............................................................39 
5.10.3  Safety Stopping Guidance ..........................................................................39 
6  ASSESSMENT OF SAFETY AND DISEASE ACTIVITY .........................................40 
6.1  ASSESSMENTS OF SAFETY .........................................................................................40 
6.2  ASSESSMENTS OF DISEASE ACTIVITY .......................................................................40 
6.3  MECHANISTIC  STUDIES ............................................................................................41 
6.3.1 
Serologic Markers ......................................................................................41 
6.3.2 
Cytokine and Chemokine Analysis .............................................................41 
6.3.3 
Transcript Profiling Studies .......................................................................42 
6.3.4 
Future Use Assays ......................................................................................42 
6.3.5 
Blood Draw Prioritization .........................................................................43 
6.4  EVALUATIONS BY STUDY VISIT ................................................................................44 
6.4.1 
Screening Period ........................................................................................44 
6.4.2 
Baseline/Randomization Visit ....................................................................45 
6.4.3 
Treatment Period .......................................................................................46 
6.4.4 
As Needed Visits .........................................................................................52 
6.4.5 
Visit Windows.............................................................................................53 
7  SAFETY MONITORING AND REPORTING ............................................................56 
7.1  OVERVIEW ................................................................................................................56 
7.2  DEFINITIONS .............................................................................................................56 


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7.2.1 
Adverse Event (or Adverse Experience) ....................................................56 
7.2.2 
Adverse Reaction and Suspected Adverse Reaction ..................................56 
7.2.3 
Unexpected Adverse Reaction ....................................................................56 
7.2.4 
Serious Adverse Event ................................................................................57 
7.3  COLLECTION AND RECORDING OF ADVERSE EVENTS ...............................................57 
7.3.1 
Investigational Product ..............................................................................57 
7.3.2 
Collection Period .......................................................................................57 
7.3.3 
Collecting Adverse Events .........................................................................57 
7.3.4 
Recording Adverse Events .........................................................................58 
7.3.5 
Recording Serious Adverse Events ............................................................58 
7.4  GRADING AND ATTRIBUTION OF ADVERSE EVENTS ..................................................58 
7.4.1 
Grading Criteria ........................................................................................58 
7.4.2 
Attribution Definitions ...............................................................................59 
7.5  REPORTING OF ADVERSE EVENTS .............................................................................60 
7.5.1 
Reporting of Adverse Events to DAIT/NIAID ............................................60 
7.5.2 
DAIT/NIAID Reporting to the Health Authority ........................................61 
7.5.3 
Reporting of Adverse Events to IRBs .........................................................61 
7.6  PREGNANCY REPORTING ...........................................................................................61 
7.6.1 
Mycophenolate REMS Program ................................................................62 
7.7  REPORTING OF OTHER SAFETY INFORMATION ..........................................................62 
7.8  REVIEW OF SAFETY INFORMATION ...........................................................................62 
7.8.1 
Medical Monitor Review ............................................................................62 
7.8.2 
DSMB Review ............................................................................................62 
8  STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ..........................63 
8.1  SAMPLE SIZE AND POWER .........................................................................................63 
8.2  ANALYSIS POPULATIONS ..........................................................................................64 
8.2.1 
Safety Population .......................................................................................64 
8.2.2 
Modified Intent-to-Treat Population ..........................................................64 
8.2.3 
Per Protocol Population ............................................................................65 
8.3  DESCRIPTION OF THE ANALYSES ...............................................................................65 
8.3.1 
Safety Analysis ...........................................................................................65 
8.3.2 
Analysis of Disease Activity Endpoints ......................................................66 
8.3.3 
Mechanism/Immunological Analysis .........................................................68 
8.4  INTERIM ANALYSIS ...................................................................................................69 
8.5  OTHER STATISTICAL CONSIDERATIONS ....................................................................70 
8.5.1 
Covariates ..................................................................................................70 
8.5.2 
Multicenter Studies ....................................................................................70 
8.5.3 
Multiple Comparisons and Multiplicity .....................................................70 
8.5.4 
Examination of Subgroups .........................................................................70 
8.5.5 
Missing Data ..............................................................................................70 
8.5.6 
Changes to the Statistical Analysis Plan ...................................................71 
9  ACCESS TO SOURCE DATA AND DOCUMENTS ..................................................71 
10  DATA COLLECTION, QUALITY CONTROL AND QUALITY ASSURANCE ...71 


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11  ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE ....................................................................................72 
11.1  COMPLIANCE WITH GOOD CLINICAL PRACTICES ......................................................72 
11.2  INSTITUTIONAL REVIEW BOARD (IRB) .....................................................................73 
11.3  INFORMED CONSENT .................................................................................................73 
11.4  DATA AND SAFETY MONITORING BOARD .................................................................73 
12  FINANCING AND INSURANCE ..................................................................................74 
13  PUBLICATION POLICY ...............................................................................................74 
14  REFERENCES .................................................................................................................75 
15  APPENDICES ..................................................................................................................78 
15.1  APPENDIX A: DEFINITION OF MILD DISEASE ............................................................79 
15.2  APPENDIX B: ACR CRITERIA FOR SLE [32] .............................................................81 
15.3  APPENDIX C: SELENA-SLEDAI* ...........................................................................82 
15.4  APPENDIX D:  SLICC/DI* [38] .................................................................................85 
15.5  APPENDIX E: BILAG* 2004 (2007 REVISION)..........................................................87 
15.6  APPENDIX F: SF-36® [39] .........................................................................................89 
15.7  APPENDIX G: SF-36® (SPANISH VERSION) [39] .........................................................96 
15.8  APPENDIX H: FACIT [40] .......................................................................................103 
15.9  APPENDIX I: FACIT [40] (SPANISH VERSION) .........................................................104 
15.10 
APPENDIX J: LUPUS QOL© [41] .........................................................................105 
15.11 
APPENDIX K: LUPUS QOL© [41] (SPANISH VERSION) ........................................110 
15.12 
APPENDIX L: REMS ..........................................................................................115 


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1 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
1.1 Disease Background 
SLE is a chronic systemic autoimmune disease characterized by great heterogeneity in 
symptoms, patterns of activity, and in prognosis. Common symptoms include severe fatigue, 
fever, joint pain, rashes, hair loss, serositis, and cytopenias. In addition, the majority of 
patients make antibodies against nuclear antigens and specific antigens such as native 
deoxyribonucleic acid (DNA). A large component of the pathogenesis is felt to be driven by 
these antibodies, which form immune complexes and lead to activation of the complement 
system. Current therapies for SLE are nonspecific, often inadequately effective, and have 
substantial potential toxicities. When patients do achieve prolonged clinical control of 
disease, it is often unclear if the control is due to the maintenance use of potentially toxic 
immunosuppressant therapy or due to natural variation in their disease activity. Stopping 
points for immunosuppressants in patients who have previously had severe manifestations of 
SLE are unknown, due to the difficulty in differentiating true disease quiescence from 
disease suppression. 
 
Description and Epidemiology of Disease 
1.1.1
SLE is a systemic autoimmune disease characterized by an autoimmune response to 
nucleosomal antigens. Onset is most common in the 30s or 40s, with approximately a 90% 
female predominance. It can also begin in childhood and at advanced ages, with lower 
frequencies. Prevalence is estimated at 1/2000 women and it is more common in ethnic 
minorities including African-Americans and Latinos. Symptoms and organ involvement vary 
greatly, with arthritis, rashes, and systemic symptoms such as fever and weight loss being 
common symptoms. The syndrome can be mild, or it can be severe. The most common 
serious manifestation is lupus nephritis, occurring in up to 40% of SLE patients. Overall 
mortality rates in SLE are approximately 15% at 10 years, with lupus nephritis and brain 
involvement being markers of a poor prognosis. Early deaths (< 8 years) most often are 
related to disease activity or infection, while later deaths most often represent thrombosis and 
accelerated atherosclerosis. Cross-sectional epidemiological studies suggest that 
approximately 40-53% of SLE patients have chronic active disease, while 14-35% are 
relapsing-remitting, and 25-37% have periods of long-term quiescence [1-3]. Additionally, 
the overall natural history of SLE is that of high activity early in disease course, and gradual 
dissipation of disease activity over time [4, 5]. 
 
Current Treatment for Disease 
1.1.2
SLE is a chronic disease with a limited repertoire of therapeutic options. Only 
hydroxychloroquine (HCQ), corticosteroids, salicylates, and (recently) belimumab are 
currently approved by the Food and Drug Administration (FDA) for the treatment of SLE 
[6]. Substantial literature documents the utility of HCQ in SLE. HCQ substantially decreases 
the flare rate in SLE, as well as decreasing damage accrual, improving survival, and 
improving pregnancy outcomes [7-9]. It is well tolerated with an excellent toxicity profile. 


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Barring contraindications, this drug clearly should be used in SLE patients as a standard of 
care. Nonetheless, HCQ alone is often inadequate to control disease during highly active 
phases, resulting in the addition of corticosteroid therapy. When corticosteroid dose 
requirements are excessive or inadequate, potentially toxic immunosuppressive agents such 
as methotrexate, azathioprine, and MMF are added to control active disease and reduce or 
eliminate steroid dependency. Such immunosuppressive therapies are non-FDA approved but 
widely used despite scarce clinical trial data to support their use [10], likely due to the severe 
and predictable toxicities of chronic corticosteroid therapy. 
1.2 Summary of Pre-Clinical and Clinical Studies 
 
Pre-Clinical Studies 
1.2.1
MMF inhibits inducible inosine-5’-monophosphate dehydrogenase, resulting in depletion of 
guanosine nucleotides in T and B lymphocytes. Thus, both cellular and antibody-mediated 
immune responses are affected by MMF. While less well substantiated, MMF may also 
affect adhesion molecule expression and decrease the production of inducible nitric oxide by 
activated macrophages [11]. 
 
Clinical Studies 
1.2.2
In regards to SLE, MMF was initially studied in the specific setting of proliferative lupus 
nephritis, and randomized clinical trials in that setting have demonstrated non-inferiority to 
cyclophosphamide as induction therapy [12, 13], as well as maintenance therapy for up to 
three years [14]. The role of MMF for lupus nephritis beyond the three-year time point is not 
known. Subsequently, numerous case reports and case series have reported efficacy of MMF 
in the treatment of hematological and dermatological manifestations of SLE [15], and a 
small, randomized, placebo-controlled cross-over trial has demonstrated efficacy with lupus 
arthritis [16]. Despite the lack of controlled clinical trials in extra-renal SLE, MMF is used 
widely in this setting, likely due to good tolerability and the clinical impression of 
effectiveness [17]. This impression of excellent tolerability compared to other 
immunosuppressants may be inaccurate. In the EXPLORER trial of rituximab in moderate to 
severe SLE, subjects on MMF had numerically higher rates of serious adverse events 
(16.7%) versus subjects on methotrexate (MTX) (9.3%) or azathioprine (AZA) (12.5%, p = 
NS [not significant]). Infectious serious adverse events (SAEs) were also numerically higher 
in the MMF-treated subjects (7.0%) compared to MTX (4.3%) or AZA (2.3%, p = NS) 
(Genentech, personal communication, July 2011). There is also evidence that MMF at 3000 
mg/day, a standard dose for lupus nephritis that is also used in refractory extra-renal SLE, 
may have greater risk of infection than lower doses of MMF [18]. Without controlled studies, 
it is not possible to correctly interpret risks and benefits of immunosuppressant therapy, and 
differentiate increased risks of the study drug from background rates of disease 
complications. There is little incentive for pharmaceutical-sponsored research on this topic, 
as the drug is now available in generic form. 


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While acute disease activity such as active nephritis and arthritis appear to respond to MMF 
initiation, the clinical course of SLE is unpredictable and the long-term utility of major 
immunosuppressants to maintain control after acute periods of activity is unclear. 
Randomized clinical trial data do support the use of HCQ in preventing flare [7]; because of 
the highly variable clinical course of SLE, medications with greater potential toxicity such as 
MMF need rigorous study to determine what, if any, role they have in the maintenance of 
clinical quiescence in moderate or severe SLE. Apparent disease “control” on drugs such as 
MMF may represent spontaneous disease amelioration rather than drug-dependent disease 
suppression in many cases. Since HCQ, a well-tolerated, inexpensive drug with few side 
effects, is known to reduce substantially the risk of flares, an important question is whether 
long-term use of major immunosuppressant drugs such as MMF is necessary or effective in 
preventing flare-ups in the subset of SLE patients whose disease had been sufficiently severe 
to initiate MMF in the past. One retrospective study [19] found flare rates by British Isles 
Lupus Assessment Group index (BILAG) to be reduced in the first year of MMF treatment 
relative to the year prior to MMF, but they could not document sustained reduction in flare 
rate in subsequent years of MMF therapy. Obviously, prospective data is needed to determine 
the role of MMF as maintenance therapy in extra-renal SLE, and in lupus nephritis beyond 
two or three years of therapy. 
1.3 Study Product Background 
 
Current Licensing of Product 
1.3.1
MMF is currently licensed to prevent rejection of solid organ transplants. 
 
Other Diseases in Which Product Use Has Been Described 
1.3.2
MMF has been used off label in myasthenia gravis, atopic dermatitis, idiopathic 
thrombocytopenic purpura, graft-versus-host disease, psoriasis, and a variety of rheumatic 
diseases including SLE, scleroderma, vasculitis, rheumatoid arthritis, inflammatory 
myopathy, and connective-tissue disease associated interstitial lung disease [20]. 
1.4 Known and Potential Risks and Benefits of Study Participation 
Currently there are no standards on when to withdraw major immunosuppressive medications 
in SLE patients with long term controlled or quiescent disease. These decisions are made 
case-by-case, without evidence on the benefits and risks of stopping medication. This trial 
proposes to enroll subjects who would be clinically eligible to be withdrawn from medication 
based on reasonable standard of care and randomize this decision. There are risks both from 
continuation of the medication and from activation of the underlying disease. This study 
provides the opportunity for 50% of participants to withdraw from MMF and be intensely 
monitored for the following 48 weeks. Although most often well tolerated, MMF has well 
documented toxicities in the setting of solid organ transplantation. Long term use is 
associated with an increased risk of lymphoproliferative disease including malignant 
lymphoma (0.4-1.0%). Non-melanoma skin cancer is also increased (1.6-4.2%). It is a known 


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teratogen (pregnancy category D) and is currently under a risk evaluation and mitigation 
strategy (REMS) program (see Section 7.6.1, Mycophenolate REMS Program), and may 
interfere with the effectiveness of oral contraceptive pills. Bone marrow suppression is 
uncommon, but classically manifests as neutropenia and less frequently anemia (including 
pure red cell aplasia) or thrombocytopenia. Patients have increased risks of common and 
opportunistic infections, including progressive multifocal leukoencephalopathy (PML). 
Commonly reported side effects are difficult to differentiate from the side effects of 
concurrent therapy in the setting of solid organ transplantation, and include hypertension, 
peripheral edema, hypercholesterolemia, electrolyte abnormalities, abdominal upset 
including nausea and diarrhea, anxiety, and headache. Serious side effects have been reported 
as an increased risk of gastrointestinal hemorrhage (rare), anemia, leukopenia, severe 
neutropenic disorder (2-3.6%), and opportunistic infections [21]. 
These known drug toxicities of MMF need to be held in perspective against the significant 
potential for organ damage, mortality, and impaired daily function in SLE, and the 
predictably severe side effects of chronic moderate to high doses of corticosteroids and/or 
cyclophosphamide in cases of very severe disease. 
MMF is known to be efficacious in the treatment of lupus nephritis [12-14], and a small 
randomized trial of MMF for lupus arthritis suggests it is useful in treating arthritis as well 
[16]. Otherwise, much literature in the form of case reports and case series suggest that MMF 
is efficacious for SLE skin disease, hematological disease, and a variety of other SLE 
manifestations [15]. In addition, MMF is thought possibly to have anti-fibrotic effects, which 
may further benefit SLE patients by inhibiting the vascular lesion of non-inflammatory 
endothelial hyperplasia seen in SLE (particularly in neuropsychiatric SLE) and the related 
condition antiphospholipid syndrome, and fibrotic damage to the kidney in the setting of 
lupus nephritis. Additionally, the purported effects of MMF on nitric oxide may improve 
endothelial dysfunction, which is widespread in SLE and is felt to be a precursor lesion to 
atherosclerosis [11]. Thus, there is reasonable and growing data to suggest MMF is beneficial 
in the acute control of SLE. What is not known, and a driving question of this study, is 
whether MMF should be continued chronically or stopped when SLE becomes clinically 
quiescent. This decision is based on the balance of the risks of chronic MMF versus the risks 
of SLE flare. 
Active SLE is clearly associated with increased damage and mortality [22]. Thus, if MMF 
withdrawal results in significant deterioration of SLE control, these patients may be at risk 
for a more severe clinical course than patients who chronically maintain MMF therapy. A 
comparison of flare rates in SLE patients on and off MMF will be a key endpoint of this 
study, as will accrual of damage and excess corticosteroid exposure due to flare. 
Based on the observational unpublished data from a subset of 49 patients in the Johns 
Hopkins Lupus Cohort who were on long term MMF for a minimum of one year (M. Petri, 
personal communication, October 2010), the probability of experiencing disease reactivation 
(described as at least one Systemic Lupus Erythematosus-Disease Activity Index [SLEDAI]-
defined flare requiring additional treatment) by month 16 was estimated at 0.10 (95% 
confidence interval [CI] [0.02, 0.19]) for subjects remaining on MMF. This is compared to 


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total SLE population risks of flare approximating 0.8/year. However, we are selecting a 
population with prolonged clinical quiescence and the rates of flare in these specific 
circumstances are unknown. 
1.5 Rationale for Study 
There is a great need for information on which SLE patients can safely discontinue major 
immunosuppressants after a significant period of disease quiescence. Currently the “stopping 
point” for such drugs is unknown in a potentially serious disease such as SLE. However, the 
clinical course of SLE is unpredictable, and it is possible that significant numbers of subjects 
will tolerate discontinuation of MMF without flare, especially on a background of continued 
HCQ therapy. Continuation of MMF results in increased risks of lymphoproliferative 
disease, hematological derangements, and infections, including severe opportunistic 
infections. Discontinuation of MMF may lower the risk for significant infection, but most 
likely will increase to some degree the risk for SLE flare. These flares themselves may 
generally be mild and easily treated, favoring the risk/benefit ratio of staying off MMF 
despite a modest increased risk of flare. In some cases, a flare could be severe and require 
intensive corticosteroid and/or immunosuppressant therapy, along with impaired quality of 
life and physical function in the subjects for the duration of their flare and even with possible 
accrual of damage related to flare or its therapy. To minimize the risk of severe, damage-
accruing flare, we will exclude patients with severe renal dysfunction and history of severe 
neuropsychiatric SLE. This study will examine the potential for the identification of low risk 
patients for discontinuation of this therapeutic agent, both on clinical and demographic 
grounds, and by biological markers of disease activity. 
This study provides an opportunity to address a relevant clinical question, has the potential to 
impact SLE clinical care, and provides longitudinal blood specimens from well-characterized 
patients to potentially help identify biomarkers or explain mechanisms of disease flare. The 
goal of the trial is to obtain data comparing risks and benefits of continuing versus 
withdrawing MMF. The hope is that the study will provide physicians with some rationale 
for medical decision making. It is important to note that in practice the decision to withdraw 
from MMF is multifactorial; one has to weigh the increased risk of flare against decreased 
risk of lymphoproliferative disease, hematological derangements, and infections as well as 
the impact of chronic medication use on quality of life and plans for pregnancy. How the 
risks and benefits should be weighed is highly individual. The primary analysis, however, is 
designed to maximize the information available for decision making (Section 8.3.2.1, 
Primary Endpoint Analysis). Depending on the actual effect estimates, estimated confidence 
level, and level of acceptable risk, the results from this trial may or may not facilitate a 
decision regarding withdrawal for an individual patient, but should provide sufficient 
information for some clinical cases.  Furthermore, the data will be of value for assessing 
feasibility and designing a larger more definitive trial, if such a trial were to be launched. In 
addition, this trial offers an opportunity to ask very practical questions about how results of 
mechanistic analyses might also guide clinical care, as well as core questions about the basis 
of the autoimmune process and the mechanism of action of MMF in SLE. 


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The primary outcome index to measure flare in this study is the Safety of Estrogens in Lupus 
Erythematosus National Assessment SLE disease activity (SELENA-SLEDAI) flare index. 
Multiple disease activity indices have been developed and successfully indicate disease 
activity in SLE; the most commonly used have been various versions of the SLEDAI and the 
BILAG. Superiority of one index over another in the setting of randomized clinical trials has 
not been clarified [23]. The SELENA-SLEDAI flare index was successfully used in the 
Combined Oral Contraceptives in Women with Systemic Lupus trial [24] and The Effect of 
Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease Activity in 
Systemic Lupus: A Randomized Trial [25]. The two studies are known as the SELENA 
studies. Both of these studies enrolled quiet or minimally active SLE patients and tracked 
their clinical course for flare. Thus, the SLE population targeted for this study resembles the 
SELENA studies in which this instrument was successful. In contrast, the BILAG has been 
used in clinical trials in which flaring SLE patients are enrolled to receive a therapeutic agent 
and has successfully measured improvement. More recently, a combined index using the 
SLEDAI, the BILAG, and a physician’s global assessment (SLE Responder Index) was 
successfully used in the phase III studies of belimumab in SLE [6]. This study showed 
clinical benefit with belimumab whether the combined index, the SLEDAI alone, or the 
BILAG alone were used. Thus, showing improvement in SLE randomized clinical trials 
appears feasible with a variety of indices. 
However, both instruments have limitations when measuring flare. False positive B flares are 
common with the BILAG instrument and complicate its use and interpretation [26, 27]. It is 
also very lengthy and time-consuming relative to the SELENA-SLEDAI. However, mild or 
moderate flares by SELENA-SLEDAI do not always correlate with a need to change therapy 
and thus may not represent clinically significant change. Previous literature suggests that 
approximately 40% of all SELENA-SLEDAI flares (mild, moderate, or severe) require 
treatment [28]. Thus, to increase specificity of clinically significant flare in this study, we 
have required dually that a SELENA-SLEDAI-defined flare and substantial increase or re-
institution of SLE medication is required. 
The BILAG will be used as a secondary outcome instrument to assist in comparison of 
results to other studies using the BILAG, and to assist in descriptions of types and severities 
of disease activity, which occur in the study. 
 
Rationale for the Inclusion Criteria  
1.5.1
Inclusion criteria require patients to have been clinically stable/quiescent for a sustained time 
period, such that by standard care principles they could consider discontinuation of MMF. 
The longer sustained period of MMF treatment in the setting of renal involvement reflects the 
randomized clinical data indicating benefit from MMF maintenance therapy for two or more 
years. Serological activity will not prohibit entry into the trial, as the predictive capacity of 
serologies for SLE flare are questionable in the setting of prolonged clinical quiescence [29]. 
Because we do not wish to have serological activity prohibit trial enrollment, a modification 
of the SLEDAI, the m-SLEDAI, will be used at screening to determine eligibility. The m-
SLEDAI is identical to the SLEDAI except for the exclusion of double-stranded DNA 
antibodies (anti-dsDNA) and hypocomplementemia [1]. An m-SLEDAI score of < 4 at 


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screening will allow enrollment in the trial. Minor/transient or nonspecific clinical symptoms 
are allowed at entry (see Appendix A, Definition of Mild Disease), as major 
immunosuppressant therapy would not be warranted for such symptoms. If the subject is on 
prednisone therapy for SLE, the dose must have been ≤ 10 mg/day (or equivalent dose of 
alternative corticosteroid) for 12 weeks and stable for 4 weeks prior to randomization as a 
reflection that the subject has been clinically quiescent (see Section 5.5.2, Prednisone (or 
Equivalent) for the definition of “stable dose”). 
 
Rationale for the Exclusion Criteria 
1.5.2
Subjects will be excluded if their SLE has substantial activity within six to twelve months, as 
the clinical question posed in this study is whether MMF is helpful as maintenance therapy in 
clinically quiescent SLE. Also, patients with high risk for organ damage will be excluded as 
the cost of relapse in very severe SLE may be too high to offset the risk of continuing MMF. 
Specifically, patients with substantial proteinuria (> 1.0 on spot protein/creatinine ratio) and 
thus may still have active nephritis will be excluded, as well as patients with relatively recent 
histories of severe neuropsychiatric SLE (within 12 months). Subjects requiring more than 10 
mg/day of prednisone (or equivalent steroid) in the 12 weeks prior or more than 25 mg/day in 
the 24 weeks prior to screening due to SLE activity are excluded as they have not had 
prolonged clinical quiescence. Subjects with chronic renal insufficiency (serum creatinine 
above 2.0 mg/dL at screening) will be excluded, because a renal flare in subjects with 
tenuous renal function may result in end stage renal disease, and thus affects risk/benefit ratio 
of stopping MMF. In addition, toxicity from MMF is more likely with advanced renal 
insufficiency. Concurrent therapy with major immunosuppressive agents (MTX, 
leflunomide, azathioprine, 6-mercaptopurine, calcineurin inhibitors or anti-tumor necrosis 
factor agents), intravenous (IV) immunoglobulin or plasmapheresis within 12 weeks of 
randomization is exclusionary as the concurrent therapy may affect flare rates in the study 
population. Subjects treated with cyclophosphamide within 24 weeks of randomization are 
excluded, as use of cyclophosphamide would indicate severe disease activity in the recent 
past. B cell depleting agents such as anti-CD20 are excluded for two calendar years prior to 
randomization, because they have been reported to have prolonged benefit in some patients 
and also may affect the nature of B cell populations in mechanistic studies [30]. Belimumab 
must be discontinued for at least 24 weeks prior to randomization, because modification of B 
cell populations by belimumab may affect risk of flare when MMF is withdrawn. Patients 
who have had solid organ transplantations are excluded, as their immunosuppressive regimen 
must be maintained for graft survival. Patients who have had stem cell transplantation are by 
definition very severe SLE patients who are best managed outside of this clinical trial. Active 
co-morbid conditions likely to require systemic steroid therapy will be exclusionary, because 
these patients may have multifactorial and thus misleading total corticosteroid requirements, 
which is a secondary outcome measure in this study. Subjects with major infectious issues 
are excluded, because discontinuation of MMF would be the standard of care in quiescent 
SLE patients with infectious complications. 


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Rationale for the MMF Withdrawal Arm 
1.5.3
The MMF withdrawal arm will provide effect estimates of discontinuing MMF in SLE 
subjects who had previously had prolonged clinical stability while taking MMF. This will 
include disease reactivation as described by the primary endpoint, need for additional 
medications to control SLE, and impact on quality of life. Subjects will be randomized 1:1 to 
continue or withdraw MMF in an unblinded manner. Subjects who enter the trial will have 
been maintained on MMF 1000-3000 mg/day because these are common dose ranges used to 
treat SLE. Those subjects who are randomized to MMF withdrawal will have a standardized 
taper over three months (see Section 3.1, Description of Study Design) so that all MMF 
withdrawal subjects are off MMF at Week 12. There is no evidence-based literature to 
support a three-month taper versus abrupt discontinuation of MMF in this setting. However, 
the rationale of taper would be that partial withdrawal of the drug each month may unmask 
smoldering SLE at a mild phase, if the subject is dependent on the MMF for SLE control. 
Thus, the intent of taper is to decrease risk of more severe flare to the subjects. The particular 
taper schedule will be determined by the baseline MMF dose, and MMF will be decreased in 
increments of 500-1000 mg at four week intervals. Although different starting doses will 
result in more rapid tapers for some subjects, the 12-week taper will allow easy comparison 
of subjects at set time points after study entry. Additionally, all subjects will be required to be 
on an anti-malarial agent as these drugs are standard of care for SLE. Anti-malarials have 
been shown to help prevent flare with a very favorable safety profile, and may be protective 
against flare as the major immunosuppressant agent is discontinued. After week 36 of the 
study  (six months after MMF discontinuation) subjects may also taper glucocorticoids if felt 
appropriate by clinical status per the investigator. This is because standard of care practice 
would be to taper steroids if disease is quiescent, as steroids can have long term health 
hazards in SLE including osteoporosis, avascular necrosis, and potentially accelerated 
atherosclerosis. SLE activity will be assessed monthly until Week 24, every other month 
until Week 48, and at the primary endpoint at Week 60. 
 
Rationale for the Continued MMF Treatment Arm 
1.5.4
Subjects randomized to continue MMF represent the control arm in this study. Levels of 
disease activity among controls will be compared to those observed for subjects withdrawn 
from MMF. Additionally, MMF has potential toxicities including infectious complications 
and hematological derangements. Our control group will allow comparison of disease 
complications and drug toxicities on and off MMF in the setting of quiescent SLE. Subjects 
in the MMF treatment arm will continue their baseline level of MMF unless MMF-related 
toxicity occurs and will similarly be concurrently treated with anti-malarial agents. Parallel 
ability to taper corticosteroids after 36 weeks in stable patients will keep non-MMF variables 
constant between groups and be consonant with good clinical practice. Ability to titrate low 
dose prednisone downward will also be informative when examining cumulative steroid 
exposures between MMF and withdrawal arms, since corticosteroids will go up with flare but 
also go down with lack of flare. 


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Rationale for Mechanistic Studies 
1.5.5
Mechanistic studies will focus on several issues. First, are there clinical or immunological 
baseline predictors to inform the practitioner in which patients it may be safest to discontinue 
MMF in quiescent SLE? Multiple potential markers will be examined for this purpose, 
including demographic data, disease duration, serological activity, baseline autoantibody 
profile, cytokine characteristics, and gene expression patterns by microarray. We will also 
utilize the cytokine and gene expression information to examine, in part, the immunologic 
and anti-inflammatory effects of MMF in SLE patients to explore potential mechanisms of 
action of MMF in SLE.  
2 STUDY OBJECTIVES AND PURPOSE  
2.1 Primary Objective 
The primary objective of this trial is to describe the effect of withdrawal from MMF on risk 
of clinically significant disease reactivation in quiescent SLE patients who have been on 
long-term MMF therapy. 
2.2 Secondary Objectives 
 
Secondary Disease Activity Objectives 
2.2.1
 To describe the effect of MMF withdrawal on measures of disease activity (including 
time to flare and severity of flare) in aggregate and in subgroups defined by 
demographics, disease manifestation (renal disease/extra-renal disease) and by 
baseline MMF dosing group (< 2000 mg per day / ≥ 2000 mg per day).  
 To describe the effect of MMF withdrawal on damage accrual, needed medications, 
and subject quality of life. 
 To describe the effect of MMF withdrawal on time to recovery from clinically 
significant disease reactivation and needed medications in the subgroup defined by 
disease reactivation during follow-up. 
 
Secondary Safety Objectives 
2.2.2
 To describe the effect of MMF withdrawal on measures of safety and drug related 
toxicities. 
 
Secondary Mechanistic Objectives 
2.2.3
 To identify baseline autoantibody, cytokine/chemokine, and gene expression 
characteristics that are associated with an increased risk of SLE flare. 


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 To identify autoantibody, cytokine/chemokine, and gene expression characteristics 
present at Week 20 or changes in those characteristics from baseline to Week 20 that 
are associated with an increased risk of flare. 
 To identify autoantibody, cytokine/chemokine and gene expression changes 
associated with withdrawal of MMF apart from flare. 
 
Markers of particular interest include: 
o Serologic markers: dsDNA antibodies, C3 levels, C4 levels, and antibodies 
toward Sm, ribonucleoprotein (RNP), SSA/Ro, & SSB/La;  
o Presence/absence of a “B cell fingerprint” assessed by gene expression 
profiling; 
o Presence/absence of an “Interferon-α biosignature” assessed by gene 
expression profiling;  
o Levels of cytokines or chemokines associated with the interferon- and γ 
pathway (measured by bead based assays or ELISA). 
3 STUDY DESIGN 
3.1 Description of Study Design 
This is a Phase II, unblinded, randomized controlled trial of MMF withdrawal in patients 
with clinically quiescent SLE on longstanding MMF therapy (1000-3000 mg/day for at least 
one year in the case of extra-renal indication for MMF or for at least two years in the case of 
renal indications for MMF), who have been on stable doses of MMF, hydroxychloroquine or 
chloroquine, and corticosteroids (if applicable) for at least 12 weeks prior to randomization, 
and have an m-SLEDAI of < 4 at screening.  
One hundred twenty eligible subjects will be randomized in a 1:1 ratio to one of the two 
study treatment arms below. 
 MMF maintenance arm: These subjects will continue MMF treatment (1000-3000 
mg/day) for the rest of their study participation (up to Week 60).  
o Baseline MMF dose = 3000 mg/day  
 Up to 60 weeks on 3000mg/day MMF 
o Baseline MMF dose = 2500 mg/day to 2750 mg/day  
 Up to 60 weeks on 2500mg/day MMF 
o Baseline MMF dose = 2000 mg/day to 2250 mg/day  
 Up to 60 weeks on 2000mg/day MMF 
o Baseline MMF dose = 1500 mg/day to 1750 mg/day  
 Up to 60 weeks on 1500mg/day MMF 
o Baseline MMF dose = 1000 mg/day to 1250 mg/day  
 Up to 60 weeks on 1000mg/day MMF 


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 MMF withdrawal arm: These subjects will taper off MMF over 12 weeks and remain 
off MMF for the rest of their study participation (up to Week 60 or until the primary 
endpoint of disease reactivation is met, whichever comes first).  
 Baseline MMF dose = 3000 mg/day 
 Four weeks on 1000 mg MMF twice a day (BID)  
 Four weeks on 1000mg (morning) & 500mg MMF (evening) 
QD  
 Four weeks on 500 mg MMF BID  
 Up to 48 weeks on no MMF 
 Baseline MMF dose = 2500 mg/day to 2750 mg/day 
 Four weeks on 1000mg MMF BID  
 Four weeks on 1000mg (morning) & 500mg (evening) MMF 
QD 
 Four weeks on 500 mg MMF BID  
 Up to 48 weeks on no MMF 
 Baseline MMF dose = 2000 mg/day to 2250 mg/day 
 Four weeks on 1000mg (morning) & 500mg (evening) MMF 
QD  
 Four weeks on 500mg MMF BID  
 Four weeks on 500 mg MMF QD  
 Up to 48 weeks on no MMF 
 Baseline MMF dose = 1500 mg/day to 1750 mg/day 
 Four weeks on 500mg MMF BID 
 Four weeks on 500 mg MMF BID  
 Four weeks on 500 mg MMF QD  
 Up to 48 weeks on no MMF 
 Baseline MMF dose = 1000 mg/day to 1250 mg/day 
 Four weeks on 500 mg MMF BID  
 Four weeks on 500 mg MMF QD  
 Four weeks on 500 mg MMF QD  
 Up to 48 weeks on no MMF 
Concurrent therapy with anti-malarial agents (hydroxychloroquine or chloroquine) is 
required and low doses of glucocorticoids are permitted per Section 5.5, Concurrent 
Medications. 
Subject visits to assess endpoints will occur every 4 weeks from Day 0 through Week 24 and 
then at Weeks 32, 40, 48, and 60. As disease flares occur, subjects will be brought in for an 
urgent flare or endpoint visit to document symptoms, collect biological samples, and 
determine whether primary endpoint has been met.  
Accrual of subjects is expected to take 36 months. 


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Stratification, Randomization, and Blinding 
3.1.1
Subjects will be randomized in a 1:1 ratio to either continue or withdraw from MMF. Given 
the relatively small number of subjects expected per site and the importance of ensuring 
balance on key disease-defining characteristics an adaptive procedure based on Frane [31] 
minimization concepts will be used to increase the likelihood of balance in treatment arms. 
The baseline characteristics that will be considered are study site, disease manifestation 
(renal disease, which will include subjects who presently have renal disease as well as those 
who have had renal manifestations in the past, versus non-renal disease, which will include 
subjects who have never had renal disease), and baseline MMF dose (< 2000 mg per day 
versus ≥ 2000 mg per day). 
Subjects and investigational staff responsible for clinical care will not be blinded to the 
randomized treatment assignment. The cumbersome scheme that would have been needed to 
maintain the blind required that subjects take different numbers of pills from multiple bottles. 
Implementation of the scheme would have placed undue burden on the subjects and had a 
high potential for dosing errors. Knowledge of the assigned treatment also has the advantage 
of facilitating rapid response in the event of a serious flare.   
Unblinding the trial has the potential to impact the estimated rates of disease reactivation, 
because the definition of this endpoint includes subjective elements. In order to assess the 
magnitude and direction of the impact on these estimates, a second blinded clinician will also 
conduct the physical exams scheduled for Weeks 8, 12, 16, and 20.  If at Week 20, the 
subject has a mild/moderate or severe SELENA-SLEDAI flare, the blinded physician should 
also participate in the Week 24 visit. These time points were selected, because we anticipate 
that most flares will occur early in the study. The blinded physician will also receive any 
additional blinded subject records needed to complete the SELENA-SLEDAI and a 
questionnaire about the need to change medications. This information will be used to 
compare the rate of disease reactivation among blinded and unblinded assessors. 
Statistical and project staff at the SACCC and the DAIT Medical Monitor and Project 
Manager will be unblinded to individual treatment assignments as well. 
 Subject Completion and Replacement 
3.1.1.1
Accrual will continue until 120 eligible subjects either initiate the taper of MMF or begin 
their ALE06-provided MMF.  A subject is considered to have completed the study if he/she 
has completed the Week 60 visit.   
3.2 Description of Primary Endpoint 
The primary endpoint is the probability in each arm of experiencing clinically significant 
disease reactivation by 60 weeks after randomization. The 60-week time point is to allow 48 
weeks of observation off MMF and minimize dropout, which is likely to occur as the trial 
lengthens. Clinically significant SLE reactivation requires both:  


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1) A SELENA-SLEDAI*-defined mild/moderate or severe flare 
and 
2) Increased immunosuppressive therapy on a sustained basis as defined by one of the 
following criteria: 
a. Sustained activity: Subject has significant prolonged SLE flare requiring 
steroid increase/burst to ≥ 15 mg/day prednisone (or its equivalent) for 
more than four weeks. 
b. Frequent relapsing/remitting: 
i. Subject flares requiring an increase/burst of steroids and is 
successfully tapered to < 15 mg/day within four weeks, but this occurs 
on two or more occasions, or 
ii. Intra-articular, intra-muscular or IV steroids, on more than one 
occasion. 
c. Clinical activity of sufficient severity to warrant resumption of or an 
increased dose of MMF or addition of other major immunosuppressive 
including azathioprine or methotrexate. Regardless of steroid use, if the 
investigator observes disease activity of sufficient severity to warrant 
resumption, addition or increase in dosage of major immunosuppressant in 
the setting of a SELENA-SLEDAI*-defined flare, subject has met the 
primary endpoint. 
*ALE06 will typically use a spot urine protein:creatinine ratio rather than a 24-hour urine 
assessment for the SELENA-SLEDAI.  However, if indicated, results from a 24-hour urine 
collection may be used. 
3.3 Description of Secondary Endpoints 
 
Secondary Disease Activity Endpoints 
3.3.1
 Time from Day 0 to clinically significant disease reactivation (as defined in Section 
3.2, Description of Primary Endpoint). The time of clinically significant disease 
reactivation is defined as the date of the first SELENA-SLEDAI* assessment that 
meets (or goes on to meet) the criteria in Section 3.2, Description of Primary 
Endpoint. 
 The probability of experiencing any SELENA-SLEDAI* flare and the probability of 
experiencing any severe SELENA-SLEDAI* flare by Week 60, in aggregate and 
within subgroups defined by disease manifestation (renal disease/extra-renal disease) 
and by baseline MMF dosing group (<2000 mg per day / ≥ 2000 mg per day). 
 Time from initiation of withdrawal to first SELENA-SLEDAI* flare and time to first 
severe SELENA-SLEDAI* flare. 
 The probability of experiencing any BILAG* A flare by Week 60.  
 Proportion of subjects in the renal subgroup with BILAG* Renal A flare by Week 60  


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 Change in Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Disease Damage Index for Systemic Lupus Erythematosus 
(SLICC/DI)* from baseline to Weeks 24, 48, and 60. 
 The probability of adding aggressive adjunctive therapy to MMF (including  IV 
immunoglobulin or rituximab) or change in MMF therapy to cytotoxic drug (e.g., 
cyclophosphamide) due to flare. 
 Cumulative systemic steroid dose (PO, IV, IM) at Week 60.  
 Change in Functional Assessment of Chronic Illness Therapy (FACIT) fatigue score 
from baseline to Weeks 24, 48, and 60. 
 Change in SF-36® Physical Functioning (PF) and Physical Component Summary 
(PCS) domains from baseline to Weeks 24, 48, and 60. 
 Change in Lupus Quality of Life (QoL)-US© from baseline to Weeks 24, 48, and 60. 
 The following endpoints will be assessed to describe the ability of subjects to recover 
from clinically significant disease reactivation:  
o Time from clinically significant disease reactivation to improvement in 
BILAG* from maximum level during flare; 
o Time from clinically significant disease reactivation to recovery to baseline 
BILAG* scores or BILAG* C, whichever is worse;  
o Cumulative excess systemic steroid dose from time of clinically significant 
disease reactivation to return to pre-flare dose or end of trial participation; 
o Time from clinically significant disease reactivation to return to pre-flare 
steroid dose. 
*ALE06 will typically use a spot urine protein:creatinine ratio rather than a 24-hour urine 
assessment for the BILAG, SELENA-SLEDAI, and SLICC/DI.  However, if indicated, results 
from a 24-hour urine collection may be used.  
 
Secondary Safety Endpoints 
3.3.2
 All Grade 3-5 adverse events, as defined by the National Cancer Institute (NCI) – 
Common Terminology Criteria for Adverse Events (CTCAE) system, which are 
defined as possibly, probably, or definitely related to SLE.  
 All Grade 3-5 adverse events, as defined by the NCI-CTCAE system, which are 
defined as possibly, probably, or definitely related to MMF.  
 All NCI-CTCAE Grade 3-5 adverse events. 
 All serious adverse events. 
 All infection related events. 
 All malignancies. 
 All NCI-CTCAE Grade 3-5 hematological events. 
 Mortality possibly, probably, or definitely related to SLE. 
 All-cause mortality, defined as any death occurring at any time after randomization. 
 
Secondary Mechanistic Assessments 
3.3.3
 Levels of C3, C4, and anti-dsDNA at Baseline, Week 20, at the time of first flare, and 
immediately prior to first flare. 


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 Changes in levels of C3, C4, and anti-dsDNA from Baseline to Week 20, from 
Baseline to the time of first flare, and from Baseline to the time point immediately 
prior to first flare. 
 Levels of antibodies to Sm, RNP, SSA/Ro, and SSB/La at Baseline. 
 Changes in levels of antibodies to Sm, RNP, SSA/Ro, and SSB/La from Baseline to 
Week 60. 
 Levels of interferon-regulated chemokines at Baseline, Week 20, at the time of first 
flare, and at time points immediately prior to and after first flare. 
 Changes in levels of interferon-regulated chemokines from Baseline to Week 20, 
from Baseline to the time of first flare, and from Baseline to the time points 
immediately prior to and after first flare. 
 Levels of inflammatory and other cytokines at Baseline, Week 20, at the time of first 
flare and at time points immediately prior to and after first flare. 
 Changes in levels of inflammatory and other cytokines at Baseline, Week 20, at the 
time of first flare and at time points immediately prior to and after first flare. 
 Presence/Absence of gene expression patterns (e.g. fingerprint or signature) at 
Baseline, Week 20, at time of first flare, and at time points immediately prior to and 
after first flare. 
 Change in gene expression patterns from Baseline to Week 20, from Baseline to the 
time of first flare, and from Baseline to the time points immediately prior to and after 
first flare. 
4 SELECTION OF SUBJECTS 
Written informed consent must be obtained prior to the subject undergoing any study-related 
procedure, including screening tests and washout periods for prohibited medications, when 
applicable. 
4.1 Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for enrollment into the study: 
1. Able and willing to give written informed consent and comply with requirements of 
the study. 
2. Age 18 - 70 years, inclusive, at randomization. 
3. Diagnosis of SLE, per ACR criteria [32]. 
4. m-SLEDAI score < 4 at screening visit (SLEDAI score without serologies). 
5. Physician Global Assessment (0-3) score of 1 or less at screening visit. 
6. On a stable dose of MMF (1000-3000 mg/day) for at least 12 weeks prior to 
randomization. 
7. Total duration of stable or decreasing MMF therapy must be at least 
a. two years for subjects initiating MMF for renal indications (with or without 
concurrent extra-renal manifestations), or  
b. one year for subjects initiating MMF for extra-renal indications. 
8. If the subject is on prednisone or other corticosteroid, the following criteria must be 
met: 


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a. the dose may not exceed 10 mg/day (or its equivalent) for the 12 weeks prior 
to randomization. However, temporary (up to 4 total days) increases, not to 
exceed 20mg/day, are permitted.   
b. the dose must be held stable for the four weeks prior to randomization (no 
temporary increases within 4 weeks of randomization are permitted). 
9. If the subject has a history of B cell depleting therapy within the past 3 years, 
presence of CD19 positive cells must be documented within 12 weeks prior to 
screening. 
10. On maintenance HCQ or chloroquine at a stable dose for at least 12 weeks prior to 
randomization. 
4.2 Exclusion Criteria 
Subjects who meet any of the following criteria are disqualified from enrollment in the study: 
1. A history of life-threatening neuropsychiatric SLE within 1 calendar year prior to 
randomization.  
2. Any of the following laboratory abnormalities at the screening visit: 
a. Proteinuria as defined by a spot protein/creatinine ratio > 1.0 mg/mg; 
b. Serum creatinine > 2.0 mg/dL (equivalent to 177.2 μmol/L); 
c. Transaminases > 2.5x the upper limit of normal (ULN); 
d. Hemoglobin < 9 g/dL, unless the subject has documented hemoglobinopathy; 
e. White blood count (WBC) < 2000/mm3 (equivalent to < 2 x109/L); 
f. Neutrophils < 1000/mm3 (equivalent to < 1 x109/L);  
g. Platelet count < 75,000/mm3 (equivalent to < 75 x 109/L). 
3. Prednisone > 25 mg/day (or its equivalent) within 24 weeks prior to randomization 
for lupus activity. 
4. Concomitant immunosuppressants including but not limited to azathioprine, 
methotrexate, 6-mercaptopurine, leflunomide, calcineurin inhibitors, anti-tumor 
necrosis factor agents within 12 weeks prior to randomization. 
5. Plasmapheresis or IV immunoglobulin within 12 weeks prior to randomization. 
6. Cyclophosphamide therapy within 24 weeks prior to randomization. 
7. Concomitant therapy with belimumab within 24 weeks prior to randomization. 
8. B cell depleting therapy within two calendar years of randomization. 
9. Experimental therapy within the 24 weeks, or five half-lives of the agent, whichever 
is longer, prior to randomization. 
10. Solid organ or stem cell transplantation. 
11. Identified definitive diagnosis of another autoimmune disease that may require 
immunosuppression for treatment, including but not limited to: rheumatoid arthritis, 
scleroderma, primary Sjogren’s syndrome, primary vasculitis, psoriasis, multiple 
sclerosis, ankylosing spondylitis, and inflammatory bowel disease. 
12. Chronic infections including, but not limited to, human immunodeficiency virus 
(HIV), active tuberculosis (TB, currently receiving therapy), hepatitis B or hepatitis 
C, or latent systemic fungal infection. 
13. At or within 12 weeks of screening, 
 history of or current positive purified protein derivative (PPD) (> 5 mm 
induration regardless of prior Bacillus Calmette-Guérin (BCG) vaccine 


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administration) or positive QuantiFERON unless documentation exists of 
completion of at least one month of prophylaxis for latent TB or completed 
treatment for active TB 
 an indeterminate QuantiFERON® unless followed by a subsequent negative 
PPD or negative QuantiFERON®.  
14. History of malignancy within the last five years, except for resected basal or 
squamous cell carcinoma, treated cervical dysplasia, or treated in situ cervical cancer 
Grade I. 
15. Pregnant or lactating, or intention to pursue pregnancy within three months after the 
completion of the study. 
16. Unable or unwilling to use reliable methods of contraception, as outlined in the 
Mycophenolate REMS brochure for health care providers, from four weeks prior to 
randomization to 6 weeks after completion of the study.  This criterion applies to 
females of reproductive potential.  Mycophenolate REMS Program acceptable 
contraceptive methods are outlined in Appendix L. 
17. Drug or alcohol abuse within one calendar year of randomization. 
18. Other medical or psychiatric conditions that the investigator feels would place the 
subject at special risk by participation in this protocol. 
 
Co-enrollment Guidelines 
4.2.1
While participating in ALE06, subjects may not be in another clinical trial, but may be in 
observational registries or cohorts as long as the total combined volume of blood to be drawn 
does not exceed the NIH limit and objectives do not confound the current study.  
4.3 Strategies for Recruitment and Retention 
In most cases, subjects with mild or quiescent disease (see Appendix A, Definition of Mild 
Disease) will be recruited from the academic clinical practices of participating 
rheumatologists who have large SLE populations and are experienced in the use of disease 
activity instruments in SLE. Advertising via local and national community resources could 
also be considered. 
5 TREATMENT OF SUBJECTS 
5.1 Description of Study Product 
 
Product Description 
5.1.1
MMF is the 2-morpholinoethyl ester of mycophenolic acid, an immunosuppressive agent, 
and inosine monophosphate dehydrogenase inhibitor. 
The chemical name for MMF is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-
methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has molecular 
formula of C23H31NO7, a molecular weight of 433.50, and the following structural formula. 


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Packaging and Labeling of Study Product 
5.1.2
MMF will be purchased from Teva Pharmaceutical Industries, Ltd., labeled and rebottled by 
Eminent Services Corporation, and distributed by sites to all subjects as required per arm. 
 
Storage and Handling of Study Product 
5.1.3
MMF should be stored at 20° to 25°C (68° to 77°F).   
ALE06 will utilize the USP Controlled Room Temperature Guidelines (section 10.30.60) and 
any excursions from the 15° to 30°C (59° to 86°F) range specified therein will be reported to 
the study sponsor [33].  
As part of the trial, we will ensure maintenance of complete and accurate records of the 
receipt, dispensation, and disposal or return of all trial drugs in accordance with Title 21 CFR 
Parts 312.57 and 312.62. 
5.2 Dosage Regimen 
Subjects will enter the trial on 1000-3000 mg/day of MMF and will be randomized to remain on 
MMF treatment or to be tapered off MMF within 12 weeks as described in Section 3.1, 
Description of Study Design. 
5.3 Administration of Study Product 
Subjects on the MMF maintenance arm will receive a new supply of MMF at each study visit 
from Baseline through Week 48.  
Subjects on the MMF withdrawal arm will receive a new supply of MMF at each study visit 
from Baseline through Week 8. 
For additional information on criteria for withholding or discontinuing study product, see 
Section 5.4, Prevention and Management of Toxicity for MMF. 


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Administration of Study Product in Response to SLE Reactivation 
5.3.1
For subjects who experience clinically significant SLE reactivation (see Section 3.2 
Description of the Primary Endpoint) before Week 60, the treatment should be guided by the 
following and the treating investigator’s medical judgment:  
 If the flare seems likely to respond to a burst of prednisone alone, the subject may 
continue on ALE06-provided MMF and the appropriate prednisone dose should be 
prescribed. If the subject has been withdrawn from MMF and the flare is likely to 
respond to a steroid burst alone, the appropriate steroid dose may be prescribed 
without additional immunosuppression. 
 If the flare is not likely to respond to a burst of prednisone alone, then:  
o if the subject is taking MMF < 3000 mg/day, the subject will discontinue 
ALE06-provided study drug, and the subject should be prescribed MMF at a 
higher dose than what (s)he is currently taking. Other alternative or additional 
immunosuppressive therapy per investigator’s discretion may be used. An 
appropriate steroid taper may be prescribed. 
o if the subject is currently taking MMF 3000 mg/day and the flare is so severe 
that either cyclophosphamide or adjunctive therapy plus MMF would be used, 
the subject will discontinue ALE06-provided study drug and the site principal 
investigator (PI) will prescribe immunosuppression as indicated.  As 
guidance, BILAG* A flares in Renal, Neuropsychiatric, or Hematological 
domains may represent such severe flares. 
 
See Section 5.10, Treatment Discontinuation and Subject Withdrawal for additional 
information.   
5.4 Prevention and Management of Toxicity for MMF 
Subjects will be monitored for potential toxicities of MMF at all study visits scheduled 
through Week 60. 
 
Malignancy 
5.4.1
Increased risk of lymphoproliferative disease and non-melanoma skin cancers will be 
addressed by the physical examinations conducted at each visit. If evidence of 
lymphoproliferative disease emerges, work up will be guided by the institution’s standard of 
care requirements. If malignancy (other than skin cancers described below) is diagnosed, the 
study drug will be discontinued and the subject will be treated according to standard of care 
per institutional requirements. If new non-melanoma skin cancer is found and fully treatable 
with local procedures, the subject may continue in the trial as planned based on investigator 
discretion. 


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Hematological Abnormalities   
5.4.2
To monitor potential hematological toxicity, the subjects will have a complete blood count at 
each visit. If neutropenia (neutrophils < 800/mm3, equivalent to 0.8 x109/L), leukopenia 
(WBC < 1500/mm3, equivalent to 1.5 x109/L), thrombocytopenia (platelets < 40,000/mm3, 
equivalent to 40 x109/L), or anemia (hemoglobin < 7.0 g/dL) develop without another more 
likely explanation and persist after a repeat check in one week, then study drug will be held 
for one week and the test repeated. Study drug may be held up to two weeks while the 
abnormality is monitored weekly for recovery. If recovery occurs then study drug can be 
resumed. Otherwise, refer to the guidelines in Section 5.10.1, Study Treatment 
Discontinuation in the event of toxicity. If subjects have symptomatic complications from the 
hematological derangements, this should be treated according to standard of care per 
institutional requirements. 
 
Hepatic Abnormalities 
5.4.3
Liver function tests will be checked every 8 to 12 weeks for signs of hepatic toxicity. If 
transaminases exceed 3x ULN and other more likely causes are not identified, then study 
drug will be held for up to two weeks, and the abnormality followed weekly for resolution. 
Should resolution occur within 14 days, the study drug may be resumed. Otherwise, refer to 
the guidelines in Section 5.10.1, Study Treatment Discontinuation in the event of toxicity. 
 
Infections 
5.4.4
Both common and opportunistic infections have been described in subjects on MMF. 
Subjects will be followed closely for signs of infection at study visits, and between visits if 
needed. Assessment and treatment for infection will be guided by standard of care per 
institutional requirements. In the setting of infection, study drug may be withheld based on 
institutional practices or investigator judgment, for up to two weeks and then resumed at 
scheduled dose. Otherwise, refer to the guidelines in Section 5.10.1, Study Treatment 
Discontinuation in the event of toxicity. Pneumocystis carinii pneumonia prophylaxis 
medications may be used based on institutional practice to lower the risk of this specific 
opportunistic infection, but is not mandated by the protocol. 
 
Gastrointestinal Abnormalities 
5.4.5
Gastrointestinal side effects including nausea and diarrhea may occur with MMF use. If these 
symptoms exacerbate without other likely explanation, study drug may be withheld for up to  
two weeks and resumed at the scheduled dose. Otherwise, refer to the guidelines in Section 
5.10.1, Study Treatment Discontinuation in the event of toxicity. 
 
Reproductive Risks 
5.4.6
Women on MMF and of childbearing potential will have a routine pregnancy test at 
screening, Week 12, 24, 40, and 60, and additionally as clinically indicated. Should 
pregnancy occur, study treatment would be discontinued immediately, study visits will 
continue as scheduled except for study drug, and the pregnancy will be followed per Section 


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7.6, Pregnancy Reporting. Appropriate referrals should be made for counseling on fetal 
effects of study drug. The pregnancy should be reported to the Mycophenolate Pregnancy 
Registry which is a part of the MMF REMS program.   
 
Male subjects and female partners capable of becoming pregnant are encouraged to use a 
contraceptive barrier method during the study.   
5.5 Concurrent Medications  
 
Anti-malarial Agents 
5.5.1
Subjects will be on concurrent anti-malarial agents (hydroxychloroquine or chloroquine). 
Hydroxychloroquine is approved by the FDA for the treatment of SLE. Hydroxychloroquine 
has been shown to help prevent flare in SLE, and to improve skin and musculoskeletal 
activity in particular [7, 8]. Even lupus nephritis outcomes appear improved on a background 
of hydroxychloroquine therapy [34]. 
 
Prednisone (or Equivalent) 
5.5.2
Once the subject is randomized into the trial, the prednisone (or other corticosteroid) dose 
must be stable through Week 36 (24 weeks following protocol taper of MMF), in the absence 
of flares as described in Section 3.2, Description of Primary Endpoint. Further taper of 
prednisone after that point is by the investigator’s discretion based on the subject’s clinical 
status. 
 
A stable dose is defined as maintenance of the baseline dose, which must be ≤ 10 mg 
prednisone/day (or equivalent dose of an alternate corticosteroid). However, to accommodate 
the occasional use of extra corticosteroids by patients for reasons not associated with SLE 
flares, increases of up to 20 mg/day that are decreased back to the baseline dose within 4 
days are permitted, but not on more than 2 occasions during the study.  These short increases 
in dose may not be accompanied by a documented flare. 
 
For subjects taking prednisone (or equivalent) every other day (QOD), to calculate their daily 
dose (per the requirements above), halve their QOD dose. 
5.6 Prohibited Medications 
All subjects are to have access to any care deemed medically necessary, but administration of 
the following medications, for the purposes of this study, are prohibited, and will be 
considered major protocol deviations unless subject has met primary endpoint as described in 
Section 3.2, Description of Primary Endpoint: 
 Immunosuppressant agents are prohibited except for glucocorticoids (as described in 
Section 3.2, Description of Primary Endpoint), hydroxychloroquine/chloroquine  and 
MMF for subjects in the MMF maintenance arm and for subjects in the MMF 
withdrawal arm during the tapering period. 


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o Prohibited immunosuppressant agents include, but are not limited to, those 
referenced in Section 4.2, Exclusion Criteria: azathioprine, methotrexate, 6-
mercaptopurine, leflunomide, calcineurin inhibitors, anti-tumor necrosis factor 
agents, plasmapheresis, IV immunoglobulin, cyclophosphamide, belimumab, 
abatacept, B cell depleting therapy, experimental therapy. 
5.7 Toxicity Management Plan for Concurrent Therapy: Hydroxychloroquine or 
Chloroquine 
Hydroxychloroquine may affect the eye, specifically the retina on rare occasions. Serious 
rare reported associations include torsade de pointes, agranulocytosis, aplastic anemia, 
leucopenia and thrombocytopenia, hepatic failure, drug-induced myopathy, neuromyopathy, 
seizure, hearing loss, and angiodema [35]. 
Chloroquine is a closely related compound which may be substituted for hydroxychloroquine 
when a more potent anti-malarial is needed, particularly for refractory cutaneous SLE. No 
common adverse events are reported, but rare serious events include atrioventricular block, 
heart failure, Stevens-Johnsons syndrome, neutropenia, anaphylaxis, seizure, and retinopathy 
[36]. 
Guidelines recommend periodic retinal monitoring for HCQ and chloroquine [37, 38]. 
Retinal monitoring should follow institutional practice. Should concern for retinal toxicity 
from anti-malarial therapy arise based on retinal examination, this medication should be 
discontinued. Subjects may continue in the trial uninterrupted if anti-malarials are stopped 
for medical reasons. 
Hematological or hepatic toxicities with anti-malarials are extremely rare in clinical use for 
SLE and no mandated monitoring is required for these toxicities. Complete blood counts and 
hepatic function will be performed at study visits as part of routine monitoring for disease 
activity and potential MMF toxicity. Should hematological or hepatic toxicities (NCI-
CTCAE Grade 3-5) occur in the absence of more likely causes, anti-malarial therapy may be 
held per investigator’s discretion while the toxicity is monitored. Anti-malarials may be 
resumed per investigator’s discretion if there does not appear to be a clear relationship of 
toxicity to anti-malarial use after observation over time. 
5.8 Other Standard of Care Recommendations  
Ideally, relevant concurrent therapy such as angiotensin inhibitor/angiotensin receptor 
blockers should be held constant throughout the trial. Osteoporosis treatment and prevention 
medications, as well as treatment for other comorbid conditions, should be considered based 
on investigator discretion due to subject characteristics and preferences. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used on an as-needed basis if the 
investigator feels the medical status of the subject permits the use of these drugs. NSAIDs 
can be associated with impairment in renal function and should be used with caution in 
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Should subjects experience deterioration in renal function NSAIDs should be discontinued 
and renal function retested. NSAIDs also increase the risk of peptic ulcer disease and GI 
bleeding, and should be used with caution and with concurrent proton pump inhibitors in 
high-risk subjects. 
5.9 Procedures for Monitoring Subject Compliance 
For the MMF maintenance arm, pill counts of the MMF will be performed at each visit, 
Week 4 through Week 60, to assess compliance. 
 
For the MMF withdrawal arm, pill counts of the MMF will be performed at each visit, Week 
4 through Week 12, to assess compliance. 
5.10 Treatment Discontinuation and Subject Withdrawal 
 
Study Treatment Discontinuation 
5.10.1
Study drug provided by the sponsor will be discontinued for any individual subject under the 
following conditions: 
1. At any time during the study at the request of the subject or subject’s guardian. 
2. If investigators or NIAID determine that the subject’s health, safety, and/or well-
being are threatened. 
3. For either disease activity or toxicity guidelines as outlined below: 
 Disease Activity: If the subject meets the primary endpoint of clinically 
significant disease reactivation, the study drug will be discontinued and subject 
treated at the discretion of the investigator per Section 5.3.1, Administration of 
Study Product in Response to SLE Reactivation, but the subject will continue 
study visits. Clinically significant disease reactivation is defined in Section 3.2 
Description of Primary Endpoint. 
 Toxicity or Infection: 
o If the subject must discontinue study drug for more than 14 sequential 
days due to ongoing, suspected MMF toxicity, then study drug will be 
discontinued, but the subject will continue study visits. 
o If the subject has study drug withheld for a cumulative total of 28 days or 
greater in the setting of multiple or recurrent MMF toxicity, study drug 
will be discontinued, but the subject will continue study visits. 
4. If the subject is female and becomes pregnant.  
5. Subject non-compliance with treatment regimens or failure to keep appointments. 
Subjects who discontinue protocol-specified treatment requirements will be treated as 
medically indicated according to discretion of the treating physician. 


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 Procedures for Discontinuation of Protocol-Specified Treatment 
5.10.1.1
Requirements 
Whenever possible, subjects who have been discontinued from study treatment for disease 
activity or toxicity should complete all remaining scheduled study visits including all exams, 
procedures, assessments, and tests. Furthermore, if study treatment discontinuation is due to 
safety concerns, subjects will be given appropriate care under medical supervision beyond 
the last scheduled study visit, if necessary, per Sections 7.3.4, Recording Adverse Events, and 
7.3.5, Recording Serious Adverse Events. If the site PI determines that completion of these 
visits is not clinically appropriate for the subject or if the subject or subject’s guardian elects 
not to complete these visits, the subject will be withdrawn from the study per the guidelines 
in Section 5.10.2, Subject Withdrawal from the Study. 
 
 Subject Withdrawal from the Study 
5.10.2
When a subject is withdrawn from the study, protocol-specified treatment requirements are 
discontinued, and all study-related visits, exams, procedures, assessments, tests and data 
collection are terminated. Individual subjects will be withdrawn from the study under the 
following conditions: 
1. The subject or subject’s guardian withdraws consent. 
2. The investigator or NIAID believes it is in the best interest of the subject. 
3. The subject is lost to follow-up. 
4. The study is terminated. 
 Procedures for Subject Withdrawal from the Study 
5.10.2.1
Whenever possible, subjects to be withdrawn from the study will be asked to consent to an 
end-of-study evaluation, which includes all scheduled exams, procedures, and laboratory 
tests planned for the Week 60 visit. Furthermore, if discontinuation is due to safety concerns, 
subjects will be given appropriate care under medical supervision beyond the last scheduled 
study visit, if necessary, until the symptoms of any AE resolve or the subject’s condition 
becomes stable. After this end-of-study visit, the PI (or designated treating physician) may 
continue to follow the subject to manage clinical care, but no additional study-related data 
will be collected. 
 
Safety Stopping Guidance  
5.10.3
The DSMB will review any event that potentially impacts safety at the request of the 
protocol chair or DAIT/NIAID.  The DSMB will have discretion to recommend actions 
regarding study conduct and continuation as a consequence of any planned or unplanned 
monitoring activity. 
The DSMB will be informed in real time of the following event: 
 Any immediately life-threatening event or death that occurs in the study, which is 
possibly, probably, or definitely related to study participation. 
 


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In addition, the following events will trigger both a comprehensive DSMB Emergency Safety 
Review and a temporary halt in enrollment: 
 Events that result in permanent discontinuation of study intervention occurring in  
o 3 of the first 10 subjects randomized to the MMF withdrawal or  
o 30% of subjects randomized to MMF withdrawal at any time point after the 
11th subject is randomized. 
 BILAG* A flares occurring in  
o 3 of the first 10 subjects randomized to MMF withdrawal or  
o 30% of subjects randomized to MMF withdrawal at any time point after the 
11th subject is randomized. 
 Severe SELENA-SLEDAI* flares occurring in  
o 3 of the first 10 subjects randomized to MMF withdrawal or  
o 30% of subjects randomized to MMF withdrawal at any time point after the 
11th subject is randomized. 
 
In the event of a temporary halt in enrollment, no new subjects will be consented, 
randomized or start on study product; subjects already on study product will continue unless 
they are the focus of the DSMB review. Subjects in the screening phase of the study may 
continue to undergo minimal risk procedures (e.g., blood tests), but more than minimal risk 
procedures should be deferred. Randomization will not occur until the DSMB review is 
complete. After careful review of the data, the DSMB will make recommendations regarding 
study conduct and/or continuation. 
 
In addition, at each planned Data Review Meeting, the DSMB will review the estimated risk 
difference for disease reactivation (i.e. risk_MMFwithdrawal - risk_MMF maintenance) and consider 
whether or not the trial should be stopped for safety concerns. (See Section 8.4 Interim 
Analysis for details.) 
6 ASSESSMENT OF SAFETY AND DISEASE ACTIVITY 
6.1 Assessments of Safety 
To assess safety in this population, peripheral blood cell counts, liver function, and serum 
creatinine will be monitored before enrollment and at frequent intervals thereafter. A 
physical examination will be conducted at each study visit. The information from these 
assessments will be used to characterize the frequency of all AEs, all SAEs, as well as the 
other safety endpoints noted in Section 3.3.2, Secondary Safety Endpoints. 
6.2 Assessments of Disease Activity 
Clinically significant disease reactivation (defined in Section 3.2 Description of Primary 
Endpoint) is the primary endpoint of this trial. Disease activity will be monitored by 
evaluating clinical outcomes at screening and serially throughout the trial.  
 


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The m-SLEDAI* will be assessed at screening and the SELENA-SLEDAI* along with 
medications will be assessed at each study visit to evaluate clinically significant disease 
reactivation. SLE disease activity will also be assessed by administration of the BILAG* and 
the SLICC/DI*. The original lupus instruments include an evaluation of proteinuria based on 
the protein:creatinine ratio derived from a 24-hour urine.  For this study, the 
protein:creatinine ratio will typically be derived from the spot urine assessment although a 
24-hour urine may be used if the spot urine assessment is not available. 
 
Quality of life will be assessed by administration of the FACIT, SF-36®, and Lupus QoL©. 
6.3 Mechanistic  Studies 
Secondary mechanistic objectives overall are to define biomarkers, which are associated with 
increased risk of disease flare in SLE patients. 
 
Serologic Markers 
6.3.1
Serum for serologic markers including C3, C4, and antibodies to dsDNA, Sm, RNP, SSA/Ro 
and SSB/La will be collected at every scheduled visit and every Flare Visit. 
 
C3, C4, and dsDNA antibodies (anti-dsDNA) are needed at each visit as part of the 
SELENA-SLEDAI* scoring system, but will also be analyzed as independent markers to 
define the utility of the markers in predicting which subjects will meet the primary endpoint 
of clinical disease activation.  
 
Antibodies to Sm, RNP, SSA/Ro, and SSB/La will be measured from a serum specimen at 
Baseline and Week 60 for all subjects. To evaluate these markers as predictors of flare, 
samples collected at pre-flare, flare, and post-flare time points may be analyzed for those 
subjects who flare. For subjects who do not flare, samples may be analyzed at three 
additional time points for comparison to the results for flaring subjects.. 
 
Cytokine and Chemokine Analysis 
6.3.2
Serum for cytokines and chemokines will be collected at every scheduled visit and every 
Flare Visit and stored until the study is completed. 
 
Hypotheses: 
i. 
Subjects with elevated levels of interferon associated cytokine or chemokines at 
baseline will be significantly more likely to flare and will have earlier time to flare 
following MMF withdrawal than those with elevated levels of interferon associated 
cytokine or chemokines who remain on MMF; 
ii. 
Subjects who flare will have elevated levels of interferon associated cytokines or 
chemokines at the visit prior to flare compared to the baseline visit, and an increase in 
levels of interferon associated cytokine or chemokines will be predictive of clinically 
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Once sample collection is completed for all subjects, assays for interferon related cytokines 
and chemokines will be performed on selected serum samples using commercially-available 
bead-based assays or  sandwich ELISAs.  For subjects who flare, samples collected at 
Baseline (Day 0), Week 20, and at pre-flare, flare, and post-flare time points will be 
analyzed. For subjects who do not flare, samples to be analyzed will include: Baseline, Week 
20, and three additional time points. 
 
Transcript Profiling Studies 
6.3.3
RNA for transcript analysis will be collected at every scheduled visit and every Flare Visit 
and stored until the study is completed. 
 
Hypotheses: 
i. 
Subjects with an “Immunologically Active B Cell Fingerprint” will be more likely to 
flare than subjects with an “Inactive B Cell Fingerprint”;  
ii. 
Subjects with an “Interferon-α Signature” will be more likely to flare than subjects 
who lack an Interferon-α Signature. 
 
Transcript profiling for gene expression will be performed on the subset of subjects who flare 
(estimated at ~15) and matched subjects who do not flare (estimated at 30).  For flaring 
subjects, RNA transcripts will be analyzed at each of 5 time points (Baseline, Week 20, first 
flare, and the time points immediately prior to and after first flare). For the subjects who do 
not flare, RNA transcripts will be analyzed at Baseline, Week 20, and time points 
comparable to the pre-flare, flare, and post-flare time points for matched flaring subjects. All 
samples will be analyzed at the end of the study, after all flares have been identified. 
Differences in gene expression at Baseline will be explored among subjects who do and do 
not flare. In addition, differences in gene expression among treatment arms will also be 
investigated.  
 
Future Use Assays 
6.3.4
Leftover serum, plasma, and/or RNA from the planned mechanistic studies (Section 6.3.2 
and 6.3.3) will be stored until the end of the study and used only to confirm mechanistic 
studies already performed and described above.   
 
If appropriate consents are given, samples for unspecified, IRB approved, future use to study 
SLE, the immune system, and the effect of treatment on SLE will be collected as specified 
below:   
 Future Use: PBMCs/Plasma will be collected as follows: 
o For subjects who do not experience any flares requiring an increase in 
prednisone or immunomodulatory medication, collect PBMCs/Plasma at 
Baseline, Week 20, and Week 60.   
o For subjects who experience a mild/moderate flare where increased 
prednisone is prescribed, collect PBMCs/Plasma at Baseline, Week 20, and 
the first Flare Visit where increased medication is prescribed.  


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 If an increase in prednisone is followed at a subsequent visit with an 
increase in immunomodulatory medication, then a fourth sample 
should be collected.  Specimens should be collected prior to the 
beginning treatment at the increased dose. 
o For subjects who experience a severe flare where increased 
immunomodulatory medication is prescribed, collect PBMCs/Plasma at 
Baseline, Week 20, and the first Flare Visit where increased medication is 
prescribed.  Specimens should be collected prior to beginning treatment at the 
increased dose. 
 Future Use: Plasma only will be collected at Weeks 4,8,12,16, 24, 32, 40, and 
48.  In addition, if a specimen (s) has been previously collected for a qualifying flare, 
plasma only will be collected at Week 60 or Endpoint. 
 Future Use: Urine will be collected at Baseline, Week 20, any (and all) Flare Visits 
where increased prednisone or immunomodulatory medication is prescribed, or at 
Week 60 if no flare occurs 
 Future Use: DNA will be extracted from the PBMC specimen and stored for 
unspecified, IRB approved, future use.  
 
Depending on the clinical results of the study, B & T Cell FACS may be done using the 
stored PBMC specimen described above. 
 
Subjects will be able to opt-out of the storage of these samples during the consent process 
with the exception of samples drawn for the B and T cell FACS analysis. These studies will 
be run on all participants in the study if the clinical data warrants them. 
 
Any future research on these samples will be reviewed and approved by an IRB prior to its 
conduct. Only coded samples would be provided to approved researchers. 
 
Blood Draw Prioritization 
6.3.5
Should the subject have been experiencing severe anemia (hemoglobin < 8g/dL) or have poor 
venous access, the blood draw limit is 30 mL and the priority of samples to collect is as 
follows: 
• 
Safety draws: chemistries, hematologies, anti-dsDNA, C3, C4 (10-13 mL, depending 
on visit) 
• 
Serum for Cytokines/Chemokines/Antibodies to Sm, RNP, SSA/Ro, SSB/La    
(except limit blood draw to approximately 2.5 mL) 
• 
RNA Assays (except limit blood draw to 2.5 mL) 
• 
Future use: PBMCs & Plasma (drawn at Baseline, Week 20, and Flare or Week 60 
Visits only, except limit blood draw to 8 mL) 
• 
Future Use: Plasma (drawn at Weeks 4, 8, 12, 16, 24, 32, 40, 48, and Week 60 only if 
the subject experienced a flare while on study) 
 
Should the subject have been experiencing moderate-severe anemia (hemoglobin 8-9 g/dL), 
the blood draw limit is 50 mL and the priority of samples to collect is as follows: 


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• 
Safety draws: chemistries, hematologies, anti-dsDNA, C3, C4 (10-13 mL, depending 
on visit) 
• 
Serum for Cytokines/Chemokines/Antibodies to Sm, RNP, SSA/Ro, SSB/La    
(except limit blood drawn to approximately 5 mL) 
• 
RNA Assays  
• 
Future use: PBMCs & Plasma (drawn at Baseline, Week 20, and Flare or Week 60 
Visits only, except limit blood draw to 24 mL) 
• 
Future Use: Plasma (drawn at Weeks 4, 8, 12, 16, 24, 32, 40, 48, and Week 60 only if 
the subject experienced a flare while on study) 
 
Subjects with hemoglobin above 9.0 mg/dL may have blood draws as scheduled. 
 
Exceptions to Blood Drawing Limits:  
 In any patient whose clinical condition might be adversely affected by removal of the 
volumes stated above, for example, patients with significant anemia or compromised 
cardiac output, investigators should consider further limiting the volume of blood 
withdrawn for research purposes. 
6.4 Evaluations by Study Visit 
Refer to Table 6.1, Schedule of Evaluations for a complete listing of evaluations by study 
visit. 
Note: all subjective assessments completed by the subject (FACIT, SF-36®, Lupus QoL©) 
must be done at the beginning of a visit, prior to any other study related procedures. 
 
Study physicians must enroll in the MMF REMS program and send a copy of the completed 
Prescriber Training Confirmation form to the sponsor. 
 
Screening Period 
6.4.1
Unless otherwise specified, the screening evaluations must be performed within 28 days prior 
to the Baseline/Randomization Visit. 
This study will be explained in lay language to each potential participant. Each participant 
will sign an informed consent form before committing to study screening procedures. 
The following labs, procedures, and assessments will determine subject eligibility: 
 Demographics 
 Medical history assessment, including Family History of Autoimmune 
Disease 
 Physical examination 
 Vitals, including height & weight 
 Physician’s global assessment 
 m-SLEDAI 


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 Medications assessment 
 PPD or QuantiFERON®-TB Gold In-Tube Test (QFT-G-IT): unless 
performed within 12 weeks prior to screening and documented as negative in 
the subject’s records, or unless subject is known to have a positive or 
indeterminate test and has documentation of appropriate therapy. 
 Chemistries (albumin, alkaline phosphatase [ALP], alanine transaminase 
[ALT], aspartate transaminase [AST], blood urea nitrogen [BUN], creatinine, 
glucose, phosphorus, potassium, bilirubin, total protein)  
 Hematologies (hemoglobin, mean corpuscular volume [MCV], platelet count, 
red cell distribution width [RDW], WBC, lymphocytes, monocytes, 
neutrophils) 
 Hematology: lymphocyte subset, only if 
o the subject was on a B cell depleting agent in the past 3 years  
and 
o a test result documenting detectable B cells was not done within 12 weeks 
prior to screening.    
 Infectious disease screen including HIV antibody, hepatitis B surface antigen, 
hepatitis C virus (HCV) antibody with HCV RNA (PCR) if antibody positive 
(unless documented as negative within 12 weeks prior to the Screening visit) 
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine 
 Pregnancy test, for women of child-bearing potential only 
o 
Review acceptable contraceptive methods per MMF REMS guidelines 
(See Appendix L).  
 
Baseline/Randomization Visit 
6.4.2
The baseline evaluations must be performed on Day 0 and within 28 days of the Screening 
visit. 
 Randomization 
 FACIT 
 SF-36® 
 Lupus QoL© 
 Physical examination 
 Vitals, including weight 
 Physician’s global assessment 
 SELENA-SLEDAI* 
 SLICC/DI* 
 BILAG* 
 Medications assessment 
 AE assessment 
 Anti-dsDNA, C3, C4 
 Serum creatinine 


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o Note: When a chemistry panel is not done, serum creatinine and Anti-
dsDNA, C3, C4 will be run from the same blood tube. 
 Hematologies (hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils)  
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine 
 Serum for Cytokines/Chemokines/Antibodies to Sm, RNP, SSA/Ro, SSB/La – 
10 mL 
 RNA Assays – 5 mL 
 Future Use: PBMCs & Plasma – 40 mL 
 Future Use: Urine – 10 mL  
 Dispense MMF to all subjects 
 
Treatment Period 
6.4.3
 Week 4 (± 7 days) 
6.4.3.1
 Physical examination 
 Vitals, including weight 
 Physician’s global assessment 
 SELENA-SLEDAI* 
 BILAG* 
 Medications assessment 
 AE assessment 
 Anti-dsDNA, C3, C4 
 Serum creatinine 
 Hematologies (hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils) 
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine 
 Serum for Cytokine/Chemokine Assays – 10 mL 
 RNA Assays – 5 mL 
 Future Use: Plasma – 8.5 mL  
 Assess MMF compliance for all subjects 
 Dispense MMF to all subjects 
 Week 8 (± 7 days) 
6.4.3.2
 Physical examination 
 Physical examination by a blinded investigator 
 Vitals, including weight 
 Physician’s global assessment 
 SELENA-SLEDAI* 
 SELENA-SLEDAI* & treatment questionnaire by a blinded investigator 
 BILAG* 


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 Medications assessment 
 AE assessment 
 Anti-dsDNA, C3, C4  
 Serum creatinine 
 Hematologies (hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils)  
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine 
 Serum for Cytokine/Chemokine Assays – 10 mL 
 RNA Assays – 5 mL  
 Future Use: Plasma – 8.5 mL 
 Assess MMF compliance for all subjects 
 Dispense MMF to all subjects 
 Week 12 (± 7 days) 
6.4.3.3
 Physical examination 
 Physical examination by a blinded investigator 
 Vitals, including weight 
 Physician’s global assessment 
 SELENA-SLEDAI* 
 SELENA-SLEDAI* & treatment questionnaire by a blinded investigator 
 BILAG* 
 Medications assessment 
 AE assessment 
 Chemistries (albumin, ALP, ALT, AST, BUN, creatinine, glucose, 
phosphorus, potassium, bilirubin, total protein) 
 Anti-dsDNA, C3, C4  
 Hematologies (hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils) 
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine 
 Serum for Cytokine/Chemokine Assays – 10 mL 
 RNA Assays – 5 mL  
 Future Use: Plasma – 8.5 mL  
 Assess MMF compliance for all subjects 
 Dispense MMF to only subjects in the MMF maintenance arm 
 Pregnancy test, for women on MMF and of child-bearing potential only 
o 
Review acceptable contraceptive methods per MMF REMS guidelines 
(See Appendix L).  
 Week 16 (± 7 days) 
6.4.3.4
 Physical examination 
 Physical examination by a blinded investigator 
 Vitals, including weight 


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 Physician’s global assessment 
 SELENA-SLEDAI* 
 SELENA-SLEDAI* & treatment questionnaire by a blinded investigator 
 BILAG* 
 Medications assessment 
 AE assessment 
 Anti-dsDNA, C3, C4  
 Serum creatinine 
 Hematologies (hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils)  
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine 
 Serum for Cytokine/Chemokine Assays – 10 mL 
 RNA Assays – 5 mL 
 Future Use: Plasma – 8.5 mL 
 Assess MMF compliance for only subjects in the MMF maintenance arm 
 Dispense MMF to only subjects in the MMF maintenance arm 
 Week 20 (± 7 days) 
6.4.3.5
 Physical examination 
 Physical examination by a blinded investigator 
 Vitals, including weight 
 Physician’s global assessment 
 SELENA-SLEDAI* 
 SELENA-SLEDAI* & treatment questionnaire by a blinded investigator 
 BILAG* 
 Medications assessment 
 AE assessment 
 Anti-dsDNA, C3, C4  
 Serum creatinine 
 Hematologies (hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils)  
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine 
 Serum for Cytokine/Chemokine Assays – 10 mL 
 RNA Assays – 5 mL  
 Future Use: PBMCs & Plasma – 40 mL  
 Future Use: Urine – 10 mL 
 Assess MMF compliance for only subjects in the MMF maintenance arm 
 Dispense MMF to only subjects in the MMF maintenance arm 
 Week 24 (± 7 days) 
6.4.3.6
 FACIT 
 SF-36® 


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 Lupus QoL© 
 Physical examination 
 Physical examination by a blinded investigator – only if at Week 20, the 
subject is being monitored for flare 
 Vitals, including weight 
 Physician’s global assessment 
 SELENA-SLEDAI* 
 SELENA-SLEDAI* & treatment questionnaire by a blinded investigator – 
only if at Week 20, the subject is being monitored for flare 
 SLICC/DI* 
 BILAG* 
 Medications assessment 
 AE assessment 
 Chemistries (albumin, ALP, ALT, AST, BUN, creatinine, glucose, 
phosphorus, potassium, bilirubin, protein ) 
 Anti-dsDNA, C3, C4 
 Hematologies (hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils)  
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine 
 Serum for Cytokine/Chemokine Assays – 10 mL 
 RNA Assays – 5 mL 
 Future Use: Plasma – 8.5 mL 
 Assess MMF compliance for only subjects in the MMF maintenance arm 
 Dispense MMF to only subjects in the MMF maintenance arm 
 Pregnancy test, for women on MMF and of child-bearing potential only 
o 
Review acceptable contraceptive methods per MMF REMS guidelines 
(See Appendix L).  
 Week 32 (± 7 days) 
6.4.3.7
 Physical examination 
 Vitals, including weight 
 Physician’s global assessment 
 SELENA-SLEDAI* 
 BILAG* 
 Medications assessment 
 AE assessment 
 Chemistries (albumin, ALP, ALT, AST, BUN, creatinine, glucose, 
phosphorus, potassium, bilirubin, protein ) 
 Anti-dsDNA, C3, C4 
 Hematologies (hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils) 
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine  
 Serum for Cytokine/Chemokine Assays – 10 mL 


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 RNA Assays – 5 mL 
 Future Use: Plasma – 8.5 mL 
 Assess MMF compliance for only subjects in the MMF maintenance arm 
 Dispense MMF to only subjects in the MMF maintenance arm 
 Week 40 (± 7 days) 
6.4.3.8
 Physical examination 
 Vitals, including weight 
 Physician’s global assessment 
 SELENA-SLEDAI* 
 BILAG* 
 Medications assessment 
 AE assessment 
 Chemistries (albumin, ALP, ALT, AST, BUN, creatinine, glucose, 
phosphorus, potassium, bilirubin, protein ) 
 Anti-dsDNA, C3, C4 
 Hematologies (hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils) 
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine 
 Serum for Cytokine/Chemokine Assays – 10 mL 
 RNA Assays – 5 mL 
 Future Use: Plasma – 8.5 mL 
 Assess MMF compliance for only subjects in the MMF maintenance arm 
 Dispense MMF to only subjects in the MMF maintenance arm 
 Pregnancy test, for women on MMF and of child-bearing potential only 
o 
Review acceptable contraceptive methods per MMF REMS guidelines 
(See Appendix L).  
 Week 48 (± 7 days) 
6.4.3.9
 FACIT 
 SF-36® 
 Lupus QoL© 
 Physical examination 
 Vitals, including weight 
 Physician’s global assessment 
 SELENA-SLEDAI* 
 SLICC/DI* 
 BILAG* 
 Medications assessment 
 AE assessment 
 Chemistries (albumin, ALP, ALT, AST, BUN, creatinine, glucose, 
phosphorus, potassium, bilirubin, protein ) 


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 Anti-dsDNA, C3, C4 
 Hematologies (hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils)  
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine 
 Serum for Cytokine/Chemokine Assays – 10 mL 
 RNA Assays – 5 mL 
 Future Use: Plasma – 8.5 mL 
 Assess MMF compliance for only subjects in the MMF maintenance arm 
 Dispense MMF to only subjects in the MMF maintenance arm  
 Week 60 (± 7 days) 
6.4.3.10
 FACIT 
 SF-36® 
 Lupus QoL© 
 Physical examination 
 Vitals, including weight 
 Physician’s global assessment 
 SELENA-SLEDAI* 
 SLICC/DI* 
 BILAG* 
 Medications assessment 
 AE assessment 
 Chemistries (albumin, ALP, ALT, AST, BUN, creatinine, glucose, 
phosphorus, potassium, bilirubin, protein) 
 Anti-dsDNA, C3, C4 
 Hematologies (hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils)  
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine 
 Serum for Cytokines/Chemokines/Antibodies to Sm, RNP, SSA/Ro, SSB/La  
– 10 mL 
 RNA Assays – 5 mL  
 Future Use: Urine – 10 mL, if the subject did not experience a flare while on 
study 
 Either  
o Future Use: Plasma – 8.5 mL, if Future Use: PBMCs & Plasma  have 
been previously collected for a flare while on study 
o Future Use: PBMCs & Plasma – 40 mL, if the subject did not 
experience a flare requiring increased prednisone or 
immunomodulatory medication while on study  
 Assess MMF compliance for only subjects in the MMF maintenance arm 
 Pregnancy test, for women on MMF and of child-bearing potential only 
o 
Review acceptable contraceptive methods per MMF REMS guidelines 
(See Appendix L).  


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As Needed Visits 
6.4.4
 Flare Visit 
6.4.4.1
A flare visit is to occur when a subject experiences a flare and may coincide with a regularly 
scheduled or unscheduled study visit. 
 FACIT 
 SF-36® 
 Lupus QoL© 
 Physical examination 
 Vitals, including weight 
 Physician’s global assessment 
 SELENA-SLEDAI* 
 SLICC/DI* 
 BILAG* 
 Medications assessment 
 AE assessment 
 Chemistries (albumin, ALP, ALT, AST, BUN, creatinine, glucose, 
phosphorus, potassium, bilirubin, total protein) 
 Anti-dsDNA, C3, C4 
 Hematologies (hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils)  
 Urinalysis including dipstick, microscopic analysis, spot protein/creatinine 
 
Collect the following specimens prior to beginning or increasing treatment 
with an increased dose of prednisone or immunomodulatory medications.   
 
 Serum for Cytokines/Chemokines/Antibodies to Sm, RNP, SSA/Ro, SSB/La – 
10 mL 
 RNA Assays – 5 mL  
 Future Use: PBMCs & Plasma – 40 mL, only for qualifying Flare visits.  See 
Section 6.3.4: Future Use Assays.   
 Future Use: Urine – 10 mL  
 Endpoint Visit 
6.4.4.2
An endpoint visit is to occur when a site needs to determine if a subject has met the primary 
endpoint, as described in Section 3.2, Description of Primary Endpoint and may coincide 
with a regularly scheduled study visit. An endpoint visit will consist of all Week 60 
assessments, see Section 6.4.3.15, Week 60. 


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 Unscheduled Visits 
6.4.4.3
If concerns arise between regularly scheduled visits, subjects should be instructed to contact 
study personnel to come in for an “unscheduled” visit. The following evaluations will be 
performed at each unscheduled visit: 
 Physical examination 
 Vitals, including weight 
 Medications assessment 
 AE assessment 
Additional evaluations may be performed according to investigator discretion. 
Note: if during the unscheduled visit, the investigator suspects a flare is occurring, the site 
must conduct a Flare Visit with all its assessments. 
 Early Withdrawal Visit 
6.4.4.4
Subjects who withdraw early from the study will be asked to complete an Early Withdrawal 
Visit. All scheduled exams, procedures, and laboratory tests scheduled for the Week 60 visit 
will be performed at this visit. Data from subjects who do not complete all study visits will 
still be included in the Intent-to-Treat and safety analyses. 
 
Visit Windows 
6.4.5
All study procedures should be performed within the designated visit window (i.e.,  7 days) 
for each scheduled visit (see Table 6.1, Schedule of Events). Whenever possible, a 
rescheduled visit should remain within the designated visit window. The coordinating center 
should be notified if the study procedures for any scheduled visit cannot be performed within 
the designated window. 


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Table 6.1, Schedule of Events 
As Needed 
Visit Name
Screen-
ing 
Base-
line 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
32 
Week 
40 
Week 
48 
Week 
601 
Flare2 End-
point3 Unsched
-uled4 
Unless otherwise noted, all assessments are to be done by unblinded personnel. 
M1 
M2 
M3 
M4 
M5 
M6 
M8 
M10 
M12
M15 
Visit Window (days) -28 to -1
0 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
n/a 
n/a 
n/a 
 
Central Clinical Draw (mL, approximate)
18.5 
10 
10 
10 
13 
10 
10 
13 
13 
13 
13 
13 
13 
13 
0 
Central Research Draw (mL)
0 
55 
23.5 
23.5 
23.5 
23.5 
55 
23.5 
23.5 
23.5 
23.5 
55 
55 
23.5 
0 
Visit Draw Total (mL, approximate)
18.5 
65 
33.5 
33.5 
36.5 
33.5 
65 
36.5 
36.5 
36.5 
36.5 
68 
68 
36.5 
0 
Physician Requirements 
REMS Program Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Assessment 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, including Family History of Autoimmune Disease 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination6 by a blinded investigator 
 
 
 
X 
X 
X 
X 
X17 
 
 
 
 
 
 
 
Vitals, including weight (& height at Screening) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician’s Global Assessment (0-3 VAS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
m-SLEDAI13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SELENA-SLEDAI*13 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SELENA-SLEDAI*13 & treatment questionnaire by a blinded investigator 
 
 
 
X 
X 
X 
X 
X17 
 
 
 
 
 
 
 
SLICC/DI*13 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
BILAG*13  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
FACIT7 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
SF-36®7 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Lupus QoL©7 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Medications Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug 
Treatment Period12 
 
60 weeks 
 
 
 
Dispense Study Drug  
 
X 
X 
X 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
 
 
 
 
Assess Study Drug Compliance  
 
 
X 
X 
X 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
 
 
 
Local Laboratory Assessments8 
Urinalysis: dipstick, microscopic, & spot protein-creatinine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test, if applicable11 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
PPD, if applicable5  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory Assessments8 
QuantiFERON®-TB Gold In-Tube Test (QFT-G_IT), if applicable5 (~3 mL) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious Disease Screen (~8.5 mL): HIV antibody, hepatitis B surface antigen, HCV 
antibody with HCV RNA ( PCR) if antibody positive10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistries (~3 mL) – albumin, ALP, ALT, AST, BUN, creatinine, glucose, phosphorus, 
potassium, bilirubin, total protein  
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Serum creatinine 
 
X19 
X19 
X19 
 
X19 
X19 
 
 
 
 
 
 
 
 
Anti-dsDNA,C3, C4 (~6 mL)  
 
X19 
X19 
X19 
X 
X19 
X19 
X 
X 
X 
X 
X 
X 
X 
 


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Table 6.1, Schedule of Events 
As Needed 
Visit Name
Screen-
ing 
Base-
line 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
32 
Week 
40 
Week 
48 
Week 
601 
Flare2 End-
point3 Unsched
-uled4 
Unless otherwise noted, all assessments are to be done by unblinded personnel. 
M1 
M2 
M3 
M4 
M5 
M6 
M8 
M10 
M12
M15 
Visit Window (days) -28 to -1
0 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
n/a 
n/a 
n/a 
 
Hematologies (~4 mL): hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology (6 mL): lymphocyte subset, if applicable9  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Mechanistic Specimens 
Serum for Cytokine/Chemokines/Antibodies18 to Sm, RNP, SSA/Ro, SSB/La (10 mL)  
 
X18
X 
X 
X 
X 
X 
X 
X 
X 
X 
X18
X18
X 
 
RNA Assays (5 mL) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Future Use: PBMCs & Plasma (40 mL) 
 
X 
 
 
 
 
X 
 
 
 
 
X15 
X 
 
 
Future Use: Plasma (8.5 mL) 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X16 
 
X16 
 
Future Use: Urine (10 mL) 
 
X 
 
 
 
 
X 
 
 
 
 
X20 
X21 
X 
 
     
 
1. Week 60: should a subject withdraw early, he/she should complete all assessments listed under the Week 60 visit. 
2. Flare visits: should occur when a subject experiences a flare and may coincide with a regularly scheduled study visit. 
3. Endpoint visits: should occur when a subject reaches primary endpoint, as described in Section 3.2, Description of Primary Endpoint and may coincide with a regularly scheduled study visit. 
4. Unscheduled visits: all noted assessments must be done, but any additional assessments that the investigator feels should be done should be collected. Note: if during the unscheduled visit, the 
investigator suspects a flare is occurring, the site must conduct a Flare Visit. 
5. PPD or QuantiFERON®-TB Gold In-Tube Test (QFT-G-IT): unless performed within 12 weeks prior to screening and documented as negative in the subject’s records, or unless subject is known to 
have a positive or indeterminate test and has documentation of appropriate therapy. 
6. Physical examinations are to include, at least, the following systems: general appearance, skin, head/eyes/ears/nose/neck/throat, respiratory/chest, cardiovascular, abdominal, neurological, & 
musculoskeletal/extremities. 
7. Subjective assessments must be done at the beginning of the visit, prior to any other study assessments (except for informed consent at Screening). 
8. Local & Central Laboratory Assessments: see Section 6.3.6, Blood Draw Prioritization 
9. Lymphocyte subset: only if the subject was on a B cell depleting agent in the past 3 years and the test was not done within 12 weeks prior to screening documenting detectable B cells 
10. Infectious disease screen: unless documented as negative within 12 weeks prior to the Screening visit. 
11. Pregnancy tests: for women on MMF and of childbearing potential only. Additional pregnancy tests should also be done when clinically indicated. 
12.Treatment Period: will end if a subject meets primary endpoint. While visits & assessments will occur as scheduled, ALE06 will no longer provide any more MMF. Any treatment medications 
chosen by the investigator will be documented on the concomitant medications log. 
13. ALE06 will typically use a spot urinalysis rather than a 24-hour urine assessment for the BILAG*, mSLEDAI, SELENA-SLEDAI*, and SLICC/DI*. However, if indicated, results from a 24-hour 
urine collection may be used. 
14. For subjects randomized to MMF maintenance arm only. 
15. Future Use: PBMCs & Plasma will be drawn at Week 60 only if the subject did not experience a mild/moderate flare requiring an increase in prednisone or a severe flare requiring increased 
immunomodulatory medication while on study. 
16. Future Use: Plasma will be drawn at Week 60 or Endpoint only if the subject did experience a flare while on study. 
17. At Week 24, a blinded physical exam and SELENA-SLEDAI* should only be conducted if the subject is being monitored for flare at the Week 20 visit. 
18. Antibodies to Sm, RNP, SSA/Ro, and SSB/La will only be assessed at the Baseline, Week 60, and if needed, the flare visit. 
19. Serum creatinine will be run off the Baseline, Weeks 4, 8, 16, and 20 Anti-dsDNA, C3, C4 blood draw.  
20. FutureUse:Urine will be collected at Week 60 only if the subject did not experience a flare while on study. 
21. FutureUse:Urine will be collected at any (and all) Flare Visits where increased predisone or immunomodulatory medication is prescribed 
 
 
 
 
 
 
 


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7 SAFETY MONITORING AND REPORTING 
7.1 Overview 
This section defines the types of safety data that will be collected under this protocol and 
outlines the procedures for appropriately collecting, grading, recording, and reporting that 
data. Adverse events that are classified as serious according to the definition of health 
authorities must be reported promptly (per Section 7.5, Reporting of Adverse Events) and 
appropriately to the sponsor (DAIT/NIAID), principal investigators in the trial, and 
Institutional Review Boards (IRBs). Information in this section complies with ICH Guideline 
E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
ICH Guideline E-6: Guideline for Good Clinical Practice, and applies the standards set forth 
in the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events 
(CTCAE), Version 4.0: http://ctep.cancer.gov/reporting/ctc.html. 
7.2 Definitions 
 
Adverse Event (or Adverse Experience) 
7.2.1
Any untoward or unfavorable medical occurrence in a human subject, including any 
abnormal sign, symptom, or disease, temporally associated with the subject’s participation in 
the research, whether or not considered related to the subject’s participation in the research 
(modified from the definition of adverse events in the 1996 International Conference on 
Harmonization E-6 Guidelines for Good Clinical Practice)." [From OHRP "Guidance on 
Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and 
Adverse Events (1/15/07)" <http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm> 
 
Adverse Reaction and Suspected Adverse Reaction 
7.2.2
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event. 
Suspected adverse reaction (SAR) means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the 
drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug (21 
CFR 312.32(a)). 
 
Unexpected Adverse Reaction 
7.2.3
A SAR is considered “unexpected” if it is not listed in the MMF package insert or is not 
listed at the specificity or severity that has been observed. 


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Serious Adverse Event 
7.2.4
An AE or SAR is considered “serious” if, in the view of either the investigator or 
DAIT/NIAID, it results in any of the following outcomes (21 CFR 312.32(a)): 
1. Death 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the 
view of either the investigator or DAIT/NIAID, its occurrence places the subject at 
immediate risk of death. It does not include an AE or SAR that, had it occurred in a 
more severe form, might have caused death.  
3. Inpatient hospitalization or prolongation of existing hospitalization 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
5. Congenital anomaly or birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
7.3 Collection and Recording of Adverse Events 
 
Investigational Product 
7.3.1
The primary investigational product in this protocol is MMF. In addition, subjects in this 
protocol are required to receive hydroxychloroquine or chloroquine. For purposes of 
reporting safety information, these drugs will be considered concurrent study mandated 
therapy. 
 
Collection Period 
7.3.2
Adverse events will be collected from the time the subject signs the informed consent until 
he/she initiates study intervention or until he/she is determined to be ineligible to receive 
study intervention, if the investigator determines that the adverse event is related to a study-
mandated procedure, treatment, or change in treatment. 
Regardless of whether the above is applicable, for all participants: Adverse events will be 
collected from the time of initiation of study intervention (i.e., the administration of the first 
dose of study-supplied MMF as defined in Section 6.4.2, Baseline/Randomization Visit) until 
he/she completes study participation or until 30 days after he/she prematurely withdraws 
(without withdrawing consent) or is withdrawn from the study. 
 
Collecting Adverse Events  
7.3.3
Adverse events (including SAEs) may be discovered through any of these methods: 
 Observing the subject. 


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 Questioning the subject in an objective manner. 
 Receiving an unsolicited complaint from the subject. 
 In addition, an abnormal value or result from a clinical or laboratory evaluation 
(including, but not limited to, a radiograph, an ultrasound, or an electrocardiogram) 
can also indicate an adverse event, as defined in Section 7.4, Grading and Attribution 
of Adverse Events. 
 
Recording Adverse Events 
7.3.4
Throughout the study, the investigator will record and grade adverse events NCI-CTCAE 
grade 2 and above on the appropriate AE electronic case report form (AE eCRF) regardless 
of their severity or relation to study medication or study procedure. 
Once recorded, an AE will be followed until it resolves with or without sequelae, or until the 
end of study participation, or until 30 days after the subject prematurely withdraws (without 
withdrawing consent)/or is withdrawn from the study, whichever occurs first. 
 
Recording Serious Adverse Events 
7.3.5
Serious AEs will be recorded on the appropriate AE eCRF and on the SAE eCRF. All 
requested information on the AE eCRF and SAE eCRF should be provided, if available, for 
submission to the Statistical and Clinical Coordinating Center (SACCC) and DAIT/NIAID. 
If a site investigator discovers a new serious adverse event within 30 days after the end of 
study participation, the SAE will be reported. 
Once recorded, an SAE will be followed until it resolves with or without sequelae. 
7.4 Grading and Attribution of Adverse Events 
 
Grading Criteria 
7.4.1
The study site will grade the severity of adverse events experienced by the study subjects 
according to the criteria set forth in the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events Version (CTCAE) 4.0. This document (referred to herein as the 
NCI-CTCAE manual) provides a common language to describe levels of severity, to analyze 
and interpret data, and to articulate the clinical significance of all adverse events. The NCI- 
CTCAE has been reviewed by the Protocol Chair(s) and has been deemed appropriate for the 
subject population to be studied in this protocol. 
Adverse events will be graded on a scale from 1 to 5 according to the following standards in 
the NCI-CTCAE manual: 
Grade 1 = mild adverse event, not recorded. 
Grade 2 = moderate adverse event. 
Grade 3 = severe and undesirable adverse event. 


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Grade 4 = life-threatening or disabling adverse event. 
Grade 5 = death. 
If NCI-CTCAE criteria are defined for grading an abnormal value or result from a clinical or 
laboratory evaluation (including, but not limited to, a radiograph, an ultrasound, or an 
electrocardiogram), then a treatment-emergent adverse event is defined as an increase in 
grade from Baseline (Day 0) or from the last post-baseline value that doesn’t meet grading 
criteria. Changes in grade from screening to Baseline (Day 0) will also be recorded as 
outlined in Section 7.3.2, Collection Period. If a specific event or result from a given clinical 
or laboratory evaluation is not included in the NCI-CTCAE manual, then an abnormal result 
would be considered an adverse event if changes in therapy or monitoring are implemented. 
 
Adverse events that are related to disease activity will be graded according to the plan 
outlined above. However, an increase in disease activity leading to an adverse event should 
also be reflected in standard measures of disease activity (BILAG* 2004 and SELENA- 
SLEDAI) measured at regularly scheduled visits as well as at flare and endpoint visits. 
 
To facilitate identification of a safety signal associated with increased disease activity, the 
modified BILAG* 2004 and SELENA-SLEDAI* tools will be used throughout the study to 
monitor changes in disease activity over time. The DSMB will receive reports on these 
assessments for each treatment arm at regularly scheduled reviews. 
 
Attribution Definitions 
7.4.2
The relation, or attribution, of an adverse event to an investigational product will initially be 
determined by the site investigator. The site investigator will also record the initial 
determination of attribution on the appropriate AE eCRF. The relation of an adverse event to 
the study intervention will be determined using the descriptors and definitions provided in 
Table 7.1, NCI-CTCAE attribution of adverse events. Final determination of attribution for 
safety reporting will be decided by DAIT/NIAID. 
For additional information and a printable version of the NCI-CTCAE manual, consult the 
NCI-CTCAE web site: http://ctep.cancer.gov/reporting/ctc.html. 


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Table 7.1 
NCI-CTCAE attribution of adverse events 
Code 
Descriptor 
Relationship (to primary investigational product and/or other 
concurrent mandated study therapy) 
Unrelated Categories  
1 
Unrelated 
The adverse event is clearly not related. 
2 
Unlikely 
The adverse event is unlikely related. 
Related Categories 
3 
Possible 
The adverse event has a reasonable possibility to be related; 
there is evidence to suggest a causal relationship. 
4 
Probable 
The adverse event is likely related. 
5 
Definite 
The adverse event is clearly related. 
7.5 Reporting of Adverse Events 
 
Reporting of Adverse Events to DAIT/NIAID 
7.5.1
This section describes the responsibilities of the site investigator to report adverse events to 
the SACCC. Timely reporting of adverse events is required by 21 CFR and ICH E6 
guidelines. For this study, adverse events of NCI-CTCAE Grade 2 and higher will be 
reported. 
 Procedure for Adverse Events Requiring 24 Hour Reporting  
7.5.1.1
The adverse events that are bulleted below must be reported by site investigators to the 
SACCC regardless of relationship or expectedness to study intervention within a 24 hour 
period of discovering the adverse event: 
 All SAEs per 21 CFR 312.32 definitions (see Section 7.2.4, Serious Adverse Event). 
 All BILAG* A flares. 
 All severe SELENA-SLEDAI* flares. 
Elective hospitalizations or hospital admissions for the purpose of conduct of protocol-
mandated procedures are not to be reported as an SAE unless hospitalization is prolonged 
due to complications. 
The following process for reporting of the adverse events bulleted above ensures compliance 
with the ICH guidelines and the Food and Drug Administration (FDA) CFR regulations. 
When an investigator identifies such an adverse event, he or she must notify the SACCC 
within 24 hours of discovering the adverse event, and complete and submit the AE/SAE 
eCRF within one business day following initial notification. The SACCC is responsible for 
notifying DAIT/NIAID upon receipt of the site’s notification of the adverse event and 
sending a SAE report form to DAIT/NIAID within two business days after receipt of the 
AE/SAE eCRF from the site. 


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 Procedure for Standard Adverse Event Reporting 
7.5.1.2
All other adverse events (Section 7.3.3, Collecting Adverse Events) must be recorded by the 
site on the appropriate AE eCRF within five business days of the site learning of the adverse 
event(s). 
BILAG* A and severe SELENA-SLEDAI* flares will be reported as described above in 
Section 7.5.1.1, Procedure for Adverse Events Requiring 24 Hour Reporting; all other 
BILAG* and SELENA-SLEDAI* flares will be reported using standard AE reporting 
timelines. 
 
DAIT/NIAID Reporting to the Health Authority 
7.5.2
This clinical study has been granted exemption from IND regulations by the FDA in accordance 
with 21 CFR 312.2(b) of the regulations, therefore, AEs will not be reported to the FDA by the 
study sponsor (NIAID).  
 
Reporting of Adverse Events to IRBs 
7.5.3
All investigators must report adverse events in a timely fashion to their respective IRBs in 
accordance with applicable regulations and local reporting guidelines. 
7.6 Pregnancy Reporting 
This study includes pregnancy information as safety data. Information about any pregnancy 
should be reported promptly to the SACCC on the same timeline as an SAE (Section 7.5.1.1, 
Procedure for Adverse Events Requiring 24 Hour Reporting). 
All pregnancies identified during the study must be followed to conclusion and the outcome 
of each must be reported. The investigator should be informed immediately of any pregnancy 
in a study subject or a partner of a study subject. A pregnant subject should be instructed to 
stop taking study medication. The investigator should report to the SACCC all pregnancies 
within 1 business day (as described in Section 7.5.1.1, Procedure for Adverse Events 
Requiring 24 Hour Reporting) using the Pregnancy eCRF. The investigator should counsel 
the subject and discuss the risks of continuing with the pregnancy and the possible effects on 
the fetus. Monitoring of the pregnant subject should continue until the conclusion of the 
pregnancy, and a follow-up Pregnancy eCRF detailing the outcome of the pregnancy should 
be submitted to the SACCC. When possible, similar information should be obtained for a 
pregnancy occurring in a partner of a study subject. 
Information requested about the delivery will include: 
 Subject’s enrollment ID 
 Gestational age at delivery 
 Birth weight, length, and head circumference 
 Gender 
 Appearance, pulse, grimace, activity, and respiration (APGAR) score at one 
minute, five minutes, and 24 hours after birth, if available 


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 Any abnormalities 
Should the pregnancy result in a congenital abnormality or birth defect, an SAE must be 
submitted to the SACCC using the SAE reporting procedures described above. 
 
Mycophenolate REMS Program 
7.6.1
ALE06 investigators are required to enroll in the FDA’s Mycophenolate Risk Evaluation and 
Mitigation Strategy (REMS) program (www.mycophenolaterems.com). An investigator will 
be required to report any pregnancy occurring in an ALE06 female subject while she is 
taking MMF or within the first 6 weeks following discontinuation of MMF treatment to the 
Mycophenolate Pregnancy Registry, which is part of the MMF REMS program. Subjects will 
be encouraged to participate in MMF REMS program as well. 
7.7 Reporting of Other Safety Information 
An investigator should promptly notify the SACCC when an “unanticipated problem 
involving risks to subjects or others” is identified, which is not otherwise reportable as an 
adverse event. 
7.8 Review of Safety Information 
 
Medical Monitor Review 
7.8.1
The DAIT Medical Monitor will receive monthly reports from the SACCC compiling new 
and accumulating information on AEs, SAEs, and pregnancies recorded by the sites on 
appropriate eCRFs. 
In addition, the Medical Monitor will receive SAE and pregnancy reports for review and 
triage after the SACCC is made aware of these events (see Sections 7.5.1, Reporting of 
Adverse Events to DAIT/NIAID, and 7.6, Pregnancy Reporting). 
 
DSMB Review 
7.8.2
The Data and Safety Monitoring Board (DSMB) will review accumulating safety data at least 
yearly during planned DSMB Data Review Meetings. Data for the planned safety reviews 
will include, at a minimum, a listing of all reported AEs and SAEs. To ensure patient safety 
between Data Review Meetings, the DSMB will be informed of all Expedited Safety Reports 
in a timely manner. 
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may 
be called upon for ad hoc reviews or emergency meetings (see Section 5.10.3, Safety 
Stopping Guidance). The DSMB will have discretion to recommend actions regarding study 
conduct and continuation as a consequence of any planned or unplanned monitoring activity. 


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8 STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
8.1 Sample Size and Power 
Sample size justification will focus on the primary endpoint of disease reactivation by Week 
60.  We anticipate that the risk of disease reactivation will likely increase with MMF 
withdrawal, and recognize that the acceptable level of increased risk will be highly variable 
among clinicians and their patients.  The planned analyses are designed to provide 
information to help clinicians make decisions for individual patients with varied levels of risk 
tolerance.  To this end, we will provide the estimated risk of disease reactivation in each arm, 
but more importantly we will provide the % confidence that the increased risk with MMF 
withdrawal ≤ a, where a is a specific value for acceptable increase in risk. To facilitate 
decisions for individual patients, we will provide a table and/or plot showing the confidence 
levels over a range of values for a. 
In deriving an appropriate sample size, we assumed most physicians would want at least 85% 
confidence that the increase in risk with MMF withdrawal ≤ a, for whatever value of a is 
selected for an individual patient.   As such, we computed, under a variety of scenarios, the 
probability that the study would yield estimates where the confidence was at least 85% that 
the increase in risk with MMF withdrawal ≤ a (the acceptable increase in risk).   Since this 
probability is analogous to power for a study designed to test a hypothesis, the term “power” 
will be used in this discussion.   
 
In addition to the study size and the selected value of a, power depends on two unknowns: 
the risk of disease reactivation for patients in the MMF maintenance arm and the increase in 
risk for patients upon withdrawal of MMF.  With respect to the former, a preliminary 
analysis was conducted on observational data from a subset of 49 patients in the Johns 
Hopkins Lupus Cohort who were on MMF for a minimum of one year. Based on these 
results, the probability of experiencing disease reactivation (defined for the preliminary 
analysis as at least one SELENA-SLEDAI-defined flare requiring additional treatment) by 
month 16 was estimated at 0.10 (95% CI 0.02-0.19) for subjects remaining on MMF. For the 
sample size and power calculations, we assumed the risk of disease reactivation in the MMF 
maintenance arm would be on the range of 0.05 to 0.15. There is no preliminary data on the 
increase in risk with MMF withdrawal, but since patients/clinicians would be more likely to 
consider withdrawal if the increased risk were low, we evaluated potential increases ranging 
from 0.05 to 0.15. 
 
Table 8.1 presents power estimates based on simulations for a sample size of 120 eligible 
subjects randomized in a 1:1 to MMF maintenance or withdrawal.  If all other factors are 
constant, power improves as a, the acceptable level of increased risk, increases.  However, 
the relevance of the study results in clinical practice decreases with increasing a.   For 
example, the statement, “We are 85% confident that the increased risk with withdrawal of 
MMF is < a = 0.20” would be useful for those patients willing to accept an increase in risk of 
a ≥ 0.20, but would not be of value for a more risk-averse patient willing to accept, say, an 
increase in risk of only a = 0.10.    Unfortunately, the sample size required to achieve 80% 


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power when a = 0.10 (or below) are not feasible for this study.  For example, if a = 0.10, 
then under a best case scenario, if the risk of flare is 0.05 in the MMF maintenance arm and 
the increase in risk with withdrawal is 0.05 (i.e. the risk with MMF withdrawal = 0.10), then 
the number of patients required for 80% power is 390.  
 
The sample size of 120 was selected to achieve reasonable power for values of a ≥ 0.15. The 
study will have the best chance of impacting a wide range of patients if both the risk of 
disease reactivation in the MMF maintenance arm and the increased risk with withdrawal are 
low.  Table 8.1 shows that if the risk in the MMF maintenance arm is 0.05 and the increase in 
risk with withdrawal is 0.05, then there is a least 85% power for a ≥ 0.15.  If either the risk in 
the MMF maintenance arm or the increase in risk with withdrawal is larger than 0.05, then 
the acceptable increase in risk (a) will have to be ≥ 0.20 in order to maintain power above 
80%. 
 
Table 8.1: Power results for 120 subjects (1:1 MMF maintenance: MMF withdrawal)  
 
Power = the probability that a random sample will yield estimates with at least 85% 
confidence that the increase in risk with MMF withdrawal ≤ a  
 
Risk in the MMF 
maintenance 
arm 
Increase in 
risk with MMF 
withdrawal 
Acceptable risk increase 
a =… 
0.15 
0.2 
0.25 
0.3 
0.05 
0.05 
85% 
98% 
100% 
100% 
0.05 
0.10 
45% 
79% 
96% 
100% 
0.05 
0.15 
42% 
74% 
93% 
0.15 
0.05 
66% 
87% 
97% 
99% 
0.15 
0.10 
36% 
63% 
85% 
96% 
0.15 
0.15 
  
35% 
61% 
83% 
8.2 Analysis Populations 
 
Safety Population 
8.2.1
The safety population (SP), which will be used for all safety analysis, will include all 
subjects for whom study intervention is initiated. 
 
Modified Intent-to-Treat Population  
8.2.2
The modified Intent-to-Treat (mITT) population will include all randomized subjects who 
begin ALE06-provided MMF and meet study entry criteria. Randomized subjects who 
withdraw from the trial prior to starting ALE06-provided MMF will be excluded from the 
mITT analysis set. The analyses for disease activity endpoints will be based on the mITT 


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population. Subjects who, for whatever reason, do not complete their assigned therapy will 
be included in the mITT population in the groups to which they were randomized. 
 
Per Protocol Population 
8.2.3
The Per Protocol (PP) population will be defined as those subjects who adequately comply 
with the assigned treatment protocol with no serious protocol deviations impacting the 
primary disease reactivation endpoint or mechanistic outcomes of the study. A masked data 
review panel will evaluate deviations from the protocol including, for example, departures 
from assigned treatment regimen, modification of concurrent therapy, failure to complete 
study visits, or administration of study procedures outside the specified visit windows to 
determine if occurrence of these deviations should exclude subjects from the PP population. 
The panel may exclude subjects with serious protocol deviations from the PP population. 
8.3 Description of the Analyses 
In presenting data from this trial, continuous data will be summarized in tables listing the 
mean, standard deviation or standard error, median, and number of subjects in a group. 
Categorical data will be summarized in tables listing the frequency and the percentage of 
subjects in a group. These summaries will be presented separately for subjects on the two 
treatment arms.  
 
Safety Analysis 
8.3.1
All safety analyses will be performed using the Safety Population. 
AEs including changes in laboratory values will be graded according to the National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
(http://ctep.cancer.gov/reporting/ctc.html). The frequency of AEs will be summarized by 
system organ class, preferred term, severity (grade), and relationship to study treatment. 
Relationship to study treatment will be categorized as either treatment related (possibly, 
probably, or definitely related to study medication) or unrelated (unlikely related or 
unrelated). Similar analyses will be performed for SAEs. To account for differential duration 
of study participation among subjects, the summaries will include the event rate (i.e. number 
of events per person-time) in addition to the number and percent of events and subjects 
experiencing events. 
For each key safety endpoint defined in Section 3.3.2, Secondary Safety Endpoints the 
proportion of subjects experiencing at least one event in each treatment group will be 
reported and the treatment groups compared based on Fisher’s Exact Test. In addition, event 
rates in the two arms will be compared using Poisson regression. 
Laboratory parameters will be summarized both overall and by treatment group using 
appropriate descriptive statistics. For each lab parameter, the number and percent of subjects 
that have an increase, decrease, or no change from baseline to Week 60 will be displayed for 
each treatment group and pooled across treatment arms. For parameters with an explicit NCI-
CTCAE grading criterion, change from baseline will be indicated by a change in grade. For 


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parameters that do not have an explicit NCI-CTCAE, observed values will be categorized as 
‘high’ (defined as >ULN) and ‘normal’ (defined as ≤ ULN).  Then, a change from baseline 
will be indicated as a change in category 
All safety comparisons and associated p-values are considered exploratory, not as formal 
tests of hypothesis. As such, no adjustments will be made for multiple comparisons and all p-
values must be interpreted cautiously. 
 
Analysis of Disease Activity Endpoints 
8.3.2
 Primary Endpoint Analysis 
8.3.2.1
The hope is that this study will provide physicians with some rationale for medical decision 
making. It is important to note that in practice the decision to withdraw from MMF is 
multifactorial; one has to weigh the increased risk of disease reactivation against decreased 
risk of lymphoproliferative disease, hematological derangements, and infections as well as 
the impact of chronic medication use on quality of life and plans for pregnancy. How the 
risks and benefits should be weighed is highly individual. For example, for one patient, an 
acceptable increase in risk with MMF withdrawal might be 0.20, but for another, it might be 
0.05, where risk is the probability of disease reactivation on a 0 to 1 scale.  Acceptable risk 
varies according to physician and patient circumstances and preferences, so a pre-specified 
margin of non-inferiority cannot be defined.  Hence, a study designed to test a non-inferiority 
hypothesis with a single pre-specified risk margin that may or may not be relevant for any 
particular patient would have limited utility.  As such, the planned analyses for this study are 
designed to maximize the information available for medical decision making.    
 
The first step will be to report effect estimates and 95% confidence intervals for the risk of 
disease reactivation by Week 60 in each arm as well as the estimated risk difference (i.e. 
risk_MMFwithdrawal - risk_MMF maintenance), which we assume will be a positive increase in risk with 
MMF withdrawal.   Next, to aid physicians and patients in making decisions based on 
individualized assessments of acceptable risk, the observed risk estimates will be used to 
compute the “% Confidence that the true increase is ≤ a”  as a function of values for the 
“Acceptable increase in risk with withdrawal of MMF (a)”.  This information can be plotted 
with values for “Acceptable increase in risk with withdrawal of MMF (a)” on the x axis and 
estimates for “% Confidence that the true increase is ≤ a” on the y axis. Our study will 
generate a single curve based on the observed risk estimates for the two arms.  Figure 8.1 
shows examples of what this plot might look like given a few possible scenarios for the 
observed risk estimates. Physicians with their patients could decide on an acceptable level of 
increased risk (a) then read from the plot the % confidence that this selected value of a 
would not be exceeded with withdrawal of MMF.  Depending on the level of confidence, 
they may or may not decide to withdraw MMF. 
 


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Figure 8.1 
 
The motivation for the curve in Figure 8.1 comes from the test of non-inferiority with the 
following hypotheses: 
H0: the increase in risk with withdrawal of MMF (T) ≥ a, and 
HA: the increase in risk with withdrawal of MMF (T) < a, 
 
where a is some value for the acceptable increase in risk. 
 
The H0 hypothesis would be rejected in favor of HA if the upper (1-) % confident limit 
about the estimated risk difference (i.e. risk_MMFwithdrawal - risk_MMF maintenance) is less than a. 
Then, we could conclude that T < a with (1-)% confidence.  Physicians and patients who are 
comfortable with both a risk increase of no more than a and a confidence level of (1-)% 
could conclude that withdrawal from MMF is “not unacceptably worse” than maintenance on 
MMF.    
 
Recognizing that the appropriate value of a will be highly variable among physicians and 
patients, a single hypothesis is not defined for this study.  Alternatively the upper 1-sided (1-
)% confidence limit (UCL) for the observed risk difference will be computed for values of 
 ranging from 0.01 to 0.99. Note that for a given value of  the computed UCL equals the 
value of a, at which a null hypothesis could be rejected with a Type I error rate of.  Results 
of these computations will be tabulated and plotted as shown in Figure 8.1. 
 
These analyses will be completed on the mITT population. 


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 Secondary Analyses 
8.3.2.2
All secondary analyses will be conducted in an exploratory fashion with p-values and 
confidence intervals presented as descriptive statistics with no adjustments for multiple 
comparisons. Interval estimates will be generated at the 95% confidence level. Analyses will 
be conducted on the mITT population and the per protocol population. 
 
Analyses described for the primary analysis of the primary endpoint will be repeated using 
the per protocol population.   
 
In addition, analysis will be conducted in a similar fashion for the secondary endpoints that 
are probability of experiencing an event including: any SELENA-SLEDAI* flare by Week 
60, any severe SELENA-SLEDAI* flare by Week 60, any BILAG* A flare by Week 60, a 
BILAG* Renal A flare (for subjects with renal manifestations) by Week 60, and addition of 
aggressive adjunctive therapy to MMF or a change in MMF therapy to cytotoxic drug due to 
flare. These analyses will be conducted on the mITT and PP populations.  
 
For the time to event endpoints (time to clinically significant disease reactivation, time to 
first SELENA-SLEDAI* flare and time to first severe SELENA-SLEDAI* flare), graphical 
summaries of time to event will be generated using Kaplan-Meier survival curves. The 
Greenwood method will be used to compute confidence intervals. 
Descriptive statistics (mean, standard deviation or standard error, median, minimum, 
maximum and number of subjects in a group) and 95% confidence intervals will be reported 
for the difference between the treatment groups in cumulative steroid dose at Week 60; 
change in FACIT fatigue score from baseline to Weeks 24, 48, and 60; change in SF-36® PF 
and PCS domains from baseline to Weeks 24, 48, and 60; change in LupusQoL-US© from 
baseline to Weeks 24, 48, and 60, and change in SLICC/DI* from baseline to Weeks 24, 48, 
and 60. 
For subjects who meet the primary endpoint of clinically significant disease reactivation, the 
time to improvement in BILAG* from maximum level during flare, time to recovery to 
BILAG* C and time to return to pre-flare steroid dose will be analyzed using Kaplan-Meier 
curves. Descriptive statistics (mean, standard deviation or standard error, median, minimum, 
maximum) and 95% confidence intervals will be reported for the difference between the 
treatment groups in cumulative excess steroid dose from the time of clinically significant 
disease reactivation until return to pre-flare dose (or end of study participation). It is likely 
that some subjects will meet the primary endpoint close to the end of follow-up and will 
therefore be censored at the end of study follow-up for some or all of these endpoints. If one 
treatment group tends to flare earlier than the other does so that they are more likely to be 
censored, then censoring will be informative. Estimates of effect will therefore be biased.  
 
Mechanism/Immunological Analysis 
8.3.3
Descriptive statistics and plots (including, but not limited to, those described subsequently) 
will be used to gain an understanding of the data prior to developing any statistical models. 
Means, medians, standard deviations, minimums, and maximums will be computed for each 


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continuous biomarker at each time point for treatment groups and separately for subjects who 
do/do not experience clinically significant disease reactivation. For dichotomous biomarkers, 
frequencies and percents will be computed at each time point for treatment groups and 
separately for subjects who do/do not experience clinically significant disease reactivation. 
To gain a better understanding of trends over time, summary statistics (e.g., means, medians, 
or percents) will be plotted versus time at the relevant time points. Plots for individual 
subjects may also be useful. 
8.4 Interim Analysis 
Interim study results will be reported to the DSMB for planned Data Review Meetings. 
Reports prepared for these meetings will focus on study conduct and subject safety and may 
include information on enrollment, randomization, site activation status, protocol deviations, 
subject status and demographics, and safety analyses. In particular, at each DSMB review, 
disease reactivation rates in each arm and the risk difference (i.e. risk_MMFwithdrawal - risk_MMF 
maintenance) will be reported along with the 2-sided 95% confidence interval.  If the lower 95% 
confidence limit about the risk difference exceeds 0.40, the DSMB should consider whether 
or not the study should be stopped for safety concerns. In order to trigger the guidance, the 
number of disease reactivations in the MMF withdrawal arm must exceed the number in the 
MMF maintenance arm, but the magnitude of the excess depends on the sample size. Some 
examples of observed scenarios that would trigger the guidance are as follows: 
# Subjects per arm 
Minimum # excess 
reactivations in the MMF 
withdrawal arm* 
10 
7  
20 
13 
30 
18 
40 
23 
50 
27 
60 
32 
* The excess needed to trigger the guidance also depends on 
the # of reactivations in the MMF maintenance arm.  
 
 
 
In addition, if ≤ 10% of the first 80 subjects experience disease reactivation after accruing 60 
weeks of post-randomization time and the study is still accruing subjects, then the pooled 
estimate of the disease reactivation rate may be used to re-estimate the required sample size. 
The pooled observed rate (and the 2-sided 95% CI) will be used to reconsider the maximum 
potential difference between the arms.  If power is at least 85% under scenarios where the 
assumed rate in the maintenance arm is ≤ 5% with an acceptable risk difference of 0.15, then 
the study team may consider reducing the sample size.  


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8.5 Other Statistical Considerations 
 
Covariates 
8.5.1
Covariates that may be considered include, but are not limited to: 
 Age 
 Race/ethnicity 
 SLE duration 
 MMF dose at baseline 
 MMF use (cumulative mg-year) 
 HCQ use (cumulative mg-year) 
 Historical organ involvement 
 Serological activity at entry (depletion of C3 or C4, presence of dsDNA antibodies) 
 Steroid dose at entry 
 Disease activity at entry (m-SLEDAI) 
 Disease damage at entry, SLICC/ACR Damage Index (SDI) 
 
Multicenter Studies 
8.5.2
Because the analyses for this study are largely descriptive, no special consideration of site 
effects is planned. 
 
Multiple Comparisons and Multiplicity 
8.5.3
The primary and secondary analyses for this trial are considered to be descriptive with p-
values and confidence intervals presented as descriptive measures of strength of evidence 
rather than formal statistical inference. Therefore, no multiplicity adjustments are needed for 
this study. 
 
Examination of Subgroups 
8.5.4
To support and further explain findings from the primary and secondary analyses, additional 
analyses may be conducted for the following subgroups: 
 Age 
 Race/ethnicity 
 Disease manifestation (renal disease/extra-renal disease) 
 SLE duration (< 5 years / ≥ 5 years) 
 Baseline MMF dosing group (<2000 mg per day / ≥ 2000 mg per day) 
 
Missing Data 
8.5.5
Standard procedures will be used to ensure that data are as complete and accurate as possible. 
In analyses, a full accounting will be made for all data items. Generally, missing data will be 
treated as randomly missing with no data imputation. Deviations from this approach will be 
specified in the Statistical Analysis Plan (SAP). If data are missing for the primary endpoint, 
sensitivity analyses will be conducted to assess whether conclusions are robust to alternative 


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analytic approaches for handling these data. If data are missing for other key endpoints, 
sensitivity analyses could also be conducted, if deemed appropriate. Details of the sensitivity 
analyses will be provided in the SAP. 
 
Changes to the Statistical Analysis Plan 
8.5.6
A detailed description of the planned analyses will be provided in a SAP to be completed and 
signed off prior to the completion of the trial. Major changes from this protocol will be noted 
in the SAP. If there is sufficient reason to do so, revised plans may be issued during the 
course of the study. Changes to the SAP that are made subsequent to database lock will be 
documented in the clinical study report. 
 
9 ACCESS TO SOURCE DATA AND DOCUMENTS 
Each participating site will maintain the highest degree of confidentiality permitted for the 
clinical and research information obtained from subjects participating in this clinical trial. 
Medical and research records should be maintained at each site in the strictest confidence. 
However, as a part of the quality assurance and legal responsibilities of an investigation, each 
site must permit authorized representatives of the sponsor, the SACCC, and health authorities 
to examine (and when required by applicable law, to copy) clinical records for the purposes 
of quality assurance reviews, audits, and evaluation of the study safety and progress. Unless 
required by the laws permitting copying of records, only the coded identity associated with 
documents or other subject data may be copied (obscuring any personally identifying 
information). Authorized representatives as noted above are bound to maintain the strict 
confidentiality of medical and research information that may be linked to identified 
individuals. Participating sites will normally be notified in advance of auditing visits. 
All subject records and study documentation will be kept after the protocol is completed. 
This will include all documentation of AEs, records of study drug receipt and dispensation, 
and all IRB correspondence. All study records will be kept for at least two years after the 
investigation is completed. 
10 DATA COLLECTION, QUALITY CONTROL AND QUALITY 
ASSURANCE 
The investigator is required to keep accurate records to ensure the conduct of the study is 
fully documented. The period of record retention should be consistent with the record 
retention policies of the sponsoring agency or applicable regulatory agencies. However, in 
certain instances, documents should be retained for a longer period if required by the 
applicable regulatory agency or by the National Institutes of Health. 
The investigator will report all protocol deviations to DAIT and the SACCC per the 
instructions in the ACE Manual of Procedures. The SACCC will forward reports of protocol 
deviations to the responsible DAIT/NIAID medical officer for review as specified in the 
ACE Manual of Procedures. 


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The SACCC is responsible for regular inspection of the conduct of the trial, for verifying 
adherence to the protocol, and for confirming the completeness, consistency, and accuracy of 
all documented data. 
Data will be obtained from a variety of sources including, but not limited to laboratory 
notebooks, automated instrument output files, and clinical subject charts. Data from these 
source materials will be transmitted to the SACCC via one of two mechanisms. Data 
collected electronically at central laboratories will be transferred electronically directly from 
the laboratory to the SACCC using standard secure data transfer procedures. Data collected 
at the clinical sites will be transmitted to the SACCC using an internet-based remote data 
entry system. Clinical site personnel use an internet browser to key data into e-CRFs; each 
CRF page is submitted to the clinical database electronically as the page is completed. 
Univariate data validation tests are performed as the data are keyed. The clinical database is 
backed up nightly; backup tapes are saved in a secure, off-site location. At any time, 
authorized site personnel may log in to the remote data entry system, review and correct 
previously entered data, or key additional data. The data will be further validated per the 
study data validation plan via a series of computerized and manual edit checks, and all 
relevant data queries will be raised and resolved on an ongoing basis. Complete, clean data 
will be frozen to prevent further inadvertent modifications. All discrepancies will be 
reviewed and any resulting queries will be resolved with the investigators and amended in the 
database. All elements of data entry (i.e., time, date, verbatim text, and the person performing 
the data entry) will be recorded in an electronic audit trail to allow all data changes in the 
database to be monitored and maintained in accordance with federal regulations. 
The SACCC will periodically visit the participating clinical sites and audit the source 
documents in order to validate the data in the SACCC central database. Data will be provided 
using the subject’s screening or enrollment number, the SACCC will not collect personally 
identifying information such as the subject’s name or social security number. Subjects will 
provide demographic information such as race, ethnicity, and birth date. 
Data collected by the SACCC will be held in the strictest confidence, and are protected from 
access that could reveal personally identifying information about any subject in the trial. 
11 ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE 
The study will be conducted according to Good Clinical Practice (GCP) guidelines, U.S. 21 
CFR Part 50 – Protection of Human Subjects, and Part 56 – Institutional Review Boards. 
11.1 Compliance with Good Clinical Practices 
This trial will be conducted in compliance with the protocol, current GCPs recommended by 
the International Conference on Harmonization (ICH) and the applicable regulatory 
requirements for participating institutions. These include the tenets of the Declaration of 
Helsinki and review and approval by the appropriate ethics review committee or IRBs of 
participating organizations. The SACCC will assure compliance through a program of quality 
assurance audits performed both at participating sites and within the SACCC for data quality 


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and adherence to protocol requirements. The SACCC is operated by Rho Federal Systems 
Division, Inc. (RhoFED), Chapel Hill, North Carolina under a contract from NIAID. 
11.2 Institutional Review Board (IRB) 
Each participating institution must provide for the review and approval of this protocol and 
associated informed consent documents by an appropriate ethics review committee or IRB. 
Any amendments to the protocol or consent materials must be approved by the IRB before 
they are placed into use. In both the United States and in other countries, only institutions 
holding a current Federal Wide Assurance issued by the Office of Human Research 
Protection (OHRP) at the Department of Health and Human Services (DHHS) may 
participate. 
The investigator will inform the IRB of serious or unexpected AEs that might occur during 
the study and are likely to affect the safety of the subjects, or the conduct of the study. The 
investigators will comply fully with all IRB requirements for both the reporting of AEs, 
protocol, or consent form changes, as well as any new information pertaining to the use of 
the study medication that might affect the conduct of the study.  
11.3 Informed Consent 
The principles of informed consent in the current edition of the Declaration of Helsinki, as 
well as compliance with all IRB requirements, will be implemented in the study, before any 
protocol-specified procedures are carried out. A standard consent form for subject 
participation will be provided with the protocol to each institution. Any modifications to the 
standard information in the template will require review and approval by DAIT/NIAID. 
Informed consent will be obtained in accordance with 21 CFR 50.52. Information may be 
given to subjects in oral, written, or video form by the investigator. All prospective subjects 
will be given ample time to read the consent form, and ask questions, before signing. 
If subjects are to be enrolled who do not speak and read English, the consent materials must 
be translated into the language appropriate for the enrolling subject. Translated documents 
must be certified to contain the complete descriptions provided in the English version of the 
document. If an interpreter is used to provide or assist in describing the consent materials to 
an enrolling subject, the interpreter must also sign the consent materials certifying their 
involvement with the consent process. 
After completion, a copy of the signed consent form will be given to the subject. The original 
signed consent form will be kept on file in the subject’s study chart, available for inspection 
by regulatory authorities, both federal and institutional. 
11.4 Data and Safety Monitoring Board 
The responsibility for reviewing the ethical conduct of the study and for monitoring reports 
of evidence of adverse or beneficial effect is assigned to the DAIT Autoimmunity DSMB. 
The DSMB is an independent group composed of biomedical ethic experts, physicians, and 
other scientists who are responsible for continuing review of study information. The DSMB 


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makes recommendations to DAIT/NIAID on issues affecting the course and conduct of this 
clinical study. 
12 FINANCING AND INSURANCE 
Participating institutions must comply with their institution’s policies on compensation, 
insurance, and indemnity. Institutions must have adequate liability insurance coverage to 
satisfy their local and national requirements for study participation. 
13 PUBLICATION POLICY 
The Autoimmunity Centers of Excellence (ACE) policy on publication of study results will 
apply to this study. Authorized participants may find details regarding the policy statement 
on the ACE internet website at http://www.rhoworld.com. Study investigators are 
encouraged to communicate and publish study results with prior notification of DAIT, 
NIAID.  


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14 REFERENCES 
1. 
Barr, S.G., et al., Patterns of disease activity in systemic lupus erythematosus. 
Arthritis Rheum, 1999. 42(12): p. 2682-8. 
2. 
Otten, M.H., et al., Disease activity patterns in juvenile systemic lupus erythematosus 
and its relation to early aggressive treatment. Lupus, 2010. 19(13): p. 1550-6. 
3. 
Nikpour, M., et al., Frequency and determinants of flare and persistently active 
disease in systemic lupus erythematosus. Arthritis Rheum, 2009. 61(9): p. 1152-8. 
4. 
Laustrup, H., et al., SLE disease patterns in a Danish population-based lupus cohort: 
an 8-year prospective study. Lupus, 2010. 19(3): p. 239-46. 
5. 
Urowitz, M.B., et al., The effect of menopause on disease activity in systemic lupus 
erythematosus. J Rheumatol, 2006. 33(11): p. 2192-8. 
6. 
Navarra, S.V., et al., Efficacy and safety of belimumab in patients with active systemic 
lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet, 2011. 
377(9767): p. 721-31. 
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A randomized study of the effect of withdrawing hydroxychloroquine sulfate in 
systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. N 
Engl J Med, 1991. 324(3): p. 150-4. 
8. 
Alarcon, G.S., et al., Effect of hydroxychloroquine on the survival of patients with 
systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort 
(LUMINA L). Ann Rheum Dis, 2007. 66(9): p. 1168-72. 
9. 
Clowse, M.E., et al., Hydroxychloroquine in lupus pregnancy. Arthritis Rheum, 2006. 
54(11): p. 3640-7. 
10. 
Bertsias, G., et al., EULAR recommendations for the management of systemic lupus 
erythematosus. Report of a Task Force of the EULAR Standing Committee for 
International Clinical Studies Including Therapeutics. Ann Rheum Dis, 2008. 67(2): 
p. 195-205. 
11. 
Allison, A.C., Mechanisms of action of mycophenolate mofetil. Lupus, 2005. 14 
Suppl 1: p. s2-8. 
12. 
Ginzler, E.M., et al., Mycophenolate mofetil or intravenous cyclophosphamide for 
lupus nephritis. N Engl J Med, 2005. 353(21): p. 2219-28. 
13. 
Appel, G.B., et al., Mycophenolate mofetil versus cyclophosphamide for induction 
treatment of lupus nephritis. J Am Soc Nephrol, 2009. 20(5): p. 1103-12. 
14. 
Wofsy, D., et al., Aspreva Lupus Management Study Maintenance Results. Lupus 
2010, 2010. 19 (Abstr. Suppl)(27): p. Abstract CS12.5. 
15. 
Mok, C.C., Mycophenolate mofetil for non-renal manifestations of systemic lupus 
erythematosus: a systematic review. Scand J Rheumatol, 2007. 36(5): p. 329-37. 
16. 
Merrill, J.T., et al., Mycophenolate Mofetil (MMF) Is Effective for Systemic Lupus 
(SLE) Arthritis, Final Results of An Organ-Specific, Double-Blind, Placebo-
Controlled Trial in ACR/ARHP Scientific Meeting. 2009: Philadelphia, PA. 
17. 
Bell, S. and M. Dall'Era, Tolerability and Efficacy of Mycophenolate Mofetil in An 
Ethnically Diverse, University Based Cohort, in ACR/ARHP Scientific Meeting. 2009: 
Philadelphia, PA. 
18. 
Pisoni, C.N., Y. Karim, and M.J. Cuadrado, Mycophenolate mofetil and systemic 
lupus erythematosus: an overview. Lupus, 2005. 14 Suppl 1: p. s9-11. 


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19. 
Posalski, J.D., et al., Does mycophenolate mofetil prevent extra-renal flares in 
systemic lupus erythematosus? Results from an observational study of patients in a 
single practice treated for up to 5 years. Lupus, 2009. 18(6): p. 516-21. 
20. 
Mycophenolate Mofetil. Micromedex® 1.0 (Healthcare Series). Thomson Reuters 
(Healthcare) Inc. DRUGDEX® System; mycophenolate mofetil package insert 2011  
July 19, 2011]; Available from: http://www.micromedex.com/products/hcs/. 
21. 
CellCept [package insert]. Genentech USA, Inc; 2012: Southern San Francisco, CA. 
22. 
Alarcon, G.S., et al., Systemic lupus erythematosus in three ethnic groups. VII 
[correction of VIII]. Predictors of early mortality in the LUMINA cohort. LUMINA 
Study Group. Arthritis and Rheumatism, 2001. 45(2): p. 191-202. 
23. 
Isenberg, D.A., et al., An assessment of disease flare in patients with systemic lupus 
erythematosus: a comparison of BILAG 2004 and the flare version of SELENA. 
Annals of the rheumatic diseases, 2011. 70(1): p. 54-9. 
24. 
Petri, M., et al., Combined oral contraceptives in women with systemic lupus 
erythematosus. The New England journal of medicine, 2005. 353(24): p. 2550-8. 
25. 
Buyon, J.P., et al., The effect of combined estrogen and progesterone hormone 
replacement therapy on disease activity in systemic lupus erythematosus: a 
randomized trial. Annals of internal medicine, 2005. 142(12 Pt 1): p. 953-62. 
26. 
Gordon, C., et al., Definition and treatment of lupus flares measured by the BILAG 
index. Rheumatology, 2003. 42(11): p. 1372-9. 
27. 
Merrill, J., et al., Assessment of flares in lupus patients enrolled in a phase II/III study 
of rituximab (EXPLORER). Lupus, 2011. 20(7): p. 709-16. 
28. 
Petri, M., et al., Definition, incidence, and clinical description of flare in systemic 
lupus erythematosus. A prospective cohort study. Arthritis Rheum, 1991. 34(8): p. 
937-44. 
29. 
Steiman, A.J., et al., Prolonged serologically active clinically quiescent systemic 
lupus erythematosus: frequency and outcome. The Journal of rheumatology, 2010. 
37(9): p. 1822-7. 
30. 
Anolik, J.H., et al., Delayed memory B cell recovery in peripheral blood and 
lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy. 
Arthritis and Rheumatism, 2007. 56(9): p. 3044-56. 
31. 
Frane, J., A method of biased coin randomization, its implementation, and its 
validation. . Drug Information Journal, 1998. 32: p. 423-432. 
32. 
Hochberg, M.C., Updating the American College of Rheumatology revised criteria 
for the classification of systemic lupus erythematosus. Arthritis Rheum, 1997. 40(9): 
p. 1725. 
33. 
USP 33-NF 28 Reissue: General Notices and Requirements. 2010, USP. 
34. 
Pons-Estel, G.J., et al., Protective effect of hydroxychloroquine on renal damage in 
patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis and 
Rheumatism, 2009. 61(6): p. 830-9. 
35. 
Plaquenil [package insert]. sanofi-aventis Canada Inc.; 2012: Laval, Quebec. 
36. 
Chloroquine [package insert]. West-ward Pharmaceutical Corp.; 2010: Eatontown, 
NJ. 


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37. 
Saag, K.G., et al., American College of Rheumatology 2008 recommendations for the 
use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid 
arthritis. Arthritis and Rheumatism, 2008. 59(6): p. 762-84. 
38. 
Wolfe, F. and M.F. Marmor, Rates and predictors of hydroxychloroquine retinal 
toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. 
Arthritis care & research, 2010. 62(6): p. 775-84. 
39. 
American College of Rheumatology. System Lupus International Collaborating 
Clinics/American College of Rheumatology Damage Index for Systemic Lupus 
Erythematosus [pdf]. Available at: 
http://www.rheumatology.org/practice/clinical/indexes/slicc.pdf. Accessed 20 
October 2011. 
40. 
QualityMetric. SF-36v2® Health Survey. 2010; Available from: 
www.qualitymetric.com. 
41. 
FACIT.org. FACIT Fatigue Scale (Version 4) Available at 
http://www.facit.org/LiteratureRetrieve.aspx?ID=42365 [pdf] 2007  [Accessed 03 
November 2011]. 
42. 
McElhone, K., et al., Development and validation of a disease-specific health-related 
quality of life measure, the LupusQol, for adults with systemic lupus erythematosus. 
Arthritis and Rheumatism, 2007. 57(6): p. 972-9. 
 
 
 


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15 APPENDICES 
 
 
 Appendix A: Definition of Mild Disease 
 Appendix B: ACR Criteria for SLE 
 Appendix C: SELENA-SLEDAI* 
o ALE06 will typically use a spot urine protein:creatinine ratio, rather than a 
24-hour urine protein:creatinine ratio.  However, if indicated, results from a 
24-hour urine collection may be used. 
 Appendix D: SLICC/DI* 
o ALE06 will typically use a spot proteinuria assessment, rather than a 24-hour 
urine proteinuria assessment   However, if indicated, results from a 24-hour 
urine collection may be used. 
 Appendix E: BILAG* 2004 
o ALE06 will typically use a spot urinalysis rather than a 24-hour urine 
assessment.  However, if indicated, results from a 24-hour urine collection 
may be used.  
 Appendix F: SF-36® 
 Appendix G: SF-36® (Spanish version) 
 Appendix H: FACIT 
 Appendix I: FACIT (Spanish version) 
 Appendix J: Lupus QoL© 
 Appendix K: Lupus QoL© (Spanish version) 
 
Appendix L: Mycophenolate REMS Program Acceptable Methods for Females of 
Reproductive Potential


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15.1 Appendix A: Definition of Mild Disease 
 
Guidelines for Defining Mild SLE for ALE06 
*Note: all timeframes are measured from ALE06 randomization. 
Severe SLEDAI Manifestations 
 
Acceptable 
Exclusionary 
Seizure 
 Only if it is definitely not attributable 
to active lupus (e.g. changes in 
seizure medications) 
 Within 12 months, if due to active 
lupus 
Pyschosis 
 
 Within 12 months  
Organic Brain 
Syndrome 
 
 Within 12 months  
Visual Disturbance  
 Within 6 months  
Cranial Nerve 
Disorder 
 
 Within 6 months 
Lupus Headache 
 Migraines 
 Within 6 months 
CVA 
 None 
 Within 12 months  
Vasculitis 
 Minor splinter hemorrhages 
 Mild digital vasculitis 
 
Arthritis 
 Arthralgias 
 Joint tenderness without swelling 
 
Moderate/Chronic SLEDAI Manifestations 
 
Acceptable 
Exclusionary if within last 6 months
Myositis/Myalgia 
 Weakness due to steroids or 
deconditioning 
 Non-specific myalgia without CPK 
elevation 
 CK elevations associated with 
clinical evidence of myositis 
(weakness, myalgia) 
Urinary Casts 
 None 
 RBC casts 
Hematuria, Pyuria 
 None due to active SLE 
 Abnormal urinary sediment as 
defined in SLEDAI, indicative of 
ongoing, active lupus nephritis  
Proteinuria 
 ≤ 1 g/day for 6 months  
 > 1 g/day  
Rash 
 Minor malar flush 
 Very small chronic discoid lesions 
 Damage 
 Ulcerating lesions 
 New or widespread, inflammatory 
SLE rashes not due to acute sun 
exposure 
Alopecia 
 Chronic (> 1 year) diffuse alopecia 
 Scarred alopecia from prior disease 
 New patches larger than 2 cm  


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Guidelines for Defining Mild SLE for ALE06 
*Note: all timeframes are measured from ALE06 randomization. 
Mucosal Ulcers 
 History of mild ulcers (not 
interfering with eating) within 1 
month 
 History of mucosal ulcers of an 
unlikely relationship to SLE based on 
location 
 Active ulcers at Screening 
Pleurisy 
 History of mild pleuritic chest pain 
(lasting < 1 hour or ascribed to non-
serositis causes) that didn’t require 
immunosuppressive treatment (i.e. 
steroids) within 1 month 
 Pleural rubs or effusions on CXR 
requiring treatment  
Pericarditis 
 
 Clinical picture consistent with 
pericarditis via rub, EKC, or 
echocardiograph 
Low Complement 
Level 
 Yes 
 
dsDNA antibodies 
 Yes 
 
Fever 
 
 If due to active lupus 
Thrombocytopenia  
 Platelets ≤ 100,000/µL  (equivalent 
to 100 x109/L 
Leukopenia 
 
 < 2.0 x109/L 
Other Manifestations 
 
Acceptable 
Exclusionary if within last 6 months
Fatigue 
 Yes 
 
Weight Loss 
 If intentional 
 If < 5 % of body weight in 6 months 
 More than 5% body weight felt to be 
due to SLE. 
Anorexia 
 Yes 
 
Lymphadenopathy  
 Palpable nodes > 1 cm at Screening 
Raynauds 
 
 Digital ulcers  
Livedo 
 Yes 
 
Sicca Symptoms 
 Yes 
 
Chilblains 
 If chronic and stable 
 
 
 


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15.2 Appendix B: ACR Criteria for SLE [32] 
To be enrolled in this study, at least 4 of the following 11 ACR/SLE criteria must have been 
present at SLE diagnosis. 
 
Criteria 
Description 
Present
1 
Malar rash 
Fixed malar erythema, flat or raised
2 
Discoid rash 
Erythematous raised patches with adherent keratotic scaling and follicular 
plugging; atrophic scarring may occur in older lesions
 
3 
Photosensitivity Skin rash as an unusual reaction to sunlight, by patient history or physician 
observation 
 
4 
Oral ulcers 
Oral and nasopharyngeal ulcers, usually painless, observed by physician 
5 
Arthritis 
Nonerosive arthritis involving two or more peripheral joints, characterized by 
tenderness, swelling, or effusion 
 
6 
Serositis 
a.  Pleuritis (convincing history of pleuritic pain or rub heard by physician 
or evidence of pleural effusion) 
OR 
b. Pericarditis (documented by ECG or rub or evidence of pericardial 
effusion) 
 
7 
Renal disorder 
a.  Persistent proteinuria > 0.5 protein:creatinine ratio or > 3+ if 
quantification not performed 
OR 
b.   Cellular casts, may be red cell, hemoglobin, granular, tubular, or mixed 
 
8 
Neurologic 
disorder 
a.  Seizures - in the absence of offending drugs or known metabolic 
derangements: e.g., uremia, ketoacidosis, or electrolyte imbalance 
OR 
b.  Psychosis - in the absence of offending drugs or known metabolic 
derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance 
 
9 
Hematologic 
disorder 
a.  Hemolytic anemia – with reticulocytosis 
OR 
b. Leukopenia (< 4000/mm3 [equivalent to 4 x109/L] total on two or more 
occasions). 
OR 
c. Lymphopenia (< 1500/mm3 [equivalent to 1.5 x109/L] on two or more 
occasions) 
OR 
d. Thrombocytopenia (< 100,000/mm3 [equivalent to 100 x109/L] in the 
absence of offending drugs)
 
10 
Immunologic 
disorder 
a.  Anti-ds DNA: antibody to native DNA in abnormal titer 
OR 
b. Anti-Sm: presence of antibody to Sm nuclear antigen 
OR 
c. Positive finding of antiphospholipid antibodies based on (1) an abnormal 
serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test 
for lupus coagulant using a standard method, or (3) a false positive 
serologic test for syphilis known to be positive for at least 6 months and 
confirmed by Treponema pallidum immobilization or fluorescent 
treponemal antibody absorption test
 
11 
Antinuclear 
antibodies 
An abnormal titer of ANA by immunofluorescence or an equivalent assay at 
any point in time and in the absence of drugs known to be associated with  
“drug induced lupus” syndrome 
 


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15.3 Appendix C: SELENA-SLEDAI* 
PHYSICIANS GLOBAL ASSESSMENT: 
(3cm) 
 
     0 
    None
  1 
 Mild
2 
Med 
3 
Severe 
Length of line (from 0 to vertical assessment line)  
cm 
 
SLEDAI SCORE 
Check “Present” if descriptor is present at the time of visit or in the preceding 10 days. 
# 
Descriptor 
Definition 
Present Weight
1 
Seizure 
Recent onset (last 10 days). Exclude metabolic, infectious, or 
drug cause, or seizure due to past irreversible CNS damage. 
 
8 
2 
Psychosis 
Altered ability to function in normal activity due to severe 
disturbance in the perception of reality.  Include hallucinations, 
incoherence, marked loose associations, impoverished thought 
content, marked illogical thinking, bizarre, disorganized, or 
catatonic behavior.  Exclude uremia and drug causes. 
 
8 
3 Organic brain 
syndrome 
Altered mental function with impaired orientation, memory, or 
other intelligent function, with rapid onset and fluctuating 
clinical features. Include clouding of consciousness with reduced 
capacity to focus, and inability to sustain attention to 
environment, plus at least 2 of the following: perceptual 
disturbance, incoherent speech, insomnia or daytime drowsiness, 
or increased or decreased psychomotor activity. Exclude 
metabolic, infectious, or drug causes. 
 
8 
4 
Visual 
disturbance 
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. 
 
8 
5 Cranial nerve 
disorder 
New onset of sensory or motor neuropathy involving cranial 
nerves.  Include vertigo due to lupus. 
 
8 
6 
Lupus 
headache 
Severe, persistent headache:  may be migrainous, but must be 
nonresponsive to narcotic analgesia. 
 
8 
7 
CVA 
New onset of cerebrovascular accident(s). Exclude 
arteriosclerosis or hypertensive causes. 
 
8 
8 
Vasculitis 
Ulceration, gangrene, tender finger nodules, periungual, 
infarction, splinter hemorrhages, or biopsy or angiogram proof 
of vasculitis. 
 
8 
9 
Arthritis 
More than 2 joints with pain and signs of inflammation (i.e., 
tenderness, swelling, or effusion). 
 
4 


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SLEDAI SCORE 
Check “Present” if descriptor is present at the time of visit or in the preceding 10 days. 
# 
Descriptor 
Definition 
Present Weight
10 
Myositis 
Proximal muscle aching/weakness, associated with elevated 
creatine phosphokinase/aldolase or electromyogram changes or a 
biopsy showing myositis. 
 
4 
11 Urinary casts 
Heme-granular or red blood cell casts. 
 
4 
12 
Hematuria 
> 5 red blood cells per high power field. Exclude stone, 
infection, or other causes. 
 
4 
13 
Proteinuria 
> 0.5 protein:creatinine ratio.  New onset or recent increase of 
more than 0.5 on the protein:creatinine ratio. 
Note: ALE06 will typically use a spot urine protein:creatinine 
ratio. If only the 24-hour urine is available, then proteinuria is 
defined as: ” >0.5 gm/24 hours. New onset or recent increase of 
more than 0.5 gm/24 hours.” 
 
4 
14 
Pyuria 
> 5 white blood cells per high power field.  
Exclude infection. 
 
4 
15 
Rash 
Ongoing inflammatory lupus rash. 
 
2 
16 
Alopecia 
Ongoing abnormal, patchy, or diffuse loss of hair due to active 
lupus. 
 
2 
17 
Mucosal 
ulcers 
Ongoing, oral or nasal ulcerations due to active lupus. 
 
2 
18 
Pleurisy 
Classic and severe pleuritic chest pain, or pleural rub, or 
effusion, or new pleural thickening due to lupus. 
 
2 
19 
Pericarditis 
Classic and severe pericardial pain, or rub, or effusion, or 
electrocardiogram confirmation. 
 
2 
20 
Low 
complement 
Decrease in CH50, C3, or C4 below the lower limit of normal 
for testing laboratory. 
 
2 
21 
Increased 
DNA binding 
> 25% binding by Farr assay or above normal range for testing 
laboratory. 
 
2 
22 
Fever 
> 38°C. Exclude infectious cause. 
 
1 
23 
Thrombo-
cytopenia 
< 100,000 platelets/mm
3 [equivalent to 100 x109/L] 
 
1 
24 
Leukopenia 
< 3,000 white blood cells/mm
3  
[equivalent to 3 x109/L] 
Exclude drug causes. 
 
1 
 
Total Score (sum of weights next to descriptors marked present):     ________              


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MILD OR MODERATE FLARE 
 Change in SLEDAI > 3 points 
 
New/Worse 
 Discoid, photosensitive, profundus, 
cutaneous vasculitis, bullous lupus  
 Nasopharyngeal ulcers 
 Pleuritis 
 Pericarditis 
 Arthritis 
 Fever attributable to SLE 
 Increase in prednisone, but not to > 0.5 mg/kg/day 
 Added NSAID or Plaquenil 
 
> 1.0 increase in Physician’s Global Assessment (PhGA), but not to more than 2.5 (on a 3.0 indexed 
VAS scale—refer to the Physican’s Global Assessment located on the Modified SLEDAI Source 
Document)  
SEVERE FLARE 
 Change in SLEDAI > 12 
 
New/Worse 
 
CNS-SLE 
 
Vasculitis 
 
Nephritis  
 
Myositis 
 
Platelet Count < 60,000/ mm
3 [equivalent to 60 x109/L] 
 
Hemolytic anemia with hemoglobin < 7% OR Decrease in hemoglobin > 3% 
*Requiring:  doubling of prednisone, prednisone > 0.5 mg/kg/day, and/or hospitalization 
 Prednisone > 0.5 mg/kg/day 
 New Cyclophosphamide (Cytoxan), Azathioprine, Methotrexate, Mycophenolate Mofetil, or 
hospitalization attributable to SLE 
 
Increase in Physician’s Global Assessment (PhGA) to > 2.5  
(on a 3.0 indexed VAS scale—refer to the Physican’s Global Assessment located on the Modified 
SLEDAI Source Document)  
 
 
 


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15.4 Appendix D:  SLICC/DI* [39] 
 
System Lupus International Collaborating Clinics/ACR  
Damage Index for SLE (SLICC/DI*) 
Check “Present” if descriptor is present at the time of visit (and circle 2 if applicable) 
Damage (nonreversible change, not related to active inflammation) occurring since onset of lupus, ascertained 
by clinical assessment and present for at least 6 months unless otherwise stated. Repeat episodes must occur 6 
months apart to score 2. The same lesion cannot be scored twice. 
 
Descriptor 
Definition 
Present 
Score 
1 
Ocular 
(either eye, by 
clinical assessment) 
Any cataract ever 
 
1 
Retinal change or optic atropy 
 
1 
2 
Neuropsychiatric 
Cognitive impairment (e.g. memory deficit, difficulty 
with calculation, poor concentration, difficulty in 
spoken or written language, impaired performance 
levels) or major psychosis 
 
1 
Seizures requiring therapy for 6 months 
 
1 
Cerebrovascular accident ever (score 2> 1) 
 
1 (2) 
Cranial or peripheral neuropathy (excluding optic) 
 
1 
Transverse myelitis 
 
1 
3 
Renal 
Estimated or measured glomerular filtration rate < 
50% 
 
1 
Proteinuria ≥ 3.5 g/24hours 
Note: ALE06 will use a spot proteinuria assessment. 
 
1 
End-stage renal disease (regardless of dialysis or 
transplantation) 
 
3 
4 
Pulmonary 
Pulmonary hypertension (right ventricular 
prominence, or loud P2) 
 
1 
Pulmonary fibrosis (physical and radiograph) 
 
1 
Shrinking lung (radiograph) 
 
1 
Pleural fibrosis (radiograph) 
 
1 
Pulmonary infarction (radiograph) 
 
1 
5 
Cardiovascular 
Angina or coronary artery bupass 
 
1 
Myocardial infarction ever (score 2 if > 1) 
 
1 (2) 
Cardiomyopathy (ventricular dysfunction) 
 
1 
Valvular disease (diastolic murmur, or systolic 
murmur > 3/6) 
 
1 
Pericarditis for 6 months, or pericardiectomy 
 
1 


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System Lupus International Collaborating Clinics/ACR  
Damage Index for SLE (SLICC/DI*) 
Check “Present” if descriptor is present at the time of visit (and circle 2 if applicable) 
Damage (nonreversible change, not related to active inflammation) occurring since onset of lupus, ascertained 
by clinical assessment and present for at least 6 months unless otherwise stated. Repeat episodes must occur 6 
months apart to score 2. The same lesion cannot be scored twice. 
 
Descriptor 
Definition 
Present 
Score 
6 
Peripheral 
vascular 
Claudication for 6 months 
 
1 
Minor tissue loss (pulp sauce) 
 
1 
Significant tissue loss ever (e.g. loss of digit or limb) 
(score 2 if > 1 site) 
 
1 (2) 
Venous thrombosis with swelling, ulceration, or 
venous stasis 
 
1 
7 
Gastrointestinal 
Infarction or resection of bowel below duodenum 
spleen, liver, or gall bladed ever, for cause any (score 
2 if > 1 site) 
 
1 (2) 
Mesenteric insufficiency 
 
1 
Chronic peritonitis 
 
1 
Stricture or upper gastrointestinal tract surgery ever 
 
1 
8 
Musculoskeletal 
Muscle atrophy or weakness 
 
1 
Deforming or erosive arthritis (including reducible 
deformities, excluding avascular necrosis) 
 
1 
Osteoporosis with fracture or vertebral collapse 
(excluding avascular necrosis) 
 
1 
Avascular necrosis (score 2 if > 1) 
 
1 (2) 
Osteomyelitis 
 
1 
9 
Skin 
Scarring chronic alopecia 
 
1 
Extensive scarring or panniculum other than scalp and 
pulp space 
 
1 
Skin ulceration (excluding thrombosis) for > 6 months 
 
1 
10 
Premature gonadal failure 
 
1 
11 
Diabetes (regardless of treatment) 
 
1 
12 
Malignancy (exclude dysplasia)  (score 2 if > 1 site) 
 
1 (2) 
Total Score (sum of scores next to descriptors marked present):
 
 


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15.5 Appendix E: BILAG* 2004 (2007 Revision) 
 
 
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However, if indicated, results from a 24-hour urine collection may be used. 


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

SAP_000.pdf: 
DAIT/Rho STATISTICAL ANALYSIS PLAN 
 14 November 2019 
 
 
Protocol # ALE06 
An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of 
Mycophenolate Mofetil (MMF) in Patients with Stable, Quiescent 
Systemic Lupus Erythematosus (SLE) 
 
Short Title: Randomized MMF Withdrawal in SLE 
 
 
VERSION: 
1.0 
DATE: 
14 November 2019 
SPONSOR: 
Division of Allergy, Immunology, and Transplantation 
National Institute of Allergy and Infectious Diseases – NIH 
5601 Fishers Lane 
Rockville, MD 20852 
Telephone:  (301) 496-5717 
Fax:  (301) 402-3573 
 
 
PREPARED BY: 
Rho 
2635 E NC Hwy 54 
Durham, NC 27713 
Telephone:  (919) 408-8000 
Fax:  (919) 408-0999 
 
 
 


Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
DAIT/Rho STATISTICAL ANALYSIS PLAN 
ACKNOWLEDGMENT AND SIGNATURE SHEET 
 
An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of 
Mycophenolate Mofetil (MMF) in Patients with Stable, Quiescent 
Systemic Lupus Erythematosus (SLE) 
 
Approved: 
__________________________________ 
Date: 
_______________ 
 
Eliza Chakravarty, MD 
 
 
 
Protocol Chair 
 
 
 
Approved: 
__________________________________ 
Date: 
_______________ 
 
Ellen Goldmuntz, MD, PhD 
 
 
 
NIAID Medical Monitor 
 
 
 
Approved: 
__________________________________ 
Date: 
_______________ 
 
Bill Barry, PhD 
 
 
 
Rho Scientist 
 
 
 
Approved: 
__________________________________ 
Date: 
_______________ 
 
Ashley Pinckney, MS 
 
 
 
Rho Statistician 
 
 
 
 
 
 
 
 
Version: 1.0 
Page  2 of 48 
 


Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
Document History 
 
Version 
 
Date 
 
Change(s) 
 
Author 
0.1 
28June2019 
Initial Draft 
Ashley Pinckney 
1.0 
14Nov2019 
Final 
Ashley Pinckney 
 
Version: 1.0 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
Table of Contents 
 
1. 
PROTOCOL SYNOPSIS..................................................................................................6 
2. 
INTRODUCTION ............................................................................................................10 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS .......................................11 
4. 
ANALYSIS SAMPLES ...................................................................................................12 
4.1. 
Safety Population ...............................................................................................12 
4.2. 
Modified Intent-to-Treat Population....................................................................12 
4.3. 
Per Protocol Population......................................................................................12 
5. 
STUDY SUBJECTS .......................................................................................................13 
5.1. 
Disposition of Subjects .......................................................................................13 
5.2. 
Demographic and Other Baseline Characteristics.............................................13 
6. 
STUDY OPERATIONS ..................................................................................................14 
6.1. 
Protocol Deviations.............................................................................................14 
6.2. 
Treatment Adherence.........................................................................................14 
7. 
ENDPOINT EVALUATION ............................................................................................16 
7.1. 
Overview of Efficacy Analysis Methods .............................................................16 
7.1.1. Multicenter Studies ........................................................................................16 
7.1.2. Assessment Time Windows ..........................................................................16 
7.2. 
Primary Endpoint ................................................................................................16 
7.2.1. Computation of the Primary Endpoint ...........................................................16 
7.2.2. Primary Analysis of the Primary Endpoint ....................................................19 
7.2.3. Sensitivity and Additional Analyses of the Primary Endpoint .......................20 
7.3. 
Secondary Clinical Disease Activity Endpoints .................................................20 
7.3.1. Time to Clinically Significant Disease Reactivation ......................................21 
7.3.2. Probability of Experiencing a SELENA-SLEDAI Flare .................................21 
7.3.3. Time to First SELENA-SLEDAI Flare............................................................22 
7.3.4. Probability of Experiencing a BILAG A Flare ................................................22 
7.3.5. Subjects in the Renal Subgroup with BILAG Renal A Flares .......................23 
7.3.6. Probability of Experiencing a BILAG A or B Flare ........................................24 
7.3.7. Changes in the SLICC/DI ..............................................................................24 
7.3.8. The Addition of Aggressive Adjunctive Therapy to MMF or Change in MMF 
Therapy to Cytotoxic Drug Due to Flare .......................................................25 
7.3.9. Systemic Steroid Dose ..................................................................................25 
7.3.10. Changes in the FACIT Score ........................................................................26 
7.3.11. Changes in SF-36 Scores .............................................................................26 
7.3.12. Change in Lupus QoL Score .........................................................................27 
7.3.13. Recovery from Clinically Significant Disease Reactivation ..........................28 
7.4. 
Secondary Mechanistic Endpoints .....................................................................29 
7.4.1. C3, C4, and anti-dsDNA Levels ....................................................................29 
7.4.2. Changes in C3, C4, and anti-dsDNA Levels.................................................29 
7.4.3. Antibody Levels .............................................................................................30 
7.5. 
Examination of Subgroups .................................................................................30 
8. 
SAFETY EVALUATION .................................................................................................30 
8.1. 
Overview of Safety Analysis Methods................................................................30 
8.2. 
Extent of Exposure .............................................................................................30 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
8.3. 
Adverse Events ..................................................................................................31 
8.3.1. Secondary Safety Endpoints .........................................................................32 
8.4. 
Deaths and Serious Adverse Events .................................................................33 
8.5. 
Clinical Laboratory Evaluation............................................................................33 
8.6. 
Vital Signs, Physical Findings, and Other Observations Related to Safety ......33 
8.6.1. Vital Signs ......................................................................................................33 
8.6.2. Physical Examinations ..................................................................................33 
9. 
PHARMACOKINETIC EVALUATION ...........................................................................33 
10. 
OTHER ANALYSES ......................................................................................................34 
10.1. 
Use of Medications .............................................................................................34 
11. 
INTERIM ANALYSES AND DATA MONITORING .......................................................35 
11.1. 
Interim Analysis ..................................................................................................35 
12. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL.............................36 
13. 
REFERENCES ...............................................................................................................37 
14. 
APPENDICES ................................................................................................................37 
14.1. 
Study Flow Chart ................................................................................................37 
14.2. 
Schedule of Events.............................................................................................38 
14.3. 
SELENA-SLEDAI ...............................................................................................40 
14.4. 
BILAG .................................................................................................................43 
14.5. 
FACIT..................................................................................................................44 
14.6. 
SF-36 ..................................................................................................................45 
 
 
 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
1. 
PROTOCOL SYNOPSIS 
Title of the Protocol: An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of 
Mycophenolate Mofetil (MMF) in Patients with Stable, Quiescent Systemic Lupus 
Erythematosus (SLE) 
ACE Protocol Number: ALE06 
Protocol Chair(s): Tammy Utset, MD, MPH and Eliza Chakravarty, MD 
Sponsor: DAIT/NIAID, NIH 
Primary Objective:  To describe the effect of withdrawal from MMF on risk of clinically 
significant disease reactivation in quiescent SLE patients who have been on long-term 
MMF therapy 
Study Arms: 
• 
MMF maintenance arm: These subjects will continue MMF treatment (1000-3000 
mg/day) for the rest of their study participation (up to Week 60).  
• 
MMF withdrawal arm: These subjects will taper off MMF per the protocol-specified 
schedule over 12 weeks and remain off MMF for the rest of their study participation 
(up to Week 60 or until the primary endpoint of disease reactivation is met, 
whichever comes first).  
Study Design: One hundred twenty eligible subjects will be randomized in a 1:1 ratio to 
one of the two study treatment arms – continuing MMF treatment for 60 weeks or tapering 
off MMF within 12 weeks. All subjects will continue on their anti-malarials and may continue 
the use of their corticosteroids. 
Subject visits to assess endpoints will occur every 4 weeks from Day 0 through Week 24 
and then at Weeks 32, 40, 48, and 60. As disease flares occur, subjects will be brought in 
for urgent, flare or endpoint visits to document symptoms, collect biological samples, and 
determine whether primary endpoint has been met. 
Endpoints: 
Primary Endpoint 
The primary endpoint is the probability in each arm of experiencing clinically significant 
disease reactivation by 60 weeks after randomization. Clinically significant SLE 
reactivation requires both:  
1) A SELENA-SLEDAI*-defined mild/moderate or severe flare and 
2) Increased immunosuppressive therapy on a sustained basis as defined by one of 
the following criteria: 
a. Sustained activity: Subject has significant prolonged SLE flare requiring 
steroid increase/burst to ≥ 15 mg/day prednisone (or its equivalent) for 
more than four weeks. 
b. Frequent relapsing/remitting:  
i. Subject flares requiring an increase/burst of steroids and is 
successfully tapered to < 15 mg/day within four weeks, but this 
occurs on two or more occasions, or  
ii. Intra-articular, intra-muscular or IV steroids, on more than one 
occasion. 
c. Clinical activity of sufficient severity to warrant resumption of or an 
increased dose of MMF or addition of other major immunosuppressive 
including azathioprine or methotrexate. Regardless of steroid use, if the 
investigator observes disease activity of sufficient severity to warrant 
resumption, addition or increase in dosage of major immunosuppressant 
in the setting of a SELENA-SLEDAI*-defined flare, subject has met the 
primary endpoint. 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
Title of the Protocol: An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of 
Mycophenolate Mofetil (MMF) in Patients with Stable, Quiescent Systemic Lupus 
Erythematosus (SLE) 
Secondary Disease Activity Endpoints 
• 
Time from Day 0 to clinically significant disease reactivation (as defined in Section 
3.2, Description of Primary Endpoint). The time of clinically significant disease 
reactivation is defined as the date of the first SELENA-SLEDAI* assessment that 
meets (or goes on to meet) the criteria in Section 3.2, Description of Primary 
Endpoint. 
• 
The probability of experiencing any SELENA-SLEDAI* flare and the probability of 
experiencing any severe SELENA-SLEDAI* flare by Week 60, in aggregate and 
within subgroups defined by disease manifestation (renal disease / extra-renal 
disease) and by baseline MMF dosing group (<2000 mg per day / ≥ 2000 mg per 
day). 
• 
Time from initiation of withdrawal to first SELENA-SLEDAI* flare and time to first 
severe SELENA-SLEDAI* flare. 
• 
The probability of experiencing any BILAG* A flare by Week 60.  
• 
Proportion of subjects in the renal subgroup with BILAG* Renal A flare by Week 60  
• 
Change in SLICC/DI from baseline to Weeks 24, 48, and 60. 
• 
The probability of adding aggressive adjunctive therapy to MMF (including  IV 
immunoglobulin or rituximab) or change in MMF therapy to cytotoxic drug (e.g., 
cyclophosphamide) due to flare. 
• 
Cumulative systemic steroid dose (PO, IV, IM) at Week 60.  
• 
Change in FACIT fatigue score from baseline to Weeks 24, 48, and 60. 
• 
Change in SF-36® PF and PCS domains from baseline to Weeks 24, 48, and 60. 
• 
Change in Lupus QoL-US© from baseline to Weeks 24, 48, and 60. 
• 
The following endpoints will be assessed to describe the ability of subjects to 
recover from clinically significant disease reactivation:  
o Time from clinically significant disease reactivation to improvement in 
BILAG* from maximum level during flare; 
o Time from clinically significant disease reactivation to recovery to baseline 
BILAG* scores or BILAG* C, whichever is worse; 
o Cumulative excess systemic steroid dose from time of clinically significant 
disease reactivation to return to pre-flare dose or end of trial participation; 
o Time from clinically significant disease reactivation to return to pre-flare 
steroid dose. 
Secondary Safety Endpoints 
• 
All Grade 3-5 adverse events, as defined by the National Cancer Institute (NCI) – 
Common Terminology Criteria for Adverse Events (CTCAE) system, which are 
defined as possibly, probably, or definitely related to SLE. 
• 
All Grade 3-5 adverse events, as defined by the NCI-CTCAE system, which are 
defined as possibly, probably, or definitely related to MMF. 
• 
All NCI-CTCAE Grade 3-5 adverse events. 
• 
All serious adverse events. 
• 
All infection related events. 
• 
All malignancies. 
• 
All NCI-CTCAE Grade 3-5 hematological events. 
• 
Mortality possibly, probably, or definitely related to SLE. 
• 
All-cause mortality, defined as any death occurring at any time after randomization 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
Title of the Protocol: An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of 
Mycophenolate Mofetil (MMF) in Patients with Stable, Quiescent Systemic Lupus 
Erythematosus (SLE) 
Secondary Mechanistic Assessments  
• 
Levels of C3, C4, and anti-dsDNA at Baseline, Week 20, at the time of first flare, 
and immediately prior to first flare. 
• 
Changes in levels of C3, C4, and anti-dsDNA from Baseline to Week 20, from 
Baseline to the time of first flare, and from Baseline to the time point immediately 
prior to first flare. 
• 
Levels of antibodies to Sm, ribonucleoprotein (RNP), SSA/Ro, and SSB/La at 
Baseline 
• 
Changes in levels of antibodies to Sm, RNP, SSA/Ro, and SSB/La from Baseline to 
Week 60 
• 
Levels of interferon-regulated chemokines at Baseline, Week 20, at the time of first 
flare, and time points immediately prior to and after first flare. 
• 
Changes in levels of interferon-regulated chemokines from Baseline to Week 20, 
from Baseline to the time of first flare, and from Baseline to the time points 
immediately prior to and after first flare. 
• 
Levels of inflammatory and other cytokines at Baseline, Week 20, at the time of first 
flare and at time points immediately prior to and after first flare. 
• 
Changes in levels of inflammatory and other cytokines at Baseline, Week 20, at the 
time of first flare and at time points immediately prior to and after first flare. 
• 
Presence/Absence of gene expression patterns (e.g. fingerprint or signature) at 
Baseline, Week 20, at time of first flare, and timepoints immediately prior to and 
after first flare. 
• 
Change in gene expression patterns from Baseline to Week 20, from Baseline to the 
time of first flare, and from Baseline to the time points immediately prior to and after 
first flare. 
Sample Size: 120 eligible subjects will be randomized within 24 months and each will be 
followed for up to Week 60, for a total study duration of 3 ¼ years. 
Data Analyses: 
For the primary analysis, the risk difference in disease reactivation by Week 60 will be 
estimated and 95% score confidence intervals calculated, where the risk difference is 
defined as the difference in the probability of disease reactivation by Week 60 between the 
treatment groups. The observed risk estimates will be used to compute the “% Confidence 
that the true increase is ≤ a” as a function of values for the “Acceptable increase in risk 
with withdrawal of MMF (a)”.  The primary endpoint analysis will be based on the ITT 
population. 
All secondary analyses will be conducted in an exploratory fashion with p-values and 
confidence intervals presented as descriptive statistics with no adjustments for multiple 
comparisons. As part of secondary analyses, appropriate contrasts will be constructed 
using model-based approaches. Analyses will be conducted on the ITT population and the 
per protocol population. 
Safety Stopping Guidance: 
The DSMB will review any event that potentially impacts safety at the request of the 
protocol chair or DAIT/NIAID.  The DSMB will have discretion to recommend actions 
regarding study conduct and continuation as a consequence of any planned or unplanned 
monitoring activity. 
The DSMB will be informed in real time of the following event: 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
Title of the Protocol: An Investigator-Initiated, Phase II, Randomized, Withdrawal Study of 
Mycophenolate Mofetil (MMF) in Patients with Stable, Quiescent Systemic Lupus 
Erythematosus (SLE) 
• 
Any immediately life-threatening event or death that occurs in the study, which is 
possibly, probably, or definitely related to study participation. 
In addition, the following events will trigger both a comprehensive DSMB Emergency Safety 
Review and a temporary halt in enrollment: 
• 
Events that result in permanent discontinuation of study intervention occurring in  
o 3 of the first 10 subjects randomized to the MMF withdrawal or  
o 30% of subjects randomized to MMF withdrawal at any time point after the 
11th subject is randomized. 
• 
BILAG* A flares occurring in  
o 3 of the first 10 subjects randomized to MMF withdrawal or  
o 30% of subjects randomized to MMF withdrawal at any time point after the 
11th subject is randomized. 
• 
Severe SELENA-SLEDAI* flares occurring in  
o 3 of the first 10 subjects randomized to MMF withdrawal or  
o 30% of subjects randomized to MMF withdrawal at any time point after the 
11th subject is randomized. 
In the event of a temporary halt in enrollment, no new subjects will be consented, 
randomized or start on study product; subjects already on study product will continue 
unless they are the focus of the DSMB review. Subjects in the screening phase of the study 
may continue to undergo minimal risk procedures (e.g., blood tests), but more than minimal 
risk procedures should be deferred. Randomization will not occur until the DSMB review is 
complete. After careful review of the data, the DSMB will make recommendations regarding 
study conduct and/or continuation. 
In addition, at each planned Data Review Meeting, the DSMB will review the estimated risk 
difference for disease reactivation (i.e. risk_MMFwithdrawal - risk_MMF maintenance) and consider 
whether or not the trial should be stopped for safety concerns. (See Section 8.4 Interim 
Analysis for details.) 
 
 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
2. 
INTRODUCTION 
This statistical analysis plan includes pre-planned analyses related to the study objectives 
outlined in the protocol. 
 
 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following analyses and reporting conventions will be used: 
• 
Categorical variables will be summarized using counts (n) and percentages (%) and will 
be presented in the form “n (%).”  Percentages will be rounded to one decimal place. 
• 
Numeric variables will be summarized using n, mean, standard deviation (SD), median, 
minimum (min), maximum (max).  The min/max will be reported at the same level of 
significance as original data.  The mean and median will be reported at one more 
significant digit than the precision of the data, and SD will be reported at two more 
significant digits than the precision of the data. 
• 
The median will be reported as the average of the two middle numbers if the dataset 
contains an even number of observations. 
• 
Test statistics including t and z test statistics will be reported to two decimal places.  
• 
P-values will be reported to three decimal places if greater than or equal to 0.001.  If less 
than 0.001, the value will be reported as “<0.001.”  A p-value can be reported as “1.000” 
only if it is exactly 1.000 without rounding.  A p-value can be reported as “0.000” only if it 
is exactly 0.000 without rounding. 
If departures from these general conventions are present in the specific evaluations section of 
this SAP, then those conventions will take precedence over these general conventions.  
 
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4. 
ANALYSIS SAMPLES 
4.1. 
Safety Population 
The safety population (SP), which will be used for all safety analysis, will include all subjects for 
whom study intervention is initiated. 
4.2. 
Modified Intent-to-Treat Population  
The modified Intent-to-Treat (mITT) population will include all randomized subjects who begin 
ALE06-provided MMF and meet study entry criteria. Randomized subjects who withdraw from 
the trial prior to starting ALE06-provided MMF will be excluded from the mITT analysis set. The 
analyses for disease activity endpoints will be based on the mITT population. Subjects who, for 
whatever reason, do not complete their assigned therapy will be included in the mITT 
population in the groups to which they were randomized. 
4.3. 
Per Protocol Population 
The Per Protocol (PP) population will be defined as those subjects who adequately comply with 
the assigned treatment protocol with no serious protocol deviations impacting the primary 
disease reactivation endpoint or mechanistic outcomes of the study. A masked data review 
panel will evaluate deviations from the protocol including, for example, departures from 
assigned treatment regimen (including <80% compliance over the subject’s treatment period, 
as defined in Section 6.2, Treatment Adherence), modification of concurrent therapy, failure to 
complete study visits, or administration of study procedures outside the specified visit windows 
to determine if occurrence of these deviations should exclude subjects from the PP population. 
The panel may exclude subjects with serious protocol deviations from the PP population. 
 
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5. 
STUDY SUBJECTS 
5.1. 
Disposition of Subjects  
The disposition of all enrolled subjects will be summarized in tables and listed. 
The numbers and percentages of subjects randomized, in each analysis sample, and 
completing selected study weeks (Weeks 12 and 60), as well as reasons for early termination 
from the study will be presented overall and by treatment arm.  For subjects discontinuing 
ALE06-provided MMF early, the reasons for discontinuing early will also be presented.   
5.2. 
Demographic and Other Baseline Characteristics  
Summary descriptive statistics for baseline and demographic characteristics will be reported for 
all analysis samples overall and by treatment arm.  Characteristics to be summarized include 
age, race, ethnicity, sex, duration of SLE, renal vs. non-renal disease, MMF dose, MMF dose 
(< 2000 mg per day versus ≥ 2000 mg per day), duration of MMF treatment at the baseline 
dose, hydroxychloroquine dose, SLEDAI score, creatinine, GFR, C3, C4, anti-double stranded 
DNA, hemoglobin, height, and weight. A listing of demographic and baseline characteristics will 
also be provided. 
No hypothesis tests will be used to compare treatment arms with respect to demographic or 
baseline characteristics. 
 
 
 
 
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6. 
STUDY OPERATIONS 
6.1. 
Protocol Deviations 
Major protocol deviations will be listed by site with information such as type of deviation, 
whether notification to the IRB was required, date of occurrence, and the reason for the 
deviation.  Protocol deviations will be summarized in tabular format by type of deviation.  No 
protocol deviation will exclude a subject from the mITT, or safety populations. 
6.2. 
Treatment Adherence 
Subjects will be randomized to one of the two study treatment arms below. 
• 
MMF maintenance arm: These subjects will continue MMF treatment (1000-3000 
mg/day) for the rest of their study participation (up to Week 60).  
o Baseline MMF dose = 3000 mg/day  
 
Up to 60 weeks on 3000mg/day MMF 
o Baseline MMF dose = 2500 mg/day to 2750 mg/day  
 
Up to 60 weeks on 2500mg/day MMF 
o Baseline MMF dose = 2000 mg/day to 2250 mg/day  
 
Up to 60 weeks on 2000mg/day MMF 
o Baseline MMF dose = 1500 mg/day to 1750 mg/day  
 
Up to 60 weeks on 1500mg/day MMF 
o Baseline MMF dose = 1000 mg/day to 1250 mg/day  
 
Up to 60 weeks on 1000mg/day MMF 
• 
MMF withdrawal arm: These subjects will taper off MMF over 12 weeks and remain off 
MMF for the rest of their study participation (up to Week 60 or until the primary endpoint 
of disease reactivation is met, whichever comes first).  
 
Baseline MMF dose = 3000 mg/day 
• 
Four weeks on 1000 mg MMF twice a day (BID)  
• 
Four weeks on 1000mg (morning) & 500mg MMF (evening) QD  
• 
Four weeks on 500 mg MMF BID  
• 
Up to 48 weeks on no MMF 
 
Baseline MMF dose = 2500 mg/day to 2750 mg/day 
• 
Four weeks on 1000mg MMF BID  
• 
Four weeks on 1000mg (morning) & 500mg (evening) MMF QD 
• 
Four weeks on 500 mg MMF BID  
• 
Up to 48 weeks on no MMF 
 
Baseline MMF dose = 2000 mg/day to 2250 mg/day 
• 
Four weeks on 1000mg (morning) & 500mg (evening) MMF QD  
• 
Four weeks on 500mg MMF BID  
• 
Four weeks on 500 mg MMF QD  
• 
Up to 48 weeks on no MMF 
 
Baseline MMF dose = 1500 mg/day to 1750 mg/day 
• 
Four weeks on 500mg MMF BID 
• 
Four weeks on 500 mg MMF BID  
• 
Four weeks on 500 mg MMF QD  
• 
Up to 48 weeks on no MMF 
 
Baseline MMF dose = 1000 mg/day to 1250 mg/day 
 
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• 
Four weeks on 500 mg MMF BID  
• 
Four weeks on 500 mg MMF QD  
• 
Four weeks on 500 mg MMF QD  
• 
Up to 48 weeks on no MMF 
Prescribed MMF doses for subjects in the study will be collected on the Study Drug Dose Log 
CRF page. Information on this page includes dates of dose changes, prescribed doses 
(including a “zero” dose when a subject completes tapering), and reasons for dose changes.  
Bottles of MMF dispensed along with pill counts will be collected on the Study Drug Accounting 
Log CRF page. This page includes information on the number of bottles dispensed, number of 
pills in the bottle, dates dispensed and returned, pills returned, and pills lost. 
For both treatment arms, the total number of expected pills to be taken will be derived based on 
a subject’s prescribed MMF dose, taken from the Study Drug Dose Log CRF page, and duration 
of time in the study.   
The actual number of pills taken will be derived based on data on the Study Drug Accounting 
Log CRF page.  Given then number of bottles dispensed and number of pills in the bottles, 
actual pills counts will be derived based on the number of pills returned and number of pills lost. 
It will be assumed that any pills not returned or reported as lost by a subject will have been 
taken by the subject. Compliance will be calculated over the 12 week taper period for the 
Withdrawal arm and over the 60 week study period for the Maintenance arm. 
Compliance will be calculated as: 
% 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶= 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇
 × 100 
For subjects who terminate early from the study or who discontinued study-provided MMF early, 
compliance will only be calculated for the time in which the subject is taking study-provided 
MMF. 
 
 
 
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7. 
ENDPOINT EVALUATION 
7.1. 
Overview of Efficacy Analysis Methods 
7.1.1. 
Multicenter Studies 
Study subjects were recruited from 19 study sites.  Because the endpoint evaluations for this 
study are largely descriptive, clinical site will not be included as a covariate in the analyses. 
7.1.2. 
Assessment Time Windows 
Allowable visit windows for all scheduled visits are provided in Table 7-1. 
Table 7-1 
Visit Windows 
Visit 
Window 
Screening 
-28 to -1 
Baseline 
0 
Weeks 4, 8, 12, 16, 20, 24, 
32, 40, 48, 60 
± 7 days 
 
Unscheduled, Flare, and Endpoint visits may also occur throughout the study. All data will be 
included in analyses, regardless of time of assessment. 
7.2. 
Primary Endpoint 
7.2.1. 
Computation of the Primary Endpoint 
The primary endpoint is the probability in each arm of experiencing clinically significant disease 
reactivation by 60 weeks after randomization. The 60-week time point is to allow 48 weeks of 
observation off MMF in the withdrawal arm and minimize dropout, which is likely to occur as the 
trial lengthens. Clinically significant SLE reactivation requires both:  
1) A SELENA-SLEDAI*-defined mild/moderate or severe flare, and 
2) Increased immunosuppressive therapy on a sustained basis as defined by one of the 
following criteria: 
a. Sustained activity: Subject has significant prolonged SLE flare requiring 
steroid increase/burst to ≥ 15 mg/day prednisone (or its equivalent) for more 
than four weeks. 
b. Frequent relapsing/remitting: 
i. Subject flares requiring an increase/burst of steroids and is successfully 
tapered to < 15 mg/day within four weeks, but this occurs on two or more 
occasions, or 
ii. Intra-articular, intra-muscular or IV steroids, on more than one occasion. 
c. Clinical activity of sufficient severity to warrant resumption of or an increased 
dose of MMF or addition of other major immunosuppressive including 
azathioprine or methotrexate. Regardless of steroid use, if the investigator 
observes disease activity of sufficient severity to warrant resumption, addition 
or increase in dosage of major immunosuppressant in the setting of a 
SELENA-SLEDAI*-defined flare, subject has met the primary endpoint. 
 
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*ALE06 will typically use a spot urine protein:creatinine ratio rather than a 24-hour 
urine assessment for the SELENA-SLEDAI.  However, if indicated, results from a 24-
hour urine collection may be used. 
SELENA-SLEDAI: 
The SELENA-SLEDAI instrument will be completed at baseline and every follow-up visit, 
including any Flare or Endpoint visits, during the course of the 60 week study period for all 
subjects. Data for this assessment will be collected on the Physician’s Global Assessment, 
SLEDAI, and SELENA Flare & Endpoint Assessment CRF pages. The SELENA-SLEDAI 
assesses SLE disease activity and flares based on changes in the SLEDAI score, the 
Physician’s Global Assessment  (PGA), medication use (prednisone, NSAIDS, Plaquenil, major 
immunosuppressives), other disease activity criteria, and hospitalization due to SLE.   
Study investigators complete the SLEDAI scale by indicating of presence of 24 SLE disease 
manifestations during the preceding 10 days.  The original SLEDAI instrument includes an 
evaluation of proteinuria based on the protein:creatinine ratio derived from a 24-hour urine. For 
this study, the protein:creatinine ratio will typically be derived from the spot urine assessment 
although a 24-hour urine may be used if the spot urine assessment is not available. Each of 
the 24 disease manifestations has an assigned weight (see Appendix 14.3).  The SLEDAI total 
score will be computed as the sum of the weights for the items indicated as present. If a 
component of the SLEDAI (urinalysis or hematological labs only) was missed at a visit, then the 
missing data will be imputed by using the last observation carried forward approach. If a 
component of the SLEDAI is missed over consecutive visits, then the subsequent components 
will not be imputed. If an entire visit was missed, the score will not be imputed. 
Mild/moderate and severe SELENA-SLEDAI flares will be defined per the table below. If one or 
more criteria for a mild/moderate or severe flare have been met, a subject will be considered as 
having a mild/moderate or severe flare at that study visit. 
MILD OR MODERATE FLARE 
 Change in SLEDAI > 3 points 
 
New/Worse 
Discoid, photosensitive, profundus, 
cutaneous vasculitis, bullous lupus  
Nasopharyngeal ulcers 
Pleuritis 
Pericarditis 
Arthritis 
Fever attributable to SLE 
 Increase in prednisone, but not to > 0.5 mg/kg/day1 
 Added NSAID or Plaquenil 
 
> 1.0 increase in Physician’s Global Assessment (PhGA), but not to more than 2.5 
(on a 3.0 indexed VAS scale—refer to the Physican’s Global Assessment located 
on the Modified SLEDAI Source Document)  
SEVERE FLARE 
 Change in SLEDAI > 12 
 
New/Worse 
CNS-SLE 
Vasculitis 
Nephritis  
Myositis 
Platelet Count < 60,000/ mm
3 [equivalent to 60 x109/L] 
 
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Hemolytic anemia with hemoglobin < 7% OR Decrease in hemoglobin > 3% 
*Requiring:  doubling of prednisone, prednisone > 0.5 mg/kg/day, and/or 
hospitalization 
 Prednisone > 0.5 mg/kg/day1 
 New Cyclophosphamide (Cytoxan), Azathioprine, Methotrexate, Mycophenolate 
Mofetil, or hospitalization attributable to SLE 
 
Increase in Physician’s Global Assessment (PhGA) to > 2.5  
(on a 3.0 indexed VAS scale—refer to the Physican’s Global Assessment located 
on the Modified SLEDAI Source Document)  
1 For ALE06, prednisone > 0.5 mg/kg/day is categorized as a severe SELENA-SLEDAI flare if the 
duration is >2 weeks. Increases in prednisone >0.5 mg/kg/day but for ≤2 weeks will be categorized as 
mild/moderate SELENA-SLEDAI flares. 
Increased immunosuppressive therapy: 
Increased steroid therapy, as defined by 2a and 2b in the definition of clinically significant SLE 
reactivation, will be taken from the SELENA Flare & Endpoint Assessment and 
Prior/Concomitant Medications CRF pages. To differentiate from any doses of steroids taken 
for non-SLE related causes, only records marked as “Yes” to the question “Is this medication a 
corticosteroid or immunosuppressant prescribed after Day 0 due to increased SLE activity?” 
will be analyzed. Prednisone started ≤10 days post-visit for a flare will be included as increased 
therapy.  
Increase/resumption of MMF therapy or the addition of major immunosuppressive therapy, as 
defined by 2c in the definition of clinically significant SLE reactivation, will be taken from the 
SELENA Flare & Endpoint Assessment CRF page. 
Endpoint: 
For each subject, a yes/no variable will be assigned to indicate whether a subject has met the 
primary endpoint of clinically significant disease reactivation between Day 0 and Week 60, as 
defined above. 
Subjects who terminate early from the study, and who had not previously met primary endpoint, 
will be handled as follows: 
1. Subjects who do not have a mild/moderate or severe SELENA-SLEDAI flare at 
their last study visit will be categorized as not experiencing clinically significant 
disease reactivation. 
2. Subjects who have a mild/moderate or severe SELENA-SLEDAI flare at their last 
study visit: 
a. Subjects will be categorized as experiencing clinically significant disease 
reactivation for the following three scenarios: 
i. Subject has a SELENA-SLEDAI mild/moderate or severe flare at 
the time of early termination, and a steroid increase/burst to ≥ 15 
mg/day prednisone that is sustained through end of study.    
ii. Subject previously experienced a flare requiring either intra-
articular, intra-muscular or IV steroids, or an increase/burst of 
steroids that was successfully tapered to < 15 mg/day within four 
 
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weeks, and is experiencing a severe flare at the time of early 
termination. 
iii. Subject has a SELENA-SLEDAI severe flare based on the 
following clinical components: SLEDAI score; New/Worse 
disease, and Increase in PhGA without considering prednisone or 
other treatments  
 
b. Subjects experiencing flare at the time of early termination, but who do 
not met the criteria in 2.a. above, will be classified as not experiencing 
clinically significant disease reactivation. 
These cases will be re-categorized under sensitivity analyses for the primary 
endpoint (see 7.2.3). 
The time of clinically significant disease reactivation is defined as the date of the first SELENA-
SLEDAI assessment that meets (or goes on to meet) the criteria for clinically significant SLE 
reactivation. The time-to-event will be defined as the interval: date of disease reactivation – 
date of Day 0 visit. Subjects who do not experience clinically significant disease will be 
censored at the last visit date on study. 
The probability, or risk, of disease reactivation by Week 60 (on a 0 to 1 scale) in each arm will 
be derived using the Kaplan-Meier product-limit estimator for the cumulative incidence of 
disease reactivation.  Standard errors and confidence intervals for the cumulative incidence will 
be obtained using Greenwood’s formula. 
7.2.2. 
Primary Analysis of the Primary Endpoint 
The planned analyses for this study are designed to maximize the information available for 
medical decision-making. The planned analyses are as follows: 
Effect estimates and 95% confidence intervals for the risk of disease reactivation by Week 60 
in each arm as well as the estimated risk difference (i.e. risk_MMFwithdrawal - risk_MMF 
maintenance) and 95% confidence intervals around the risk difference will be reported using 
the Kaplan-Meier product-limit estimator. 
The observed risk estimates will be used to compute the “% Confidence that the true increase 
is ≤ a” as a function of values for the “Acceptable increase in risk with withdrawal of MMF (a)”.  
This information will be plotted with values for “Acceptable increase in risk with withdrawal of 
MMF (a)” on the x axis and estimates for “% Confidence that the true increase is ≤ a” on the y 
axis. The study will generate a single curve based on the observed risk estimates for the two 
arms.  Physicians with their patients could decide on an acceptable level of increased risk (a) 
then read from the plot the % confidence that this selected value of a would not be exceeded 
with withdrawal of MMF.  Depending on the level of confidence, they may or may not decide to 
withdraw MMF. 
 
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The motivation for the curve comes from the test of non-inferiority with the following 
hypotheses: 
H0: the increase in risk with withdrawal of MMF (T) ≥ a, and 
HA: the increase in risk with withdrawal of MMF (T) < a, 
 
where a is some value for the acceptable increase in risk. 
The H0 hypothesis would be rejected in favor of HA if the upper (1-α) % confident limit about the 
estimated risk difference (i.e. risk_MMFwithdrawal - risk_MMF maintenance) is less than a. Then, we could 
conclude that T < a with (1-α)% confidence.  Physicians and patients who are comfortable with 
both a risk increase of no more than a and a confidence level of (1-α)% could conclude that 
withdrawal from MMF is “not unacceptably worse” than maintenance on MMF.    
Recognizing that the appropriate value of a will be highly variable among physicians and 
patients, a single hypothesis is not defined for this study.  Alternatively the upper 1-sided (1-
α)% confidence limit (UCL) for the observed risk difference will be computed for values of α 
ranging from 0 to 0.99, in 0.01 increments. Note that for a given value of α the computed UCL 
equals the value of a, at which a null hypothesis could be rejected with a Type I error rate of α.  
Results of these computations will be tabulated and plotted. 
The primary analyses of the primary endpoint will be performed on the mITT population.  
7.2.3. 
Sensitivity and Additional Analyses of the Primary Endpoint 
Sensitivity and additional analyses on the primary endpoint will include the following: 
1. Analyses analogous to the primary will be run on the PP population. 
 
2. Sensitivity analyses will be performed to assess the robustness of the conclusions under 
different assumptions for missing data for subjects who terminated early from the study. 
All subjects who have a mild/moderate or severe SELENA-SLEDAI flare at their last 
study visit will be re-categorized as experiencing clinically significant disease 
reactivation. Additional sensitivity analyses may be performed including single and 
multiple imputation methods.   
 
3. A sensitivity analysis will be run to assess the impact of new or increased major 
immunosuppressive medications as the only cause of flare and therefore meeting 
primary endpoint. Subjects who re-start or increase a major immunosuppressive, but 
have no other disease activity that would categorize them as having a mild/moderate or 
severe flare will be categorized as not meeting primary endpoint (which requires both a 
SELENA-SLEDAI flare and increased immunosuppressive activity).  Analyses analogous 
to the primary will be run for this sensitivity analysis.  
7.3. 
Secondary Clinical Disease Activity Endpoints 
All secondary analyses will be conducted in an exploratory fashion with any p-values and 
confidence intervals presented as descriptive statistics with no adjustments for multiple 
comparisons. Interval estimates will be generated at the 95% confidence level. Analyses will be 
conducted on the mITT population and the PP population.  
 
 
 
 
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7.3.1. 
Time to Clinically Significant Disease Reactivation 
Endpoint: See Section 7.2.1, Computation of the Primary Endpoint, for details on the definition 
of clinically significant SLE reactivation.   
The time of clinically significant disease reactivation is defined as the date of the first SELENA-
SLEDAI assessment that meets (or goes on to meet) the criteria for clinically significant SLE 
reactivation. The time-to-event will be defined as the interval: date of disease reactivation – 
date of Day 0 visit. Subjects who do not experience clinically significant disease will be 
censored at the last visit date on study.  
Analysis: Time to disease reactivation will be summarized by treatment group.  Kaplan-Meier 
curves will be created for each treatment arm and will include 95% confidence intervals based 
on the Greenwood method. Estimated percent probability of disease reactivation will be 
calculated at Weeks 12, 24, 36, 48 and 60. Analyses will be conducted on the mITT population 
and the PP population. 
7.3.2. 
Probability of Experiencing a SELENA-SLEDAI Flare 
Endpoint: The SELENA-SLEDAI instrument will be completed at baseline and every follow-up 
visit, including any Flare or Endpoint visits, during the course of the 60 week study period for all 
subjects. The SELENA-SLEDAI assesses SLE disease activity and flares based on changes in 
the SLEDAI score, the Physician’s Global Assessment  (PGA), medication use (prednisone, 
NSAIDS, Plaquenil, major immunosuppressives), other disease activity criteria, and 
hospitalization due to SLE.  See Section 7.2.1., Computation of the Primary Endpoint, for more 
information on scoring of the SELENA-SLEDAI flare assessment. 
For each subject, a yes/no variable will be created to indicate whether a subject had at least 
one mild/moderate or severe SELENA-SLEDAI flare by Week 60 and separately whether the 
subject had at least one severe SELENA-SLEDAI flare by Week 60.   Subjects who terminate 
early from the study prior to experiencing any SELENA-SLEDAI flare will be categorized as not 
experiencing any SELENA-SLEDAI flare by Week 60. 
Additionally, for each subject, the total number of visits with mild/moderate or severe SELENA-
SLEDAI flares will be tabulated, including categorizing number of flare visits for a subject into 0, 
1, or >1 flare. 
The probability of experiencing any SELENA-SLEDAI flare and the probability of experiencing 
any severe SELENA-SLEDAI flare by Week 60 will be calculated in aggregate and within 
subgroups defined by disease manifestation (renal disease/extra-renal disease) and by 
baseline MMF dosing group (<2000 mg per day / ≥ 2000 mg per day).  
Analysis: Analyses analogous to those specified for the primary endpoint (effect estimates and 
95% confidence intervals, risk difference, and summaries of increased risk (a) vs.% confidence 
the “true” risk is ≤ a) will be performed for the probability of experiencing any SELENA-SLEDAI 
flare and any severe SELENA-SLEDAI flare by Week 60, including analyses within subgroups 
for disease manifestation and baseline MMF dose.  See Section 7.2.2, Primary Analysis of the 
Primary Endpoint, for more details on the analyses.   
The total number of visits that a subject has with a SELENA-SLEDAI flare will be summarized 
by treatment group and overall. Summary tables detailing the reasons for mild/moderate or 
severe flares, along with reason for new or increased major immunosuppressives will be 
provided.  Additionally, sensitivity analysis may be run to assess the impact of new or 
increased major immunosuppressives as the only cause of severe flare. Subjects who re-start 
 
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or increase major immunosuppressives, but have no other disease activity that would 
categorize them as having a severe flare, will be categorized as not having a severe SELENA-
SLEDAI flare and analyses would be replicated using this definition of a severe flare.  
The study day of flare, type (mild/moderate or severe), and number of flares for each subject 
will also be shown graphically over time by subject and treatment group.   
7.3.3. 
Time to First SELENA-SLEDAI Flare 
Endpoint: The SELENA-SLEDAI instrument will be completed at baseline and every follow-up 
visit during the course of the 60 week study period for all subjects. The SELENA-SLEDAI 
assesses flares based on changes in the SLEDAI score, the Physician’s Global Assessment  
(PGA), medication use (prednisone, NSAIDS, Plaquenil, major immunosuppressives), other 
disease activity criteria, and hospitalization due to SLE.  See Section 7.2.1., Computation of the 
Primary Endpoint, for more information on scoring of the SELENA-SLEDAI flare assessment. 
For each subject, time from Day 0 to first SELENA-SLEDAI flare and time to first severe 
SELENA-SLEDAI flare will be calculated in study days as: date of first flare – date of Day 0 
visit. Subjects who do not experience SELENA-SLEDAI flare will be censored at their last visit 
date on study. 
Analysis: Analyses analogous to those specified in Section 7.3.1, Time to Clinically Significant 
Disease Reactivation, will be performed for time to SELENA-SLEDAI flare. Additionally, 
sensitivity analysis may be run to assess the impact of new or increased major 
immunosuppressives as the only cause of severe flare. Subjects who re-start or increase major 
immunosuppressives, but have no other disease activity that would categorize them as having 
a severe flare, will be categorized as not having a severe SELENA-SLEDAI flare (i.e. 
categorized as a mild/moderate flare) and analyses would be replicated using this definition of 
a severe flare.  
7.3.4. 
Probability of Experiencing a BILAG A Flare 
Endpoint: The British Isles Lupus Assessment Group (BILAG) 2004 (2007 Revision) 
instrument will be completed at baseline and every follow-up visit, including any Flare or 
Endpoint visits, during the course of the 60 week study period for all subjects. Data for this 
assessment will be collected on the Modified BILAG: Constitutional, Modified BILAG: 
Mucocutaneous, Modified BILAG: Neuropsychiatric, Modified BILAG: Musculoskeletal, 
Modified BILAG: Cardiorespiratory, Modified BILAG: Gastrointestinal, Modified BILAG: 
Ophthalmic, Modified BILAG: Renal, and Modified BILAG: Hematological CRF pages. 
The rules for scoring the BILAG 2004 are in Appendix 14.4 BILAG 2004 Index Scoring. In each 
of the nine body system categories (constitutional, mucocutaneous, neuropsychiatric, 
musculoskeletal, cardiorespiratory, gastrointestinal, ophthalmic, renal, and hematological) 
subjects are assessed on a variety of disease activity criteria. Each category is then scored as 
an A, B, C, or D/E, where A indicates most severe disease activity and D/E indicates 
inactive/no disease activity.  For this study the following additional scoring rules are applied: 
1. According to the scoring algorithm, D means "Inactive disease but previously affected", and 
E means "System never involved".  Since we may not know whether the subject has ever 
experienced involvement in a particular system prior to starting the study, we will not 
attempt to distinguish between D and E.  Subjects will be assigned the score “D/E” if they 
did not meet the criteria for A, B, or C at the particular visit.   
 
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2. In the Renal category, some of the scoring rules require looking at previous measurements 
to assess change (e.g., 24 hour protein > 1g that has not decreased (improved) by >=25%). 
At Screening the BILAG is not collected as it is not required for eligibility purposes.  As 
such, no previous BILAG assessment is available to refer to for applying such rules at the 
Day 0 visit and therefore subjects will not have a renal score assigned at Day 0. 
3. In the Renal category, the original instrument includes an evaluation of proteinuria based 
on the protein:creatinine ratio derived from a 24-hour urine. For this study, the 
protein:creatinine ratio will typically be derived from the spot urine assessment although a 
24-hour urine may be used if the spot urine assessment is not available. 
For each subject, a yes/no variable will be created to indicate whether a subject had at least 
one BILAG A flare, in any body system, by Week 60. Subjects who terminate early from the 
study prior to experiencing a BILAG A flare will be categorized as not experiencing a BILAG A 
flare by Week 60. 
The probability of experiencing any BILAG A flare will be calculated for each study arm. 
Additionally, for each subject, the total number of visits with BILAG A flare will be tabulated. 
Analysis: Analyses analogous to those specified for the primary endpoint (effect estimates and 
95% confidence intervals, risk difference, and summaries of increased risk (a) vs.% confidence 
the “true” risk is ≤ a) will be performed for the probability of experiencing a BILAG A flare by 
Week 60.  See Section 7.2.2, Primary Analysis of the Primary Endpoint, for more details on the 
analyses.  The total number of visits that a subject has with a BILAG A flare will be summarized 
by treatment group and overall. Summary tables for BILAG A scoring by body system will be 
provided.   
7.3.5. 
Subjects in the Renal Subgroup with BILAG Renal A Flares  
Endpoint: The BILAG instrument will be completed at baseline and every follow-up visit during 
the course of the 60 week study period for all subjects. See Section 7.3.4, Probability of 
Experiencing a BILAG A Flare, for more information on the BILAG and its scoring. The renal 
disease subgroup includes subjects who presently have renal disease as well as those who 
have had renal manifestations in the past, as specified by the site at randomization. 
For each subject in the renal subgroup, a yes/no variable will be created to indicate whether a 
subject had at least one BILAG A flare in the renal body system by Week 60. Subjects in the 
renal subgroup, who terminate early from the study prior to experiencing a BILAG A renal flare, 
will be categorized as not experiencing a BILAG A flare by Week 60. 
The proportion of subjects in the renal subgroup with at least one BILAG A flare in the renal 
body system by Week 60 will be calculated for each study arm. 
Analysis: Analyses analogous to those specified for the primary endpoint (effect estimates and 
95% confidence intervals, risk difference, and summaries of increased risk (a) vs.% confidence 
the “true” risk is ≤ a) will be performed for the probability of experiencing a BILAG A renal flare 
by Week 60 in the renal subgroup.  See Section 7.2.2, Primary Analysis of the Primary 
Endpoint, for more details on the analyses. 
 
 
 
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7.3.6. 
Probability of Experiencing a BILAG A or B Flare 
Endpoint: The BILAG instrument will be completed at baseline and every follow-up visit, 
including any Flare or Endpoint visits, during the course of the 60 week study period for all 
subjects. See Section 7.3.4, Probability of Experiencing a BILAG A Flare, for more details on 
the BILAG assessment.  
For each subject, a yes/no variable will be created to indicate whether a subject had at least 
one BILAG A or B flare, in any body system, by Week 60. Subjects who terminate early from 
the study prior to experiencing a BILAG A or B flare will be categorized as not experiencing a 
BILAG A or B flare by Week 60. 
The probability of experiencing any BILAG A or B flare will be calculated for each study arm by 
each body system and overall. 
Additionally, for each subject, the total number of visits with a BILAG A or B flare will be 
tabulated by arm for each body system and overall. 
Analysis: Analyses analogous to those specified for the primary endpoint (effect estimates and 
95% confidence intervals, risk difference, and summaries of increased risk (a) vs.% confidence 
the “true” risk is ≤ a) will be performed for the probability of experiencing a BILAG A flare by 
Week 60.  See Section 7.2.2, Primary Analysis of the Primary Endpoint, for more details on the 
analyses. Summary tables for BILAG scoring by body system will be provided.  The total 
number of visits that a subject has with a BILAG A or B flare will be summarized by treatment 
group and overall. 
The study day of flare, type (A or B), body system, and number of flares for each subject will 
also be shown graphically over time by subject and treatment group. 
7.3.7. 
Changes in the SLICC/DI 
Endpoint: The Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Disease Damage Index for Systemic Lupus Erythematosus (SLICC/DI) will be 
assessed at Baseline, Weeks 24, 48 and 60, and any Flare or Endpoint visits that occur during 
the course of the trial.  Data for the SLICC/DI will be captured on the SLICC/ACR Damage 
Index for Systemic Lupus Erythematosus CRF page. 
The SLICC/DI measures accumulated damage that has occurred since the onset of SLE, 
regardless of cause, in 12 organ systems. SLE damage is defined as an irreversible change in 
an organ or system that has been present for at least 6 months. The original SLICC/DI 
instrument includes an evaluation of proteinuria based on a 24-hour urine assessment. For this 
study, the protein:creatinine ratio will typically be derived from the spot urine assessment 
although a 24-hour urine may be used if the spot urine assessment is not available.  
The SLICC/DI includes 39 areas of damage in 12 domains, where each item is rated as 
present or absent; if evidence of damage is present for a particular item, it is given a score of 1. 
Some items are scored with 2 or 3 points in the case of recurring events or end stage renal 
disease.  The SLICC/DI total score will be computed as the sum of all scores for items 
indicated as present; scores can range from 0 to 45. Higher scores indicate more damage. 
Missing scores will not be imputed. 
Change from baseline in the SLICC/DI score at Weeks 24, 48, and 60 will be computed for 
each subject. 
 
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Analysis: Descriptive statistics (mean, standard deviation or standard error, median, minimum, 
maximum and number of subjects in a group) and 95% confidence intervals will be reported for 
the difference in the change from baseline in the SLICC/DI score between the treatment groups 
at each specified time point. The SLICC/DI score and change from baseline in will be shown 
graphically by treatment arm. Spaghetti plots and summary statistics including 25th percentile, 
mean, median, and 75th percentile will be plotted for each visit by treatment group. 
7.3.8. 
The Addition of Aggressive Adjunctive Therapy to MMF or Change in 
MMF Therapy to Cytotoxic Drug Due to Flare 
Endpoint: Medications are assessed at each study visit throughout the duration of the study 
and are collected on the Prior/Concomitant Medications CRF page. 
For both the maintenance and withdrawal arms, the addition of aggressive adjunctive therapy 
can include IV immunoglobulin or rituximab at any point during the subject’s participation in the 
study.  A change in therapy to cytotoxic drug due to flare can include drugs such as 
cyclophosphamide, etc. A blinded list of study medications will be reviewed to identify the 
addition of aggressive adjunctive therapy or cytotoxic drugs.  
For each subject, a yes/no variable will be created to indicate whether a subject added 
aggressive adjunctive therapy to MMF or changed MMF therapy to cytotoxic drug due to flare 
by Week 60.  Subjects off MMF in the withdrawal arm will be included in the endpoint if 
aggressive adjunctive therapy or cytotoxic drugs were added to treat a flare.  Subjects who 
terminate early from the study prior to adding aggressive adjunctive therapy to MMF or 
changing MMF therapy to cytotoxic drug due to flare will be categorized as not meeting the 
endpoint.  
The probability of adding aggressive adjunctive therapy to MMF or changing MMF therapy to 
cytotoxic drug due to flare will be calculated for each study arm. 
Analysis: Analyses analogous to those specified for the primary endpoint (effect estimates and 
95% confidence intervals, risk difference, and summaries of increased risk (a) vs.% confidence 
the “true” risk is ≤ a) will be performed for adding aggressive adjunctive therapy to MMF or 
changing MMF therapy to cytotoxic drug due to flare by Week 60.  See Section 7.2.2, Primary 
Analysis of the Primary Endpoint, for more details on the analyses.  Additionally, type of new 
therapy will be summarized by treatment arm and overall. 
7.3.9. 
Systemic Steroid Dose 
Endpoint: Medications, including steroid use, are assessed at each study visit throughout the 
duration of the study and are collected on the Prior/Concomitant Medications CRF page.  
Steroids include medications that code to a medication class which includes the terms 
“glucocorticoid” or “corticosteroid”. Systemic steroids will include any of these steroids that are 
taken by mouth (PO), intravenous (IV), or intramuscular (IM).  
Total cumulative systemic steroid dose, in milligrams, will be summarized over the 60 week 
study period, or until early study termination, for each subject.  Total cumulative systemic 
steroid dose, in milligrams, given specifically to treat a SLE flare may also be summarized. 
Additionally, the excess steroid dose given over the course of the 60 week study period, or until 
early study termination, will be calculated for each subject.  Excess steroid dose will be 
 
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calculated based on the difference between expected steroid dose (extrapolated from baseline 
steroid dose) and actual total cumulative steroid dose given during the course of the study.  
Analysis: Analyses analogous to those specified in Section 7.3.6, Changes in the SLICC/DI, 
will be performed on the total steroid dose and excess steroid dose at Week 60.  
7.3.10. Changes in the FACIT Score 
Endpoint: The Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scale will be 
assessed at Baseline, Weeks 24, 48 and 60, and any Flare or Endpoint visits that occur during 
the course of the trial.  Data for the FACIT fatigue scale will be captured on the FACIT CRF 
page. 
The FACIT fatigue scale assesses fatigue in subjects with chronic illness. Thirteen fatigue-
related questions are measured on a 4-point scale. The FACIT fatigue subscale scoring guide 
(see Appendix 14.5, FACIT-Fatigue Subscale Scoring Guidelines) identifies those items that 
must be reversed before being added to obtain subscale totals.  Negatively stated items are 
reversed by subtracting the response from “4”.  After reversing proper items, all subscale items 
are summed to a total, which is the subscale score.  High scores represent less fatigue and 
better quality of life. 
If there are missing items, subscale scores can be prorated.  This is done by multiplying the 
sum of the subscale by the number of items in the subscale, then dividing by the number of 
items actually answered.  This can be done on the scoring guide or by using the formula below: 
Prorated subscale score = [Sum of item scores] x [N of items in subscale] ÷ [N of items answered] 
When there are missing data, prorating by subscale in this way is acceptable as long as more 
than 50% of the items were answered (e.g., a minimum of 7 of 13 items).   
Change from baseline in the FACIT score at Weeks 24, 48, and 60 will be computed for each 
subject. 
Analysis: Analyses analogous to those specified in Section 7.3.6, Changes in the SLICC/DI, 
will be performed on the FACIT score. 
7.3.11. Changes in SF-36 Scores 
Endpoint: The Short Form Health Survey (SF-36) will be assessed at Baseline, Weeks 24, 48 
and 60, and any Flare or Endpoint visits that occur during the course of the trial.  Data for the 
SF-36 will be captured on the SF-36 Survey CRF page. 
The SF-36 is a 36-item, patient-reported survey of patient health.  Higher scores indicate better 
outcomes while lower scores indicate more disability.  
The following SF-36 scale scores will be calculated: Physical Functioning, Role-Physical, 
Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health.  
From these scale scores, two summary scores that aggregate measures will be created.  The 
Physical Component Score is comprised of the Physical Functioning Scale, the Role-Physical 
Scale, the Bodily Pain Scale, and the General Health Scale.  The Mental Component Score is 
comprised of the Vitality Scale, the Social Functioning Scale, the Role-Emotional Scale, and 
the Mental Health Scale. 
 
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Norm-based scores will also be generated for the eight SF-36 scales and the two summary 
measures.  All eight SF-36 scales and the two summary scores will be normalized to have a 
mean of 50 and a standard deviation of 10 for the 1998 general US population.  The advantage 
of the standardization is that results for one scale can be meaningfully compared with the other 
scales, and the scores have a direct interpretation in relation to the distribution of scores in the 
1998 general US population.  Specifically, scores above or below 50 are above or below the 
average, respectively, for the 1998 general US population.  Because the standard deviation is 
10 for all 8 scales, each one point difference in scores is equivalent to one-tenth of a standard 
deviation unit or an effect size of 0.10.  See Appendix 14.6, Scoring the SF-36 Version 2, of 
this SAP for details regarding calculation of these scores. 
Change from baseline in the SF-36 Physical Functioning (PF) and Physical Component 
Summary (PCS) domains at Weeks 24, 48, and 60 will be computed for each subject. 
Analysis: Analyses analogous to those specified in Section 7.3.6, Changes in the SLICC/DI, 
will be performed on the SF-36 PF and PCS. 
7.3.12. Change in Lupus QoL Score 
Endpoint: The Lupus Quality of Life (QoL) instrument will be assessed at Baseline, Weeks 24, 
48 and 60, and any Flare or Endpoint visits that occur during the course of the trial.  Data for 
the Lupus QoL will be captured on the Lupus QoL CRF page. 
The Lupus QoL assessment is a 34 item questionnaire across 8 domains that is designed to 
find out how SLE affects a subject’s life over the preceding 4 weeks. The physical health 
domain comprises item numbers 1–8, pain comprises 9–11, planning comprises 12–14, 
intimate relationships comprises 15 and 16, burden to others comprises 17–19, emotional 
health comprises 20– 25, body image comprises 26–30, and fatigue comprises 31–34. Each of 
the 34 questions are answered on a 5-point scale, where 0 = all of the time, 1 = most of the 
time, 2 = a good bit of the time, 3 = occasionally, and 4 = never.  
Item response scores are totaled for each domain and the mean raw domain score is obtained 
by dividing the total score by the number of items in that domain. The mean raw domain score 
is transformed to scores ranging from 0 (worst QOL) to 100 (best QOL) by dividing by 4 (the 
number of Likert responses [5 responses] minus 1) and then multiplying by 100, as below: 
mean raw domain score
4
 × 100 = transformed score for domain 
Transformed domain scores are obtainable when at least 50% of the items are answered. The 
mean raw domain score is then calculated by totaling the item response scores of the 
answered items and dividing by the number of answered items. A nonapplicable response is 
treated as unanswered and the domain score is calculated as above. 
Change from baseline in the Lupus QoL scores at Weeks 24, 48, and 60 will be computed for 
each subject. 
Analysis: Analyses analogous to those specified in Section 7.3.6, Changes in the SLICC/DI, 
will be performed on the Lupus QoL scores. 
 
 
 
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7.3.13. Recovery from Clinically Significant Disease Reactivation 
The following endpoints will be assessed to describe the ability of subjects to recover from 
clinically significant disease reactivation.   
7.3.13.1. Time from clinically significant disease reactivation to improvement in 
BILAG from maximum level during flare 
Endpoint: See Section 7.2.1, Computation of the Primary Endpoint, for details on the definition 
of clinically significant SLE reactivation, and Section 7.3.4, Probability of Experiencing a BILAG 
A Flare, for more information on the BILAG and its scoring. 
For each subject who experiences disease reactivation, time from clinically significant disease 
reactivation to improvement in BILAG from maximum level (at least an A or B) during the flare 
will be calculated in study days as: date of clinically significant disease reactivation – date of 
BILAG improvement. If multiple body systems have a BILAG flare at the visit, then the body 
system with the most severe score will be tracked for improvement; if multiple body systems 
have the same score (at least an A or B), then just one needs to show improvement.     
Subjects who do not experience improvement in the BILAG prior to the end of their study 
participation or if the subject doesn’t experience an increase in their BILAG score to a B or 
higher will be censored at their last visit date on study. 
Analysis: Kaplan-Meier curves will be created for each treatment arm and will include 95% 
confidence intervals based on the Greenwood method. 
7.3.13.2. Time from clinically significant disease reactivation to recovery to 
baseline BILAG scores or BILAG C, whichever is worse 
Endpoint: See Section 7.2.1, Computation of the Primary Endpoint, for details on the definition 
of clinically significant SLE reactivation, and Section 7.3.4, Probability of Experiencing a BILAG 
A Flare, for more information on the BILAG and its scoring. 
For each subject who experiences disease reactivation, time from clinically significant disease 
reactivation to recovery to baseline BILAG scores or BILAG C, whichever is worse, will be 
calculated in study days as: date of clinically significant disease reactivation – date of BILAG 
recovery.  
If a subject does not recover to their baseline BILAG score or BILAG C, whichever is worse, 
prior to the end of their study participation, or if the subject doesn’t experience an increase in 
their BILAG score, then their BILAG score will be censored at their last visit date on study. 
Analysis: Kaplan-Meier curves will be created for each treatment arm and will include 95% 
confidence intervals based on the Greenwood method. 
7.3.13.3. Cumulative excess systemic steroid dose from time of clinically 
significant disease reactivation to return to pre-flare dose or end of trial 
participation 
Endpoint: See Section 7.2.1, Computation of the Primary Endpoint, for details on the definition 
of clinically significant SLE reactivation, and Section 7.3.8., Systemic Steroid Dose, for details 
on the definition of systemic steroids. 
For each subject who experiences disease reactivation, excess systemic steroid dose will be 
summed from the time of clinically significant disease reactivation until the dose returns to pre-
flare levels or the end of study participation, whichever occurs first. Excess systemic steroid 
dose will be defined as the total dose given for the flare – a subject’s pre-flare steroid dose. 
 
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Subjects who do not have an increase in their steroid use due to the flare will have their excess 
dose set to zero. 
Analysis: Descriptive statistics (mean, standard deviation or standard error, median, minimum, 
maximum and number of subjects in a group) and 95% confidence intervals will be reported for 
the cumulative excess steroid dose in each treatment group. 
7.3.13.4. Time from clinically significant disease reactivation to return to pre-flare 
steroid dose. 
Endpoint: See Section 7.2.1, Computation of the Primary Endpoint, for details on the definition 
of clinically significant SLE reactivation.  Medications, including steroid use, are assessed at 
each study visit throughout the duration of the study and are collected on the Prior/Concomitant 
Medications CRF page. 
For each subject who experiences disease reactivation, time from clinically significant disease 
reactivation to recovery to pre-flare steroid dose will be calculated in study days as: date of 
clinically significant disease reactivation – date of return to pre-flare steroid dose.  
If a subject does not return to their pre-flare steroid dose prior to the end of their study 
participation, or if the subject does not have in increase in steroid dose due to their flare, then 
the variable will equal the duration of follow-up for that subject. Appropriate censor variables 
will be defined to indicate whether the time-to variable represents an event time or a censor 
time. 
Analysis: Kaplan-Meier curves will be created for each treatment arm and will include 95% 
confidence intervals based on the Greenwood method. 
7.4. 
Secondary Mechanistic Endpoints 
7.4.1. 
C3, C4, and anti-dsDNA Levels 
Endpoint: C3, C4, and anti-dsDNA are run at baseline and every follow-up visit, including any 
Flare or Endpoint visits, during the course of the 60 week study period and run by a central 
laboratory.   
Specifically, levels of C3, C4, and anti-dsDNA at Baseline, Week 20, at the time of first flare, 
and immediately prior to first flare will be analyzed. 
Analysis: Descriptive statistics (mean, standard deviation, median, minimum, maximum and 
number of subjects in a group) will be computed by treatment group and separately for subjects 
who do/do not experience clinically significant disease reactivation at each specified time point. 
Summary statistics will be plotted versus time at the relevant time points. Plots for individual 
subjects will also be created. 
7.4.2. 
Changes in C3, C4, and anti-dsDNA Levels 
Endpoint: C3, C4, and anti-dsDNA are run at baseline and every follow-up visit, including any 
Flare or Endpoint visits, during the course of the 60 week study period and run by a central 
laboratory.  Change from baseline will be calculated for each test and time point. 
Specifically, change from baseline in levels of C3, C4, and anti-dsDNA at Week 20, the time of 
first flare, and immediately prior to first flare will be analyzed. 
 
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Analysis: Descriptive statistics (mean, standard deviation, median, minimum, maximum and 
number of subjects in a group) will be computed by treatment group and separately for subjects 
who do/do not experience clinically significant disease reactivation at each specified time point. 
Summary statistics will be plotted versus time at the relevant time points. Plots for individual 
subjects will also be created. 
7.4.3. 
Antibody Levels 
Endpoint: Antibody levels, including, but not limited to Sm, ribonucleoprotein (RNP), SSA/Ro, 
& SSB/La are assessed at the Baseline, Week 60, and if needed, the flare visit and run by a 
central laboratory.   
Analysis: Descriptive statistics (mean, standard deviation, median, minimum, maximum and 
number of subjects in a group) and/or a summary of categorical response (positive, negative, 
indeterminate, etc.) will be computed by treatment group for each antibody result. Summary 
statistics will be plotted versus time at the relevant time points as applicable.  
7.5. 
Examination of Subgroups 
Secondary analyses of the primary and secondary objectives may be conducted for the 
following subgroups, including, but not limited to: 
• 
Age 
• 
Race/ethnicity 
• 
Disease manifestation (renal disease/extra-renal disease), as defined in Section 7.3.5. 
• 
SLE duration (< 5 years / ≥ 5 years) 
• 
Baseline MMF dosing group (<2000 mg per day / ≥ 2000 mg per day) 
• 
Baseline autoantibody status 
Additionally, exploratory analyses of subgroups defined through the mechanistic and 
immunological studies may also be conducted. 
8. 
SAFETY EVALUATION 
8.1. 
Overview of Safety Analysis Methods 
All safety analyses will be carried out using the safety sample defined in Section 4.2 unless 
otherwise noted.  Missing safety information will not be imputed.  These analyses will not be 
stratified by site.  All safety comparisons and associated p-values are considered exploratory, 
not as formal tests of hypothesis. As such, no adjustments will be made for multiple 
comparisons and all p-values must be interpreted cautiously. 
Listings will be prepared for all safety measurements.  All listings will be sorted in order of 
treatment, subject identifier (ID), and time of assessment (e.g., visit, time, and/or event). 
8.2. 
Extent of Exposure 
Extent of exposure during the trial will be described for MMF.  Exposure will be measured as the 
total number of days on medication defined as last dose date – first dose date + 1 and the 
cumulative dose of that medication defined as the sum of the doses in mg taken up to the 
relevant cutoff date.  Exposure will be summarized until a subject stops taking study provided 
MMF. 
 
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8.3. 
Adverse Events 
All AEs will be classified by system organ class (SOC) and preferred term, according to a 
standardized thesaurus (Medical Dictionary for Regulatory Activities [MedDRA] version 16.1).  
The severity of AEs will be classified using the National Cancer Institute’s (NCI’s) Common 
Toxicity Criteria for Adverse Events (CTCAE) version 4.0.  Each AE is entered on the electronic 
case report form (eCRF) once at the highest severity. As such, no additional data manipulation 
is needed to identify events. 
Adverse events will be collected from the time the subject signs the informed consent until 
he/she initiates study intervention or until he/she is determined to be ineligible to receive study 
intervention, if the investigator determines that the AE is related to a study-mandated 
procedure, treatment, or change in treatment. 
Regardless of whether the above is applicable, for all participants: AEs will be collected from 
the time of initiation of study intervention (i.e., the administration of the first dose of study-
supplied MMF as defined in Protocol Section 6.4.2, Baseline/Randomization Visit) until he/she 
completes study participation or until 30 days after he/she prematurely withdraws (without 
withdrawing consent) or is withdrawn from the study.   
Treatment-emergent AEs will be identified as those with an onset date on or after the first dose 
of study medication as well as those with onset before first dose but that continued and 
worsened in severity after first dose.  If the start of the AE in relation to the start of study 
medication cannot be established (e.g., the start date for the AE is missing), then the AE will be 
considered treatment-emergent.  All data tabulations will be of only treatment-emergent events 
while non-treatment-emergent AEs will be listed separately, unless otherwise noted.  
Indicator variables will be derived for the following categories of AEs: infections, malignancies, 
BILAG A flares, and severe SELENA-SLEDAI flares. Yes/no questions for each of these types 
of events are included on the Adverse Events CRF page. 
Relationship to study treatment will be categorized as either treatment related (possibly, 
probably, or definitely related to study medication) or unrelated (unlikely related or unrelated). 
An overall summary table will be developed to report the number of events and the number and 
percentage of subjects having at least one event in the following categories:  
• 
AEs 
• 
AEs indicated as serious 
• 
AEs that lead to study drug discontinuation 
• 
AEs with an outcome of death 
• 
AEs that were reported as being related to MMF 
• 
AEs that were reported as being related to SLE 
• 
AEs reported by maximum severity 
• 
AEs that are BILAG A flares 
• 
AEs that are severe SELENA-SLEDAI flares 
 
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In addition, AEs classified by MedDRA SOC and preferred term will be summarized for each 
treatment group and overall for each of the following: 
• 
All AEs 
• 
AEs by maximum severity  
• 
AEs by relationship to study drug 
Summary tables will present the total number of events as well as the number and percentage 
of subjects experiencing the events.  If a subject experiences the same AE on multiple 
occasions, the event will be counted once for each occurrence when reporting the number of 
AEs.  When reporting the number of subjects experiencing the events, a subject will only be 
counted once if they experience an event within the particular SOC or preferred term.  
Percentages will be based on the number of subjects in the safety population. To account for 
differential duration of study participation among subjects, the summaries will include the event 
rate (i.e. number of events per person-time) in addition to the number and percent of events 
and subjects experiencing events. 
Separate data listings will be provided for treatment-related AEs and AEs leading to study drug 
discontinuation. 
8.3.1. 
Secondary Safety Endpoints 
Secondary safety endpoints include the following: 
1. All Grade 3-5 adverse events, as defined by the NCI–CTCAE system, which are 
defined as possibly, probably, or definitely related to SLE.  
2. All Grade 3-5 adverse events, as defined by the NCI-CTCAE system, which are defined 
as possibly, probably, or definitely related to MMF.  
3. All NCI-CTCAE Grade 3-5 adverse events. 
4. All serious adverse events. 
5. All infection related events. 
6. All malignancies. 
7. All NCI-CTCAE Grade 3-5 hematological events. 
8. Mortality possibly, probably, or definitely related to SLE. 
9. All-cause mortality, defined as any death occurring at any time after randomization. 
Serious adverse events will include only those events deemed serious per 21 CFR 312.32 
(See Protocol Section 7.2.4). Events that require 24-hour reporting to the sponsor, such as 
BILAG A and severe SELENA-SLEDAI flares, will not be included unless they also meet SAE 
reporting criteria per 21 CFR 312.32; these events will be summarized separately.  
Infections will include those events that are coded to the SOC of “Infections and infestations” 
along with any AE with an answer of Yes to the question “Was this AE an infection?” on the 
Adverse Events CRF page. 
Malignancies will include those events that are coded to the SOC of “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps)” along with any AE with an answer of Yes to 
the question “Was this AE a malignancy?” on the Adverse Events CRF page. 
Hematological events will include AEs that are coded to the SOC of “Blood and lymphatic 
system disorders”.  
For each of the safety endpoints listed above, the AEs, classified by MedDRA system organ 
class and preferred term, will be summarized for each treatment group and overall. The 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
summaries will include the event rate (i.e. number of events per person-time) in addition to the 
number and percent of events and subjects experiencing events.  
The proportion of subjects experiencing at least one event specified aobve in each treatment 
group will be reported and the treatment groups compared based on Fisher’s Exact Test. In 
addition, event rates in the two arms will be compared using Poisson regression.  
8.4. 
Deaths and Serious Adverse Events 
Serious adverse events (SAEs) will be listed and summarized in a similar manner as described 
in Section 8.3.  Separate displays listing and summarizing death, including time to death and 
cause of death, will also be created if a death occurs. 
8.5. 
Clinical Laboratory Evaluation 
Clinical laboratory measurements include serum chemistry, urinalysis, and hematology.  
Results will be converted to standardized units where possible. Chemistry and hematology 
panels are run by a central lab; as such, normal ranges will come from the central lab.     
Laboratory data will be plotted to show patterns over time.  Summary statistics including 25th 
percentile, median, and 75th percentile will be plotted for each visit by treatment group.  Lines 
connecting individual subject results from subjects with grade 2 or higher values will be overlaid 
on each figure. For lab results that are not gradable, results from subjects with values outside 
of 2 *ULN or 0.5*LLN will be overlaid. Tests with qualitative results (such as “present” or 
“positive”) will not be plotted. 
8.6. 
Vital Signs, Physical Findings, and Other Observations Related to Safety 
8.6.1. 
Vital Signs 
Vital sign information will be collected on the Vital Signs CRF page at every study visit. Data 
listings sorted by treatment group, subject, vital sign parameter, and time of assessment will be 
provided for vital signs measurements. 
8.6.2. 
Physical Examinations 
Physical exam information will be collected on the Physical Exam CRF page at every study 
visit. Data listings will be provided for physical examination results and sorted by treatment 
group, subject, body system, and time of assessment. 
9. 
PHARMACOKINETIC EVALUATION 
No pharmacokinetic evaluations will be performed for ALE06. 
 
 
 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
10. 
OTHER ANALYSES 
10.1. Use of Medications 
Medications will be coded according to the World Health Organization (WHO) Drug Dictionary 
(version 2013.03).  Medications reported on the CRF will be categorized for analysis as prior, 
concomitant, or after study treatment by comparing the medication start and stop dates with the 
first and last dose of study medication dates.  Prior medications will have both the medication 
start and stop dates prior to the first dose of study medication date.  After medications will have 
both the medication start and stop dates after the last dose of study medication date.  All other 
medications will be classified as concomitant, indicating that use of the medication overlapped 
with use of the study medication by at least one day. 
The number and percentage of subjects receiving prior, concomitant, and after medications will 
be presented overall and by medication class.  When reporting the number of subjects 
receiving the medication, a subject will only be counted once if they ever received the 
medication within the medication class.  Percentages will be based on the number of subjects 
in the analysis population.   
 
 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
11. 
INTERIM ANALYSES AND DATA MONITORING 
The progress of the study will be monitored by the Data and Safety Monitoring Board (DSMB).  
The NIAID Autoimmune DSMB will be chartered to review safety data and to make 
recommendations regarding continuation, termination, or modification of the study.  The DSMB 
will formally review the safety data at least yearly.  The discontinuation of study treatment will 
also be periodically reported to the DSMB.  
In addition, safety data will be reviewed by the DSMB when an event occurs that is of sufficient 
concern to the National Institute of Allergy and Infectious Diseases (NIAID) medical monitor or 
protocol chair to warrant review, or when an event occurs that could contribute to a predefined 
stopping rule specified in the protocol.  
Findings will be reported to Institutional Review Boards (IRBs) and health authorities. 
11.1. Interim Analysis  
Interim study results will be reported to the DSMB for planned Data Review Meetings. Reports 
prepared for these meetings will focus on study conduct and subject safety and may include 
information on enrollment, randomization, site activation status, protocol deviations, subject 
status and demographics, and safety analyses. In particular, at each DSMB review, disease 
reactivation rates in each arm and the risk difference (i.e. risk_MMFwithdrawal - risk_MMF maintenance) will 
be reported along with the 2-sided 95% confidence interval.  If the lower 95% confidence limit 
about the risk difference exceeds 0.40, the DSMB should consider whether or not the study 
should be stopped for safety concerns. In order to trigger the guidance, the number of disease 
reactivations in the MMF withdrawal arm must exceed the number in the MMF maintenance 
arm, but the magnitude of the excess depends on the sample size. Some examples of 
observed scenarios that would trigger the guidance are as follows: 
# Subjects per arm 
Minimum # excess 
reactivations in the MMF 
withdrawal arm* 
10 
7  
20 
13 
30 
18 
40 
23 
50 
27 
60 
32 
* The excess needed to trigger the guidance also 
depends on the # of reactivations in the MMF 
maintenance arm.  
 
 
 
In addition, if ≤ 10% of the first 80 subjects experience disease reactivation after accruing 60 
weeks of post-randomization time and the study is still accruing subjects, then the pooled 
estimate of the disease reactivation rate may be used to re-estimate the required sample size. 
The pooled observed rate (and the 2-sided 95% CI) will be used to reconsider the maximum 
potential difference between the arms.  If power is at least 85% under scenarios where the 
assumed rate in the maintenance arm is ≤ 5% with an acceptable risk difference of 0.15, then 
the study team may consider reducing the sample size.  
 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
12. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
1. Section 7.2. Primary Endpoint.  Statistical methods to obtain effect estimates and 
confidence intervals for the probability of observing clinically significant disease 
reactivation by 60 weeks have been changed from exact methods for complete 
data (proportions with Clopper Pearson intervals) to Kaplan-Meier predict-limit 
estimators to allow for censoring of subjects who terminated early without 
evidence of disease reactivation.  
2. Section 7.3.3. Time to First SELENA-SLEDAI Flare:  Time to first SELENA-
SLEDAI flare has been changed from using withdrawal date to using Day 0 date. 
This allows us to calculate time to first SELENA-SLEDAI flare in both arms, since 
the Maintenance arm does not start withdrawal, and is consistent with the timing 
of the time to disease reactivation endpoint specified in Section 7.3.1. 
3. Section 7.3.6. Probability of Experiencing a BILAG A or B Flare:  This is a new 
endpoint was added to the SAP by the study team.   
4. Section 11.1. Interim Analysis: The sample size re-estimation specified if ≤ 10% 
of the first 80 subjects experienced disease reactivation was not performed. We 
observed that after 60 weeks of post-randomization, 8 of the first 80 (10%) 
subjects experienced disease reactivation. Although the rate of disease 
reactivation was low, the team opted not to re-estimate the sample size. Rates of 
BILAG and SELENA-SLEDAI flares, which will also be important for evaluating 
the impact of MMF withdrawal, are higher than 10%. The larger sample size is 
necessary to improve precision for these important secondary endpoints and will 
strengthen the primary analysis. 
 
 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
13. 
REFERENCES 
14. 
APPENDICES  
14.1. Study Flow Chart 
 
 
Flare Visit 
To occur w henever a subject experiences a flare. 
May coincide w ith a regularly scheduled study visit. 
Endpoint Visit 
To occur w henever a subject meets primary 
endpoint. 
Week 12 
Continue on MMF
Week 12 
Completes the MMF taper. No further study
Monthly Study Visits at  
Monthly Study Visits at  
Monthly Study Visits at Weeks 16, 20, 24,  
Monthly Study Visits at Weeks 16, 20, 24,  
Week 60  
Final assessments for efficacy, safety, and
Week 60 
Final assessments for efficacy, safety, and
Pre-screening/Screening Period 
Randomization / Baseline / Day 0 
Randomize 120 eligible subjects w ith
MMF Maintenance Arm: 
Continue on MMF
MMF Withdrawal Arm: 
Begin a protocol-defined MMF taper
60 
60 
 
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14.2. Schedule of Events 
Table 6.1, Schedule of Events 
As Needed 
Visit Name Screen-
ing 
Base-
line 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
32 
Week 
40 
Week 
48 
Week 
601 
Flare2 End-
point3 
Unsched
-uled4 
Unless otherwise noted, all assessments are to be done by unblinded personnel. 
M1 
M2 
M3 
M4 
M5 
M6 
M8 
M10 M12 M15 
Visit Window (days) -28 to -1 
0 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
n/a 
n/a 
n/a 
 
Central Clinical Draw (mL, approximate) 
18.5 
10 
10 
10 
13 
10 
10 
13 
13 
13 
13 
13 
13 
13 
0 
Central Research Draw (mL) 
0 
55 
23.5 23.5 23.5 23.5 
55 
23.5 23.5 
23.5 23.5 
55 
55 
23.5 
0 
Visit Draw Total (mL, approximate) 
18.5 
65 
33.5 33.5 36.5 33.5 
65 
36.5 36.5 
36.5 36.5 
68 
68 
36.5 
0 
Physician Requirements 
REMS Program Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Assessment 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, including Family History of Autoimmune Disease 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination6 by a blinded investigator 
 
 
 
X 
X 
X 
X 
X17 
 
 
 
 
 
 
 
Vitals, including weight (& height at Screening) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician’s Global Assessment (0-3 VAS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
m-SLEDAI13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SELENA-SLEDAI*13 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SELENA-SLEDAI*13 & treatment questionnaire by a blinded investigator 
 
 
 
X 
X 
X 
X 
X17 
 
 
 
 
 
 
 
SLICC/DI*13 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
BILAG*13  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
FACIT 7 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
SF-36®7 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Lupus QoL©7 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
Medications Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug 
Treatment Period12 
 
60 weeks 
 
 
 
Dispense Study Drug  
 
X 
X 
X 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
 
 
 
 
Assess Study Drug Compliance  
 
 
X 
X 
X 
X14 
X14 
X14 
X14 
X14 
X14 
X14 
 
 
 
Local Laboratory Assessments8 
Urinalysis: dipstick, microscopic, & spot protein-creatinine 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test, if applicable11 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
PPD, if applicable5  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory Assessments8 
QuantiFERON®-TB Gold In-Tube Test (QFT-G_IT), if applicable5 (~3 mL) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious Disease Screen (~8.5 mL): HIV antibody, hepatitis B surface antigen, HCV 
antibody with HCV RNA ( PCR) if antibody positive10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistries (~3 mL) – albumin, ALP, ALT, AST, BUN, creatinine, glucose, phosphorus, 
potassium, bilirubin, total protein  
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Serum creatinine 
 
X19 
X19 
X19 
 
X19 
X19 
 
 
 
 
 
 
 
 


Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
Table 6.1, Schedule of Events 
As Needed 
Visit Name Screen-
ing 
Base-
line 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
32 
Week 
40 
Week 
48 
Week 
601 
Flare2 End-
point3 
Unsched
-uled4 
Unless otherwise noted, all assessments are to be done by unblinded personnel. 
M1 
M2 
M3 
M4 
M5 
M6 
M8 
M10 M12 M15 
Visit Window (days) -28 to -1 
0 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
n/a 
n/a 
n/a 
 
Anti-dsDNA,C3, C4 (~6 mL)  
 
X19 
X19 
X19 
X 
X19 
X19 
X 
X 
X 
X 
X 
X 
X 
 
Hematologies (~4 mL): hemoglobin, MCV, platelet count, RDW, WBC, lymphocytes, 
monocytes, neutrophils 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology (6 mL): lymphocyte subset, if applicable9  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Mechanistic Specimens 
Serum for Cytokine/Chemokines/Antibodies18 to Sm, RNP, SSA/Ro, SSB/La (10 mL)  
 
X18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X18 
X18 
X 
 
RNA Assays (5 mL) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Future Use: PBMCs & Plasma (40 mL) 
 
X 
 
 
 
 
X 
 
 
 
 
X15 
X 
 
 
Future Use: Plasma (8.5 mL) 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X16 
 
X16 
 
Future Use: Urine (10 mL) 
 
X 
 
 
 
 
X 
 
 
 
 
X20 
X21 
X 
 
1. Week 60: should a subject withdraw early, he/she should complete all assessments listed under the Week 60 visit. 
2. Flare visits: should occur when a subject experiences a flare and may coincide with a regularly scheduled study visit. 
3. Endpoint visits: should occur when a subject reaches primary endpoint, as described in Section 3.2, Description of Primary Endpoint and may coincide with a regularly scheduled study visit. 
4. Unscheduled visits: all noted assessments must be done, but any additional assessments that the investigator feels should be done should be collected. Note: if during the unscheduled visit, the investigator 
suspects a flare is occurring, the site must conduct a Flare Visit. 
5. PPD or QuantiFERON®-TB Gold In-Tube Test (QFT-G-IT): unless performed within 12 weeks prior to screening and documented as negative in the subject’s records, or unless subject is known to have a 
positive or indeterminate test and has documentation of appropriate therapy. 
6. Physical examinations are to include, at least, the following systems: general appearance, skin, head/eyes/ears/nose/neck/throat, respiratory/chest, cardiovascular, abdominal, neurological, & 
musculoskeletal/extremities. 
7. Subjective assessments must be done at the beginning of the visit, prior to any other study assessments (except for informed consent at Screening). 
8. Local & Central Laboratory Assessments: see Section 6.3.6, Blood Draw Prioritization 
9. Lymphocyte subset: only if the subject was on a B cell depleting agent in the past 3 years and the test was not done within 12 weeks prior to screening documenting detectable B cells 
10. Infectious disease screen: unless documented as negative within 12 weeks prior to the Screening visit. 
11. Pregnancy tests: for women on MMF and of childbearing potential only. Additional pregnancy tests should also be done when clinically indicated. 
12.Treatment Period: will end if a subject meets primary endpoint. While visits & assessments will occur as scheduled, ALE06 will no longer provide any more MMF. Any treatment medications chosen by the 
investigator will be documented on the concomitant medications log. 
13. ALE06 will typically use a spot urinalysis rather than a 24-hour urine assessment for the BILAG*, mSLEDAI, SELENA-SLEDAI*, and SLICC/DI*. However, if indicated, results from a 24-hour urine 
collection may be used. 
14. For subjects randomized to MMF maintenance arm only. 
15. Future Use: PBMCs & Plasma will be drawn at Week 60 only if the subject did not experience a mild/moderate flare requiring an increase in prednisone or a severe flare requiring increased immunomodulatory 
medication while on study. 
16. Future Use: Plasma will be drawn at Week 60 or Endpoint only if the subject did experience a flare while on study. 
17. At Week 24, a blinded physical exam and SELENA-SLEDAI* should only be conducted if the subject is being monitored for flare at the Week 20 visit. 
18. Antibodies to Sm, RNP, SSA/Ro, and SSB/La will only be assessed at the Baseline, Week 60, and if needed, the flare visit. 
19. Serum creatinine will be run off the Baseline, Weeks 4, 8, 16, and 20 Anti-dsDNA, C3, C4 blood draw.  
20. FutureUse:Urine will be collected at Week 60 only if the subject did not experience a flare while on study. 
21. FutureUse:Urine will be collected at any (and all) Flare Visits where increased predisone or immunomodulatory medication is prescribed 
 
 
 
 
 
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14.3. SELENA-SLEDAI  
PHYSICIANS GLOBAL ASSESSMENT: 
(3cm) 
 
     0 
     
None 
  1 
  Mild 
2 
Med 
3 
Sever
e 
Length of line (from 0 to vertical assessment line)  
cm 
SLEDAI SCORE 
Check “Present” if descriptor is present at the time of visit or in the preceding 10 days. 
# 
Descriptor 
Definition 
Presen
t 
Weight 
1 
Seizure 
Recent onset (last 10 days). Exclude metabolic, infectious, 
or drug cause, or seizure due to past irreversible CNS 
damage. 
 
8 
2 
Psychosis 
Altered ability to function in normal 
activity due to severe disturbance in the 
perception of reality.  Include 
hallucinations, incoherence, marked loose 
associations, impoverished thought content, 
marked illogical thinking, bizarre, 
disorganized, or catatonic behavior.  
Exclude uremia and drug causes. 
 
8 
3 
Organic 
brain 
syndrome 
Altered mental function with impaired orientation, memory, or 
other intelligent function, with rapid onset and fluctuating 
clinical features. Include clouding of consciousness with reduced 
capacity to focus, and inability to sustain attention to 
environment, plus at least 2 of the following: perceptual 
disturbance, incoherent speech, insomnia or daytime drowsiness, 
or increased or decreased psychomotor activity. Exclude 
metabolic, infectious, or drug causes. 
 
8 
4 
Visual 
disturbance 
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. 
 
8 
5 
Cranial 
nerve 
disorder 
New onset of sensory or motor neuropathy involving 
cranial nerves.  Include vertigo due to lupus. 
 
8 
6 
Lupus 
headache 
Severe, persistent headache:  may be migrainous, but 
must be nonresponsive to narcotic analgesia. 
 
8 
7 
CVA 
New onset of cerebrovascular accident(s). Exclude 
arteriosclerosis or hypertensive causes. 
 
8 
8 
Vasculitis 
Ulceration, gangrene, tender finger nodules, periungual, 
infarction, splinter hemorrhages, or biopsy or angiogram 
proof of vasculitis. 
 
8 


Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
9 
Arthritis 
More than 2 joints with pain and signs of inflammation (i.e., 
tenderness, swelling, or effusion). 
 
4 
10 
Myositis 
Proximal muscle aching/weakness, associated with 
elevated creatine phosphokinase/aldolase or 
electromyogram changes or a biopsy showing myositis. 
 
4 
11 
Urinary 
casts 
Heme-granular or red blood cell casts. 
 
4 
12 
Hematuria 
> 5 red blood cells per high power field. Exclude stone, 
infection, or other causes. 
 
4 
13 Proteinuria 
> 0.5 protein:creatinine ratio.  New onset or recent increase of 
more than 0.5 on the protein:creatinine ratio. 
Note: ALE06 will typically use a spot urine protein:creatinine 
ratio. If only the 24-hour urine is available, then proteinuria is 
defined as: ” >0.5 gm/24 hours. New onset or recent increase of 
more than 0.5 gm/24 hours.” 
 
4 
14 
Pyuria 
> 5 white blood cells per high power field.  
Exclude infection. 
 
4 
15 
Rash 
Ongoing inflammatory lupus rash. 
 
2 
16 
Alopecia 
Ongoing abnormal, patchy, or diffuse loss of hair due to 
active lupus. 
 
2 
17 
Mucosal 
ulcers 
Ongoing, oral or nasal ulcerations due to active lupus. 
 
2 
18 
Pleurisy 
Classic and severe pleuritic chest pain, or pleural rub, or 
effusion, or new pleural thickening due to lupus. 
 
2 
19 Pericarditis Classic and severe pericardial pain, or rub, or effusion, or 
electrocardiogram confirmation. 
 
2 
20 
Low 
complement 
Decrease in CH50, C3, or C4 below the lower limit of 
normal for testing laboratory. 
 
2 
21 
Increased 
DNA binding 
> 25% binding by Farr assay or above normal range for 
testing laboratory. 
 
2 
22 
Fever 
> 38°C. Exclude infectious cause. 
 
1 
23 
Thrombo-
cytopenia 
< 100,000 platelets/mm
3 [equivalent to 100 x109/L] 
 
1 
24 Leukopenia 
< 3,000 white blood cells/mm
3  
[equivalent to 3 x109/L] 
Exclude drug causes. 
 
1 
Total Score (sum of weights next to descriptors marked present):     ________                  
 
 
 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
MILD OR MODERATE FLARE 
 Change in SLEDAI > 3 points 
 
New/Worse 
• Discoid, photosensitive, profundus, cutaneous 
vasculitis, bullous lupus  
• Nasopharyngeal ulcers 
• Pleuritis 
• Pericarditis 
• Arthritis 
• Fever attributable to SLE 
 Increase in prednisone, but not to > 0.5 mg/kg/day 
 Added NSAID or Plaquenil 
 
> 1.0 increase in Physician’s Global Assessment (PhGA), but not to more than 2.5 (on a 
3.0 indexed VAS scale—refer to the Physican’s Global Assessment located on the Modified 
SLEDAI Source Document)  
SEVERE FLARE 
 Change in SLEDAI > 12 
 
New/Worse 
• 
CNS-SLE 
• 
Vasculitis 
• 
Nephritis  
• 
Myositis 
• 
Platelet Count < 60,000/ mm
3 [equivalent to 60 x109/L] 
• 
Hemolytic anemia with hemoglobin < 7% OR Decrease in hemoglobin > 3% 
*Requiring:  doubling of prednisone, prednisone > 0.5 mg/kg/day, and/or hospitalization 
 Prednisone > 0.5 mg/kg/day 
 New Cyclophosphamide (Cytoxan), Azathioprine, Methotrexate, Mycophenolate Mofetil, or 
hospitalization attributable to SLE 
 
Increase in Physician’s Global Assessment (PhGA) to > 2.5  
(on a 3.0 indexed VAS scale—refer to the Physican’s Global Assessment located on the 
Modified SLEDAI Source Document)  
 
 
 
 
 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
14.4. BILAG  
Note: ALE06 will typically use a spot urinalysis rather than a 24-hour urine assessment.  
However, if indicated, results from a 24-hour urine collection may be used. 
 
 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
14.5. FACIT 
FACIT-Fatigue Subscale Scoring Guidelines (Version 4) – Page 1 
Instructions:* 
1. Record answers in "item response" column. If missing, mark with an X 
    
2. Perform reversals as indicated, and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the subscale, then divide 
by the  number of items answered.  This produces the subscale score. 
4. The higher the score, the better the QOL. 
 
 
 
Subscale 
         Item Code       Reverse item?            Item response          Item Score  
 
FATIGUE 
 
HI7 
      
4 
- 
________ 
 
=________ 
SUBSCALE 
 
HI12 
 
4 
- 
________ 
 
=________ 
    
 
 
An1 
 
4 
- 
________ 
 
=________ 
An2 
 
4 
- 
________ 
 
=________ 
An3 
 
4 
- 
________ 
 
=________ 
An4 
 
4 
- 
________ 
 
=________ 
An5 
 
0 
+ 
________ 
 
=________ 
An7 
 
0 
+ 
________ 
 
=________ 
An8 
 
4 
- 
________ 
 
=________ 
An12 
 
4 
- 
________ 
 
=________ 
An14 
 
4 
- 
________ 
 
=________ 
An15 
 
4 
- 
________ 
 
=________ 
An16 
 
4 
- 
________ 
 
=________ 
 
                Sum individual item scores:________   
 
 
 
                         Multiply by 13: ________ 
            Divide by number of items answered: ________=Fatigue 
Subscale score 
*For guidelines on handling missing data and scoring options, please refer to the Administration and 
Scoring Guidelines in the manual or on-line at www.facit.org. 
 
 
 
 
Score range: 0-52 
 
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Autoimmunity Centers of Excellence 
Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
14.6. SF-36 
Eight scale scores are derived from responses to the 36 items on the SF-36 questionnaire which 
are combined to produce the Physical Component Score and the Mental Component Score.  The 
Physical Component Score is based upon the Physical Functioning Scale (10 items), the Role-
Physical Scale (4 items), the Bodily Pain Scale (2 items), and the General Health Scale (5 items).  
The Mental Component Score is based upon the Vitality Scale (4 items), the Social Functioning 
Scale (2 items), the Role-Emotional Scale (3 items) and the Mental Health Scale (5 items).  One 
item (self-reported health transition) is not used in the calculation of either component score.  All 
methodology described below for scoring version 2 of the SF-36 (the version used in this study) 
is documented in How to Score Version 2 of the SF-36® Health Survey .  
Step 1:  Create numeric versions of the SF-36 questions (SF36. QUES1, QUES2, QUES3A, 
QUES3B, QUES3C, QUES3D, QUES3E, QUES3F, QUES3G, QUES3H, QUES3I, QUES3J, 
QUES4A, QUES4B, QUES4C, QUES4D, QUES5A, QUES5B, QUES5C, QUES6, QUES7, 
QUES8, QUES9A, QUES9B, QUES9C, QUES9D, QUES9E, QUES9F, QUES9G, QUES9H, 
QUES9I, QUES10, QUES11A, QUES11B, QUES11C, QUES11D).   
Step 2:  Recode the numeric values for certain questions as follows: 
Question 1:  
1 --> 5.0 
2 --> 4.4 
3 --> 3.4 
4 --> 2.0 
5 --> 1.0 
 
Questions 6, 9a, 9d, 9e, 9h, 11b, 11d: 
1 --> 5 
2 --> 4 
3 --> 3 
4 --> 2 
5 --> 1 
 
Question 7: 
1 --> 6.0 
2 --> 5.4 
3 --> 4.2 
4 --> 3.1 
5 --> 2.2 
6 --> 1.0 
 
 
Question 8: 
Note that the (raw) numeric value is the answer to question 7 before recoding. 
• If the numeric value of question 8=1 and the (raw) numeric value of question 7=1, 
then the recoded value=6 
 
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Statistical Analysis Plan 
Protocol No. ALE06 
14 November 2019 
 
• If the numeric value of question 8=1 and (2 <= the (raw) numeric value of question 7 
<= 6), then the recoded value=5 
• If the numeric value of question 8=2 and (1 <= the (raw) numeric value of question 7 
<= 6), then the recoded value=4 
• If the numeric value of question 8=3 and (1 <= the (raw) numeric value of question 7 
<= 6), then the recoded value=3 
• If the numeric value of question 8=4 and (1 <= the (raw) numeric value of question 7 
<= 6), then the recoded value=2 
• If the numeric value of question 8=5 and (1 <= the (raw) numeric value of question 7 
<= 6), then the recoded value=1 
• If the (raw) numeric value of question 7 is missing, then recode as follows: 
1 --> 6.0 
2 --> 4.75 
3 --> 3.5 
4 --> 2.25 
5 --> 1.0 
Step 3:  Count the number of missing items for each scale for each subject and visit. 
Physical Functioning:  
Questions 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j 
Role-Physical:  
 
Questions 4a, 4b, 4c, 4d 
Bodily Pain: 
 
 
Questions 7, 8 
General Health:  
 
Questions 1, 11a, 11b, 11c, 11d 
Vitality:  
 
 
Questions 9a, 9e, 9g, 9i 
Social Functioning: 
 
Questions 6, 10 
Role-Emotional:  
 
Questions 5a, 5b, 5c 
Mental Health: 
 
Questions 9b, 9c, 9d, 9f, 9h 
Step 4:  Calculate the mean value of the non-missing items for each scale in Step 3. 
Step 5:  Use the mean values from Step 4 for imputation of any missing values if at least half of 
the scale items are non-missing. 
For example, if subject 1 had a missing value for item 3b at Visit 1, and the mean of the other 
Physical Functioning items was 3.2 for that subject and visit, the missing value would be 
imputed as 3.2. 
To impute a missing value, 
• No more than 5 items can be missing on the Physical Functioning scale 
• No more than 2 items can be missing on the Role-Physical scale 
• No more than 1 item can be missing on the Bodily Pain scale 
• No more than 2 items can be missing on the General Health scale 
• No more than 2 items can be missing on the Vitality scale 
 
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• No more than 1 item can be missing on the Social Functioning scale 
• No more than 1 item can be missing on the Role-Emotional scale 
• No more than 2 items can be missing on the Mental Health scale 
Step 6:  Calculate the raw scale scores for each scale in step 3 on the recoded and imputed 
answers to the questions specified below.   
PF_RAW = sum of Questions 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j 
RP_RAW = sum of Questions 4a, 4b, 4c, 4d 
BP_RAW = sum of Questions 7, 8 
GH_RAW = sum of Questions 1, 11a, 11b, 11c, 11d 
VT_RAW = sum of Questions 9a, 9e, 9g, 9i 
SF_RAW = sum of Questions 6, 10 
RE_RAW = sum of Questions 5a, 5b, 5c 
MH_RAW = sum of Questions 9b, 9c, 9d, 9f, 9h 
Step 7:  Calculate transformed scale scores as the (actual raw score – lowest possible raw score) 
/ (range of possible raw scores), and multiplying by 100.   
PF_TRAN = 100*(PF_RAW-10) / 20 
RP_TRAN = 100*(RP_RAW-4) / 16 
BP_TRAN = 100*(BP_RAW-2) / 10 
GH_TRAN = 100*(GH_RAW-5) / 20 
VT_TRAN = 100*(VT_RAW-4) / 16 
SF_TRAN = 100*(SF_RAW-2) / 8 
RE_TRAN = 100*(RE_RAW-3) / 12 
MH_TRAN = 100*(MH_RAW-5) / 20 
Step 8:  Calculate z-scores for each scale using the below formulas: 
PF_Z = (PF_TRAN -83.29094) / 23.75883 
RP_Z = (RP_TRAN -82.50964) / 25.52028 
BP_Z = (BP_TRAN -71.32527) / 23.66224 
GH_Z = (GH_TRAN -70.84570) / 20.97821 
VT_Z = (VT_TRAN -58.31411) / 20.01923 
SF_Z = (SF_TRAN -84.30250) / 22.91921 
RE_Z = (RE_TRAN -87.39733) / 21.43778 
MH_Z = (MH_TRAN -74.98685) / 17.75604 
Step 9:  Calculate norm-based scores by multiplying the z-score by 10 and adding 50.  Use the 
following names: PF_NORM, RP_NORM, BP_NORM, GH_NORM, VT_NORM, SF_NORM, 
RE_NORM, MH_NORM. 
 
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Step 10:  Calculate aggregate scores for Physical and Mental Component Scores using the 
following formulas: 
AGG_PHYS = (PF_Z * .42402) + (RP_Z * .35119) + (BP_Z * .31754) + (GH_Z * .24954) + 
(VT_Z * .02877) + (SF_Z * -.00753) + (RE_Z * -.19206) + (MH_Z * -.22069) 
AGG_MENT = (PF_Z * -.22999) + (RP_Z * -.12329) + (BP_Z * -.09731) + (GH_Z * -.01571) 
+ (VT_Z * .23534) + (SF_Z * .26876) + (RE_Z * .43407) + (MH_Z * .48581) 
Step 11:  Calculate norm-based versions of the Physical and Mental Component Scores by 
multiplying by 10 and adding 50.  Use the following names: PCS_NORM, MCS_NORM. 
 
 
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