A Phase II Multicenter, Randomized, Double-blind, Placebo Controlled, Dose-range Finding Study to Evaluate the Safety and Efficacy of ALX-0061 Administered Subcutaneously in Subjects With Moderate to Severe Active Systemic Lupus Erythematosus
Phase: PHASE2
Conditions: Lupus Erythematosus, Systemic
Sponsor: Ablynx, a Sanofi company

 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
ALX0061-C204 
 
 
 
A Phase II Multicenter, Randomized, Double-blind, 
Placebo-controlled, Dose-range Finding Study to Evaluate the 
Safety and Efficacy of ALX-0061 Administered Subcutaneously in 
Subjects with Moderate to Severe Active Systemic Lupus 
Erythematosus  
 
 
 
Short Title: 
A Phase II Study to Evaluate Safety and 
Efficacy of ALX-0061 in Subjects with 
Systemic Lupus Erythematosus 
Study Drug: 
ALX-0061 
EudraCT n°: 
2015-000372-95 
IND:  
123233 
Sponsor Protocol Code: 
ALX0061-C204 
 
Sponsor: 
Ablynx NV  
Technologiepark 21 
9052 Zwijnaarde, Belgium 
 
Phase of Development: 
Phase II 
Indication: 
Systemic Lupus Erythematosus (SLE) 
Protocol Date: 
May 3, 2016 
Protocol Version: 
V3.0 
Protocol Status: 
Final 
This study will be performed in compliance with the Clinical Study Protocol, the principles of 
Good Clinical Practice (GCP), and the applicable regulatory requirement(s). 
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Clinical Trial Protocol ALX0061-C204 
 
 
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May 3, 2016 
CONFIDENTIAL 
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CONFIDENTIALITY STATEMENT 
 
The information contained in this document, especially unpublished data, is the property of 
Ablynx NV (or under its control), and therefore provided to you in confidence as an 
Investigator, potential Investigator, or consultant, for review by you, your study staff, and 
applicable Independent Ethics Committee (IEC) /Institutional Review Board (IRB), and 
Competent Authorities (CA). It is understood that this information will not be disclosed to 
others without written authorization from Ablynx NV, except to the extent necessary to 
obtain informed consent from those persons to whom the study drug may be administered. 
 
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APPROVAL OF CLINICAL STUDY 
PROTOCOL 
The Sponsor and the Investigator(s) agree to conduct the study as outlined in this 
Clinical Study Protocol. Any modification of the Clinical Study Protocol must be 
agreed upon by the Sponsor and the Investigator(s), and must be documented in 
writing. 
Sponsor: 
Name:
Function: Medical Director, Ablynx NV 
Signature – Date: See signature page at the end of the document 
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May 3, 2016 
CONFIDENTIAL 
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Investigator:  
 
 
 
 
 
 
I have read Clinical Study Protocol ALX0061-C204 and agree to personally 
conduct or supervise the clinical study in accordance with the Clinical Study 
Protocol. 
 
I agree to ensure that all associates, colleagues, and employees assisting 
in the conduct of the study are informed about their obligations. 
Mechanisms are in place to ensure that site staff receives the appropriate 
information throughout the study. 
 
I confirm that the study team and I will not implement any deviations from 
the Clinical Study Protocol without agreement of Ablynx NV, except where 
necessary to eliminate an immediate hazard to the patients. 
 
I confirm that I am thoroughly familiar with the appropriate use of the 
study drug, as described in the Clinical Study Protocol and any other 
information provided by Ablynx NV. 
 
I confirm that I am aware of and will comply with ICH-GCP.  
 
Hence, I agree to supply Ablynx NV with any necessary information 
regarding the ownership interest and financial ties, to promptly update this 
information if any relevant changes occur during the course of the study, 
and that Ablynx NV may disclose any available information about such 
ownership interest and financial ties to regulatory authorities. 
 
 
Signature – Date: 
 
Principal Investigator Name: 
 
 
Degree/Function: 
 
 
Site details/Address: 
 
 
 
 
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CONTACT INFORMATION 
 
Serious adverse event (SAE) reporting contact information and other contact details 
of the Sponsor and third parties are available in the “Investigator Site File”. 
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CONFIDENTIAL 
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TABLE OF CONTENTS 
 
CONFIDENTIALITY STATEMENT .............................................................................. 2 
APPROVAL OF CLINICAL STUDY PROTOCOL ........................................................... 3 
CONTACT INFORMATION ........................................................................................ 5 
TABLE OF CONTENTS .............................................................................................. 6 
LIST OF ABBREVIATIONS ....................................................................................... 9 
CHANGES COMPARED TO PREVIOUS VERSION(S) .................................................13 
PROTOCOL SYNOPSIS ...........................................................................................16 
SCHEDULE OF ASSESSMENTSA ...............................................................................29 
1. 
INTRODUCTION .............................................................................................32 
1.1. SYSTEMIC LUPUS ERYTHEMATOSUS ............................................................32 
1.1.1. 
Treatment of Systemic Lupus Erythematosus ......................................... 32 
1.1.2. 
Role of IL-6(R) in Pathophysiology of Systemic Lupus Erythematosus ........ 33 
1.2. ALX-0061 ....................................................................................................35 
1.2.1. 
General Properties .............................................................................. 35 
1.2.2. 
Manufacture ....................................................................................... 36 
1.2.3. 
Nonclinical Studies .............................................................................. 36 
1.2.4. 
Effects in Humans ............................................................................... 37 
1.2.5. 
Benefits and Risk Assessment .............................................................. 40 
2. 
OBJECTIVES ...................................................................................................42 
3. 
STUDY DESIGN ..............................................................................................43 
3.1. OVERALL STUDY DESIGN .............................................................................43 
3.1.1. 
Study Overview .................................................................................. 43 
3.1.2. 
Blinding ............................................................................................. 47 
3.2. SELECTION OF STUDY POPULATION ............................................................51 
3.2.1. 
Inclusion Criteria ................................................................................ 51 
3.2.2. 
Exclusion Criteria ................................................................................ 53 
3.2.3. 
Removal of Subjects from Therapy or Assessment .................................. 55 
3.3. TREATMENT OF SUBJECTS ...........................................................................58 
3.3.1. 
Randomization.................................................................................... 58 
3.3.2. 
Identity of Study Drug ......................................................................... 58 
3.3.3. 
Drug Accountability ............................................................................. 59 
3.3.4. 
Study Drug Handling ........................................................................... 59 
3.3.5. 
Study Drug Injections .......................................................................... 60 
3.3.6. 
Medications Other than study Drug ....................................................... 61 
3.3.7. 
Treatment Compliance ......................................................................... 64 
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3.4. ASSESSMENTS .............................................................................................65 
3.4.1. 
Timing of Assessments ........................................................................ 65 
3.4.2. 
Demographics and Medical History ........................................................ 67 
3.4.3. 
Assessments of Efficacy ....................................................................... 67 
3.4.4. 
Pharmacokinetic Assessments .............................................................. 74 
3.4.5. 
Pharmacodynamic Assessments ............................................................ 74 
3.4.6. 
Additional Pharmacodynamic Assessments (Exploratory) ......................... 75 
3.4.7. 
Immunogenicity Assessments ............................................................... 77 
3.4.8. 
Assessments of Safety ......................................................................... 77 
3.4.9. 
Total Blood Volume ............................................................................. 81 
3.4.10. 
Appropriateness and Timing of Measurements ........................................ 82 
3.5. ADVERSE EVENT EVALUATION AND REPORTING .........................................83 
3.5.1. 
Adverse Events ................................................................................... 83 
3.5.2. 
Serious Adverse Events ....................................................................... 85 
3.5.3. 
Suspected Unexpected Serious Adverse Reactions (SUSAR) ..................... 87 
3.5.4. 
Reporting of Adverse Events ................................................................ 87 
3.5.5. 
Follow-up of Adverse Events ................................................................ 88 
3.5.6. 
Other Reportable Information ............................................................... 88 
3.6. STATISTICS .................................................................................................90 
3.6.1. 
Study Populations ............................................................................... 90 
3.6.2. 
Statistical and Analytical Plan ............................................................... 90 
3.6.3. 
Determination of Sample Size .............................................................. 90 
3.6.4. 
Initial Characteristics of Subject Sample ................................................ 91 
3.6.5. 
Evaluation of Efficacy Parameters ......................................................... 91 
3.6.6. 
Evaluation of Pharmacokinetic Parameters ............................................. 93 
3.6.7. 
Evaluation of Pharmacodynamic Parameters ........................................... 94 
3.6.8. 
Evaluation of Safety Parameters ........................................................... 94 
3.7. DATA 
QUALITY 
ASSURANCE 
AND 
DIRECT 
ACCESS 
TO 
SOURCE 
DATA/DOCUMENTS ......................................................................................96 
3.8. DATA PROTECTION ......................................................................................97 
4. 
ETHICS ..........................................................................................................98 
4.1. ETHICS COMMITTEES AND COMPETENT AUTHORITIES ................................98 
4.2. ETHICAL CONDUCT OF THE STUDY ..............................................................99 
4.3. SUBJECT INFORMATION AND CONSENT ....................................................100 
4.4. PRIVACY ....................................................................................................101 
5. 
DATA HANDLING AND RECORD KEEPING .....................................................102 
5.1. DISTRIBUTION OF ACTIVITIES .................................................................102 
5.2. DOCUMENTATION ......................................................................................102 
5.2.1. 
Case Report Form Completion ............................................................ 102 
5.2.2. 
Source Documentation ...................................................................... 102 
5.2.3. 
Record Retention .............................................................................. 103 
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5.2.4. 
Monitoring ....................................................................................... 104 
6. 
FINANCING AND INSURANCE ......................................................................105 
7. 
USE OF INFORMATION AND PUBLICATION ..................................................106 
8. 
REFERENCES ................................................................................................107 
9. 
APPENDICES ................................................................................................110 
9.1. 1997 AMERICAN ACR CLASSIFICATION CRITERIA ....................................110 
9.2. 2012 SYSTEMIC LUPUS INTERNATIONAL COLLABORATING CLINICS (SLICC) 
CLASSIFICATION CRITERIA ......................................................................112 
9.3. THE 
NEW 
YORK 
HEART 
ASSOCIATION 
(NYHA) 
FUNCTIONAL 
CLASSIFICATION .......................................................................................115 
9.4. MODIFICATION OF DIET IN RENAL DISEASE’ (MDRD) FORMULA ..............116 
9.5. OVERVIEW OF CORTICOSTEROID HANDLING THROUGHOUT THE STUDY ..117 
9.6. BILAG-2004 ...............................................................................................118 
9.7. SLEDAI-2K .................................................................................................120 
9.8. CLASI  ......................................................................................................122 
9.9. SLICC/DAMAGE SCORE ..............................................................................123 
 
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LIST OF ABBREVIATIONS 
 
ACE 
Angiotensin converting enzyme 
aCL 
Anti-cardiolipin 
ACR 
American College of Rheumatology 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANA 
Anti-nuclear antibodies 
Anti-dsDNA 
Anti double-stranded DNA 
AST 
Aspartate aminotransferase 
β2 GPI 
β2-glycoprotein I 
BICLA 
BILAG-based composite lupus assessment 
BILAG 
British Isles Lupus Assessment Group 
BLyS 
B lymphocyte stimulator 
C3 
Complement component 3 
C4 
Complement component 4 
CA 
Competent Authority 
CDAI 
Clinical Disease Activity Index 
CH50 
Hemolytic complement component 50 
CHF 
Congestive heart failure 
CL 
Total body clearance 
CLASI 
Cutaneous lupus erythematosus disease area and severity index 
CMV 
Cytomegalovirus  
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CSF 
Cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTD 
Clinical Trial Directive 
CYP450 
Cytochrome P450 
DAS28 
Disease activity score using 28 joint counts  
dsDNA 
Double-stranded deoxyribonucleic acid 
DSMB 
Data safety monitoring board 
EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
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(e)CRF 
(Electronic) Case report form 
eGFR 
Estimated glomerular filtration rate 
ESR 
Erythrocyte sedimentation rate 
EULAR 
European League Against Rheumatism 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyltransferase 
GLP 
Good Laboratory Practice 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HDL 
High density lipoprotein 
HIV 
Human immunodeficiency virus 
HSA 
Human serum albumin 
i.a. 
Intra articular 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ID 
Identification 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IGRA 
Interferon-gamma release assay 
IL-6 
Interleukin-6 
IL-6R 
Interleukin-6 receptor 
i.m. 
Intramuscular(ly) 
INR 
International normalized ratio 
IRB 
Institutional review board 
i.v. 
Intravenous(ly) 
IWRS 
Interactive web response system 
JAK 
Janus kinase 
LA 
Lupus anti-coagulant  
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
MAD 
Multiple ascending dose 
mADA 
Modified anti-drug antibodies 
mBICLA 
Modified BILAG-based composite lupus assessment 
MCP 
Metacarpophalangeal 
MDRD 
Modification of diet in renal disease 
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mIL-6R 
Membrane-bound interleukin-6 receptor 
mITT 
Modified intent-to-treat 
mSLEDAI 
Modified systemic lupus erythematosus disease activity index 
mSRI 
Modified systemic lupus erythematosus responder index 
MTX 
Methotrexate 
NSAID 
Non-steroidal anti-inflammatory drug 
PBO 
Placebo 
PD 
Pharmacodynamic 
PGA 
Physician global assessment 
PIP 
Proximal interphalangeal 
PK 
Pharmacokinetic  
PP 
Per-protocol 
q2w 
Every 2 weeks 
q4w 
Every 4 weeks 
RA 
Rheumatoid arthritis 
SAA 
Serum amyloid A 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
s.c. 
Subcutaneous(ly) 
SF-36 
Short Form (36) Health Survey 
SFI 
SLEDAI flare index 
sIL-6R 
Soluble interleukin-6 receptor 
SLE 
Systemic lupus erythematosus 
SLEDAI-2K 
Systemic lupus erythematosus disease activity index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
SRI 
Systemic lupus erythematosus responder index 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TGFβ 
Transforming growth factor-β 
Th17 
T helper 17 cell 
TK 
Toxicokinetics 
Treg 
Regulatory T cell 
TTP 
Thrombotic thrombocytopenic purpura 
ULN 
Upper limit of normal 
uMCP-1 
urinary monocyte chemoattractant protein-1 
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VAS 
Visual analogue scale 
VH 
Heavy chain variable region 
WHO 
World Health Organization 
 
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CHANGES COMPARED TO PREVIOUS 
VERSION(S) 
 
Version 2.0 (dated May 7, 2015) compared to Version 1.0 (dated March 25, 2015)  
Version n° and date were adapted throughout the document (incl. headers and footers). 
Section “Changes compared to previous version(s)” was completed. 
Original section/page 
Change/Rationale 
P 1 Title page, P 13 (protocol synopsis) 
For consistency, the IND n° was added in addition to the EudraCT n°. 
P 1 (Title page) 
Contact information with regard to the CRO was deleted as multiple 
CROs are involved in this study. 
P 14-15 (protocol synopsis) 
P 48 (Section 3.2.1.) 
Inclusion criterion 1 was updated to take into account that the definition 
of adult age can differ between countries and regions. In addition, 
inclusion criterion 7 was reworded for clarification purposes. 
P 16-17 (protocol synopsis) 
P 50-51 (Section 3.2.2.) 
Exclusion criterion 1 was updated to clarify which assessment result 
(screening) is to be considered for eligibility. In addition, a typo has 
been corrected in exclusion criterion 6 and a clarification was added in 
exclusion criterion 20. 
P 19-21 (protocol synopsis) 
P 52 (Section 3.2.3.2.) 
P 57-59 (Section 3.3.6.) 
Wording with regard to the terms background and rescue medication 
was changed to clarify that this concerns the standard of care 
medication as per local practice or a change of this medication. 
P 21 (protocol synopsis) 
P 52 (Section 3.2.3.2.) 
A discontinuation criterion was updated to clarify that discontinuation of 
study drug administration will be considered in case subjects experience 
a renal or CNS flare. 
P 26-27 (Schedule of Assessments) 
The schedule of assessments was updated to clarify that CLASI and 
exploratory biomarkers will also be assessed at the time of early 
termination. 
P 27 (Schedule of Assessments) 
P 78 (Section 3.4.10.) 
An incorrect abbreviation was corrected. 
P 28 (Schedule of Assessments) 
P 46 (Section 3.1.2.) 
P 75-76 (Section 3.4.8.2.) 
P 77-78 (Section 3.4.9.) 
The assessment of ESR was removed from the protocol for following 
reasons: 
- This is not an essential parameter needed for the planned analysis. 
- Other parameters (CRP, fibrinogen) that reflect the inflammation 
status of the subject are measured.  
- Avoid unblinding of the treatment when ESR is locally assessed and 
reported by study staff. 
P 31 (Section 1.1.2.) 
A sentence with missing verb was completed. 
P 75 (Section 3.4.8.2.) 
For pregnancy testing, it was clarified that in case local regulations 
require more frequent pregnancy testing, this will apply. 
P 76 (Section 3.4.8.2.) 
The wording on laboratory re-tests was updated to differentiate between 
re-test at screening and re-tests during the study. 
P 83 (Section 3.5.3.)  
A statement was deleted as it only applies in European countries and 
this study will be conducted in non-EU countries as well. 
P 84 (Section 3.5.5.) 
The text in the section with regard to follow-up of AEs was updated to 
clarify that all AEs will be followed until satisfactory outcome. 
P 106 (Appendix 9.1.) 
Appendix 9.1. was updated to correct a typo error. 
 
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Version 3.0 (dated May 3, 2016) compared to Version 2.0 (dated May 7, 2015)  
Version n° and date were adapted throughout the document (incl. headers and footers). 
Table of Contents and List of Abbreviations was updated and the Section “Changes Compared to Previous 
Version(s)” was completed. 
Section 
Change/Rationale 
Synopsis and Section 3.2.1. 
Clarification of inclusion criterion 2 to reflect that the diagnosis of SLE 
should have occurred for at least 6 months prior to screening and that 
at screening the ACR and/or SLICC criteria need to be fulfilled.  
Synopsis and Sections 3.2.1. and 
3.4.5.2. 
Wording has been updated to delete the incorrect reference range of the 
assay to measure anti-dsDNA (inclusion criterion 5) and clarify that the 
Farr assay is used at the central lab. 
Synopsis, Sections 3.2.1., 3.2.2., and 
3.3.6.1. 
The dose of the allowed medication mycophenolate mofetil has been 
updated from max 1.5 g/day to max 2.0 g/day to allow inclusion of 
patients receiving the usual dose in SLE patients (inclusion and 
exclusion criteria 6). In addition, the units of methotrexate and 
cyclosporine dosing regimens have been corrected/further specified 
(typographical errors). 
Synopsis and Section 3.2.2. 
Wording has been updated to specify that exclusion criterion 1, i.e., 
having an A score on the revised BILAG-2004, not only applies to the 
screening assessment but also at baseline for the organ systems that 
can be clinically assessed at that timepoint. Exclusion criterion 3 (on 
concurrent infections) has been updated to clarify that subjects with 
clinically non-significant infections (e.g., mild localized herpes simplex 
infections or tinea pedis) can be enrolled in the study and exclusion 
criterion 7 (on central neurological problems) has been updated for 
clarification purposes. 
Synopsis, Sections 3.2.3.2. and 3.3.6.2. 
Wording has been updated to clarify that “until Week 4” means the 
Week 4 visit (including the per-protocol allowed time window of 5 days). 
Synopsis and Section 3.6.5.1. 
Wording has been added in the description of the analysis of the primary 
efficacy endpoint to specify that only subjects discontinuing before 
Week 24 will be treated as non-responders for this endpoint at this 
timepoint. 
Schedule of Assessments 
For clarity, the local laboratory assessment has been emphasized by 
moving this to a separate line in the Schedule of Assessments. 
Sections 3.1.1. and 3.6.8. 
A typographical error has been corrected. 
Section 3.1.2. 
The volume of syringe A with placebo was corrected from 0.5 mL to 
1 mL (typographical error) in the description of blinding for dosing 
Group 3. 
Section 3.3.6.1. 
A clarification with regard to prior therapies has been added. 
Sections 3.3.6.1. and 3.3.6.2. 
Wording has been added to clarify that after Week 24, the dose of 
NSAIDs may be adjusted based on the Investigator’s discretion. 
Section 3.3.6.3. 
Wording has been added to clarify that an intrauterine device or 
diaphragm with condom by partner is also acceptable in case the 
Investigator judges that hormonal contraception is not appropriate. 
Section 3.4.1.1. 
Wording has been added to clarify that if the screening period has to be 
exceeded due to exceptional logistical issues, the Medical Monitor is to 
be contacted as soon as possible for further instructions. 
Sections 3.4.3.8. and 3.6.2. 
Wording has been added to specify that the SFI will be calculated as 
detailed in the statistical analysis plan (SAP). 
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Sections 3.4.5.1., 3.4.7.1., 3.4.8., and 
3.4.9. 
The blood volumes needed for some assessments have been corrected 
(e.g, due to use of other tubes than originally planned). 
Section 3.4.8.1. 
Wording has been added to clarify that the Investigator may 
exceptionally decide to interrupt study drug treatment for one dose 
according to his/her medical judgment in case of an AE. 
Section 3.4.8.2. 
The laboratory parameter creatine phosphokinase (CPK) has been added 
to the list of biochemistry parameters to be analyzed, as is creatinine to 
the list of urinalysis parameters. Wording has been added to more 
accurately reflect what will be tested to screen for hepatitis and to 
clarify that additional pregnancy testing can be done in case local 
medical practice requires this. In addition, clarifications have been 
added to the statements with regard to follow up of unexplained or 
unexpected clinical laboratory tests. 
Section 3.5.1.1. 
To avoid confusion, the statement on assessment of severity of AEs 
related to laboratory abnormalities has been deleted. 
Appendix 9.6. 
Appendix 9.6 of the protocol, which included the initial version of the 
BILAG-2004, was updated to include the current version of BILAG-2004 
(dated 2009) as this version will be used during the course of this study 
(as this is the latest validated version).  
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PROTOCOL SYNOPSIS 
 
 
Protocol Title: 
 
A Phase II Multicenter, Randomized, Double-blind, Placebo-controlled, Dose-range Finding 
Study to Evaluate the Safety and Efficacy of ALX-0061 Administered Subcutaneously in 
Subjects with Moderate to Severe Active Systemic Lupus Erythematosus  
 
 
Protocol Short Title: 
 
A Phase II Study to evaluate safety and efficacy of ALX-0061 in subjects with systemic 
lupus erythematosus 
 
 
Study Drug: 
 
ALX-0061, a Nanobody directed towards the interleukin-6 receptor (IL-6R) 
 
 
EudraCT n°:  
 
IND n°:  
 
2015-000372-95 
 
123233 
 
 
Sponsor Protocol Code: 
 
ALX0061-C204 
 
 
Sponsor: 
 
Ablynx NV  
Technologiepark 21 
9052 Zwijnaarde, Belgium 
 
 
Phase of Development: 
 
Phase II 
 
 
Indication: 
 
Systemic Lupus Erythematosus (SLE) 
 
 
Study centers: 
 
Multicenter, multinational study  
 
 
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Objectives:  
 
Primary objective: 
• 
To assess the efficacy and safety of different dose regimens of ALX-0061 administered 
subcutaneously (s.c.) to subjects with moderate to severe active, seropositive SLE 
compared to placebo. 
 
Secondary objectives: 
• 
To assess the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, flare 
rate, steroid reduction and health-related quality of life, with different dose regimens of 
ALX-0061. 
 
 
Study Type and Treatments Administered: 
 
This is a multicenter, randomized, double-blind, placebo-controlled, dose-range finding 
Phase II study of ALX-0061 administered s.c. on top of standard of care, in subjects with 
moderate to severe active, seropositive SLE.  
 
Subjects will be randomly assigned in a 1:1:1:1:1 ratio to receive either 75 mg ALX-0061 
every 4 weeks (q4w), 150 mg ALX-0061 q4w, 150 mg ALX-0061 every 2 weeks (q2w), 
225 mg ALX-0061 q2w or placebo, up to and including Week 46. To maintain the blind, all 
randomized subjects will receive study drug as 2 s.c. injections every 2 weeks, as described 
further below. 
 
Subjects will be followed for efficacy through Week 48, and for safety through Week 58.  
 
 
Study Population: 
 
Subjects with moderate to severe active, seropositive SLE 
 
 
Number of Subjects: 
 
 
Approximately 300 subjects in 5 treatment arms randomized in a 1:1:1:1:1 ratio, stratified 
by geographic region. 
 
 
Inclusion Criteria: 
 
Each subject must satisfy the following criteria at screening and baseline to be enrolled in 
the study:   
 
1. 
Male or female adults ≥ 18 years and < 65 years of age at the time of signing the 
informed consent form (ICF). The minimum age for adults will depend on local 
regulations. 
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2. 
Have a diagnosis of SLE for at least 6 months prior to screening and fulfill the 1997 
American College of Rheumatology (ACR) or 2012 Systemic Lupus International 
Collaborating Clinics (SLICC) classification criteria. 
3. 
Have moderate to severe active SLE, for the purpose of this study defined by a 2000 
SLE disease activity index (SLEDAI-2K) score ≥ 6 at screening. 
4. 
Have at least one A or one B score on the revised 2004 British Isles Lupus Assessment 
Group (BILAG-2004) criteria for the mucocutaneous and/or musculoskeletal system. 
5. 
Have seropositive disease at screening for antinuclear antibodies (ANA ≥ 1:80) and/or 
anti-dsDNA (value above upper limit of laboratory normal range as measured by Farr 
assay) measured at the central laboratory. 
6. 
Subject at least must be on one or more of the following treatments for SLE: 
a. If subject is on oral corticosteroids, the dose should be equivalent to a maximum 
dose of 25 mg of prednisone/day and stable for at least 4 weeks prior to baseline.  
b. If subject is on antimalarials, he or she must have received antimalarials for at least 
12 weeks with a stable dose of max. 400 mg/day for at least 4 weeks prior to 
baseline.  
c. If 
subject 
is 
on 
immunosuppressants: 
azathioprine 
(max. 
150 
mg/day), 
mycophenolate mofetil (max. 2.0 g/day), methotrexate (max. 25 mg/week), 
cyclosporine (max. 200 mg/day), leflunomide (max. 20 mg/day), treatment duration 
must be at least 12 weeks with a stable dose for at least 4 weeks prior to baseline; 
either alone or in combination with corticosteroids and/or hydroxychloroquine. 
7. 
If immunosuppressants were previously given but have been stopped, the last dose 
should have been received more than 4 weeks prior to baseline; for leflunomide and 
hydroxychloroquine, a leflunomide or hydroxychloroquine treatment-free period of at 
least 12 weeks should be respected (unless an adequate cholestyramine wash-out was 
done for leflunomide). 
8. 
If subject is on angiotensin-converting-enzyme (ACE) inhibitor or angiotensin receptor 
blocker, the dose should have been stable for 4 weeks prior to baseline. 
9. 
Chest radiograph performed within 12 weeks prior to the screening visit (or performed 
during the screening period) documenting no evidence of malignancy, infection, or 
abnormalities suggestive of tuberculosis (TB; report must be obtained and available in 
the subject’s study file prior to baseline). 
10. Are considered eligible according to the following TB screening criteria: 
a. Have no history of latent or active TB prior to screening. An exception is made for 
subjects with a history of latent TB and documentation of having completed 
appropriate treatment for latent TB prior to screening. It is the responsibility of the 
Investigator to verify the adequacy of previous anti-TB treatment and provide 
appropriate documentation. 
b. Have no signs or symptoms suggestive of active TB upon medical history and/or 
physical examination during screening. 
c. Have had no recent close contact with a person with active TB or, if there has been 
such contact, will be referred to a physician specialized in TB to undergo additional 
evaluation and, if warranted, receive appropriate treatment. 
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d. Have a negative interferon gamma release assay (IGRA) screening test result. A 
subject whose initial IGRA test result is indeterminate should have the test repeated 
while still fulfilling the other TB criteria for inclusion. The test should not be repeated 
in case other risk factors for TB are present. In case the test is again indeterminate, 
the subject will be excluded. In case of a positive IGRA test result due to previous 
latent TB, the subject is eligible if adequate documentation of completed anti-TB 
treatment prior to screening is available. 
e. Have a chest radiograph, read by a qualified radiologist, whose diagnostic 
assessment is consistent with no evidence of current active TB or old inactive TB, 
and taken within 12 weeks prior to screening as part of standard of care or during 
the screening period. In case local regulations do not allow radiographs during the 
study, a radiograph as part of standard of care should be available prior to 
screening. 
11. Female subjects of childbearing potential (excluding postmenopausal women, sterilized, 
ovariectomized and hysterectomized women) must have a negative pregnancy test and 
must agree to use two generally accepted adequate contraceptive methods (1 highly 
effective and 1 barrier method e.g., hormonal contraception in combination with 
condom by partner) from screening until at least 3 months after last dosing.  
Male subjects must use condoms for the duration of the study and for at least 3 months 
after last dosing. 
12. Capability to comprehend and willingness to sign an ICF, which must be obtained prior 
to any study-related procedures (vulnerable subjects will be excluded, except subjects 
from ethnic minority groups who may participate). 
13. An understanding, ability and willingness to adhere to the study visit schedule and other 
protocol requirements. 
 
 
Exclusion Criteria: 
 
Subject meeting the following criteria at screening and baseline will not be enrolled in the 
study:   
 
1. 
Have an A score on the revised BILAG-2004 other than in the mucocutaneous and/or 
musculoskeletal system at screening and at baseline for the organ systems that can be 
clinically assessed.   
2. 
Have a systemic inflammatory disease other than SLE, including but not limited to 
psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis or Lyme disease. 
3. 
Clinically significant infection treated or needing treatment with intravenous (i.v.) 
antibiotics, i.v. antivirals, or i.v. antifungals within 4 weeks prior to baseline or oral 
antibiotics, oral antivirals, or oral antifungals within 2 weeks prior to baseline. Patients 
with clinically non-significant infections, e.g., mild cases of localized herpes simplex 
infections or tinea pedis can be enrolled. 
4. 
Any active or recurrent viral infection that based on the Investigator´s clinical 
assessment 
makes 
the 
subject 
unsuitable 
for 
the 
study, 
such 
as 
current 
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Cytomegalovirus (CMV) or Epstein-Barr Virus (EBV) infection or recurrent / 
disseminated herpes zoster.  
5. 
Have a history of, or current, class III or IV congestive heart failure (CHF), as defined 
by the New-York Heart Association; history of unstable angina pectoris, myocardial 
infarction, cerebrovascular accident, thromboembolic event within 12 months before 
screening. 
6. 
Have active lupus nephritis requiring cyclophosphamide or mycophenolate mofetil more 
than 2.0 g/day or other therapy not permitted by the protocol.  
7. 
Have active or recent (within 6 months) lupus-related central neurological problems 
(including lupus headache) or severe central nervous system (CNS) disease.  
8. 
Have drug-induced lupus. 
9. 
Have a history of demyelinating diseases such as multiple sclerosis. 
10. History of diverticulitis or symptoms of acute diverticulitis with confirmatory imaging 
(i.e., CT scan). 
11. Any history of malignancy or lymphoproliferative disease, except for successfully-
treated non-melanoma skin cancer or resected cervical carcinoma in situ.  
12. Have a transplanted organ or received stem cell transplantation. 
13. Major surgery (including joint surgery) within 8 weeks prior to screening or 
hospitalization for a clinically relevant event within the 4 weeks prior to screening or 
planned major surgery during study or within 3 months after study end. 
14. Have been treated with i.v. immunoglobulins, cyclophosphamide or tacrolimus within 
12 months prior to baseline.  
15. Have 
received 
i.v., 
intra-articular 
(i.a.), 
intramuscular 
(i.m.) 
or 
high 
dose 
(> 25 mg/day) oral corticosteroids during the 4 weeks prior to baseline. 
16. Have a known hypersensitivity to the active product or any excipient of the study drug. 
17. Have received approved or investigational biological therapies within 6 months or 
5 half-lives of the concerned therapy (whichever is longer) prior to baseline. 
18. Have received non-biological investigational therapies within 4 weeks or 5 half-lives of 
the concerned therapy (whichever is longer) prior to baseline. 
19. Have received prior therapy blocking the IL-6 pathway, such as but not limited to 
ALX-0061, sirukumab, tocilizumab, sarilumab, clazakizumab, olokizumab, or Janus 
kinase (JAK) inhibitors at any time. 
20. Abnormality in screening laboratory test results:  
a. Alanine 
aminotransferase 
(ALT) 
and/or 
aspartate 
aminotransferase 
(AST) 
≥ 1.5 times the upper limit of normal (ULN). 
b. Hemoglobin ≤ 85 g/L (8.5 g/dL). 
c. Platelet count ≤ 75 x 109/L (75,000 cells/mm³). 
d. White blood cell count ≤ 2.2 x 109/L (2,200 cells/mm³).  
e. Neutrophils: ≤ 1.5 X 109/L. 
f. 
Estimated proteinuria > 1 g/day measured by spot urine protein to creatinine ratio of 
1.  
g. Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m² (based on the 
‘modification of diet in renal disease’ [MDRD] formula). 
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h. Any other clinically significant abnormal screening laboratory results as evaluated by 
the Investigator.  
21. Positive screening for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).  
22. Known history or presence of alcohol or drug abuse. 
23. Blood donation (> 500 mL) or a comparable blood loss within 3 months prior to 
baseline.  
24. Planned donation of germ cells, blood, organs, bone marrow during the course of the 
study or within 6 months thereafter. 
25. Female subjects who are planning to become pregnant during the study or within 
3 months after last dosing or male subjects who are considering fathering a child during 
the study and within 3 months after last dosing. 
26. Pregnant woman or female subjects who are breastfeeding. 
27. History of anaphylactic reactions. 
28. Administration of a live, attenuated vaccine within 3 months before dosing with 
ALX-0061, or anticipation that such a live attenuated vaccine will be required during the 
study or within 6 months after last dosing. 
29. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate 
for the study. 
 
 
Study medication and treatments administered: 
 
• ALX-0061 Drug Product:  
- Active substance: ALX-0061 Nanobody 
- Activity: ALX-0061 Nanobody binds to the Interleukin-6 receptor (IL-6R) and inhibits 
the interaction between the IL-6 ligand and the receptor subunit, thereby preventing 
receptor signaling. 
- Pharmaceutical formulation: ALX-0061 Drug Product is a clear, yellow to brown-yellow 
solution in an aqueous medium with a nominal concentration of 150 mg/mL of 
ALX-0061 and containing the following excipients: L-histidine, L-histidine hydrochloride 
monohydrate, polysorbate 80 (Tween 80), sucrose, and water for injection. ALX-0061 
will be supplied as a sterile liquid for s.c. injection at a volume of 0.5 mL or 1.0 mL in 
pre-filled single-use syringes. No preservatives are present. 
- Route and volume of administration: s.c. injections at a volume of 0.5 mL or 1 mL. 
 
• Placebo:  
- Substance: placebo 
- Activity: none 
- Pharmaceutical formulation: the composition of placebo is identical to that of ALX-0061 
Drug Product, except for the active substance. Placebo will be supplied as a sterile 
liquid for s.c. injection at a volume of 0.5 mL or 1.0 mL in pre-filled single-use 
syringes. No preservatives are present. 
- Route and volume of administration: s.c. injections at a volume of 0.5 mL or 1 mL. 
 
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To maintain the blind, all randomized subjects will receive study medication as 2 s.c. 
injections (one of 0.5 mL and one of 1.0 mL) every 2 weeks as described in detail in section 
“Treatment Blinding”. 
 
Group 1 (N=60) 
Placebo 
Placebo s.c. injections at Week 0 (Day 1) and q2w thereafter, up to 
and including Week 46.  
 
Group 2 (N=60) 
75 mg q4w 
ALX-0061 75 mg s.c. injections at Week 0 and q4w thereafter, up to 
and including Week 44. To maintain the blind, subjects in this group 
will also receive placebo s.c. q2w up to and including Week 46.  
 
Group 3 (N=60) 
150 mg q4w 
ALX-0061 150 mg s.c. injections at Week 0 and q4w thereafter, up to 
and including Week 44. To maintain the blind, subjects in this group 
will also receive placebo s.c. q2w, up to and including Week 46.  
 
Group 4 (N=60) 
150 mg q2w 
ALX-0061 150 mg s.c. injections at Week 0 and q2w thereafter, up to 
and including Week 46. To maintain the blind, subjects in this group 
will also receive placebo s.c. q2w, up to and including Week 46.  
 
Group 5 (N=60) 
225 mg q2w 
ALX-0061 225 mg s.c. injections at Week 0 and q2w thereafter, up to 
and including Week 46. These subjects will not receive placebo 
injections.  
 
 
Standard of care medication for SLE: 
 
• The dose of oral corticosteroids (equivalent to ≤ 25 mg of prednisone/day) should have 
been stable for at least 4 weeks prior to baseline, and the corticosteroid dose needs to be 
kept stable as much as possible through Week 24.  
• As an exception, the protocol allows for both dose decrease (tapering) and dose increase 
with the following limits:  
a) If necessary based on the Investigator’s clinical judgment, initiation of a short period 
(maximum 1 week) increase of prednisone (up to a maximum dose 
of 
15/20/25/30 mg/day depending on the baseline dose; see table below) is allowed 
until the Week 4 visit (i.e., Week 4 ± 5 days) with a return to the baseline value by 
Week 12. This increase is not allowed if the disease activity improves. 
b) In case lowering of the dose of prednisone is desired before the primary endpoint, 
tapering can be allowed up to Week 12 according to the specifications below: 
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Baseline dose 
Increase for max. 1 week  
during first 4 weeks 
Tapering allowed between  
Baseline and Week 12 
1 
16 to 25 mg/day 
Increase to a maximum of 30 mg/day 
No dose decrease below 50% of 
baseline dose 
2 
11 to <16 mg/day 
Increase to a maximum of 25 mg/day 
No dose decrease below 75% of 
baseline dose 
3 
7.5 to <11 mg/day 
Increase to a maximum of 20 mg/day 
No dose decrease < 7.5 mg/day 
4 
<7.5 mg/day 
Increase to a maximum of 15 mg/day 
No tapering will be allowed 
c) Between Week 12 and Week 24, no increase nor decrease of the dose in prednisone 
is allowed. 
d) After Week 24, tapering of the dose of oral corticosteroids to a target of 
≤ 7.5 mg/day by Week 40 is recommended, at a rate that can be decided by the 
Investigator as clinically indicated. While tapering the dose between Weeks 24 and 
40, an increase to the dose preceding the last taper step will be allowed.  
e) Doses for concomitant antimalarials and/or immunosuppressants must be stable for 
the duration of the entire study. The dose may be reduced or the medication 
temporarily discontinued for abnormal laboratory values, side effects, concurrent 
illness, or the performance of a surgical procedure, but the dose change and reason 
should be clearly documented. 
f) In case of worsening of disease or a flare, the Investigator will decide on the need for 
increase of dose of oral corticosteroids, use of i.v. or i.m. corticosteroids, start or 
increase of the dose of anti-malarial or immunosuppressant, according to his/her 
local clinical practice. The Investigator can also decide on whether study drug can be 
continued or not. Subjects needing such change to standard of care therapy for SLE 
will be considered as treatment failures and imputed as non-responders in the 
analysis of the primary endpoint. This does not apply to the transient increase in oral 
corticosteroid dose that is allowed within the protocol until the Week 4 visit (Week 4 
± 5 days; see above).  
 
 
Study Duration: 
 
The anticipated maximum study duration per subject is 58 weeks after randomization; 
subjects will be followed for efficacy through Week 48 and for safety through Week 58.  
 
The end of study is defined as the time of the last visit of the last subject participating in the 
study.  
 
• Screening Period:  
Subjects will be screened to confirm their eligibility for participation in this study within 
4 weeks prior to baseline.  
 
• Treatment and Assessment Period: 
Eligible subjects will receive treatment at Week 0/Day 1 and up to and including 
Week 46. Subjects will return for ambulatory visits every 2 weeks. 
All post-baseline visits may occur at the indicated week ± 5 days throughout the study.  
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• Final Visit/ Early Termination Visit: 
- Subjects should return for the assessment visit at Week 48, and for the Follow-Up Visit 
at Week 58 (12 weeks after the last study drug administration at Week 46).  
- Subjects who discontinue study drug but are not withdrawing consent for 
post-treatment follow-up, should return for an early termination visit within 3 weeks 
after the last study drug administration. Subjects should also return for a Follow-up 
Visit 12 weeks after last study drug administration.  
 
For details on visit assessments, see the Schedule of Assessments. 
 
 
Discontinuation criteria: 
 
Study drug administration must be discontinued in case of:  
 
• Withdrawal of consent. 
• Serious hypersensitivity reaction. 
• Abnormalities in laboratory test results:  
- ALT and/or AST elevations: 
o 
> 3 - ≤5 x ULN, confirmed by repeat testing on 2 consecutive visits  
o 
> 5 x ULN (CTCAE ≥ grade 3)  
- absolute neutrophil count < 1 x 109/L (CTCAE ≥ grade 3) 
- platelet count < 50 x 103/μL (CTCAE ≥ grade 3)  
• Diagnosis or suspicion of a serious infection (requiring parenteral antibiotics and/or 
hospitalization) if interruption of study drug is needed for more than one dose or if 
deemed necessary by the Investigator. 
• Diagnosis of TB. 
• Malignancy. 
• Pregnancy or pregnancy planned within study period. 
• Initiation of prohibited medication, as discussed with Sponsor/Medical monitor. 
• In case of interruption of study drug administration for 2 consecutive doses. 
• The randomization code is broken prematurely by the Investigator or his/her staff. 
• Demyelinating disease. 
• CHF class III or IV as defined by the New York Heart Association, unstable angina 
pectoris, myocardial infarction, cerebrovascular accident, thromboembolic event. 
• If the Investigator or the Sponsor’s Medical Monitor deems it is in the subject’s best 
interest, e.g., in case of renal or CNS flare.  
 
Discontinuation of study drug must be considered for subjects who develop a severe study 
drug injection-site reaction or a severe hypersensitivity reaction. 
The Investigator will assess if study drug administration can be continued or not in case of 
change to standard of care therapy for SLE (except for forbidden treatment e.g., 
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cyclophosphamide 
or 
another 
biologic, 
when 
study 
drug 
administration 
will 
be 
discontinued).  
 
Assessments: 
 
The following assessments are performed at the time points defined in the Schedule of 
Assessments: 
 
Efficacy evaluation 
 
Primary endpoint: The primary endpoint is the percentage of subjects who achieved a 
response at Week 24 according to the composite mBICLA (BILAG-based Combined Lupus 
Assessment) score. mBICLA responders are defined as subjects who meet all of the 
following criteria: 
 
(1)  BILAG-2004 improvement: all A scores at baseline improved to B/C/D, and all B scores 
improved to C or D.  
(2)  no worsening in disease activity: no new BILAG-2004 A scores and ≤1 new B score.  
(3)  no worsening of total mSLEDAI-2K score from baseline.  
(4)  no significant deterioration (< 10% worsening) in Physician global assessment (PGA). 
(5) no treatment failure (i.e., new or increased immunosuppressives or anti-malarials; or 
non-protocol allowed increased oral or parenteral corticosteroids; or premature 
discontinuation from study treatment). 
 
A modified SLEDAI-2K index (mSLEDAI-2K) will be derived from the standard index by 
omitting 1 of the standard items (low complement).  
 
Secondary endpoints will include: 
• Composite endpoint (m)BICLA over time. 
• Composite endpoint mSRI as well as standard SRI over time. 
• (m)SRI with more stringent (m)SLEDAI-cut-offs: SRI-5, SRI-6, SRI-7, SRI-8 over time. 
• Change from baseline in mSLEDAI-2K total score as well as standard SLEDAI-2K 
measured over time. 
• Number and percent of subjects with BILAG-2004 improvement. 
• BILAG-2004 (total score) over time. 
• Improvement in individual organ systems of the BILAG-2004 over time. 
• Number of BILAG-2004 systems in which activity increased, decreased or remained the 
same compared to previous visit (BILAG-2004 systems tally) over time. 
• Change from baseline in PGA over time. 
• Change from baseline in patient’s global assessment over time. 
• Change from baseline in proteinuria/urine sediment/serum creatinine/eGFR over time. 
• Proportion of treatment failures (defined as non-protocol allowed increase in steroid dose, 
start i.v. or i.m. steroids, start or increase of immunosuppressant) at Week 24 and at 
Week 48.   
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• Reduction in flare rate at Week 24 and at Week 48.  
- Severe flare defined as a new A score in any system of the BILAG-2004 index; 
moderate flare defined as a new B score following a C, D or E score.   
- SLEDAI flare index (SFI). 
• Percent change from baseline in daily dose of steroids at Week 24 and 48. 
• Percent subjects whose prednisone equivalent dose was >7.5 mg/day at baseline and 
reduced to ≤7.5 mg/day during Weeks 40–48 without experiencing a flare.  
• Percent subjects who are able to discontinue prednisone by Week 48 without 
experiencing a flare. 
• Changes from baseline in the physical and mental component scores of SF-36 at Week 24 
and at Week 48. 
• 28 Joints count over time and change from baseline in 28 joint count over time. 
• Cutaneous lupus erythematosus disease area and severity index (CLASI) over time and 
change from baseline evaluation at Week 12, 24 and Week 48. 
• PK parameters. 
• PD markers, including total sIL-6R, CRP, fibrinogen, anti-dsDNA, C3, C4, CH50. 
 
Pharmacokinetics 
 
Samples for determination of ALX-0061 serum levels. 
 
Pharmacodynamics 
 
Samples for determination of biomarker levels, including but not limited to total sIL-6R, 
CRP, fibrinogen, anti-dsDNA, C3, C4, CH50. 
 
Samples for determination of additional biomarker levels (exploratory), including but not 
limited to uMCP-1, plasma cells, T helper 17 (Th17) and regulatory T (Treg) cells. 
 
Immunogenicity 
 
Samples for determination of anti-ALX-0061 antibodies. 
 
Safety 
 
Safety assessments will include: 
• Physical examination. 
• Vital signs measurement. 
• Electrocardiogram (ECG). 
• Blood chemistry (including liver enzymes and lipids), hematology (including neutrophils 
and platelets) and coagulation parameters. Lupus anti-coagulant (LA), anti-cardiolipin 
(aCL) and anti-β2-glycoprotein I (β2-GPI) antibodies will be evaluated at screening and 
Week 24.  
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• Adverse events (AEs) (including local tolerability and hypersensitivity reactions) and 
serious AEs. 
 
Statistical Methods: 
 
Sample size and Power 
Up to approximately 300 subjects will be randomized over 5 treatment arms in a 1:1:1:1:1 
ratio. Randomization will be stratified by geographic region. 
 
Simulations were performed to evaluate the power of detecting a significant dose-response 
relationship, i.e., whether changes in ALX-0061 dose regimen lead to significant changes in 
mBICLA response rate at Week 24 by using the MCP-Mod methodology [1]. A set of 
5 plausible candidate models containing both monotonous and non-monotonous exposure-
response shapes was defined. For these models an estimated placebo response rate of 25%, 
and a difference in response rate between the ALX-0061 dose regimen with the largest 
response rate and placebo of 25% was assumed, taking into account a discontinuation rate 
of 15% (homogeneous over treatment arms). With this methodology a sample size of 
60 subjects per arm will provide at least 85% power at a family-wise 5% significance level. 
 
Primary efficacy endpoint evaluation: 
mBICLA response rates at Week 24 will be analyzed using the MCP-Mod methodology. The 
analysis will be performed using the modified intent-to-treat (mITT) population of all 
subjects who have received at least 1 administration of study drug and according to the 
treatment for which they were assigned.  
 
Subjects with missing mBICLA response data at Week 24, including those who have 
discontinued study drug before Week 24, as well as subjects with treatment failure, will be 
treated as non-responders (non-response imputation approach). Treatment failure is 
defined as non-protocol allowed increase in steroid dose, start i.v. or i.m. steroids, start or 
increase of immunosuppressant. 
 
Primary efficacy endpoint evaluation will also be performed using the per-protocol (PP) 
population. 
 
Summary statistics (frequencies, proportions) for mBICLA response rate at Week 24 and 
Week 48 will be provided by treatment group. 
 
All other evaluations: 
All secondary efficacy endpoints will be summarized by treatment group, using the observed 
data in the mITT population. For continuous secondary efficacy endpoints, summary 
statistics include mean, standard deviation, median, minimum and maximum, while for 
categorical secondary efficacy endpoints frequencies and proportions are provided. 
 
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All safety, PD and ADA analyses will be performed using the safety population of all subjects 
who received at least 1 dose of study drug. Analyses will be performed using the treatment 
that the subject actually received. 
 
Pharmacokinetic analysis will be performed on the PK population. 
 
PK/PD modeling will be performed to characterize the change of efficacy endpoints versus 
ALX-0061 exposure. The results of this exploratory analysis will be presented in a separate 
report. 
 
All other data will be summarized using descriptive statistics as appropriate. 
 
 
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SCHEDULE OF ASSESSMENTSA 
 
Study Period 
Screening 
 
Base-
line 
(Day) 
Treatment and Assessment Period 
(Week ± 5 days) 
Early 
Termination 
Visit 
Follow-up 
(± 2 weeks)
Study Visit 
Within 
28 days 
prior to 
baseline 
1 
2 
4 
6 
8 
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 
Within 
3 weeks 
after last 
dosing 
12 weeks 
after last 
dosing 
Written informed 
consent  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, 
medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
Vital signs b 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
12-lead ECG c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Screening Hep B, 
Hep C, HIV d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IGRA test  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest radiograph e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB evaluation f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of entry 
criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANA, LA, aCL, 
β2-GPI g 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug allocation 
and administration 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
SLEDAI-2K  
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
BILAG-2004 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
Physician’s Global 
Assessment 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
Patient’s Global 
Assessment 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
SF-36 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
28 joint count 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
CLASI h 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
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Study Period 
Screening 
 
Base-
line 
(Day) 
Treatment and Assessment Period 
(Week ± 5 days) 
Early 
Termination 
Visit 
Follow-up 
(± 2 weeks)
Study Visit 
Within 
28 days 
prior to 
baseline 
1 
2 
4 
6 
8 
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 
Within 
3 weeks 
after last 
dosing 
12 weeks 
after last 
dosing 
SLICC/ 
ACR damage score 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventsi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
analysesj 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
Urinalysis 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
Pregnancy test 
(serum at 
screening/urine at 
other visits) 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
PK k 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
PD biomarker 
(sIL-6R) k,  
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
x 
PD biomarker 
(others) k,l 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
Exploratory 
biomarkersm 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Immunogenicity k,i 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
Local lab analyses 
(Direct Coombs) n 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
a 
If assessments are planned at the same time, following guidance should be followed: 1) ECG and vital signs should be assessed prior to blood sampling, 
2) Patient assessments (patient’s global assessment and SF-36) should occur prior to physician's assessments, 3) Study drug should be dosed after all other 
assessments have been performed. 
b 
Vital signs (assessment after 5 min in supine position): including height, weight, blood pressure, pulse and temperature. Height measurement is only 
required at the screening visit. 
c 
To be performed after 5 min in supine position. 
d 
Lab tests for hepatitis B will be done according to the guidelines [2].  
e 
If a chest radiograph has not been performed within 12 weeks prior to screening as part of standard of care, a chest radiograph must be performed during 
the screening period. In case local regulations do not allow radiographs during the study, a radiograph as part of standard of care should be available prior 
to screening. 
f 
If TB is suspected at any time during the study, chest radiography and IGRA or a comparable local practice test should be performed.  
g 
Lupus anti-coagulant (LA), anticardiolipin (aCL) and anti-β2-glycoprotein I (β2-GPI) antibodies will be evaluated at screening and Week 24. Anti-nuclear 
antibodies (ANA) will be evaluated at screening only. 
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h 
The CLASI will be performed in interested sites having experience in this assessment. 
i 
In case of acute or delayed severe/serious hypersensitivity reactions, an additional blood sample should be collected as soon as possible after the start of 
the event. 
j 
On dosing days, blood sampling will be performed pre-dose. Subjects will be fasted for at least 10h at baseline and Weeks 4, 8, 12, 24, 36 and 48 and/or 
the Early Termination Visit for assessment of fasting serum lipids. Samples will be assessed by a central laboratory. 
k 
On dosing days, PK, PD biomarker and immunogenicity samples will be taken predose. 
l 
CRP, fibrinogen, anti-dsDNA, C3, C4, CH50.  
m Urine samples for uMCP-1 will be collected in all subjects. Blood samples for immunophenotyping will be collected in a subset of subjects (at selected sites 
based on qualification).  
n 
Parameters to be assessed by the local laboratory include Direct Coombs and INR (INR for subjects on vitamin K antagonist only). INR will be performed at 
Weeks 0, 2, 4, 8, and 12, and every 4 weeks (or more frequent if considered necessary by Investigator) thereafter up to Week 48 (or Early Termination 
Visit), and Follow-Up Visit. 
 
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1. INTRODUCTION 
 
ALX-0061 has been developed by the Sponsor as a new compound neutralizing pro-
inflammatory activity in the Interleukin-6 (IL-6) pathway. Based on its mode of action, 
ALX-0061 is currently in development for the treatment of autoimmune diseases such as 
systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).  
 
The currently proposed clinical study is intended to evaluate the efficacy and safety of 
different dose regimens of ALX-0061 administered subcutaneously (s.c.) on top of standard 
of care to subjects with moderate to severe active, seropositive SLE.  
 
1.1. SYSTEMIC LUPUS ERYTHEMATOSUS 
 
SLE is a complex autoimmune disorder, characterized by the presence of pathogenic 
autoantibodies directed against nuclear components, such as anti-nuclear antibodies [ANA] 
and anti-double-stranded deoxyribonucleic acid [anti-dsDNA] antibodies. More than 90% of 
patients with SLE have ANA, which are sensitive but not specific for SLE. Anti-dsDNA are 
more specific and fluctuate with disease activity [3]. 
 
The prevalence of SLE is estimated to be approximately 1 per 1000, but varies with 
ethnicity (higher in African-Americans and Hispanics compared to Caucasians). The disease 
is approximately 10-times more prevalent in women compared to men [3].  
 
SLE is a clinically heterogeneous disease that affects multiple organs, with the most 
common manifestations ranging from rash, fatigue and mucocutaneous and musculoskeletal 
conditions, to more severe renal and neurological manifestations. SLE is characterized by 
periods of active disease, alternated with temporary remission and relapses.  
 
1.1.1. 
TREATMENT OF SYSTEMIC LUPUS 
ERYTHEMATOSUS 
 
Treatment aims to manage and control symptoms during the acute periods of active 
disease, and to minimize the risk of flares during periods of remission. In mild, non-organ 
threatening disease, antimalarials, low-dose steroids, and transient use of non-steroidal 
anti-inflammatory drug (NSAIDs) can be recommended [4]. In case of worsening of disease, 
hydroxychloroquine is usually maintained along with additional therapy, and the steroid 
doses are usually increased [3].  
 
For patients with more severe disease, or when steroid dose cannot be reduced to 
acceptable levels, immunosuppressive agents such as azathioprine, mycophenolate mofetil, 
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and methotrexate (MTX) are usually recommended. For renal disease, cyclophosphamide 
and mycophenolate mofetil in combination with steroid treatment is often evaluated.  
 
In addition to these more conventional therapies, biological agents which target specific 
cells or molecules within the abnormally functioning immune system are being developed. 
Belimumab, a B-lymphocyte stimulator (BLyS)-specific inhibitor, has been approved among 
others by the United States (US) Food and Drug Administration (FDA) and the European 
Medicines Agency (EMA) in addition to standard therapy to treat adults with active, 
autoantibody-positive SLE with a high degree of disease activity. In addition, rituximab, an 
anti-CD20 monoclonal antibody that induces B-cell depletion, is used in patients with severe 
disease not responding to conventional treatments, albeit off-label [5]. 
 
The drugs currently used to treat SLE can be associated with additional risks and 
complications. The chronic use of steroids for instance can lead to Cushingoid syndrome, 
increased risk of opportunistic infections, and the development of osteoporosis. Not 
surprisingly, ability to limit tapering chronic use of corticosteroids is generally considered of 
great clinical value in SLE management. Overall, there is substantial unmet medical need for 
newer, more effective and better-tolerated therapies for the treatment of SLE [6].  
 
1.1.2. 
ROLE OF IL-6(R) IN PATHOPHYSIOLOGY 
OF SYSTEMIC LUPUS ERYTHEMATOSUS 
 
Several lines of evidence indicate that overexpression of IL-6 and IL-6R, as well as extended 
activation of the IL-6 pathway, are important factors in chronic auto-immune, inflammatory 
and proliferative diseases, B cell malignancy, Castleman’s disease and various cancers [7, 
8]. Based on its mode of action, ALX-0061 is currently under development for the treatment 
of autoimmune diseases such as SLE and RA. The IL-6 pathway is considered to be an 
important factor in SLE: 
 
• An association between IL-6 and progression of lupus has been published for several 
murine models of SLE [9]. Therapeutic inhibition or knockout of IL-6(R) in several mouse 
models 
abrogated 
the 
SLE 
phenotype, 
while 
exogenous 
IL-6 
increased 
SLE 
manifestations [10-16].  
• In SLE patients, IL-6 levels are elevated in serum, urine, skin and cerebrospinal fluid 
(CSF), and are closely linked with specific disease manifestations, such as anti-dsDNA 
antibodies [10, 11, 14, 17, 18]. IL-6 levels are also increased in urine and in glomerular 
and tubular tissue of lupus nephritis patients [19-21].  
• In addition, IL-6 plays a role in the B-cell hyperactivity and immune pathology of human 
SLE, and may have a direct role in mediating tissue damage (Figure 1) [10-12]. The 
dominant role of IL-6 in SLE pathogenesis is to accelerate autoantibody production by 
promoting the proliferation of autoreactive B cells. SLE autoreactive B cells constitutively 
express IL-6R and produce high levels of IL-6. Local production of IL-6 also contributes 
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to tissue damage via induction of chemokines and cell-adhesion molecules, leading to 
recruitment and infiltration of inflammatory cells. Furthermore, in SLE, an imbalance has 
been described between T-helper 17 (Th17) cells, a subset of inflammatory T cells that 
drives autoimmunity, and regulatory T (Treg) cells, which are important for the 
maintenance of immune tolerance [22, 23]. IL-6 is a crucial factor in the Th17/Treg cell 
balance, as it promotes the generation of Th17 cells and inhibits Treg cell development.  
 
 
 
Figure 1: Involvement of IL-6(R) in the pathophysiology of SLE. 
 
Several IL-6(R) targeting drugs, either receptor blockers or cytokine inhibitors, have been 
evaluated in early phase clinical studies in SLE, and preliminary safety and efficacy data 
have been obtained with e.g., the anti-IL-6R monoclonal antibody (mAb) tocilizumab, the 
anti-IL-6 (ligand) mAb sirukumab and a human anti-IL-6 (ligand) mAb (PF-04236921).   
A small open-label study with tocilizumab (an anti-IL-6R monoclonal antibody [mAb]) in 
16 patients with SLE showed encouraging results, with improvements in inflammatory and 
serologic markers, as well as clinical manifestations of lupus (including efficacy on joints and 
skin) [24]. Sirukumab was well tolerated in a Phase I study in patients with mild, stable, 
active cutaneous lupus erythematosus and SLE [25]. In a phase II study a notable reduction 
in proteinuria was observed in approximately 15-20% of treated immunosuppressed 
patients with refractory lupus nephritis (but no median improvement in proteinuria) and a 
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high frequency of serious adverse events (SAEs) [26]. A Phase II clinical trial with PF‑
04236921 in patients with active generalized SLE showed an efficacy signal, i.e., an 
improvement in composite endpoints of disease activity and a reduction of the risk for 
severe flares [27].    
 
1.2. ALX-0061 
 
The following paragraphs provide summary information on ALX-0061; for more detailed 
background information, please refer to the Investigator’s Brochure. 
 
1.2.1. 
GENERAL PROPERTIES 
 
The active component in ALX-0061 solution for injection is a therapeutic protein, designated 
“ALX-0061 Nanobody”. Nanobodies are a novel class of therapeutic proteins, and are based 
on the smallest functional fragments of single-chain antibodies that occur naturally in the 
Camelidae family. They have a high degree of homology (in terms of sequence and 
structure) to human immunoglobulin heavy chain variable region (VH) domains, and can be 
further engineered and expressed by a variety of expression systems such as Pichia 
pastoris. 
 
ALX-0061 Nanobody consists of 2 humanized and sequence-optimized variable domains 
derived from heavy chain-only llama: 
 
• One domain (designated 20A11) binds to human IL-6 receptor (IL-6R).  
• The second domain (designated ALB11) binds to human serum albumin (HSA), as a 
means to improve the pharmacokinetic (PK) properties of the Nanobody (half-life 
extension).  
 
ALX-0061 Nanobody inhibits the interaction between the IL-6 ligand and receptor subunit, 
thereby preventing receptor signaling.  
 
• IL-6 is a pleiotropic cytokine with a wide range of biological activities in the immune, 
hematopoietic, hepatic and neural system. IL-6 exerts its effect through binding to a 
non-signaling IL-6R subunit. This complex further interacts with two glycoprotein 130 
(gp130) subunits, enabling signal transduction and subsequent biological effects. 
• IL-6R is present in both a membrane-bound and a soluble form (mIL-6R and sIL-6R 
respectively). In its soluble form, IL-6R can activate gp130-positive cells that do not 
express mIL-6R on their surface (such as endothelial cells and synoviocytes), through a 
process called trans-signaling. Cells expressing the membrane-bound form of IL-6R (such 
as hepatocytes and selected white blood cell populations) can directly engage IL-6 in a 
process called classical signaling.  
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• ALX-0061 is a highly specific biological drug that targets and neutralizes both forms of 
IL-6R, with higher affinity for sIL-6R than mIL-6R.  
 
The second domain of ALX-0061 was designed to improve the PK properties of the 
Nanobody by binding to HSA. Albumin is the most abundant protein in plasma and has a 
half-life of approximately 19 days in humans [28]. Binding to albumin (as a carrier) has 
been shown to lead to retention of the bound protein in circulation, with a resident time 
approaching that of the carrier molecule [28]. The domain directed against HSA (designated 
ALB11) extends the half-life of ALX-0061 by (i) minimizing Nanobody excretion via renal 
filtration through the formation of a Nanobody-albumin complex, and (ii) exploiting the long 
inherent half-life of albumin due to the neonatal Fc receptor mediated pathway, similar as 
for monoclonal antibodies via their Fc domain, but avoiding the effector functions of the 
latter. 
 
1.2.2. 
MANUFACTURE 
 
The manufacture of ALX-0061 Nanobody consists of an upstream process (i.e., fermentation 
of a Pichia pastoris strain that expresses the ALX-0061 Nanobody and secretes the product 
into the medium), and a downstream process (essentially harvest, capture, intermediate 
purification, polish, and formulation of the Nanobody). Additional information on the 
manufacture and pharmaceutical properties of ALX-0061 is included in the Investigator’s 
Brochure. 
 
1.2.3. 
NONCLINICAL STUDIES 
 
Pharmacology 
ALX-0061 was extensively characterized in vitro. The in vivo efficacy and the 
PK/pharmacodynamic (PD) properties of ALX-0061 were examined in naive cynomolgus 
monkeys, in an acute cynomolgus monkey model of IL-6-induced inflammation, and in a 
collagen-induced arthritis model in rhesus monkeys. PK was assessed during the toxicology 
studies in cynomolgus monkeys (toxicokinetics [TK]). Additionally, the impact of anti-drug 
antibodies (ADA) on the PK and PD of ALX-0061 was evaluated.  
 
Toxicology 
The toxicology program was carried out in cynomolgus monkeys, and consists of a single-
dose intravenous (i.v.) dose-range finding toxicity study, Good Laboratory Practice 
(GLP)-compliant 13-week and 26-week repeated-dose i.v. toxicity studies, and a 
GLP-compliant 4-week repeated dose i.v./s.c. toxicity study. 
 
All relevant nonclinical studies conducted with ALX-0061 are described in the Investigator’s 
Brochure. The nonclinical data revealed no specific safety risks, based on the available 
safety pharmacology data, and local and systemic tolerability assessment. 
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1.2.4. 
EFFECTS IN HUMANS 
 
A combined Phase I/II study in subjects with moderately to severely active RA, on a stable 
background of MTX, has been completed (Study ALX-0061-1.1/10). This placebo-controlled 
study included 28 subjects in an initial single ascending dose (SAD) part where single i.v. 
doses of 0.3, 1, 3, or 6 mg/kg were administered. In a subsequent multiple ascending dose 
(MAD) part, 37 subjects received multiple i.v. doses of 1 or 3 mg/kg every 4 weeks (q4w), 
or 6 mg/kg every 8 weeks, for 24 weeks in total.  
 
A Phase I study (Study ALX0061-C102) assessing the bioavailability of single doses of 
ALX-0061, administered s.c. at 3 dose levels, using 2 corresponding single i.v. dose levels 
as reference, in healthy adult subjects, has been completed. This study included 70 subjects 
and studied doses of 50, 150, and 300 mg. The PK and PD results were used to bridge from 
i.v. to s.c. administration, and to determine the appropriate doses for the current Phase II 
study. 
 
In addition, 2 Phase II studies in RA are ongoing: 
 
• Study ALX0061-C201 is a multicenter, randomized, double-blind, placebo-controlled dose 
range finding Phase IIb study, conducted to evaluate the efficacy and safety of ALX-0061 
administered s.c. in combination with MTX, in subjects with active RA despite MTX 
therapy. 
• Study ALX0061-C202 is a multicenter, randomized, double-blind Phase IIb study 
conducted to evaluate efficacy and safety of dose regimens of ALX-0061 administered 
s.c. as monotherapy in subjects with active RA who are intolerant to MTX or for whom 
continued MTX treatment is inappropriate. 
 
1.2.4.1. 
STUDY ALX-0061-1.1/10 IN 
SUBJECTS WITH MODERATELY TO 
SEVERELY ACTIVE RHEUMATOID 
ARTHRITIS  
 
The results of the SAD and MAD parts of this study are discussed in detail in the 
Investigator’s Brochure, and are briefly summarized below.  
 
Efficacy 
In the MAD part of the study, all ALX-0061 treatment combinations showed rapid and long-
lasting improvements in disease activity (as measured by American College of 
Rheumatology [ACR], European League Against Rheumatism [EULAR], Disease Activity 
Score using 28 joint counts [DAS28], C-reactive protein [CRP], Clinical Disease Activity 
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Index [CDAI], and Boolean remission responses). There were high numbers of responders in 
all ALX-0061 treatment groups, with DAS28 remission or low disease activity observed in 
54% of ALX-0061-treated subjects at Week 12. Overall, the efficacy profile obtained at 
Week 12 continued to improve during the subsequent 12 weeks of ALX-0061 treatment. 
 
Pharmacokinetics 
The PK of ALX-0061 appears dose-dependent, suggesting target-mediated disposition of the 
drug. A 2-compartment disposition model with parallel first-order (linear total body 
clearance [CL]) and Michaelis-Menten elimination (nonlinear or concentration-dependent CL) 
describes well the PK behavior of the drug, and is consistent with the more than 
proportional increase of exposure and half-life of drug with the increase of dose. Similar to 
monoclonal antibodies, the nanobody has a limited volume of distribution, corresponding to 
the plasma volume.  
 
Pharmacodynamics 
• All ALX-0061 groups received biologically effective doses: rapid and long-lasting 
increases in IL-6 and sIL-6R concentrations were observed across all ALX-0061 dose 
groups. The PD results confirmed that sIL-6R (and IL-6) concentrations can be used as a 
biomarker for target engagement by ALX-0061. 
• Dosing q4w at 3 mg/kg yielded the highest exposure, as indicated by the observed 
average trough levels (~ 10 µg/mL), strongest biomarker response (based on sIL-6R 
profile), and the highest clinical remission rates. 
 
Safety 
• Single and repeated administration of ALX-0061 was well tolerated in all treatment 
groups, with a manageable and consistent safety profile for all ALX-0061 dose 
combinations.  
• In the MAD part, the most commonly reported adverse events (AEs) observed after 
intake of ALX-0061 included headache, increased alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST), arthralgia, back pain, and joint swelling. Most of the 
events were mild or moderate and resolved during the treatment period. 
• There were no clear trends in the occurrence or type of treatment-related AEs when 
comparing the individual ALX-0061 treatment groups, and there was no evidence to 
suggest that an maximum tolerated dose was reached. 
• 3 subjects reported SAEs. 
In the SAD part, 1 subject (3 mg/kg ALX-0061) experienced an acute hypersensitivity 
during the first infusion of ALX-0061, which was stopped immediately. The subject was 
successfully treated in the hospital with anti-histaminic drugs, prednisone, and 
salbutamol.  
In the MAD part of the study, 1 subject (3 mg/kg q4w ALX-0061) experienced an SAE of 
cerebrovascular accident after having received 2 infusions of ALX-0061 in total. Although 
the subject recovered from the initial event, a second, more severe SAE of 
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cerebrovascular accident occurred several days later and the subject died. Both events 
were considered remotely related to study treatment by the Investigator.  
One other subject with a confirmed Helicobacter pylori gastritis and history of short 
NSAID intake experienced an SAE of hemorrhagic gastritis (not related) and a linked SAE 
of upper gastrointestinal hemorrhage (remotely related). Both SAEs resolved before the 
end of the study. 
• Four subjects reported AEs leading to withdrawal of study drug in the MAD part of the 
study: 1 subject with the SAE cerebrovascular accident (described above), 1 subject with 
rash and non-immunoglobulin (Ig) E mediated hypersensitivity reaction (probably related 
to the study drug), 1 subject with uncontrolled hypertension (remotely related to the 
study drug), and 1 subject with infected dermal cyst (remotely related to the study 
drug). 
• Regarding laboratory abnormalities, a rapid and reversible decrease in neutrophils and 
platelets was seen in the majority of subjects after administration of ALX-0061. These 
decreases in neutrophil and platelet count seemed to be dose-related but did not reach 
clinically relevant levels. No AEs related to the decreases in neutrophil and platelet count 
(or other hematology parameters) were reported, except for 1 subject with mild 
leukopenia (without neutropenia).  
• With the exception of individual subjects showing increases in liver parameters (mainly 
AST and/or ALT) beyond the normal range, there were no clinically relevant trends in 
mean liver or other safety-related biochemistry parameters (including lipids) across dose 
levels.  
 
1.2.4.2. 
STUDY ALX-0061-C102 IN HEALTHY 
VOLUNTEERS 
 
Overall, a single s.c. dose of ALX-0061 in the dose range of 50 to 300 mg was well-tolerated 
in a group of healthy male and female subjects. There were no severe AEs, deaths, other 
SAEs or AEs that resulted in study drug discontinuation. 
 
In the s.c. treatment groups, the majority of possibly-related AEs were injection site 
reactions (mainly pain and/or erythema), which appeared to be dose-dependent across the 
dose range tested (50 mg to 300 mg). All injection site reactions were transient and of mild 
intensity and apart from these reactions, no specific AEs were reported very frequently or 
showed a dose relationship. Apart from these injection site reactions, no differences were 
observed compared to the i.v. administration groups.  
 
As expected from the mechanism of action, a mild transient decrease in fibrinogen, 
neutrophils and high sensitivity (hs) CRP levels was observed following administration of 
ALX-0061. One subject in the 300 mg i.v. group showed an increase in ALT up to a 
maximum of 150 U/L, accompanied by a mild rise in AST and no rise in bilirubin. The ALT 
level had returned to baseline at follow-up. 
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The PK and PD results were used to determine the appropriate doses for the current 
Phase II study and are summarized in the Investigator’s Brochure, and section 3.1.1. 
 
1.2.5. 
BENEFITS AND RISK ASSESSMENT 
 
IL-6 is a pleiotropic cytokine with an important role in a broad spectrum of biological events, 
therefore, potential risks related to inhibition of the IL-6 pathway, as well as potential risks 
inherent to the administration of therapeutic proteins, are considered. 
 
• Inhibition of the IL-6 pathway has immunomodulatory effects, and has been reported to 
increase the risk for infection [29, 30]. So far, serious infections have not been reported 
for ALX-0061.  
 
• Suppression of IL-6 activity is known to reduce the levels of acute phase proteins such as 
CRP, serum amyloid A (SAA), and fibrinogen [31, 32].  
- Rapid and long-lasting decreases in CRP, erythrocyte sedimentation rate (ESR), 
fibrinogen and SAA were observed across all ALX-0061 dose groups in study 
ALX-0061-1.1/10. In general, these pharmacological effects were reversible and 
associated with clinical response in signs and symptoms of RA. 
- In Study ALX0061-C102, results indicate a trend towards a minor decrease in 
fibrinogen and high sensitive (hs)CRP levels following administration of ALX-0061 in 
most subjects.  
 
• Suppression of IL-6 signaling has been shown to lead to decreases in neutrophil and 
platelet counts [33].  
- In Study ALX-0061-1.1/10, a rapid and reversible decrease in neutrophils and platelets 
was seen in the majority of subjects after administration of ALX-0061 in the MAD part 
of the study. No AEs related to the decreases in neutrophil and platelet count (or other 
hematology parameters) were reported, except for 1 subject with mild leukopenia 
(without neutropenia; MAD part of the study). 
- In Study ALX0061-C102, the results show a tendency towards a mild and transient 
decrease neutrophil count. 
 
• Increased transaminase levels (AST/ALT) in serum and increased cholesterol (high 
density lipoproteins [HDL], low density lipoproteins [LDL], and triglycerides) levels have 
been reported following pharmacological inhibition of the IL-6 pathway [34]. With the 
exception of individual subjects showing increases beyond the normal range, there were 
no clinically relevant trends in mean liver (ALT/AST/gamma glutamyltransferase 
[GGT]/lactate dehydrogenase [LDH]/bilirubin) parameters, mean lipid concentrations, or 
other safety-related biochemistry parameters across dose levels in Study ALX-0061-
1.1/10 or ALX0061-C102. 
 
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• Recent data indicate that RA subjects have a generally increased rate of gastrointestinal 
perforation [35]. At this time, it is not clear whether IL-6 inhibitors further increase the 
risk of this complication beyond that observed in the general RA population. To date, no 
cases 
of 
gastrointestinal 
perforation 
have 
been 
observed 
following 
ALX-0061 
administration. 
 
• As with all therapeutic proteins used in humans, infusion reactions (e.g., either 
anaphylactic or anaphylactoid) cannot be excluded.  
- In Study ALX-0061-1.1/10, two hypersensitivity reactions were reported (one serious 
and one moderate). For additional details, please refer to the Investigator’s Brochure 
(also see section 1.2.4.1). 
- In Study ALX0061-C102, no hypersensitivity reactions were reported. 
 
• Administration of any protein therapeutic can lead to the development of ADA [36]. The 
currently available immunogenicity (ADA) results after i.v. and s.c. administration of 
ALX-0061 do not indicate risks related to pre-existing or treatment-emergent antibodies 
to ALX-0061. 
 
In view of the early stage of development, it is not established whether the above-
mentioned risks are clinically relevant for administration of ALX-0061. Potential benefit of 
ALX-0061 has been observed in Study ALX-0061-1.1/10, where RA patients had clinical 
response in signs and symptoms of their disease activity. Given the preclinical rationale, and 
the preliminary clinical data showing that IL-6 could be a relevant target in SLE patients, 
the currently proposed study will allow further assessment of the potential benefits as well 
as the risks in this patient population with an important unmet medical need.   
 
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2.  OBJECTIVES 
 
Primary objective: 
• 
To assess the efficacy and safety of different dose regimens of ALX-0061 administered 
s.c. to subjects with moderate to severe active, seropositive SLE compared to placebo. 
 
Secondary objectives: 
• 
To assess the PK, PD, immunogenicity, flare rate, steroid reduction and health-related 
quality of life, with different dose regimens of ALX-0061. 
 
 
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3. STUDY DESIGN 
 
3.1. OVERALL STUDY DESIGN  
 
3.1.1. 
STUDY OVERVIEW 
 
This is a multicenter, randomized, double-blind, placebo-controlled, dose-range finding 
Phase II study of ALX-0061 administered s.c. on top of standard of care, in subjects with 
moderate to severe active, seropositive SLE. Approximately 300 subjects will be enrolled. 
An overview of the study design is included in Figure 2. 
 
Figure 2: Overview of the design of Study ALX0061-C204 
 
 
This study is expected to allow dose-range-finding of s.c. ALX-0061 in subjects with 
moderate to severe SLE. The selection of the doses to be used in this study was based on 
the results of study ALX0061-C102 in healthy volunteers (for PK, safety and tolerability), 
study ALX-0061-1.1/10 in RA patients (for efficacy or pharmacological activity), and the 
exposure levels measured in preclinical toxicology studies (for safety margin calculation).  
 
A PK/PD model, developed based on data pooled from studies ALX-0061-1.1/10 and 
ALX0061-C102, was used to predict pharmacological activity or efficacy (using the available 
DAS28 response in RA patients) at different dose levels/regimens. 
• Simulations of the PK assumed a mean body weight of 78 kg, with a standard deviation 
of 19 kg and a minimum and maximum body weight of 40 kg and 150 kg, respectively. 
• The exposure-response provided an estimate of the EC50 (1.46 µg/mL) based on DAS28 
as an indicator of pharmacological activity. To assess ALX-0061 exposure at doses 
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relevant for future Phase II studies, Ctrough levels for different s.c. dosing regimens were 
simulated by the PK model, based on a typical individual with 78 kg body weight. These 
data suggest that trough serum levels after 75 mg q4w and 150 mg q4w dosing 
regimens would be below the estimated EC50 for pharmacological activity (DAS28). 
 
Under the assumption that ALX-0061 activity is mainly driven by trough concentrations, and 
based on these simulations, the following dosing regimens were proposed for this study: 
• 75 mg q4w 
• 150 mg q4w 
• 150 mg every 2 weeks (q2w) 
• 225 mg q2w 
 
The highest dose of 225 mg s.c. q2w is expected to be safe and well tolerated, based on the 
observations that doses of 3 mg/kg i.v. q4w, 6 mg/kg i.v. q8w and 6 mg/kg i.v. q4w (last 
dose evaluated in few non-responders) were well tolerated and had an acceptable safety 
profile in study ALX-0061-1.1/10. 
 
The median model-predicted exposure at steady state for the highest dose group (225 mg 
s.c. q2w) was estimated at 595 day*µg/mL. This estimated exposure in human (AUCss,Tau) 
was compared with the observed exposure at steady state (AUCss,Tau) in the repeated dose 
toxicity studies in cynomolgus monkeys: 
• In the 26-week repeated dose toxicity study, a median exposure at steady state of 
17867 day*µg/mL was reported for the 100 mg/kg weekly i.v. dose, leading to an 
estimated safety margin of 60. 
• In the 4-week repeated dose toxicity study, a median exposure at steady state of 
10381 day*µg/mL was reported for the 100 mg/kg weekly s.c. dose, leading to an 
estimated safety margin of 35. 
 
Based on these calculations, the doses selected to assess the exposure-response 
relationship of ALX-0061 in this study are covered by appropriate exposure margins. 
 
As this is an add-on therapy study, all subjects (including subjects in the placebo group) will 
receive standard of care treatment for SLE in line with their severity of disease and 
according the Investigator’s clinical practice. Having this placebo group will be of great value 
in the assessment of whether or not any abnormalities observed were due to ALX-0061 or 
to study procedures, and to allow statistical comparison of efficacy between ALX-0061 and 
placebo.  
 
Subjects will have visits q2w up to Week 48. A Follow-up Visit is planned 12 weeks after the 
last dosing. 
 
The composite British Isles Lupus Assessment Group (BILAG)-based composite lupus 
assessment (BICLA) response was chosen as primary endpoint to evaluate reduction in 
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disease activity in this diverse and heterogeneous disease since this composite endpoint 
allows an assessment of improvement in the involved organ system(s) without a concurrent 
worsening of the general condition or worsening in other organ systems. For details on 
primary statistical analysis in this study, please refer to section 3.6.5.1.  
 
An adjudication process of the BILAG-2004 and Systemic lupus erythematosus disease 
activity index 2000 (SLEDAI-2K) assessments will be performed at Baseline, Week 24, and 
Week 48 (also see section 3.4.1.1). 
 
Secondary endpoints will include the composite systemic lupus erythematosus responder 
index (SRI), the individual components (SLEDAI-2K, BILAG-2004 [normal improvement, 
enhanced improvement, and individual item improvement], and physician’s global 
assessment [PGA]), patient’s global assessment, 28 joint count, cutaneous lupus 
erythematosus disease area and severity index (CLASI), incidence of flare rate and potential 
for steroid reduction. Health-related quality of life (SF-36) will be used as supportive 
evidence of efficacy. In addition, endpoints, including BICLA responses, SRI responses and 
SLEDAI-2K, and BILAG-2004, will be documented over time, including earlier time points 
allowing assessment of time of onset of the effect.  
 
Safety and tolerability assessments will include evaluation of (serious) AEs (including 
injection site and hypersensitivity reactions), laboratory assessment (including but not 
limited to acute phase proteins, neutrophils, platelets, liver enzymes and lipids), urinalysis, 
vital signs, electrocardiogram (ECG), and physical examination. 
 
Additional planned assessments include the determination of ALX-0061 levels in serum and 
PD biomarkers (including sIL-6R) in blood. To assess immunogenicity, the presence of ADA 
will be measured in serum using a conventional ADA assay, with potentially further 
characterization by modified ADA (mADA) and neutralizing antibody (nAb) assay. 
 
Study Treatment Allocation and Eligibility Process 
At the Screening Visit, informed consent will be obtained from all subjects who are deemed 
potentially eligible for the study, according to the protocol-specified inclusion and exclusion 
criteria, for enrollment in the study. All data obtained at screening will also be centrally 
assessed in an eligibility evaluation, the sites will be informed whether a subject can be 
randomized.  
  
At randomization, subjects will be randomized to receive either ALX-0061 or placebo, as 
described below (also see section 3.4.1.2 for additional information on randomization). 
 
Eligible subjects will be randomized to 1 of 5 treatment groups in a 1:1:1:1:1 ratio. 
Subjects and investigational staff will be blinded for treatment and dose. Subjects will be 
followed for efficacy through Week 48, and for safety through Week 58. 
 
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Treatment Arms 
Subjects assigned to one of the 4 ALX-0061 treatment groups will receive blinded treatment 
with ALX-0061 at a dose of 75 mg q4w, 150 mg q4w, 150 mg q2w, or 225 mg q2w. As the 
highest dose of ALX-0061 will be administered via 2 injections q2w, subjects in Groups 1-4 
will also be administered 2 injections q2w with 1 or both syringes containing placebo, 
depending on the assigned treatment group, to maintain the blind. Blinding will be 
maintained until the last subject enrolled completes the final evaluations and the database 
is locked. 
 
Group 1 (N=60) 
Placebo 
Placebo s.c. injections at Week 0 (Day 1) and q2w thereafter, up to 
and including Week 46.  
 
 
Group 2 (N=60) 
75 mg q4w 
ALX-0061 75 mg s.c. injections at Week 0 and q4w thereafter, up to 
and including Week 44. To maintain the blind, subjects in this group 
will also receive placebo s.c. q2w up to and including Week 46.   
 
Group 3 (N=60) 
150 mg q4w 
ALX-0061 150 mg s.c. injections at Week 0 and q4w thereafter, up to 
and including Week 44. To maintain the blind, subjects in this group 
will also receive placebo s.c. q2w, up to and including Week 46.   
 
Group 4 (N=60) 
150 mg q2w 
ALX-0061 150 mg s.c. injections at Week 0 and q2w thereafter, up to 
and including Week 46. To maintain the blind, subjects in this group 
will also receive placebo s.c. q2w, up to and including Week 46.  
 
Group 5 (N=60) 
225 mg q2w 
ALX-0061 225 mg s.c. injections at Week 0 and q2w thereafter, up to 
and including Week 46. These subjects will not receive placebo 
injections.   
 
Subjects will come to the site every 2 weeks for study drug administration, up to and 
including Week 46. 
 
ALX-0061 will be supplied as a sterile liquid for s.c. injection at a volume of 1.0 mL or 
0.5 mL in prefilled single-use syringes. More details (including information on drug 
accountability) are provided in section 3.3. 
 
Each subject will stay in the study for approximately 62 weeks (up to 4 weeks of screening 
and 58 ± 2 weeks after randomization). The end of the study is defined as the last visit of 
the last subject participating in the study. 
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3.1.2. 
BLINDING 
 
Since the 225 mg dose of ALX-0061 exceeds the volume that can be administered in a 
single injection, the placebo and ALX-0061 groups will have 2 different combinations of 
dosing to ensure the double-blinded design. All subjects are to receive 2 injections in 
succession (syringe A containing 1 mL and syringe B containing 0.5 mL) at each dosing day, 
every two weeks. Syringes containing ALX-0061 or placebo are a visual match. 
 
Therefore, there will be a total of 5 dosing combinations in the study, with 4 possible active 
dose regimens. These dosing combinations are shown below: 
 
When containing the active product, syringes A and B contain 150 mg and 75 mg of 
ALX-0061, respectively. 
 
Placebo (Group 1) 
 
Syringe A with placebo (1 mL) q2w starting at Week 0 (Day 1), up to and including 
Week 46. 
Syringe B with placebo (0.5 mL) q2w starting at Week 0, up to and including Week 46. 
 
Table 1: 
Dosing schedule for Group 1 
 
Visit (Weeks) 
 
0 
2 
4 
6 
8 
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 
Placebo
1 mL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Placebo 
0.5 mL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALX 
1 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALX 
0.5 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
75 mg q4w (Group 2) 
 
Syringe A with placebo (1 mL) q2w starting at Week 0, up to and including Week 46. 
Syringe B with ALX-0061 (0.5 mL) q4w at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40 and 
44, and syringe B with placebo (0.5 mL) q4w at Weeks 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 
42 and 46. 
 
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Table 2: 
Dosing schedule for Group 2 
 
Visit (Weeks) 
 
0 
2 
4 
6 
8 
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 
Placebo
1 mL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Placebo 
0.5 mL 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
ALX 
1 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALX 
0.5 mL 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
150 mg q4w (Group 3) 
 
Syringe A with ALX-0061 (1 mL) q4w at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40 and 
44, and syringe A with placebo (1 mL) q4w at Weeks 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 
42 and 46. 
Syringe B with placebo (0.5 mL) q2w starting at Week 0, up to and including Week 46. 
 
Table 3: 
Dosing schedule for Group 3 
 
Visit (Weeks) 
 
0 
2 
4 
6 
8 
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 
Placebo
1 mL 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Placebo 
0.5 mL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALX 
1 mL 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ALX 
0.5 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
150 mg q2w (Group 4) 
 
Syringe A with ALX-0061 (1 mL) q2w starting at Week 0, up to and including Week 46. 
Syringe B with placebo (0.5 mL) q2w starting at Week 0, up to and including Week 46. 
 
Table 4: 
Dosing schedule for Group 4 
 
Visit (Weeks) 
 
0 
2 
4 
6 
8 
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 
Placebo
1 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
0.5 mL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALX 
1 mL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALX 
0.5 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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225 mg q2w (Group 5) 
 
Syringe A with ALX-0061 (1 mL) q2w starting, at Week 0, up to and including Week 46. 
Syringe B with ALX-0061 (0.5 mL) q2w starting at Week 0, up to and including Week 46. 
 
Table 5: 
Dosing schedule for Group 5 
 
Visit (Weeks) 
 
0 
2 
4 
6 
8 
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 
Placebo
1 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo 
0.5 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALX 
1 mL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALX 
0.5 mL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
In order to protect the integrity of the data, ALX-0061 treatment assignment will be kept 
blinded for investigative sites, site monitors, subjects, vendors and Sponsor until the final 
database lock (including the Follow-up Visit 12 weeks after the last dosing). 
 
Identification of Sponsor and vendor personnel who will have access to the unblinded data 
before final database lock, will be documented prior to their unblinding. The number of 
Sponsor personnel having access to the unblinded data will be limited. 
 
Given the pronounced effect of an anti-IL-6 compound on the acute phase reactants, the 
results of CRP and fibrinogen tests performed by the central laboratory will not be 
communicated 
to 
the 
investigational 
sites 
and 
Contract 
research 
organization 
(CRO)/Sponsor (unless in case of an alert). If an investigational site requests these data, it 
will be provided after the end of the study. 
 
Except for CRP and fibrinogen, laboratory values outside the normal range will be flagged 
and clinical relevance will be assessed by the Investigator.  
If the clinical condition of the subject warrants knowledge of the values of CRP or fibrinogen 
in order to provide appropriate medical care, the Investigator can request these 
assessments to be performed locally. 
 
Emergency unblinding procedure 
Code-breaking and unblinding in the event of medical emergencies can be done by the 
Investigator via the Interactive web response system (IWRS), which will be accessible 
24 hours per day/7 days per week. 
 
Unblinding by the Investigator should occur only in the event of AE for which it is necessary 
to know the study treatment to determine an appropriate course of therapy for the subject. 
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If the Investigator must identify the treatment assignment of an individual subject, the 
Investigator or qualified designee is to call the IWRS. Unblinding performed by the IWRS at 
the request of the Investigator is to be reported to the Sponsor. When possible the 
Investigator must first discuss options with the Medical Monitor. 
 
Subjects for whom the code has been broken by the Investigator will have to discontinue 
treatment and all efforts must be made to conduct the Early Termination Visit and Follow-up 
Visit. 
 
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3.2. SELECTION OF STUDY POPULATION 
 
It is estimated that 300 subjects will be enrolled in the study at approximately 100 sites 
globally. 
 
3.2.1. 
INCLUSION CRITERIA 
 
Each subject must satisfy the following criteria at screening and baseline to be enrolled in 
the study:   
 
1. 
Male or female adults ≥ 18 years and < 65 years of age at the time of signing the 
informed consent form (ICF). The minimum age for adults will depend on local 
regulations. 
2. 
Have a diagnosis of SLE for at least 6 months prior to screening and fulfill the 1997 ACR 
(see Appendix 9.1) or 2012 Systemic Lupus International Collaborating Clinics (SLICC) 
classification criteria (see Appendix 9.2). 
3. 
Have moderate to severe active SLE, for the purpose of this study defined by a 
SLEDAI-2K score ≥ 6 at screening. 
4. 
Have at least one A or one B score on the revised BILAG-2004 criteria for the 
mucocutaneous and/or musculoskeletal system. 
5. 
Have seropositive disease at screening for ANA (≥ 1:80) and/or anti-dsDNA (value 
above upper limit of laboratory normal range as measured by Farr assay) measured at 
the central laboratory. 
6. 
Subject at least must be on one or more of the following treatments for SLE: 
a. If subject is on oral corticosteroids, the dose should be equivalent to a maximum 
dose of 25 mg of prednisone/day and stable for at least 4 weeks prior to baseline.  
b. If subject is on antimalarials, he or she must have received antimalarials for at least 
12 weeks with a stable dose of max. 400 mg/day for at least 4 weeks prior to 
baseline.  
c. If 
subject 
is 
on 
immunosuppressants: 
azathioprine 
(max. 
150 
mg/day), 
mycophenolate mofetil (max. 2.0 g/day), methotrexate (max. 25 mg/week), 
cyclosporine (max. 200 mg/day), leflunomide (max. 20 mg/day), treatment duration 
must be at least 12 weeks with a stable dose for at least 4 weeks prior to baseline; 
either alone or in combination with corticosteroids and/or hydroxychloroquine. 
7. 
If immunosuppressants were previously given but have been stopped, the last dose 
should have been received more than 4 weeks prior to baseline; for leflunomide and 
hydroxychloroquine, a leflunomide or hydroxychloroquine treatment-free period of at 
least 12 weeks should be respected (unless an adequate cholestyramine wash-out was 
done for leflunomide). 
8. 
If subject is on angiotensin-converting-enzyme (ACE) inhibitor or angiotensin receptor 
blocker, the dose should have been stable for 4 weeks prior to baseline. 
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9. 
Chest radiograph performed within 12 weeks prior to the screening visit (or performed 
during the screening period) documenting no evidence of malignancy, infection, or 
abnormalities suggestive of tuberculosis (TB; report must be obtained and available in 
the subject’s study file prior to baseline). 
10. Are considered eligible according to the following TB screening criteria: 
a. Have no history of latent or active TB prior to screening. An exception is made for 
subjects with a history of latent TB and documentation of having completed 
appropriate treatment for latent TB prior to screening. It is the responsibility of the 
Investigator to verify the adequacy of previous anti-TB treatment and provide 
appropriate documentation. 
b. Have no signs or symptoms suggestive of active TB upon medical history and/or 
physical examination during screening. 
c. Have had no recent close contact with a person with active TB or, if there has been 
such contact, will be referred to a physician specialized in TB to undergo additional 
evaluation and, if warranted, receive appropriate treatment. 
d. Have a negative interferon gamma release assay (IGRA) screening test result. A 
subject whose initial IGRA test result is indeterminate should have the test repeated 
while still fulfilling the other TB criteria for inclusion. The test should not be repeated 
in case other risk factors for TB are present. In case the test is again indeterminate, 
the subject will be excluded. In case of a positive IGRA test result due to previous 
latent TB, the subject is eligible if adequate documentation of completed anti-TB 
treatment prior to screening is available. 
e. Have a chest radiograph, read by a qualified radiologist, whose diagnostic 
assessment is consistent with no evidence of current active TB or old inactive TB, 
and taken within 12 weeks prior to screening as part of standard of care or during 
the screening period. In case local regulations do not allow radiographs during the 
study, a radiograph as part of standard of care should be available prior to screening. 
11. Female subjects of childbearing potential (excluding postmenopausal women, sterilized, 
ovariectomized and hysterectomized women) must have a negative pregnancy test and 
must agree to use two generally accepted adequate contraceptive methods (1 highly 
effective and 1 barrier method e.g., hormonal contraception in combination with 
condom by partner) from screening until at least 3 months after last dosing.  
Male subjects must use condoms for the duration of the study and for at least 3 months 
after last dosing. 
12. Capability to comprehend and willingness to sign an ICF, which must be obtained prior 
to any study-related procedures (vulnerable subjects will be excluded, except subjects 
from ethnic minority groups who may participate). 
13. An understanding, ability and willingness to adhere to the study visit schedule and other 
protocol requirements. 
 
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3.2.2. 
EXCLUSION CRITERIA 
 
Subject meeting the following criteria at screening and baseline will not be enrolled in the 
study:   
 
1. Have an A score on the revised BILAG-2004 other than in the mucocutaneous and/or 
musculoskeletal system at screening and at baseline for the organ systems that can be 
clinically assessed.   
2. Have a systemic inflammatory disease other than SLE, including but not limited to 
psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis or Lyme disease. 
3. Clinically significant infection treated or needing treatment with i.v. antibiotics, i.v. 
antivirals, or i.v. antifungals within 4 weeks prior to baseline or oral antibiotics, oral 
antivirals, or oral antifungals within 2 weeks prior to baseline. Patients with clinically 
non-significant infections, e.g., mild cases of localized herpes simplex infections or tinea 
pedis can be enrolled. 
4. Any active or recurrent viral infection that based on the Investigator´s clinical 
assessment 
makes 
the 
subject 
unsuitable 
for 
the 
study, 
such 
as 
current 
Cytomegalovirus (CMV) or Epstein-Barr Virus (EBV) infection or recurrent / disseminated 
herpes zoster.  
5. Have a history of, or current, class III or IV congestive heart failure (CHF), as defined by 
the New-York Heart Association (Appendix 9.3); history of unstable angina pectoris, 
myocardial infarction, cerebrovascular accident, thromboembolic event within 12 months 
before screening. 
6. Have active lupus nephritis requiring cyclophosphamide or mycophenolate mofetil more 
than 2.0 g/day or other therapy not permitted by the protocol.  
7. Have active or recent (within 6 months) lupus-related central neurological problems 
(including lupus headache) or severe central nervous system (CNS) disease.  
8. Have drug-induced lupus. 
9. Have a history of demyelinating diseases such as multiple sclerosis. 
10. History of diverticulitis or symptoms of acute diverticulitis with confirmatory imaging 
(i.e., CT scan). 
11. Any history of malignancy or lymphoproliferative disease, except for successfully-treated 
non-melanoma skin cancer or resected cervical carcinoma in situ.  
12. Have a transplanted organ or received stem cell transplantation. 
13. Major surgery (including joint surgery) within 8 weeks prior to screening or 
hospitalization for a clinically relevant event within the 4 weeks prior to screening or 
planned major surgery during study or within 3 months after study end. 
14. Have been treated with i.v. immunoglobulins, cyclophosphamide or tacrolimus within 
12 months prior to baseline.  
15. Have received i.v., intra-articular (i.a.), intramuscular (i.m.) or high dose (> 25 mg/day) 
oral corticosteroids during the 4 weeks prior to baseline. 
16. Have a known hypersensitivity to the active product or any excipient of the study drug. 
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17. Have received approved or investigational biological therapies within 6 months or 5 half-
lives of the concerned therapy (whichever is longer) prior to baseline. 
18. Have received non-biological investigational therapies within 4 weeks or 5 half-lives of 
the concerned therapy (whichever is longer) prior to baseline. 
19. Have received prior therapy blocking the IL-6 pathway, such as but not limited to 
ALX-0061, sirukumab, tocilizumab, sarilumab, clazakizumab, olokizumab, or JAK 
inhibitors at any time. 
20. Abnormality in screening laboratory test results:  
a. ALT and/or AST ≥ 1.5 times the upper limit of normal (ULN). 
b. Hemoglobin ≤ 85 g/L (8.5 g/dL). 
c. Platelet count ≤ 75 x 109/L (75,000 cells/mm³).  
d. White blood cell count ≤ 2.2 x 109/L (2,200 cells/mm³).  
e. Neutrophils: ≤ 1.5 X 109/L. 
f. 
Estimated proteinuria > 1 g/day measured by spot urine protein to creatinine ratio of 
1.  
g. Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m² (based on the 
‘modification of diet in renal disease’ [MDRD] formula [Appendix 9.4]). 
h. Any other clinically significant abnormal screening laboratory results as evaluated by 
the Investigator.  
21. Positive screening for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).  
22. Known history or presence of alcohol or drug abuse. 
23. Blood donation (> 500 mL) or a comparable blood loss within 3 months prior to 
baseline.  
24. Planned donation of germ cells, blood, organs, bone marrow during the course of the 
study or within 6 months thereafter. 
25. Female subjects who are planning to become pregnant during the study or within 
3 months after last dosing or male subjects who are considering fathering a child during 
the study and within 3 months after last dosing. 
26. Pregnant woman or female subjects who are breastfeeding. 
27. History of anaphylactic reactions. 
28. Administration of a live, attenuated vaccine within 3 months before dosing with 
ALX-0061, or anticipation that such a live attenuated vaccine will be required during the 
study or within 6 months after last dosing. 
29. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate 
for the study. 
 
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3.2.3. 
REMOVAL OF SUBJECTS FROM THERAPY 
OR ASSESSMENT 
 
3.2.3.1. 
CRITERIA FOR WITHDRAWAL OF 
SUBJECTS FROM STUDY 
 
Participation in the study is strictly voluntary. A subject has the right to withdraw from the 
study at any time, for any reason. 
 
Subjects who terminate study participation for reasons of lost to follow-up, informed 
consent withdrawal, or death will not have any follow-up assessments. 
 
In the event a subject is discontinued from the study, the study monitor and the Sponsor 
will be informed immediately. 
 
3.2.3.2. 
DISCONTINUATION OF STUDY DRUG 
 
Subjects who have to discontinue study drug but are not withdrawing consent for post-
treatment follow-up should return for the Early Termination Visit, planned within 3 weeks 
after the last study drug administration, as well as for the Follow-up Visit planned 12 weeks 
after the last study drug administration, according to section 3.4.1.3. 
 
Study drug administration must be discontinued in case of:  
 
• Withdrawal of consent. 
• Serious hypersensitivity reaction. 
• Abnormalities in laboratory test results:  
- ALT and/or AST elevations: 
o 
> 3 - ≤5 x ULN, confirmed by repeat testing on 2 consecutive visits  
o 
> 5 x ULN (CTCAE ≥ grade 3)  
- absolute neutrophil count < 1 x 109/L (CTCAE ≥ grade 3) 
- platelet count < 50 x 103/μL (CTCAE ≥ grade 3)  
• Diagnosis or suspicion of a serious infection (requiring parenteral antibiotics and/or 
hospitalization) if interruption of study drug is needed for more than one dose or if 
deemed necessary by the Investigator. 
• Diagnosis of TB. 
• Malignancy. 
• Pregnancy or pregnancy planned within study period. 
• Initiation of prohibited medication, as discussed with Sponsor/Medical Monitor. 
• In case of interruption of study drug administration for 2 consecutive doses. 
• The randomization code is broken prematurely by the Investigator or his/her staff. 
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• Demyelinating disease. 
• CHF class III or IV as defined by the New York Heart Association, unstable angina 
pectoris, myocardial infarction, cerebrovascular accident, thromboembolic event. 
• If the Investigator or the Sponsor’s Medical Monitor deems it is in the subject’s best 
interest, e.g., in case of renal or CNS flare. 
 
Discontinuation of study drug must be considered for subjects who develop a severe study 
drug injection-site reaction or a severe hypersensitivity reaction. 
 
In case of worsening of disease or a flare, the Investigator will decide on the need for 
increase of dose of oral corticosteroids, use of i.v. or i.m. corticosteroids, start or increase of 
the dose of anti-malarial or immunosuppressant, according to his/her local clinical practice. 
The Investigator will also assess if study drug administration can be continued or not, 
except in case of initiation of forbidden treatment e.g., cyclophosphamide or another 
biologic, when study drug administration will be discontinued. Subjects needing such change 
to standard of care therapy for SLE will be considered as treatment failures and imputed as 
non-responders in the analysis of the primary endpoint. This does not apply to the transient 
increase in oral corticosteroid dose that is allowed within the protocol until the Week 4 visit 
(i.e., Week 4 ± 5 days). 
 
A description of assessments to be performed for subjects who discontinue from the study 
or study drug is provided in section 3.4.1.3 (also see Early Termination Visit in the Schedule 
of Assessments).  
 
For all subjects, every effort should be made to contact the Medical Monitor prior to 
discontinuing study drug administration, where medically feasible. If there is a medical 
reason for discontinuation, the subject will remain under the supervision of the Investigator 
until satisfactory health has returned unless the subject withdraws his/her consent and is no 
longer willing to come to the visits. Subjects who discontinue will not be replaced.  
 
3.2.3.3. 
STUDY TERMINATION  
 
If the Sponsor abandons the study prior to commencement of any protocol activities, and/or 
after IEC/IRB and Competent Authority (CA) approvals have been received, the Investigator 
or Sponsor must notify the IEC/IRB and CA by letter outlining the reasons for abandonment 
of the study, as required per national regulations. 
 
At any time during the study, the Sponsor may suspend or terminate the study or part of 
the study for any reason. If the Investigator plans to suspend or terminate participation in 
the study, the Investigator will promptly inform the Sponsor and the IEC/IRB and provide 
them with a detailed written explanation.  
 
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Upon study completion, the Sponsor will provide the Investigator, IEC/IRB, and CA with 
final reports and summaries as required by regulations.  
 
In case of suspension or halt due to safety reasons, the CA and IEC/IRB will be notified 
immediately and at the latest within the number of days as specified by local regulations 
after the study is halted, clearly explaining the reasons, and describe follow-up measures, if 
any, taken for safety reasons. 
 
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3.3. TREATMENT OF SUBJECTS 
 
For an overview of the treatments to be administered, please refer to section 3.1. 
 
3.3.1. 
RANDOMIZATION 
 
After obtaining oral and written informed consent, subjects will be screened according to the 
inclusion and exclusion criteria and will receive a unique subject identification (ID) number, 
assigned by IWRS.  
 
After approval by the eligibility review committee (also see section 3.4.1.1), subjects can be 
randomized.  
 
At randomization, subjects will be reassessed and, if they meet the specified entry criteria, 
subjects will be allocated in a randomization to 1 of 5 treatment groups in a 1:1:1:1:1 ratio, 
and will receive a randomization number just prior to dosing according to the randomization 
scheme. Randomization will be stratified by geographic region. 
 
3.3.2. 
IDENTITY OF STUDY DRUG 
 
• ALX-0061 Drug Product:  
- Active substance: ALX-0061 Nanobody. 
- Activity: ALX-0061 Nanobody binds to the IL-6R and inhibits the interaction between 
the IL-6 ligand and the receptor subunit, thereby preventing receptor signaling. 
- Pharmaceutical formulation: ALX-0061 Drug Product is a clear, yellow to brown-yellow 
solution in an aqueous medium with a nominal concentration of 150 mg/mL of 
ALX-0061 
and 
containing 
the 
following 
excipients: 
L-histidine, 
L-histidine 
hydrochloride monohydrate, polysorbate 80 (Tween 80), sucrose, and water for 
injection. ALX-0061 will be supplied as a sterile liquid for s.c. injection at a volume of 
0.5 mL or 1.0 mL in pre-filled single-use syringes. No preservatives are present. 
- Route and volume of administration: s.c. injections at a volume of 0.5 mL and/or 
1.0 mL. 
 
• Placebo:  
- Substance: placebo. 
- Activity: none. 
- Pharmaceutical formulation: the composition of placebo is identical to that of 
ALX-0061 Drug Product, except for the active substance, and consists of excipients: 
L-histidine, L-histidine hydrochloride monohydrate, polysorbate 80 (Tween 80), 
sucrose, and water for injection. Placebo will be supplied as a sterile liquid for s.c. 
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injection at a volume of 0.5 mL or 1.0 mL in pre-filled single-use syringes. No 
preservatives are present. 
- Route and volume of administration: s.c. injections at a volume of 0.5 mL and/or 
1.0 mL. 
 
The Sponsor will be providing adequate supplies of ALX-0061 and placebo for this study. 
 
Details on study drug allocation and dosing are provided in section 3.1.1.   
 
3.3.3. 
DRUG ACCOUNTABILITY 
 
The Pharmacist or his/her designee is responsible for acknowledge receipt of each shipment 
of study drug and will verify the condition and quantity of the study drug. 
 
The study drug will be kept in a locked and secured storage facility accessible only to those 
authorized by the Investigator to dispense the study drug. 
 
The responsible person will keep an inventory. This will include the quantity of study drug 
received for the study and a record of the materials that are dispensed, to whom (subject 
number) and when. 
 
The pharmacist, the Investigator and/or designated personnel will conduct a final inventory 
of the study drug supply and will record the results of this inventory in the Drug 
Accountability Form. Upon Sponsor approval, all study drug supplies will be returned to the 
depot, and/or will be locally destroyed according to local regulations and site procedures. 
 
Instructions for drug accountability are available in the manuals concerning study drug and 
IWRS. 
 
3.3.4. 
STUDY DRUG HANDLING 
 
Instructions for study drug receipt, handling, storage and administration are available in the 
manuals concerning study drug and IWRS.  
 
Packaging and Labeling 
The study drug will be labeled in accordance with Annex 13 of EudraLex Volume 4 
requirements and local regulations. Each label will contain but will not be limited to, study 
number, storage conditions, dosing instructions, Sponsor’s name, address and telephone 
number. 
 
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One kit consists of a box containing 2 syringes. A randomization system will assign each of 
the treatment kits to a subject. The content of each treatment kit will be determined 
according to the randomization schedule. 
 
Storage  
Study drug will be provided under refrigerated conditions and must be stored in a secure, 
limited-access location under the storage conditions specified by the Sponsor.  
 
ALX-0061 and placebo must be refrigerated at 2°C to 8°C (35.6 °F to 46.4 °F) and should 
be stored in the secondary packaging (sealed box) until administration. It should not be 
frozen or shaken.  
 
Site storage conditions should be monitored by the site personnel and reviewed by the 
monitor during site visits. Deviations from the storage requirements must be documented 
and reported to the Sponsor, according to the instructions provided in the manual 
concerning study drug.  
 
Dispensing 
The Investigator or qualified designee(s) will dispense study drug to subjects who have met 
the entry criteria. Clinical supplies may not be used for any purpose other than that which is 
stated in this protocol. 
 
Product Quality Complaint 
Any malfunctioning pre-filled syringe has to be communicated (written or electronically) and 
returned to the Sponsor or its designee upon Sponsor’s request.  
 
3.3.5. 
STUDY DRUG INJECTIONS 
 
ALX-0061 s.c. or placebo s.c. injections, as applicable, will be administered using the single-
use pre-filled syringe by an appropriate licensed and authorized health professional. 
 
At each administration, the subject will receive two s.c. injections in succession at a 
different quadrant in the abdominal region. As injections are to be performed q2w, the 
injections can be performed in an abdominal quadrant of choice. However, note that the 
area of administration needs to be evaluable for local skin reaction (normal skin without 
skin burns, scars or large tattoos in the area of administration). The abdominal quadrants 
used for the administrations will be recorded in the (electronic) Case Report Forms 
([e]CRFs). At least until Week 12, subjects will remain at the site for 60 minutes after the 
injection in order to assess adverse reactions.  
In case of an injection site reaction, it has to be followed-up and documented in which exact 
quadrant the skin reaction appears.  
 
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Detailed instructions for study drug administration are available in the manual concerning 
study drug. 
 
3.3.6. 
MEDICATIONS OTHER THAN STUDY DRUG 
 
Previous and concomitant medication will be recorded in the Patient’s Medical File and in the 
(e)CRF up to the Follow-up Visit. 
 
An overview of corticosteroid handling throughout the study can be found in Appendix 9.5. 
 
3.3.6.1. 
MEDICATIONS STARTED PRIOR TO 
FIRST DOSING 
 
Standard of care therapy for SLE: 
 
The dose of oral corticosteroids (equivalent to ≤ 25 mg of prednisone/day) should have 
been stable for at least 4 weeks prior to baseline.  
 
If subject is on antimalarials, he or she must have received antimalarials for at least 
12 weeks with a stable dose of max. 400 mg/day for at least 4 weeks prior to baseline. 
 
If subject started immunosuppressants prior to first dosing and is still taking this medication 
at baseline: azathioprine (max. 150 mg/day), mycophenolate mofetil (max. 2.0 g/day), 
methotrexate (max. 25 mg/week), cyclosporine (max. 200 mg/day), leflunomide (max. 
20 mg/day), treatment duration must be at least 12 weeks with a stable dose for at least 
4 weeks prior to baseline; either alone or in combination with corticosteroids and/or 
hydroxychloroquine. 
 
If subject is on ACE inhibitor or angiotensin receptor blocker, the dose should have been 
stable for 4 weeks prior to baseline. 
 
If subject is on NSAIDs, including aspirin and selective cyclooxygenase 2 inhibitors and 
other analgesics for SLE-related symptoms, the subject should receive stable doses of the 
usual marketed doses approved in the country in which the study is being conducted. After 
Week 24, the dose may be adjusted based on Investigator’s discretion. 
 
Prior use of any of the following medications is prohibited: 
 
• If prior medications include immunosuppressants (i.e., if immunosuppressants were 
taken prior to first dosing but were stopped prior to the baseline visit), the last dose 
should have been received more than 4 weeks prior to baseline; for leflunomide and 
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hydroxychloroquine, a leflunomide or hydroxychloroquine treatment-free period of at 
least 12 weeks should be respected (unless an adequate cholestyramine wash-out was 
done for leflunomide). 
• Use of any investigational or biological drug starting 6 months or 5 half-lives (whichever 
is longer) prior to baseline.  
• Use of non-biological investigational therapies starting 4 weeks or 5 half-lives of the 
concerned therapy (whichever is longer) prior to baseline. 
• Use of i.v. immunoglobulins, cyclophosphamide or tacrolimus within 12 months prior to 
baseline.  
• Use of i.v., i.a., i.m. or high dose (> 25 mg/day) oral corticosteroids during the 4 weeks 
prior to baseline.  
• Use of prior therapy blocking the IL-6 pathway, such as but not limited to ALX-0061, 
sirukumab, tocilizumab, sarilumab, clazakizumab, olokizumab, or JAK inhibitors at any 
time.  
• Any live, attenuated vaccine within 3 months before dosing with ALX-0061, during the 
study or within 6 months after dosing. 
 
3.3.6.2. 
THERAPY STARTED AFTER FIRST 
DOSING 
 
Standard of care therapy for SLE: 
 
• The dose of oral corticosteroids (equivalent to ≤ 25 mg of prednisone/day) should be 
kept stable as much as possible through Week 24.  
• As an exception, the protocol allows for both dose decrease (tapering) and dose increase 
with the following limits: 
- If necessary based on the Investigator’s clinical judgment, initiation of a short period 
(maximum 
1 week) 
increase 
of 
prednisone 
(up 
to 
a 
maximum 
dose 
of 
15/20/25/30 mg/day depending on the baseline dose; see table below) is allowed until 
the Week 4 visit (i.e., Week 4 ± 5 days) with a return to the baseline value by 
Week 12. This increase is not allowed if the disease activity improves. 
- In case lowering of the dose of prednisone is desired before the primary endpoint, 
tapering can be allowed up to Week 12 according to the specifications below: 
 
Baseline dose 
Increase for max. 1 week  
during first 4 weeks 
Tapering allowed between  
Baseline and Week 12 
1 
16 to 25 mg/day 
Increase to a maximum of 30 mg/day 
No dose decrease below 50% of 
baseline dose 
2 
11 to <16 mg/day 
Increase to a maximum of 25 mg/day 
No dose decrease below 75% of 
baseline dose 
3 
7.5 to <11 mg/day 
Increase to a maximum of 20 mg/day 
No dose decrease < 7.5 mg/day 
4 
<7.5 mg/day 
Increase to a maximum of 15 mg/day 
No tapering will be allowed 
- Between Week 12 and Week 24, no increase nor decrease of the dose in prednisone is 
allowed. 
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- After Week 24, tapering of the dose of oral corticosteroids to a target of ≤ 7.5 mg/day 
by Week 40 is recommended, at a rate that can be decided by the Investigator as 
clinically indicated. While tapering the dose between Weeks 24 and 40, an increase to 
the dose preceding the last taper step will be allowed. 
 
• Doses for concomitant antimalarials and/or immunosuppressants must be stable for the 
duration of the entire study. The dose may be reduced or the medication temporarily 
discontinued for abnormal laboratory values, side effects, concurrent illness, or the 
performance of a surgical procedure, but the dose change and reason should be clearly 
documented. 
 
• NSAIDs, including aspirin and selective cyclooxygenase 2 inhibitors and other analgesics 
for SLE-related symptoms during the study should receive the usual marketed doses 
approved in the country in which the study is being conducted. Doses must remain stable 
but may be changed at the discretion of the Investigator after Week 24 or if the subject 
develops unacceptable side effects.   
 
Change to Standard of care therapy for SLE 
 
In case of worsening of disease or a flare, the Investigator will decide on the need for 
increase of dose of oral corticosteroids, use of i.v. or i.m. corticosteroids, start or increase of 
the dose of anti-malarial or immunosuppressant. Subjects needing such change to standard 
of care therapy for SLE will be considered as treatment failures and imputed as non-
responders in the analysis of the primary endpoint. This does not apply to the transient 
increase in oral corticosteroid (prednisone) dose that is allowed within the protocol until the 
Week 4 visit (i.e., Week 4 ± 5 days) of the study (see above).  
 
Prohibited Medication 
 
Concomitant use of any of the following medications is prohibited while the subject is 
receiving the study drug and will prompt discontinuation of study drug: 
 
• any investigational or biological drug.  
• any live, attenuated vaccine within 3 months before dosing with ALX-0061, during the 
study or within 6 months after dosing. 
• i.v. immunoglobulins, cyclophosphamide or tacrolimus.  
• therapy blocking the IL-6 pathway, such as but not limited to ALX-0061, sirukumab, 
tocilizumab, sarilumab, clazakizumab, olokizumab, or JAK inhibitors.  
 
Medicinal products which are metabolized via CYP450 3A4  
 
Since IL-6 blocking might influence cytochrome P450 (CYP450) expression, subjects taking 
medicinal products which are metabolized via CYP450 3A4 (please refer to Flockhart, 2007 
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and Endres et al., 2006) will be closely monitored and their treatment will be adapted if 
necessary. For example, subjects on vitamin K antagonists will be monitored by assessment 
of international normalized ratio (INR) (see Schedule of Assessments), for subjects on 
statins, the lipid levels will be evaluated (see Schedule of Assessments), for subjects on 
cyclosporine, drug monitoring according to site routine practice should be performed. 
 
3.3.6.3. 
CONTRACEPTIVES 
 
Female subjects of childbearing potential (excluding postmenopausal women, sterilized, 
ovariectomized, and hysterectomized women) must agree to use 2 generally accepted 
adequate contraceptive methods of which 1 is a barrier method and 1 is a highly effective 
method (e.g., hormonal contraception stabilized for at least 1 month [oral, patch, depot, 
injectable, vaginal ring] in combination with condom by partner or should agree upon 
continuous abstinence from heterosexual contact from screening until at least 3 months 
after last dosing. If hormonal contraception is not appropriate according to the 
Investigator’s judgment, an intrauterine device or diaphragm with condom by partner may 
also be acceptable.  
 
No additional contraceptive method is needed in case of surgical sterilization (at least 
3 months prior to screening), hysterectomy, or a partner who has been vasectomized (at 
least 3 months prior to screening).  
 
Male subjects should use condoms for the duration of the study and for at least 3 months 
after last administration of study drug. 
 
If additional local regulations apply, contraceptives should be used consistent with these. 
 
3.3.7. 
TREATMENT COMPLIANCE 
 
To ensure treatment compliance, study drug dosing will be administered by the Investigator 
or his/her designee at all visits. 
 
The exact times of medication dosing at the clinical site will be recorded in the (e)CRF. 
Compliance will be further confirmed by bioanalytical assessment of ALX-0061 in serum 
samples. Treatments that are administered outside of the scheduled windows, as well as 
missed visits, will be recorded on the (e)CRF. 
 
All subject’s (e)CRFs will be monitored by a site monitor (also see section 5.2.4).  
 
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3.4. ASSESSMENTS 
 
3.4.1. 
TIMING OF ASSESSMENTS 
 
Written informed consent will be obtained before the first study-related procedure. 
 
After informed consent has been obtained, each subject will be assigned a unique subject ID 
number. 
 
AEs and prior/concomitant medications will be recorded from the time a signed and dated 
ICF is obtained until completion of the subject’s last visit. 
 
3.4.1.1. 
ELIGIBILITY PROCEDURES 
 
At screening, which will take place within 28 days prior to baseline, subjects will be asked to 
attend the clinical site to be screened according to the inclusion and exclusion criteria 
(section 3.2) and to have other assessments performed as specified in the Schedule of 
Assessments. If the baseline visit cannot be performed within the 28-day screening period 
due to exceptional logistical issues, the Medical Monitor is to be contacted as soon as 
possible for further instructions. 
 
Subjects discontinuing, for any reason, without completing all screening evaluations 
successfully and all subjects completing all screening evaluations successfully but who 
discontinue prior to randomization, will be considered “screen failures”.  
 
The results from the screening procedures needed to evaluate eligibility must be available 
prior to randomization. Assessment of eligibility of subjects will also be performed centrally 
and the sites will be informed if a subject can be randomized. 
 
Week 0/Day 1 (Baseline) 
For details with regard to randomization, please refer to section 3.3.1. 
 
On Week 0/Day 1, assessments and procedures should be performed as outlined in the 
Schedule of Assessments. 
 
3.4.1.2. 
TREATMENT AND ASSESSMENT 
PERIOD 
 
Post-randomization Assessments 
Eligible subjects will receive treatment at Week 0/Day 1 and q2w up to and including 
Week 46. Subjects will return for 24 ambulatory visits planned at Weeks 2, 4, 6, 8, 10, 12, 
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14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, and 48. All visits during 
the treatment and assessment period may occur at the indicated week ± 5 days throughout 
the study versus the date of the Baseline Visit.  
 
Subjects prematurely discontinuing the study will return for an Early Termination Visit within 
3 weeks after the last administration of study drug and a Follow-up Visit 12 weeks after the 
last administration of study drug. Note that for subjects who withdraw for reasons of lost to 
follow-up, informed consent withdrawal, or death, will not have any follow-up assessments. 
 
The End of Treatment Visit will take place at Week 48 and a Follow-up Visit will be 
performed 12 weeks after the last administration of study drug.  
 
All assessments will be performed as specified in the Schedule of Assessments. 
 
Adjudication of BILAG and SLEDAI scores of baseline, Week 24, and Week 48 visits will be 
done centrally upon receipt of results. 
 
Unscheduled visits may be planned to assess, confirm, and follow up on clinically relevant 
AEs or laboratory abnormalities. Findings made during these unscheduled visits should be 
reported in the designated sections of the (e)CRF. 
 
Missed Visits:   
• If a subject misses a visit/dose but a new visit can be performed within 1 week of the 
originally planned missed visit (i.e., within 3 weeks of the previous visit), then all 
assessments per missed visit should be performed at this new visit and the study staff 
should administer the study drug to the subject and maintain the subject’s original 
injection schedule. In case of rescheduling of missed visits, total duration of the 
assessment period should remain 48 weeks. 
- 
For example, if a subject receives the first dose of study drug on January 1st, that is 
considered “Day 1 (Week 0) of the study”; the next target day of administration will 
be January 15th. 
- 
If the subject misses this second visit and comes in on January 19th (i.e., within 
3 weeks of the previous visit), then the study staff should administer the study drug 
on that day. The next visit should be scheduled for January 29th (i.e., 4 weeks after 
January 1st). 
• If a subject misses a visit and the visit cannot be performed within 3 weeks of the 
previous visit, the site should contact the monitor. 
 
For all subjects, injections should not occur less than 1 week apart. The monitor/Sponsor 
should be contacted if this cannot be respected.  
 
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In case of interruption of 2 consecutive drug administrations, the subject should discontinue 
from the study. 
 
3.4.1.3. 
END OF TREATMENT VISIT AND 
FOLLOW-UP 
 
Subjects who have received all study medication through Week 46 should return for the 
assessment visit at Week 48, and for the Follow-Up Visit at Week 58 (12 weeks after the 
last study drug administration at Week 46). 
 
Discontinuation of Study Drug Administration 
Subjects who have to discontinue study drug but are not withdrawing consent for post-
treatment follow-up, should return for an early termination visit within 3 weeks after the 
last study drug administration. Subjects should also return for a Follow-up Visit 12 weeks 
after last study drug administration to undergo the assessments as specified in the Schedule 
of Assessments.  
 
Termination of Study Participation 
Subjects who terminate study participation for reasons of lost to follow-up, informed 
consent withdrawal, or death should not return for the Early Termination Visit or for the 
Follow-up Visit.  
 
3.4.2. 
DEMOGRAPHICS AND MEDICAL HISTORY 
 
Demographic and medical history data will be collected at visits as indicated in the Schedule 
of Assessments. 
 
Demographic data will include (but are not limited to): age, date of ICF signed, gender, race 
(if allowed), ethnicity (if allowed), and smoking history/smoking status. 
 
Both general and SLE-specific medical history will be collected. 
 
3.4.3. 
ASSESSMENTS OF EFFICACY 
 
3.4.3.1. 
BRITISH ISLES LUPUS ASSESSMENT 
GROUP INDEX 
 
The clinical BILAG-2004 assessments will be performed by the Investigator and the 
laboratory assessments will be performed by local and central laboratory at visits as 
indicated in the Schedule of Assessments. 
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The same trained and qualified physician should preferably be performing the assessment at 
each visit for each subject. 
 
A process to check eligibility will also be installed centrally as well as central adjudication of 
BILAG-2004 at baseline, Week 24 and Week 48. 
 
The BILAG-2004 is a comprehensive composite clinical index that has been developed based 
on the principle of a physician's intention to treat using a nominal consensus approach. In 
the index, the nine systems (not organs) considered are: constitutional, mucocutaneous, 
neuropsychiatric, musculoskeletal, cardiorespiratory, gastrointestinal, renal, ophthalmic and 
hematology. Disease activity in each of the nine systems is categorized into five levels 
(Grades A-E) [37-39].  
 
• 
Grade A, is defined as the individual clinical features, or combinations of features, which 
the group believes would lead to the prescriptions of medium/large doses of 
corticosteroids (> 20  mg prednisolone or equivalent) and/or starting or increasing 
immunosuppressive drugs or high-dose anticoagulation (INR > 3).  
• 
Grade B is given to those subjects with known disease activity requiring somewhat 
lower doses of immunosuppressives (e.g., < 20  mg prednisolone) and/or specific drugs, 
such as antimalarial, anti-epileptic, antidepressant and NSAIDs or topical steroids.  
• 
Grade C in each system defines subjects with mild persistent activity only requiring 
symptomatic therapy (e.g., analgesics or NSAIDs).  
• 
Grade D implies the organ or system was once active but is no longer so. 
• 
Grade E indicates that the organ or system has never been active. 
 
The BILAG-2004 score will be evaluated as an individual item (normal and enhanced 
improvement and individual organ system score) as well as a component of the composite 
BICLA and SRI score.  
 
The BILAG-2004 scoring table is provided in Appendix 9.6. 
 
3.4.3.2. 
SYSTEMIC LUPUS ERYTHEMATOSUS 
DISEASE ACTIVITY INDEX 2000 
 
The clinical SLEDAI-2K [40] assessments will be performed by the Investigator and the 
laboratory assessments will be performed by the central laboratory at visits as indicated in 
the Schedule of Assessments.  
 
The same trained and qualified physician should preferably be performing the assessment at 
each visit for each subject. 
 
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A process to check eligibility will also be installed centrally as well as central adjudication of 
SLEDAI-2K at baseline, Week 24 and Week 48. 
 
The SLEDAI-2K is a one-page weighted scale for 24 items (seizure, psychosis, organic brain 
syndrome, visual disturbance, cranial nerve disorder, lupus headache, cerebrovascular 
accident, vasculitis, arthritis, myositis, urinary casts, hematuria, proteinuria, pyuria, rash, 
alopecia, mucosal ulcers, pleurisy, pericarditis, low complement, increased DNA binding, 
fever, thrombocytopenia, leukopenia). The manifestations felt to be most commonly 
contributing to disease activity are included and scored based on the presence or absence 
within 30 days prior to the evaluation. The total score can range from 0-105 and reflects all 
aspects of disease activity.  
 
A modified SLEDAI-2K index (mSLEDAI-2K) will be derived from the standard index by 
omitting 1 of the standard items (low complement). An anti-IL-6R compound strongly 
decreases production of acute phase reactants, including complement [24, 25]. Therefore, 
the complement (C3/C4) values (parameters of the low complement item in the SLEDAI-2K 
index) may be decreased due to decreased production while effect on complement 
consumption (relevant for disease activity evaluation) cannot be assessed. 
 
The SLEDAI-2K (both the standard and modified [excluding the low component item] 
version) score will be evaluated as an individual item as well as a component of the 
composite mBICLA score, composite mSRI index and SLEDAI flare index (SFI) index. Note 
that the mBICLA score and mSRI index uses the mSLEDAI-2K score only.  
 
The SLEDAI-2K scoring table is provided in Appendix 9.7. 
 
3.4.3.3. 
PHYSICIAN’S GLOBAL ASSESSMENT 
OF DISEASE ACTIVITY (VAS) 
 
The PGA of disease activity will be measured at visits as indicated in the Schedule of 
Assessments.  
 
The physician must complete the physician’s global assessment independently of the subject 
when completing the patient’s global assessment (see section 3.4.3.4). 
 
The same physician should preferably be performing the assessment at each visit for each 
subject.  
 
The physician will make a mark between 0 (“very good”) and 100 mm (“very bad”) on the 
visual analogue scale (VAS) scale to indicate disease activity (independent of the subject’s 
self-assessment). 
 
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The PGA will be evaluated as an individual item as well as a component of the composite 
(m)BICLA and SRI score, and SFI index. 
 
3.4.3.4. 
PATIENT’S GLOBAL ASSESSMENT OF 
DISEASE ACTIVITY (VAS) 
 
The patient’s global assessment of disease activity will be measured at visits as indicated in 
the Schedule of Assessments.  
 
The subject must complete the patient’s global assessment independently of the physician 
when completing the physician global assessment (see section 3.4.3.3).  
 
The subject will make a mark between 0 (“very good”) and 100 mm (“very bad”) on the 
visual analogue scale (VAS) scale to indicate disease activity. 
 
3.4.3.5. 
MEDICAL OUTCOME SURVEY SHORT 
FORM 36 (SF-36)  
 
The SF-36 will be completed by the subject at visits as indicated in the Schedule of 
Assessments. 
 
The SF-36 consists of 36 items that can be summarized into 8 domains: physical 
functioning, role limitations due to physical health problems (role-physical), bodily pain, 
general health, vitality, social functioning, role limitations due to emotional problems (role-
emotional), and mental health. Two summary measures, the physical component summary 
and the mental component summary, can be derived based on these domain scores.  
 
The concepts measured by the SF-36 are not specific to any disease, allowing comparison of 
relative burden of different diseases, in addition to the relative benefit of different 
treatments.  
 
3.4.3.6. 
BILAG-BASED COMPOSITE LUPUS 
ASSESSMENT (BICLA) 
 
The composite BICLA response comprises criteria of 3 different validated indices (SLEDAI, 
BILAG, and PGA) and is defined as follows: 
• 
BILAG-2004 improvement: all A scores at baseline improved to B/C/D, and all B scores 
improved to C or D.  
• 
no worsening in disease activity: no new BILAG-2004 A scores and ≤1 new B score.  
• 
no worsening of total (m)SLEDAI-2K score from baseline.  
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• 
no significant deterioration (< 10% worsening) in PGA. 
• 
no treatment failure (i.e., new or increased immunosuppressives or anti-malarials; or 
non-protocol allowed increased oral or parenteral corticosteroids; or premature 
discontinuation from study treatment). 
 
3.4.3.7. 
SYSTEMIC LUPUS ERYTHEMATOSUS 
RESPONDER INDEX (SRI) 
 
The composite index SRI enables quantification of decrease and increase in disease activity 
in a broad spectrum of manifestations thereby offering a comprehensive assessment of SLE 
disease status [41].  
SRI combines advantages from three validated measurement tools: 
• 
SLEDAI covers global disease improvement,  
• 
BILAG covers organ specific disease worsening or improvement and  
• 
PGA is used as a validity and safety net for items that were not addressed by the other 
two indices. 
 
The composite SRI criteria for response are: 
• 
SLEDAI-2K: ≥ 4 point reduction. 
• 
BILAG: no new A domain score and no more than 1 new B domain score. 
• 
PGA: no worsening (<10% increase). 
 
When all three criteria are met, the subject is a responder according to the SRI at that time 
point, i.e., a clinically meaningful improvement of disease is detected. 
 
In addition the modified SRI (mSRI) will be assessed, i.e., using the modified (excluding the 
low component item) version of the SLEDAI-2K as a criterion. 
 
3.4.3.8. 
SLEDAI FLARE INDEX (SFI) 
 
Because of the relapsing remitting pattern of SLE, lupus 'flare' is an important outcome 
variable in clinical studies in subjects with SLE [42]. 
The SFI provides definitions of mild/moderate flare and severe flare that can be used in a 
clinical trial setting and encompasses (1) SLEDAI disease activity index scores, (2) disease 
activity scenarios that might be missed by the indices, (3) treatment changes, and (4) PGA.  
 
In this study, the number of flares will be assessed as determined by the SFI (which will be 
calculated as detailed in the Statistical Analysis Plan [SAP]). 
 
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3.4.3.9. 
CUTANEOUS LUPUS ERYTHEMATOSUS 
DISEASE AREA AND SEVERITY INDEX 
 
The CLASI will be performed in interested sites having experience in this assessment at 
visits as indicated in the Schedule of Assessments. 
 
The CLASI is a measurement instrument for SLE developed by Dermato-Rheumatologists 
and validated by the “American College of Rheumatology Response Criteria Committee on 
SLE [43]. 
 
The CLASI consists of two scores, i.e., one for damage and one for activity:  
• Activity is scored based on erythema, scale/hyperkeratosis, mucous membrane 
involvement, acute hair loss and nonscarring alopecia.  
• Damage is scored based on dyspigmentation and scarring, including scarring alopecia.  
 
Subjects are asked whether dyspigmentation due to SLE lesions usually remains visible for 
more than 12 months, which is considered to be permanent and resulting in doubling of the 
dyspigmentation score. The scores are calculated by addition of the different subscores for 
clinical symptoms.  
The CLASI is designed as a table where the rows represent anatomical areas and the 
columns represent major clinical symptoms. The extent of involvement for each of the skin 
symptoms is documented according to specific anatomic areas taking into account the worst 
affected lesion within that area for each symptom. 
 
A sample of the CLASI is provided in Appendix 9.8. 
 
3.4.3.10. 28-JOINT ASSESSMENT  
 
To be performed by qualified study staff at visits as indicated in the Schedule of 
Assessments. 
 
An overview of the joints to be assessed is provided in Table 6. 
 
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Table 6: 
Tender and swollen joint count 
 
Joint 
Patient Right 
Patient Left 
 
 
Tender 
Swollen 
Tender 
Swollen 
1 
Shoulder 
 
 
 
 
2 
Elbow 
 
 
 
 
3 
Wrist 
 
 
 
 
4 
MCP I 
 
 
 
 
5 
MCP II 
 
 
 
 
6 
MCP III 
 
 
 
 
7 
MCP IV 
 
 
 
 
8 
MCP V 
 
 
 
 
9 
Thumb Interphalangeal 
 
 
 
 
10 
PIP II 
 
 
 
 
11 
PIP III 
 
 
 
 
12 
PIP IV 
 
 
 
 
13 
PIP V 
 
 
 
 
14 
Knee 
 
 
 
 
 
TOTAL  
 
 
 
 
 
TOTAL Tender Joint Count: 
 
TOTAL Swollen Joint Count: 
MCP=metacarpophalangeal; PIP=proximal interphalangeal 
 
If tenderness or swelling is noted, enter a ”1” for that joint in the appropriate field. If 
tenderness or swelling is absent, enter a “0” for that joint in the appropriate field. 
 
Joints that undergo intra-articular corticosteroid injection will be considered as swollen and 
tender for 28 days/4 weeks in the data analyses from the date of the procedure onward.  
 
3.4.3.11. SLICC/DAMAGE SCORE  
 
The SLICC/damage score assessment is to be performed by the Investigator at the baseline 
visit as indicated in the Schedule of Assessments. 
 
The SLICC/damage index is developed as an instrument to allow evaluation of accumulated 
damage over time and identifies changes in damage seen in subjects with active and 
inactive disease [44]. 
 
The 
SLICC/damage 
index 
consists 
of 
12 
different 
organ 
systems, 
i.e., 
ocular, 
neuropsychiatric, renal, pulmonary, cardiovascular, peripheral vascular, gastrointestinal, 
musculoskeletal, skin, premature gonadal failure, diabetes, and malignancy and it records 
damage regardless of its cause (e.g., previous disease activity, medications). An item has to 
be present for at least 6 months to be included in the damage index to differentiate 
between active inflammation and damage. 
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A sample of the SLICC/damage score is provided in Appendix 9.9. 
 
3.4.4. 
PHARMACOKINETIC ASSESSMENTS 
 
3.4.4.1. 
SAMPLE COLLECTION AND HANDLING 
 
Throughout the study, blood samples of approximately 3.5 mL will be taken for analysis of 
ALX-0061 in serum, according to the time points defined in the Schedule of Assessments.  
 
The times of blood sampling will be recorded. Of note, the day and approximate time of 
administration of the last dose will be available in the (e)CRF. 
 
The blood samples will be collected via an indwelling i.v. catheter or by direct venipuncture. 
For further details on sample collection, shipment, storage and processing, please refer to 
the Lab Manual. 
 
Samples that remain after protocol-specific assessments have been performed may be used 
by the Sponsor for further exploratory work on PK, PD, immunogenicity, metabolites, 
plasma protein binding, protein analysis, potency, and biochemistry (only in case allowed 
per local regulations). No human DNA or RNA analysis will be performed. 
 
3.4.4.2. 
BIOANALYSIS 
 
Concentrations of ALX-0061 in serum will be determined by a validated ligand-binding assay 
method according to the bioanalytical methodology and procedures described in a dedicated 
Bioanalytical Analysis Plan. Results will be presented in a Bioanalytical Analysis Report. 
 
3.4.5. 
PHARMACODYNAMIC ASSESSMENTS 
 
3.4.5.1. 
SAMPLE COLLECTION AND HANDLING 
 
Throughout the study, blood samples will be taken for analysis of the biomarkers sIL-6R, 
anti-dsDNA, C3, C4, and CH50 according to the time points defined in the Schedule of 
Assessments.  
 
• For determination of plasma sIL-6R, blood samples of approximately 2.7 mL will be 
collected and aliquoted.  
• For determination of serum anti-dsDNA, C3, C4, and CH50 blood samples of 
approximately 6 mL will be collected and aliquoted.  
 
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For more details on the acute phase response parameters CRP and fibrinogen, please refer 
to section 3.4.8.2. 
 
All PD blood samples will be taken via an indwelling i.v. catheter or by direct venipuncture. 
The times of blood sampling will be recorded. For further details on sample collection, 
shipment, storage and processing, please refer to a separate Lab Manual.  
 
Samples that remain after protocol-specific assessments have been performed may be used 
by the Sponsor for further exploratory work on PK, PD, immunogenicity, metabolites, 
plasma protein binding, protein analysis, potency, and biochemistry (only in case allowed 
per local regulations). No human DNA or RNA analysis will be performed. 
 
3.4.5.2. 
BIOANALYSIS 
 
Concentrations of sIL-6R in plasma will be determined by a validated enzyme-linked 
immunosorbent assay (ELISA) method according to the bioanalytical methodology and 
procedures described in a dedicated Bioanalytical Analysis Plan. Results will be presented in 
a Bioanalytical Analysis Report. 
Concentrations of C3, C4, and CH50 in serum will be determined by qualified ELISA 
methods and anti-dsDNA will be determined by the Farr-assay.  
 
Information on CRP and fibrinogen is specified in section 3.4.8.2. 
 
3.4.6. 
ADDITIONAL PHARMACODYNAMIC 
ASSESSMENTS (EXPLORATORY) 
 
Additional (exploratory) biomarkers that will be analyzed are the frequency of specific cell 
types (plasma cells, Th17 and Treg cells) by chipcytometry and the concentration of 
Monocyte Chemotactic Protein-1 in urine (uMCP-1).  
 
In SLE patients, plasma cells are responsible for the production of (pathogenic) 
autoantibodies and the frequency of these cells in peripheral blood correlates with SLE 
disease activity [45]. IL-6 induces the differentiation of activated B cells into plasma cells 
[46] and a phase I study with tocilizumab showed a reduction in circulating plasma cells 
upon treatment [24, 47]. 
The imbalance between Th17 cells, which are potent inflammatory cells, and Treg cells, 
which are crucial for maintenance of peripheral tolerance, contributes to the pathogenesis of 
SLE [48, 49]. These cell types are of particular interest because of their correlation with SLE 
disease activity and the crucial role of IL-6 in their differentiation [45]. In the presence of 
IL-6 and Transforming Growth Factor-β (TGFβ), naïve T cells differentiate into Th17 cells, 
while in the absence of IL-6, Treg cells are induced. This mode of action is also reflected in 
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the observation that tocilizumab treatment corrected the Th17/Treg balance in RA patients 
[50, 51].  
Currently, no validated biomarkers are available to detect early kidney disease in SLE. 
MCP-1 has been proposed as a potential biomarker for renal involvement in SLE, as MCP-1 
levels are increased in urine of SLE patients and in particular those with kidney involvement 
[52, 53]. Furthermore, IL-6 is implicated in the (local) production of MCP-1. 
 
3.4.6.1. 
SAMPLE COLLECTION AND HANDLING 
 
Throughout the study, urine samples of at least 1.0 mL will be taken for determination of 
the exploratory urine biomarker uMCP-1 according to the time points defined in the 
Schedule of Assessments.  
 
In a subset of subjects (at selected sites based on qualification), additional blood samples of 
approximately 4.0 mL will be collected at the same time points for immune cell phenotyping 
including, but not limited to, plasma cells, Th17 and Treg cells. 
 
All blood samples for these exploratory assessments will be taken via an indwelling i.v. 
catheter or by direct venipuncture. The times of blood sampling will be recorded. For further 
details on sample collection, shipment, storage and processing, please refer to a separate 
Lab Manual. 
 
Samples that remain after protocol-specific assessments have been performed may be used 
by the Sponsor for further exploratory work on PK, PD, immunogenicity, metabolites, 
plasma protein binding, protein analysis, potency, and biochemistry (only in case allowed 
per local regulations). No human DNA or RNA analysis will be performed. 
 
3.4.6.2. 
BIOANALYSIS 
 
Concentrations of uMCP-1 in urine will be determined by a qualified ELISA method and 
immune cell phenotyping will be performed using the chipcytometry method. Both 
exploratory analyses will be performed according to the bioanalytical methodology and 
procedures described in dedicated Bioanalytical Analysis Plans. Results will be presented in 
dedicated Bioanalytical Analysis Reports. 
 
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3.4.7. 
IMMUNOGENICITY ASSESSMENTS 
 
3.4.7.1. 
SAMPLE COLLECTION AND HANDLING 
 
To assess systemic immunogenicity of ALX-0061, blood samples of approximately 8.5 mL 
will be collected at the time points defined in the Schedule of Assessments for the 
determination of anti-ALX-0061 antibodies (ADA). 
 
Blood samples will be taken via an indwelling i.v. catheter or by direct venipuncture. The 
times of blood sampling will be recorded. For further details on sample collection, shipment, 
storage and processing, please refer to a separate Lab Manual. 
 
As described previously (see section 3.4.6), in case of acute or delayed severe/serious 
hypersensitivity reactions, an additional blood sample should be collected as soon as 
possible after the start of the event (blood volume: 8.5 mL) to characterize the cause of 
hypersensitivity by immunogenicity testing and/or protein analysis. No human DNA or RNA 
analysis will be performed. 
 
Samples that remain after protocol-specific assessments have been performed may be used 
by the Sponsor for further exploratory work on PK, PD, immunogenicity, metabolites, 
plasma protein binding, protein analysis, potency, and biochemistry (only in case allowed 
per local regulations). No human DNA or RNA analysis will be performed. 
 
3.4.7.2. 
BIOANALYSIS 
 
ADA will be determined using a validated screening and confirmation ADA bridging assay, 
potentially with further characterization by mADA assay and nAb assay. The immunogenicity 
data will be processed according to a dedicated Bioanalytical Analysis plan. Results will be 
presented in a Bioanalytical Analysis Report. 
 
3.4.8. 
ASSESSMENTS OF SAFETY 
 
Safety and tolerability assessments consist of AEs (including local tolerability and injection 
reactions), as well as laboratory assessments, urinalysis, vital signs, 12-lead ECG, and 
physical examinations. The time points are defined in the Schedule of Assessments.  
 
In case of acute or delayed severe/serious hypersensitivity reactions, an additional blood 
sample should be collected as soon as possible after the start of the event (blood volume: 
8.5 mL) to characterize the cause of hypersensitivity by immunogenicity testing and/or 
protein analysis. No human DNA or RNA analysis will be performed. 
 
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Independent Data and Safety Monitoring Board (DSMB) 
The DSMB will be an independent committee. None of the members will be participating in 
the study. The major function of this committee will be to monitor the safety of the subjects 
participating in the ALX-0061 clinical program by periodically reviewing unblinded safety 
data. They will advise concerning continuation, modification or termination of study. 
 
Prior to any DSMB review, the DSMB charter will define and document the content of the 
safety summaries, the DSMB’s role and responsibilities, and the general procedures 
(including communications). 
 
3.4.8.1. 
ADVERSE EVENTS 
 
General information on definition, evaluation and reporting of AEs is provided in section 3.5. 
 
All AEs occurring during the clinical investigation must be documented in the source 
documents and the (e)CRF. 
 
Criteria for determining whether an abnormal objective test finding (e.g., laboratory, vital 
signs), a complication of a protocol mandated procedure (e.g., blood draw, injection of 
study drug) or a change in physical examination findings should be reported as an AE are as 
follows, but not limited to: 
 
1. 
Result/finding is associated with accompanying clinical signs and symptoms (new onset 
or aggravated in severity of frequency from baseline condition), and/or 
2. 
Result/finding requires extra diagnostic testing (other than diagnostic exclusion tests) 
or medical/surgical intervention, and/or 
3. 
Result/finding would require a change in study drug dosing or discontinuation from the 
study, significant additional concomitant drug treatment or other therapy, and/or 
4. 
Result/finding leads to any of the outcomes included in the definition of an SAE, and/or 
5. 
Result/finding is considered to be an AE by the Investigator. 
 
Any abnormal test result that is determined to be an error and merely repeating an 
abnormal test does not require reporting as an AE. 
 
A “serious infection” is any infection that fulfills seriousness criteria and/or requires 
intravenous antibiotics. 
 
The Investigator may exceptionally decide to interrupt study drug treatment for one dose 
according to his/her medical judgment in case of an AE. 
 
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3.4.8.2. 
LABORATORY ASSESSMENTS 
 
Blood samples for clinical laboratory analysis will be collected predose at the time points 
indicated in the Schedule of Assessments.  
 
In general, blood samples will be collected via an indwelling i.v. catheter or by direct 
venipuncture. Detailed laboratory instructions on sample handle and processing will be 
provided. 
 
All samples will be assessed by a central laboratory, except for samples for Direct Coombs 
and INR (for subjects on vitamin K antagonist) that will be assessed by a local laboratory. 
 
The following tests will be included in the clinical laboratory analysis: 
• Biochemistry: 
total 
bilirubin, 
alkaline 
phosphatase, 
GGT, 
AST, 
ALT, 
lactate 
dehydrogenase, creatinine, creatine phosphokinase (CPK), urea, total protein, albumin, 
glucose, inorganic phosphate, sodium, potassium, calcium, and chloride.  
• Hematology: leukocytes, erythrocytes, hemoglobin, hematocrit, thrombocytes, partial 
automated differentiation (lymphocytes, monocytes, eosinophils, basophils, neutrophils), 
mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration. 
• Acute phase proteins: fibrinogen, and CRP. 
• Urinalysis: erythrocytes/blood, albumin, creatinine, urobilinogen, ketones, glucose, 
protein, pH, leukocytes, and urine sediment. 
• Coagulation: activated partial prothrombin time, prothrombin time, INR (the latter for 
subjects on vitamin K antagonists only). 
 
Fasting samples (i.e., samples taken after the subject has been fasting for at least 10 h) will 
be collected at baseline and Weeks 4, 8, 12, 24, 36 and 48 (or the Early Termination Visit) 
for assessment of total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides (i.e., 
fasting serum lipids).  
 
Lupus anti-coagulant (LA), anti-cardiolipin (aCL) and anti-β2-glycoprotein I (β2 GPI) 
antibodies will be evaluated at screening and at Week 24. ANA will be evaluated at 
screening only. 
 
For subjects on vitamin K antagonists, INR will be performed at Weeks 0, 2, 4, 8 and 12, 
and every 4 weeks (or more frequent if considered necessary by Investigator) thereafter up 
to Week 48 (or Early Termination) visit, and Follow-Up Visit. 
 
In females of childbearing potential, a blood pregnancy test will be performed at screening 
by the central laboratory and urine pregnancy screening locally at timepoints as indicated in 
the Schedule of Assessments. If local regulations or local medical practice require more 
frequent pregnancy testing, this will apply. 
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At screening, seropositivity for hepatitis B, hepatitis C, anti-HIV1 and anti-HIV2 will be 
tested. Lab tests for hepatitis B will be done according to the guidelines and will include 
Hepatitis B core antibody (HBcAb), Hepatitis B surface antibody (HBsAb) and Hepatitis B 
surface antigen (HBsAg)[2]. HBsAg positivity and/or HBcAb positivity will be considered as 
positive screening for hepatitis B. Anti-HCV antibody positivity will be considered as positive 
screening for hepatitis C. In case anti-HCV is indeterminate HCV-RNA viral load test will be 
done by central lab to confirm subject’s eligibility. 
 
In addition, an IGRA test to detect active TB and a chest radiograph (performed within 
12 weeks prior to the screening visit as part of standard of care or performed during the 
screening period) to detect evidence of malignancy, infection, or abnormalities suggestive of 
TB will be performed at screening and at any time during the study if TB is suspected. 
 
Except for CRP and fibrinogen, laboratory values outside the normal range will be flagged 
and clinical relevance will be assessed by the Investigator. If clinical signs and symptoms 
are present for which the Investigator needs to know values of CRP or fibrinogen for medical 
care, he/she can request this to be assessed locally. 
 
All clinically significant abnormal laboratory findings will be recorded as AEs in the (e)CRF 
(also see section 3.4.8.1) and lab results will be repeated and followed up until the results 
have returned to within the normal range and/or an adequate explanation for the 
abnormality is found. 
 
In the event of unexplained or unexpected clinical laboratory test values during the study, 
the test(s) will be redone and the retest value can be considered for further assessment and 
management of the subject in the study.  
 
Unexplained or unexpected clinical laboratory screening values, can be retested once within 
the screening period. 
 
3.4.8.3. 
VITAL SIGNS 
 
Vital signs parameters (assessed after 5 min in supine position) will be measured at the 
time points indicated in the Schedule of Assessments. All parameters will be recorded in the 
(e)CRF. 
 
The following vital signs parameters will be assessed: height, weight, blood pressure, pulse, 
and temperature. 
 
To obtain the actual body weight, subjects must be weighed lightly clothed. The height 
should be measured barefoot at the Screening Visit. 
 
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Clinically relevant abnormalities occurring during the study should be recorded as AE in the 
(e)CRF.  
 
3.4.8.4. 
ELECTROCARDIOGRAM 
 
12-lead ECG assessed after 5 min in supine position will be recorded at the time points 
indicated in the Schedule of Assessments.  
 
ECG assessment will include the Investigator’s conclusion on the ECG profile (as “normal”, 
“abnormal, not clinically significant”, or “abnormal, clinically significant”). 
 
3.4.8.5. 
PHYSICAL EXAMINATION 
 
A complete physical examination will be performed at the time points indicated in the 
Schedule of Assessments. Of note, additional physical examinations may be performed upon 
the discretion of the Investigator (e.g., in case of AEs). 
 
Physical examination will be recorded as “normal”, “abnormal, not clinically significant”, or 
“abnormal, clinically significant” at every assessment. A new finding or a change of a finding 
that is judged as an undesirable medical event (including all findings recorded as “abnormal, 
clinically significant”) shall be reported as an AE. 
 
The physical examination will include at least: head, eyes, ears, nose, throat; respiratory, 
cardiovascular, gastrointestinal, and musculoskeletal systems; central and peripheral 
nervous system; skin; lymph node palpation; urogenital system (kidneys); and general 
appearance. 
 
Any clinically relevant changes occurring during the study must be recorded in the (e)CRF 
and any clinically significant abnormalities persisting at the end of the study will be followed 
by the Investigator until resolution or until reaching a clinically stable endpoint. 
 
3.4.9. 
TOTAL BLOOD VOLUME 
 
The estimated number and volume of blood samples and the total volume of blood that will 
be collected per subject throughout the study are provided in Table 7. 
 
If necessary, in order to obtain additional information to ensure safety to the subject, 
additional blood (and urine) samples may be taken at the discretion of the Investigator. Due 
to this possibility, the blood volumes presented in the following tables are provided as best 
estimations. 
The total volume of blood taken during the study (over the one-year study duration) will be 
approximately 600 mL. 
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Table 7: 
Estimated number and volume of blood samples to be obtained during 
the study 
Assessments 
# samples 
Volume (mL) 
/Sample 
Volume (mL) 
Pharmacokinetics 
16 
3.5 
56 
Pharmacodynamics: sIL-6R 
10 
2.7 
27 
Pharmacodynamics: anti-dsDNA, C3, C4, CH50 
15 
6 
90 
Exploratory biomarkers a 
4 
4 
16 
Laboratory analysis (central lab, including 
serum pregnancy test at screening) 
16 
10.7 
171.2 
Laboratory analysis (local lab) 
16 
4.7 
75.2 
Serology (at screening only) 
1 
6 
6 
IGRA test 
1 
3 
3 
Antinuclear antibodies 
1 
2 
2 
LA, aCL, β2-GPI 
2 
12.7 
25.4 
Immunogenicity  
15 
8.5 
127.5 
Total 
 
 
599.3 b 
a To be taken in a subset of subjects (at selected sites based on qualification) 
b In case of acute or delayed severe/serious hypersensitivity reactions, an additional blood sample should be 
collected as soon as after the start of the event (blood volume: 8.5 mL) 
 
3.4.10. APPROPRIATENESS AND TIMING OF 
MEASUREMENTS 
 
The assessments which will be made in this study are standard, and generally recognized as 
reliable, accurate and relevant. 
 
The timing of all assessments is detailed in the Schedule of Assessments. 
 
All visits should occur in the specified week (± allowed time window) without further 
specification of the timing (visit may be planned at the time most appropriate for the 
subject). At baseline and at Weeks 4, 8, 12, 24, 36, 48 (or the Early Termination Visit), 
blood samples should be taken after at least 10 hours of fasting. 
For PK, PD, immunogenicity and safety, predose samples will be obtained between arriving 
at site and dosing. 
 
If assessments are planned at the same time, following guidance should be followed: 
• ECG and vital signs should be assessed prior to blood sampling.  
• Patient assessments (patient’s global assessment and SF-36) should occur prior to 
physician’s assessments. 
• Study drug should be dosed after all other assessments have been performed. 
 
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3.5. ADVERSE EVENT EVALUATION AND 
REPORTING 
 
3.5.1. 
ADVERSE EVENTS 
 
AE definitions will be followed as stated in the “Note for Guidance on clinical safety data 
management: definitions and standards for expedited reporting” (International Conference 
on Harmonization [ICH] topic E2A). 
 
An AE is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An AE does not necessarily have 
a causal relationship with the treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
considered related to that medicinal (investigational or non-investigational) product. 
 
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities. 
 
In differentiating between medical history and AEs, the following points will be considered: 
• Conditions that started before signing of informed consent and for which no symptoms or 
treatment are present up to the timing of signing of informed consent are recorded as 
medical history (e.g., seasonal allergy without acute complaints). 
• Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, but with unchanged severity, 
are recorded as medical history (e.g., allergic pollinosis). 
• Conditions that started before signing of informed consent but deteriorated after signing 
of informed consent will be documented as AEs. 
 
All AEs will be reported from the time a signed and dated ICF is obtained until completion of 
the subject’s last visit. 
 
A treatment-emergent AE (TEAE) is any AE temporally associated with the use of study 
drug, whether considered related to the study drug or not. TEAEs are recorded from the 
start of study drug administration, until completion of the subject’s last visit. 
 
It is the responsibility of the Investigator to collect all AEs (both serious and non-serious) 
derived by spontaneous, unsolicited reports of subjects, by observation, and by routine 
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open questioning (e.g., “How have you felt since I saw you last?”; “Is there anything new 
that you wish to discuss?”). 
 
All AEs will be assessed by the Investigator and documented in both source documents and  
the AE CRF page. AE entry should indicate time of onset and end time and rating of the 
seriousness (see section 3.5.2), severity (see section 3.5.1.1), and outcome (see 
section 3.5.1.2) of the AEs, and relationship to study drug and study procedures (see 
section 3.5.1.3), action taken regarding study drug (see section 3.5.1.4), and concomitant 
therapy taken for the AE. 
 
The Investigator will judge upon the severity of the AEs and relation to study drug and 
study procedures.  
 
3.5.1.1. 
AE SEVERITY 
 
The severity of AEs will be rated on a 3-point scale:  
• Mild: discomfort noticed but no disruption of normal daily activity.  
• Moderate: discomfort sufficient to reduce or affect normal daily activity. 
• Severe: incapacitating with inability to work or perform normal daily activity.  
 
It is emphasized that the term severe is a measure of intensity: a severe AE is not 
necessarily serious. For example, itching for several days may be rated as severe, but may 
not be clinically serious. 
 
3.5.1.2. 
OUTCOME 
 
The outcome of the AE is to be documented as follows: 
• 
Recovered / resolved. 
• 
Recovering / resolving. 
• 
Recovered / resolved with sequelae. 
• 
Not recovered / not resolved. 
• 
Fatal. 
• 
Unknown. 
 
3.5.1.3. 
RELATION TO STUDY DRUG OR STUDY 
PROCEDURES 
 
The assessment of the causal relationship between an AE and the administration of 
treatment is a clinical decision based on all available information at the time of the 
completion of the (e)CRF. 
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The assessment is based on the question whether there was a “reasonable causal 
relationship” to the study treatment in question. Possible answers are: 
• Unlikely/Not related. 
• Possibly related. 
• Related. 
• Not applicable. 
 
If the causal relationship to the study drug is unknown, the answer is defined as “related”. 
If an Investigator's opinion of no reasonable possibility of being related to study drug is 
given, another cause of event must be provided by the Investigator for the SAE. 
 
Note that only AEs starting after administration of study drug can be assigned a causal 
relationship between the AE and study drug administration. For AEs starting prior to study 
drug administration, causal relationship between the AE and study drug should be not 
applicable. 
 
Assessment of causal relationship of any AE to protocol-required procedures can be 
completed with: 
• Yes (specify). 
• No. 
 
3.5.1.4. 
ACTION TAKEN REGARDING STUDY 
DRUG  
 
Any action taken regarding study drug due to an AE is to be documented using following 
categories: 
• 
Dose not changed. 
• 
Drug interrupted. 
• 
Drug withdrawn. 
• 
Not applicable. 
• 
Unknown. 
 
3.5.2. 
SERIOUS ADVERSE EVENTS 
 
An SAE is any untoward medical occurrence that at any dose meets any of the following 
conditions: 
• Results in death. 
• Is life-threatening: the subject is at risk of death at the time of the event. It does not 
refer to an event that hypothetically might cause death if it were more severe. 
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• Requires 
in-subject 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization; 
an AE associated with a hospitalization or prolongation of hospitalization will not be 
regarded as an SAE if at least one of the following exceptions is met: 
- 
The admission results in a hospital stay of less than 12 hours. 
- 
The admission is pre-planned (i.e., elective or scheduled surgery arranged prior to the 
start of the study). 
- 
The admission is not associated with an AE (e.g., social hospitalization for purposes of 
respite care). 
However, it should be noted that invasive treatment during any hospitalization may fulfill 
the criterion of “medically important” and as such may be reportable as an SAE 
dependent on clinical judgment. In addition, where local regulatory authorities specifically 
require a more stringent definition, the local regulation takes precedence. 
• Results in persistent or significant disability/incapacity. Disability means a substantial 
disruption of a person’s ability to conduct normal life’s functions. 
• Results in a congenital anomaly/birth defect. 
• Is another medically important serious event as judged by the Investigator, or is defined 
as requiring intervention to prevent one of the outcomes listed in the definition above 
(including suspected transmission of an infectious agent by a medicinal product should be 
reported as an SAE). Other examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse. 
Any AE is considered an SAE if it is associated with clinical signs or symptoms judged by 
the Investigator to have a significant clinical impact. 
 
Infections that meet the above SAE criteria or require intravenous antibiotics should be 
reported as SAE. 
 
The Investigator or clinical site personnel should notify the CRO of all SAEs, regardless of 
relationship to the study drug, within 24 hours of clinical site personnel becoming aware of 
the event (see Investigator Site File).  
The Investigator will provide the initial notification a completed “SAE Notification Form”, 
which must include the Investigator’s assessment of the relationship of the event to study 
drug, and must be signed by the Investigator.  
 
The first report of an SAE may also be made by telephone. The Reporter must provide the 
minimal information: i.e., reporter identification, study number, age, medication code 
number, period of intake, nature of the AE, and relation to study drug. 
 
This report of an SAE by telephone must always be confirmed by a written, more detailed 
report (the SAE Form) to be completed and signed by the Investigator.  
 
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Follow-up information, or new information regarding an ongoing SAE, must be provided 
promptly to the contacts provided in the Investigator Site File. 
 
The SAE should also be recorded in the (e)CRF. Any medications necessary for the 
treatment of the SAE must be recorded on the concomitant medication section of the 
(e)CRF. 
 
SAEs that begin after the subject’s participation in the study is complete, but that the 
Investigator considers to be related to study drug, should be reported to the CRO/Sponsor 
at any time. 
 
3.5.3. 
SUSPECTED UNEXPECTED SERIOUS 
ADVERSE REACTIONS (SUSAR) 
 
Unexpected adverse reactions are adverse reactions of which the nature or severity is not 
consistent with the applicable product information (as described in the Reference Safety 
Information, provided in the Investigator’s Brochure). 
 
The following SUSARs will be reported expedited to the IEC/IRB: 
• SUSARs that have arisen in the current clinical study that was assessed by the IEC/IRB. 
• SUSARs that have arisen in other clinical studies of the same Sponsor and with the same 
study drug and that could have consequences for the safety of the subjects involved in 
the current clinical study that was assessed by the IEC/IRB. 
 
The CRO will report expedited all SUSARs to the relevant CA on behalf of the Sponsor. 
 
The Sponsor (or the CRO on behalf of the Sponsor) will also report to all concerned 
Investigators all SAEs that are unlisted (unexpected) and associated with the use of the 
drug. 
 
The expedited reporting will occur no later than 15 calendar days after the Sponsor (or the 
CRO on behalf of the Sponsor) has first knowledge of the adverse reactions.  
 
For fatal or life-threatening cases the term will be maximal 7 calendar days for a preliminary 
report with another 8 days for completion of the report. 
 
3.5.4. 
REPORTING OF ADVERSE EVENTS 
 
AEs reporting, including SUSARs, will be carried out in accordance with applicable local 
regulations. For reported deaths, the Investigator should supply the Sponsor and the 
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IEC/IRB with any additional requested information (e.g., autopsy reports and terminal 
medical reports). 
 
After termination of the clinical study (last subject last visit in the study), any unexpected 
safety issue that changes the risks benefit analysis and is likely to have an impact on the 
subjects who have participated in it, will be reported by the Sponsor as soon as possible to 
the competent authority(ies) concerned together with proposed actions. 
 
3.5.5. 
FOLLOW-UP OF ADVERSE EVENTS 
 
AEs will be handled according to common clinical practice. If necessary, in order to obtain 
additional information to ensure safety to the subject, additional blood and urine samples 
may be taken at the discretion of the Investigator. Information relative to other means of 
investigational diagnostics used in relation to the AE will also be communicated. 
 
AEs are recorded from signing the ICF until completion of the subject’s last visit.  
 
All AEs occurring at any time during the study (including the follow-up period) will be 
followed until satisfactory outcome.  
 
3.5.6. 
OTHER REPORTABLE INFORMATION 
 
3.5.6.1. 
PREGNANCY 
 
The Investigator must report to the Sponsor any pregnancy occurring in a study subject, or 
in his partner, during the subject’s participation in this study and until 3 months after last 
study drug dose. The report should be submitted within the same timelines as an SAE, 
although a pregnancy per se is not considered an SAE.  
 
For a study subject, the outcome of the pregnancy should be followed up carefully, and any 
abnormal outcome of the mother or the child (e.g., stillbirth, spontaneous abortion or 
elective abortion) should be reported. 
 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain similar 
information on course and outcome. 
 
All pregnancies including study subjects and female partners should be reported using the 
pregnancy form. 
 
Note that as indicated in section 3.2.3.2, subjects who get pregnant during the study should 
be withdrawn from the study. 
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3.5.6.2. 
MEDICATION ERROR 
 
Medication errors include, but are not limited to, the following: 
• Administration of the wrong dosage (including overdose) to the subject.  
• Administration of the study drug that has not been assigned to the subject. 
• Administration of expired study drug.  
• Administration by a route (e.g., i.m.) other than s.c. 
• Deviations to the study drug storage conditions only when administered to the subject. 
 
Medications errors with signs and symptoms need to be reported as an AE/SAE. 
 
Medication errors that occur during the study should be documented and reported to the 
Sponsor or designee whether or not it results in an AE/SAE.  
 
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3.6. STATISTICS 
 
3.6.1. 
STUDY POPULATIONS 
 
The following populations will be considered for analysis: 
• Modified Intent-to-treat (mITT) Population: All randomized subjects who received 
at least 1 administration of study drug, as randomized. 
• Safety Population: All subjects who received at least 1 administration of study drug, as 
treated. 
• PK Population: Consists of a subset of the safety population, for whom the primary PK 
data are considered to be sufficient and interpretable. 
• Per Protocol (PP) Population: Consists of a subset of the mITT population, and 
excludes those subjects who have had a major protocol violation or deviation. All 
violations and deviations will be reviewed prior to database lock and classified as major 
or minor. 
 
Unless otherwise specified, the mITT Population will be used for the analysis of efficacy, the 
safety population for analysis of safety, PD, and immunogenicity data, while the PK 
population will be used for analysis of the PK variables. 
 
3.6.2. 
STATISTICAL AND ANALYTICAL PLAN 
 
The SAP, will be generated under responsibility of the Sponsor. The SAP will be finalized 
prior to database lock. Any deviation from the reporting and analysis plan will be reported in 
the section “Changes in the planned analysis” in the Clinical Study Report. 
 
Details of the data analyses will be specified in the SAP. 
 
3.6.3. 
DETERMINATION OF SAMPLE SIZE 
 
Up to approximately 300 subjects will be randomized over 5 treatment arms in a 1:1:1:1:1 
ratio. Randomization will be stratified by geographic region. 
 
Simulations were performed to evaluate the power of detecting a significant dose-response 
relationship, i.e., whether changes in ALX-0061 dose regimen lead to significant changes in  
mBICLA response rate at Week 24 by using the MCP-Mod methodology [1]. A set of 
5 plausible candidate models containing both monotonous and non-monotonous exposure-
response shapes was defined. For these models an estimated placebo response rate  of 
25%, and a difference in response rate between the ALX-0061 dose regimen with the 
largest response rate and placebo of 25% was assumed, taking into account a 
discontinuation rate of 15% (homogeneous over treatment arms). With this methodology a 
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sample size of 60 subjects per arm will provide at least 85% power at a family-wise 5% 
significance level. 
 
3.6.4. 
INITIAL CHARACTERISTICS OF SUBJECT 
SAMPLE 
 
The statistical evaluation will be descriptive and by treatment (including mean, standard 
deviation, median, maximum, and minimum) for continuous variables and counts and 
percentages for categorical variables. 
 
3.6.5. 
EVALUATION OF EFFICACY PARAMETERS 
 
The adjudication committee will also evaluate appropriateness of data for evaluating the 
primary endpoint. 
 
The primary endpoint is the percentage of subjects who achieved a response at Week 24 
according to the composite mBICLA (BILAG-based Combined Lupus Assessment) score. 
BICLA responders are defined as subjects who meet all of the following criteria: 
 
(1)  BILAG-2004 improvement: all A scores at baseline improved to B/C/D, and all B scores 
improved to C or D.  
(2)  no worsening in disease activity: no new BILAG-2004 A scores and ≤1 new B score.  
(3)  no worsening of total mSLEDAI-2K score from baseline.  
(4)  no significant deterioration (< 10% worsening) in PGA. 
(5) no treatment failure (i.e., new or increased immunosuppressives or anti-malarials; or 
non-protocol allowed increased oral or parenteral corticosteroids; or premature 
discontinuation from study treatment). 
 
The following efficacy analyses will be performed in addition to the primary analysis: 
• Composite endpoint (m)BICLA over time (through Week 48) will be summarized by 
treatment group.  
• Composite endpoint mSRI as well as standard SRI over time (through Week 48) will be 
summarized by treatment group. 
• (m)SRI with more stringent (m)SLEDAI-cut-offs: SRI-5, SRI-6, SRI-7, SRI-8 over time 
(through Week 48) will be summarized by treatment group. 
• Change from baseline in mSLEDAI-2K total score as well as standard SLEDAI-2K 
measured over time (through Week 48) will be summarized by treatment group. 
• Number and percent of subjects with BILAG-2004 improvement. 
• BILAG-2004 (total score) over time (through Week 48) will be summarized by treatment 
group. 
• Improvement in individual organ systems of the BILAG-2004 over time (through 
Week 48) will be summarized by treatment group. 
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• Number of BILAG-2004 systems in which activity increased, decreased or remained the 
same compared to previous visit (BILAG-2004 systems tally) over time (through 
Week 48) will be summarized by treatment group. 
• Change from baseline in PGA over time (through Week 48) will be summarized by 
treatment group. 
• Change from baseline in patient’s global assessment over time (through Week 48) will be 
summarized by treatment group.  
• Change from baseline in proteinuria/urine sediment/serum creatinine/eGFR over time 
(through Week 48) will be summarized by treatment group. 
• Proportion of treatment failures (defined as non-protocol allowed increase in steroid dose, 
start i.v. or i.m. steroids, start or increase of immunosuppressant) at Week 24 and at 
Week 48 will be summarized by treatment group.   
• Reduction in flare rate at Week 24 and at Week 48.  
- Severe flare defined as a new A score in any system of the BILAG-2004 index; 
moderate flare defined as a new B score following a C, D or E score.   
- SFI. 
• Percent change from baseline in daily dose of steroids at Week 24 and 48 will be 
summarized by treatment group. 
• Percent subjects whose prednisone equivalent dose was >7.5 mg/day at baseline and 
reduced to ≤7.5 mg/day during Weeks 40–48 without experiencing a flare will be 
summarized by treatment group.  
• Percent subjects who are able to discontinue prednisone by Week 48 without 
experiencing a flare will be summarized by treatment group. 
• Changes from baseline in the physical and mental component scores of SF-36 at Week 24 
and at Week 48 will be summarized by treatment group.  
• 28 Joints count over time and change from baseline in 28 joint count over time will be 
summarized by treatment group. 
• CLASI over time and change from baseline evaluation at Week 12, 24 and Week 48 will 
be summarized by treatment group. 
• PK parameters. 
• PD markers, including total sIL-6R, CRP, fibrinogen, anti-dsDNA, C3, C4, CH50. 
 
Descriptive subgroup analyses may be performed to evaluate consistency of the primary 
endpoint over covariates including demographics (including weight and region), baseline 
disease, and prior and concomitant medications. Details will be provided in the SAP. 
 
3.6.5.1. 
PRIMARY EFFICACY ENDPOINT 
 
mBICLA response rates at Week 24 will be analyzed using the MCP-Mod methodology [1]. 
The method entails a unified strategy to the analysis of data from dose-response studies 
which combines multiple comparison and modeling techniques. In general, the existence of 
several candidate parametric models is assumed and multiple comparison techniques are 
used to choose the model most likely to represent the true underlying dose-response curve, 
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while preserving the family-wise error rate. The selected model may further be used to 
guide the choice of adequate doses. 
 
The analysis will be performed using the mITT population of all subjects who have received 
at least 1 administration of study drug and according to the treatment for which they were 
assigned.  
 
Subjects with missing mBICLA response at Week 24, including those who have discontinued 
study drug before Week 24, as well as subjects with treatment failure, will be treated as 
non-responders (non-response imputation approach). Treatment failure is defined as non-
protocol allowed increase in steroid dose, start i.v. or i.m. steroids, start or increase of 
immunosuppressant. Details on how missing mBICLA response is defined and handled will 
be provided in the SAP. 
 
Primary efficacy endpoint evaluation will also be performed using the PP population. 
 
Summary statistics (frequencies, proportions) for mBICLA response rate at Week 24 will be 
provided by treatment group. 
 
3.6.5.2. 
SECONDARY EFFICACY ENDPOINTS 
 
All secondary efficacy endpoints will be summarized by treatment group, using the observed 
data in the mITT population. For continuous secondary efficacy endpoints, summary 
statistics include mean, standard deviation, median, minimum and maximum, while for 
categorical secondary efficacy endpoints frequencies and proportions are provided. 
 
3.6.6. 
EVALUATION OF PHARMACOKINETIC 
PARAMETERS 
 
The procedures for obtaining ALX-0061 serum concentrations are found in section 3.4.4. 
 
Evaluation of Pharmacokinetics  
PK analysis will be performed on the PK population. 
 
Individual study drug concentrations will be listed. In addition a listing of the actual 
sampling times relative to the study drug administration times will be presented.  
 
Drug concentrations will be summarized by treatment group and scheduled sampling time.  
 
The descriptive statistics on study drug concentrations will be performed under the 
responsibility of Ablynx NV. 
 
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Pharmacokinetic Model 
ALX-0061 serum concentrations obtained from all subjects in the study will be pooled 
together with available data collected so far in previous studies. A population PK analysis 
will be conducted to describe the population mean and variability of ALX-0061 exposure in 
the study population based on pharmaco-statistical nonlinear mixed effect models.  
 
PK Modeling will be performed under the responsibility of Ablynx NV. Results will be 
provided in a separate Modeling and Simulation report. 
 
3.6.7. 
EVALUATION OF PHARMACODYNAMIC 
PARAMETERS 
 
All PD data will be summarized using descriptive statistics and will be listed and summarized 
in tabular and/or graphical form. Additional exploratory modeling (e.g., predictive analysis 
of specific biomarkers) may be performed. 
 
Exposure-response Model(s) 
An Exposure-Response analysis will be performed to determine the relationship between 
ALX-0061 serum exposure and PD and efficacy endpoints, e.g., BICLA, mSRI, SLEDAI-2K, 
and BILAG-2004 using nonlinear mixed effects modeling.  
 
Details on the exposure-response modeling will be included in a separate Data Analysis 
Plan, and will be performed under the responsibility of Ablynx NV. Results of this analysis 
will be provided in a separate Modeling and Simulation report. 
 
3.6.8. 
EVALUATION OF SAFETY PARAMETERS 
 
The following analyses will be used to assess the safety of subjects in this study. 
• The incidence and type of AEs. 
• The incidence and type of SAEs. 
• The incidence and type of related AEs (including study drug injection-site reactions and 
hypersensitivity reactions). 
• The laboratory parameters and change from baseline in these laboratory parameters. 
• The incidence of antibodies to ALX-0061. 
 
All summaries will display, by treatment group, the overall frequency of subjects with 
events, the frequency of subjects with events within each primary system organ class and 
by preferred term. For each preferred term and each system organ class a subject will be 
counted only once. For summaries of severe or drug-related AEs, for a given subject, the 
highest severity or relationship for a specific preferred term will be considered. 
 
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All safety, PD and immunogenicity analyses will be performed using the Safety Population of 
all subjects who received at least 1 dose of study drug. Analyses will be performed using the 
treatment that the subject actually received. In addition, subgroup analyses will be 
performed to evaluate consistency of safety over covariates including demographics 
(including weight), and concomitant medication (including immunosuppressants and 
corticosteroids). 
 
AEs will be fully described and coded according to the Medical Dictionary for regulatory 
Activities. A treatment-emergent analysis of AEs will be done. Frequency of subjects 
presenting AEs, AEs leading to withdrawal, AEs considered to be related to the study drug, 
and SAEs will be tabulated for each treatment group by system organ class and preferred 
term. 
 
For laboratory parameters, descriptive statistics (mean, median, standard deviation, 
minimum, and maximum) will be computed on the actual values and the change from 
baseline (absolute) for each parameter. All laboratory values will be categorized according 
to their normal ranges as below, within or above normal. A shift table versus baseline 
(including final value versus baseline and worst value versus baseline) will be created.  
 
Vital signs variables will be fully depicted using descriptive statistics (for actual values and 
changes from baseline) and shift tables according to their normal ranges. ECG values will be 
assessed through listing of individual results by subject and summary tables. 
 
Abnormal findings in physical examinations will be listed. 
 
Immunogenicity will be assessed through listing of individual results by subject and 
summary tables. 
 
The DSMB will periodically evaluate the safety data (see section 3.4.8). 
 
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3.7. DATA QUALITY ASSURANCE AND 
DIRECT ACCESS TO SOURCE 
DATA/DOCUMENTS 
 
An audit could be conducted to evaluate systems, processes, and expertise for the 
subcontracted activities and to assess compliance with the contractual agreements, the 
protocol, applicable Standard Operating Procedures, and regulatory requirements. During or 
after the conduct of the study, process-related audits may be performed as well. When 
performed, an audit certificate will be provided in appendix of the final study report.  
 
The clinical research facility will be monitored by the study monitor, to ensure correct 
performance of the study procedures and to assure that the study is conducted according to 
the relevant regulatory requirements. 
 
Regulatory authorities, the IEC/IRB, and/or the Sponsor representative may request access 
to all source documents, (e)CRFs and other study documentation for on-site audit or 
inspection. Direct access to these documents must be guaranteed by the Investigator, who 
must provide support at all times for these activities. 
 
Quality control principles will be applied throughout the performance of this study. 
 
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3.8. DATA PROTECTION 
 
During this clinical study, all clinical data will be identified only through an ID number in 
order to protect the rights of the subjects to privacy and to the protection of their personal 
data in accordance with the European Data Protection Directive 95/46/EC. Global principles 
and standards for Processing Personal Data and for meeting Data Transfer Obligations will 
be applied. If local requirements are more specific or expansive, Ablynx NV and 
subcontractors will abide to the strongest requirements. 
 
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4. ETHICS 
 
4.1. ETHICS COMMITTEES AND 
COMPETENT AUTHORITIES 
 
The Clinical Study Protocol(s) and the ICF(s) will be submitted for review and approval by 
the IEC/IRB prior to the eligibility screening/baseline. The composition of the IEC/IRB is in 
accordance with the recommendations of the World Health Organization, the ICH E6 
Guideline for GCP, and the European Union Clinical Trial Directive (CTD) (Directive 
2001/20/EC).  
 
The Investigator/Sponsor (or CRO on behalf of the sponsor) will keep the IEC/IRB informed 
about the progress of the study. All changes in research activities and all unanticipated 
problems involving risks to human subjects will be immediately reported to the responsible 
persons. The study may be suspended pending further review by the IEC/IRB, unless 
suspension would jeopardize the subject’s health. The Investigator will take care that all 
subjects are kept informed.  
 
No substantial amendments will be made to the study without prior IEC/IRB approval and 
CA approval (if applicable according to local regulations), except when required to eliminate 
apparent immediate hazards to human subjects. 
 
Notification of the end of the study will be sent to the CA and to the IEC/IRB, within the 
number of days as specified by local regulations after completion of follow-up for the last 
subject. In case the study is ended prematurely, the IEC/IRB and the CA will be notified 
within the number of days as specified by local regulations, including the reasons for the 
premature termination. A summary of the results of the study will be sent to the CA and the 
IEC/IRB within 1 year after the end of the study. 
 
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4.2. ETHICAL CONDUCT OF THE STUDY 
 
This study will be conducted in compliance with the ICH Guidance for Industry E6 GCP 
(including archiving of essential study documents), the Declaration of Helsinki, the 
applicable regulations of the country(ies) in which the study is conducted, and with the 
Commission Directives 2001/20/EC and 2005/28/EC. 
 
ICH-adopted guidelines and other relevant international guidelines, recommendations, and 
requirements will be taken into account as comprehensively as possible, as long as they do 
not violate Local laws. 
 
The Investigator will be responsible for the care of the subjects throughout the study. If the 
Investigator is not present at the study site, he/she will leave instructions for the staff and a 
telephone number where he/she can be reached. 
 
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4.3. SUBJECT INFORMATION AND 
CONSENT 
 
Each subject must give written consent according to local requirements after the nature of 
the study has been fully explained. The consent form must be signed before performance of 
any study-related activity. The consent form that is used must be approved by both the 
Sponsor or designee and by the reviewing IEC/IRB. The informed consent should be in 
accordance with principles that originated in the Declaration of Helsinki, current ICH and 
GCP guidelines, applicable regulatory requirements, and Sponsor policy. 
 
Before undertaking any study-related procedure in the study, the Investigator or an 
authorized member of the investigational staff must explain to potential subjects the aims, 
methods, objectives, no intended clinical benefits, and potential hazards of the study, and 
any discomfort participation in the study may entail. Subjects will be informed that their 
participation is voluntary and that the subject may refuse to participate or withdraw from 
the study, at any time, without penalty or loss of benefits to which the subject is otherwise 
entitled and that all data collected up to the point of withdrawal will be used and reported in 
an anonymized way. Finally, they will be told that the Investigator will maintain a subject 
identification register for the purposes of long-term follow-up if needed and that their 
records may be accessed by health authorities, authorized Sponsor staff, and Sponsor 
representative without violating the confidentiality of the subject, to the extent permitted by 
the applicable law(s) or regulations. By signing the ICF the subject is authorizing such 
access, and agrees to allow his/her study physician to recontact the subject for the purpose 
of obtaining consent for additional safety evaluations, if needed. 
 
The language used in the oral and written information about the study, including the ICF, 
should be as nontechnical as practical and should be understandable to the subject. The 
subject will be given sufficient time to read the ICF and given the opportunity to ask 
questions. After this explanation and before entry into the study, consent should be 
appropriately recorded by means of the subject's personally dated signature and by the 
Investigator or an authorized member of the investigational staff who conducted the ICF 
discussion. After having obtained the consent, a copy of the ICF must be given to the 
subject. The other original of the ICF will be retained by the Investigator in the “Investigator 
Site File”. 
  
In addition, insurance coverage provided during the study is explained. 
 
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4.4. PRIVACY 
 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to investigate the safety, quality, and utility of the 
investigational study drug(s) used in this study. 
 
These data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and regulations. 
Appropriate technical and organizational measures to protect the personal data against 
unauthorized disclosures or access, accidental or unlawful destruction, or accidental loss or 
alteration must be put in place. Sponsor personnel whose responsibilities require access to 
personal data agree to keep the identity of study subjects confidential. Subjects will be 
identified by his/her assigned unique subject number or subjects ID number and his/her 
age. Personal data will only be collected and processed using these unique identification 
items. 
 
The informed consent obtained from the subject includes explicit consent for the processing 
of personal data and for the Investigator to allow direct access to his/her original medical 
records for study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This 
consent also addresses the transfer of the data to other entities and to other countries. 
 
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5. DATA HANDLING AND RECORD 
KEEPING  
 
5.1. DISTRIBUTION OF ACTIVITIES 
 
Contact details of the Sponsor and third parties are available in the “Investigator Site File”. 
 
5.2. DOCUMENTATION 
 
Study documentation required for study start (as specified in the ICH E6 Guideline for GCP 
(CPMP/ICH/135/95) shall be exchanged between Ablynx NV and the CRO prior to the 
administration of study drug. 
 
5.2.1. 
CASE REPORT FORM COMPLETION 
 
Case report forms are provided for each subject (incl. screen failures).  
 
The Investigator will ensure that data are recorded on the (e)CRF as specified in the Clinical 
Study Protocol and in accordance with the instructions in the (e)CRF. The Investigator will 
ensure the accuracy, completeness, legibility, and timeliness of the data recorded in the 
(e)CRF, and of the provision of answers to data queries according to the Clinical Study 
Agreement. All (e)CRF entries, corrections, and alterations must be made by the 
Investigator or other authorized study-site personnel. The Investigator will sign the 
completed (e)CRF. A copy of the completed (e)CRF will be archived at the study site. 
 
5.2.2. 
SOURCE DOCUMENTATION 
 
At a minimum, source documentation must be available for the following: informed consent 
process, medical history, subject identification, eligibility, and study identification; date of 
informed consent; dates of visits; results of all efficacy evaluations; results of safety 
parameters as required by the protocol; record of all AEs; and follow-up of AEs; prior and 
concomitant medication; study drug receipt records; study drug administration information; 
any medical notes (original documents, data and records, e.g., laboratory data); date of 
study completion, and reason for early discontinuation of study procedures or withdrawal 
from the study, if applicable. 
 
In addition, the author of an entry in the source documents should be identifiable. 
 
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At a minimum, the type and level of detail of source data available for a study subject 
should be consistent with that commonly recorded at the site as a basis for standard 
medical care (Patient’s Medical File). 
 
Following the ICH-GCP guidelines, direct access to source documentation (medical records) 
must be allowed. 
 
5.2.3. 
RECORD RETENTION 
 
In compliance with the ICH/GCP guidelines, the Investigator/Institution will maintain all 
(e)CRFs and all source documents that support the data collected from each subject, as well 
as all study documents as specified in ICH/GCP section 8, Essential Documents for the 
Conduct of a Clinical Study, and all study documents as specified by the applicable 
regulatory requirement(s). The Investigator/ Institution will take measures to prevent 
accidental or premature destruction of these documents. 
 
Essential documents must be retained until at least 15 years after completion of the study, 
at least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or until at 
least 2 years have elapsed since the formal discontinuation of clinical development of the 
study drug. These documents will be retained for a longer period if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. It is the 
responsibility of the Sponsor to inform the Investigator/Institution as to when these 
documents no longer need to be retained. The Sponsor will receive the original (e)CRFs and 
study-related documents. 
 
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who 
will accept the responsibility. The Sponsor must be notified in writing of the name and 
address of the new custodian. Under no circumstance shall the Investigator relocate or 
dispose of any study documents before having obtained written approval from the Sponsor. 
 
The Investigator should take measures to prevent accidental or premature destruction of 
the study documents.    
 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review 
any documentation relating to this study, the Investigator must permit access to such 
reports. 
 
The vendor is responsible for organizing and maintaining a clear documentation of the 
course of the study. 
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The Trial Master File maintained during the study by the responsible persons will be sent 
back to the Sponsor upon Sponsor approval. 
 
Patients medical files, consent forms, and identification codes if relevant, will be kept by the 
Investigator in his/her personal files during the timeframe specified in local regulations or 
until the Sponsor decides that these documents no longer need to be retained 
(CPMP/ICH/135/95 § 4.95). 
 
5.2.4. 
MONITORING 
 
The monitor will perform on-site monitoring visits as specified in a monitoring plan to 
ensure that all aspects of the protocol, contractual agreements and regulatory requirements 
are followed and that subjects’ human rights, safety, and well-being are protected. The 
monitor will record dates of monitoring in a study center visit log that will be kept at the 
site. At these visits, the monitor will perform source data verification and check the data 
entered into the (e)CRF for completeness and accuracy. The nature and location of all 
source documents will be identified to ensure that all sources of original data required to 
complete the (e)CRF are known to the Sponsor and investigational staff and are accessible 
for verification by the Sponsor site contact. If electronic records are maintained at the 
investigational site, the method of verification must be discussed with the investigational 
staff.  
 
Direct access to source documentation ([electronic] medical records) must be allowed at 
any time. Findings from this review of captured data will be discussed with the 
investigational staff. The Sponsor expects that, during on-site monitoring visits, the relevant 
investigational staff will be available, the source documentation will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor 
will meet with the Investigator on a regular basis during the study to provide feedback on 
the study conduct. The Investigator agrees to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits will be resolved. 
 
 
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6. FINANCING AND INSURANCE 
 
Insurance 
 
Ablynx NV holds and will maintain an adequate insurance policy covering damages arising 
from Ablynx-sponsored clinical research studies. 
 
Ablynx NV will indemnify the Investigator in accordance with the provisions as set in an a 
separate written agreement between Ablynx and the relevant Investigator/clinical site. 
 
Financing 
 
The financial aspects of the study will be documented in an agreement between the Sponsor 
and the Investigator/Institution. 
 
The subjects will be compensated for reasonable expenses made related to the study such 
as travel costs to visit the study center for assessments related to the study. 
 
Financial Disclosure 
 
Any identified Investigator or subinvestigator directly involved in the treatment or 
evaluation of research subjects will disclose for the time period during which the 
Investigator is participating in the study and for 1 year following completion of the study 
that 
he/she 
entered 
a 
financial 
arrangement 
between 
the 
Sponsor 
and 
the 
Investigator/Institution. The Investigator should promptly update this information if any 
relevant changes occur during this period. 
 
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7. USE OF INFORMATION AND 
PUBLICATION 
 
By signing this protocol, the Investigator reaffirms to the Sponsor that he or she will 
maintain in confidence all information furnished to him, or resulting from this study. He or 
she will only divulge such information as may be necessary to the IEC/IRB and the members 
of the staff and the subjects who are involved in this study.  
 
All data and records provided by the Sponsor or generated during the study (other than 
subject’s medical records) and all data and inventions covered in the course of conducting 
the study, whether patentable or not, are the sole and exclusive property of the Sponsor. 
 
The Investigator and all other study team members at any service provider involved will 
keep strictly confidential all information provided by the Sponsor related to this study and 
all data and records generated in the course of the study. They will not use the information, 
data, or records for any other purpose than conducting the study without prior written 
approval of the Sponsor. 
 
Publication of any results from this study will be according to the principles of the 
Declaration of Helsinki, in particular point 30, and will require prior review and written 
agreement of the Sponsor. 
 
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8. REFERENCES 
 
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Guo, Y., et al. Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer 
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lupus erythematosus and correlate with local late T-cell activation markers. Lupus, 
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preliminary efficacy, and impact on circulating plasma cells from an open-label phase 
I dosage-escalation study. Arthritis and rheumatism, 2010. 62(2): p. 542-52. 
25. Szepietowski, J.C., et al. Phase I, randomized, double-blind, placebo-controlled, 
multiple intravenous, dose-ascending study of sirukumab in cutaneous or systemic 
lupus erythematosus. Arthritis and rheumatism, 2013. 65(10): p. 2661-71. 
26. van Vollenhoven, R., et al. A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-
Controlled, Proof-Of-Concept Study To Evaluate The Efficacy And Safety Of 
Sirukumab In Patients With Active Lupus Nephritis. EULAR abstract [OP0047] - Ann 
Rheum Dis 2014;73(Suppl2), 2014. 
27. Wallace, J., et al. Improvement of Disease Activity and Reduction of Severe Flares 
Following Subcutaneous Administration of an IL-6 Monoclonal Antibody (mAb) in 
Subjects with Active Generalized Systemic Lupus Erythematosus (SLE). ACR 2014 - 
Late breaking abstract [L5], oral session (18 Nov). 
28. Dennis, M.S., et al. Albumin binding as a general strategy for improving the 
pharmacokinetics of proteins. J.Biol.Chem., 2002. 277(38): p. 35035-35043. 
29. Edwards, C. IL-6 inhibition and infection: treating patients with tocilizumab. Is there a 
greater risk for infections? Rheumatology, 2012. 51: p. 769-770. 
30. Lang, V., Englbrecht, M, Rech, J et al. Risk of Infections in rheumatiod arthritis 
patients 
treated 
with 
tocilizumab. 
Rheumatology 
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852-857, 
doi:10.1093/rheumatology/ker223, 2012. 
31. Gruys, E., et al. Acute phase reaction and acute phase proteins. Zhejiang Univ Sci, 
2005. 6B(11): p. 1045-1056. 
32. Kishimoto, T. IL-6: from its discovery to clinical applications. Int Immunol 22, 347-
352, doi:10.1093/intimm/dxq030., 2010. 
33. Gibiansky, L., Frey, N. Linking interleukin-6 receptor blockade with tocilizumab and its 
hematological effects using a modeling approach. J Pharmacokinet Pharmacodyn, 
2012. 39, 5-16, doi:10.1007/s10928-011-9227-z  
34. Hennigan, S. and A. Kavanaugh. Interleukin-6 inhibitors in the treatment of 
rheumatoid arthritis. Therapeutics and clinical risk management, 2008. 4(4): p. 767-
75. 
35. Curtis, J., et al. Factors Associated with Gastrointestinal Perforation in a Cohort of 
Patients with Rheumatoid Arthritis. Arthritis Care Res, 2012. 64(12): p. 1819-1828. 
36. Shankar, G., C. Pendley, and K.E. Stein. A risk-based bioanalytical strategy for the 
assessment of antibody immune responses against biological drugs. Nature 
biotechnology, 2007. 25(5): p. 555-61. 
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37. Isenberg, D.A., et al. BILAG 2004. Development and initial validation of an updated 
version of the British Isles Lupus Assessment Group's disease activity index for 
patients with systemic lupus erythematosus. Rheumatology, 2005. 44(7): p. 902-6. 
38. Yee, C.S., et al. Numerical scoring for the BILAG-2004 index. Rheumatology, 2010. 
49(9): p. 1665-9. 
39. Yee, C.S., et al. BILAG-2004 index captures systemic lupus erythematosus disease 
activity better than SLEDAI-2000. Annals of the rheumatic diseases, 2008. 67(6): p. 
873-6. 
40. Gladman, D.D., D. Ibanez, and M.B. Urowitz. Systemic lupus erythematosus disease 
activity index 2000. The Journal of rheumatology, 2002. 29(2): p. 288-91. 
41. Luijten, K.M., et al. The Systemic Lupus Erythematosus Responder Index (SRI); a new 
SLE disease activity assessment. Autoimmunity reviews, 2012. 11(5): p. 326-9. 
42. Petri, M., J. Buyon, and M. Kim. Classification and definition of major flares in SLE 
clinical trials. Lupus, 1999. 8(8): p. 685-91. 
43. Albrecht, J., et al. The CLASI (Cutaneous Lupus Erythematosus Disease Area and 
Severity Index): an outcome instrument for cutaneous lupus erythematosus. The 
Journal of investigative dermatology, 2005. 125(5): p. 889-94. 
44. Gladman, D., et al. The development and initial validation of the Systemic Lupus 
International Collaborating Clinics/American College of Rheumatology damage index 
for systemic lupus erythematosus. Arthritis and rheumatism, 1996. 39(3): p. 363-9. 
45. Wahren-Herlenius, M. and T. Dorner. Immunopathogenic mechanisms of systemic 
autoimmune disease. Lancet, 2013. 382(9894): p. 819-31. 
46. Tanaka, T. and T. Kishimoto. The biology and medical implications of interleukin-6. 
Cancer immunology research, 2014. 2(4): p. 288-94. 
47. Shirota, Y., et al. Impact of anti-interleukin-6 receptor blockade on circulating T and B 
cell subsets in patients with systemic lupus erythematosus. Annals of the rheumatic 
diseases, 2013. 72(1): p. 118-28. 
48. Crispin, J.C., et al. T cells as therapeutic targets in SLE. Nature reviews. 
Rheumatology, 2010. 6(6): p. 317-25. 
49. Konya, C., Z. Paz, and G.C. Tsokos. The role of T cells in systemic lupus 
erythematosus: an update. Current opinion in rheumatology, 2014. 26(5): p. 493-
501. 
50. Pesce, B., et al. Effect of interleukin-6 receptor blockade on the balance between 
regulatory T cells and T helper type 17 cells in rheumatoid arthritis patients. Clinical 
and experimental immunology, 2013. 171(3): p. 237-42. 
51. Samson, M., et al. Brief report: inhibition of interleukin-6 function corrects Th17/Treg 
cell imbalance in patients with rheumatoid arthritis. Arthritis and rheumatism, 2012. 
64(8): p. 2499-503. 
52. Barbado, J., et al. MCP-1 in urine as biomarker of disease activity in Systemic Lupus 
Erythematosus. Cytokine, 2012. 60(2): p. 583-6. 
53. Schwartz, N., J.S. Michaelson, and C. Putterman. Lipocalin-2, TWEAK, and other 
cytokines as urinary biomarkers for lupus nephritis. Annals of the New York Academy 
of Sciences, 2007. 1109: p. 265-74. 
54. Petri, M., et al. Derivation and validation of the Systemic Lupus International 
Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis 
and rheumatism, 2012. 64(8): p. 2677-86. 
 
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9. APPENDICES 
 
9.1. 1997 AMERICAN ACR 
CLASSIFICATION CRITERIA 
 
1997 Update of the 1982 American College of Rheumatology Revised Criteria for 
Classification of Systemic Lupus Erythematosus 
Criterion 
Definition 
1. 
Malar Rash 
Fixed erythema, flat or raised, over the malar eminences, tending to spare the 
nasolabial folds 
2. 
Discoid rash 
Erythematous raised patches with adherent keratotic scaling and follicular 
plugging; atrophic scarring may occur in older lesions 
3. 
Photosensitivity 
Skin rash as a result of unusual reaction to sunlight, by patient history or 
physician observation 
4. 
Oral ulcers 
Oral or nasopharyngeal ulceration, usually painless, observed by physician 
5. 
Nonerosive 
Arthritis 
Involving 2 or more peripheral joints, characterized by tenderness, swelling, or 
effusion 
6. 
Pleuritis or 
Pericarditis 
1. Pleuritis--convincing history of pleuritic pain or rubbing heard by a 
physician or evidence of pleural effusion 
1. OR 
2. Pericarditis--documented by electrocardigram or rub or evidence of 
pericardial effusion 
7. 
Renal Disorder 
1. Persistent proteinuria > 0.5 grams per day or > than 3+ if quantitation not 
performed 
1. 
OR 
2. Cellular casts--may be red cell, hemoglobin, granular, tubular, or mixed 
8. 
Neurologic 
Disorder 
1. 
Seizures--in the absence of offending drugs or known metabolic 
derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance 
1. 
OR 
2. 
Psychosis--in the absence of offending drugs or known metabolic 
derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance 
9. 
Hematologic 
Disorder 
1. Hemolytic anemia--with reticulocytosis 
1. 
OR 
2. Leukopenia--< 4,000/mm3 on ≥ 2 occasions 
1. 
OR 
3. Lyphopenia--< 1,500/ mm3 on ≥ 2 occasions 
1. 
OR 
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4. Thrombocytopenia--<100,000/ mm3 in the absence of offending drugs 
10. Immunologic 
Disorder 
1. 
Anti-DNA: antibody to native DNA in abnormal titer 
1. 
OR 
2. 
Anti-Sm: presence of antibody to Sm nuclear antigen 
1. 
OR 
3. 
Positive finding of antiphospholipid antibodies on: 
1. 
1. an abnormal serum level of IgG or IgM anticardiolipin antibodies, 
2. 
2. a positive test result for lupus anticoagulant using a standard 
method, or 
3. 
3. a false-positive test result for at least 6 months confirmed by 
Treponema pallidum immobilization or fluorescent treponemal 
antibody absorption test 
11. Positive 
Antinuclear 
Antibody 
An abnormal titer of antinuclear antibody by immunofluorescence or an 
equivalent assay at any point in time and in the absence of drugs 
 
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9.2. 2012 SYSTEMIC LUPUS 
INTERNATIONAL COLLABORATING 
CLINICS (SLICC) CLASSIFICATION 
CRITERIA  
 
Clinical and Immunologic Criteria Used in the SLICC Classification Criteria [54] 
 
Clinical Criteria 
1. Acute cutaneous lupus 
Including: lupus malar rash (do not count if malar discoid) 
bullous lupus 
toxic epidermal necrolysis variant of SLE 
maculopapular lupus rash 
photosensitive lupus rash 
in the absence of dermatomyositis 
or subacute cutaneous lupus 
(nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring, 
although occasionally with postinflammatory dyspigmentation or telangiectasias) 
 
2. Chronic cutaneous lupus 
Including: classical discoid rash 
localized (above the neck) 
generalized (above and below the neck) 
hypertrophic (verrucous) lupus 
lupus panniculitis (profundus) 
mucosal lupus 
lupus erythematosus tumidus  
chillblains lupus 
discoid lupus/lichen planus overlap 
 
3. Oral ulcers: palate  
buccal 
tongue 
or nasal ulcers 
in the absence of other causes, such as vasculitis, Behcets, infection (herpes), 
inflammatory bowel disease, reactive arthritis, and acidic foods 
 
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Clinical Criteria 
4. Nonscarring alopecia (diffuse thinning or hair fragility with visible broken hairs) 
in the absence of other causes such as alopecia areata, drugs, iron deficiency and androgenic 
alopecia 
 
5. Synovitis involving two or more joints, characterized by swelling or effusion OR tenderness in 2 or 
more joints and thirty minutes or more of morning stiffness. 
 
6. Serositis 
typical pleurisy for more than 1 day  
or pleural effusions 
or pleural rub 
typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 day  
or pericardial effusion 
or pericardial rub 
or pericarditis by EKG 
in the absence of other causes, such as infection, uremia, and Dressler's pericarditis 
 
7. Renal 
Urine protein/creatinine (or 24 hr urine protein) representing 500 mg of protein/24 hr 
or 
Red blood cell casts 
 
8. Neurologic 
Seizures 
psychosis 
mononeuritis multiplex 
in the absence of other known causes such as primary vasculitis 
myelitis 
peripheral or cranial neuropathy 
in the absence of other known causes such as primary vasculitis, infection, and diabetes 
mellitus 
acute confusional state 
in the absence of other causes, including toxic-metabolic, uremia, drugs 
 
9. Hemolytic anemia 
 
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Clinical Criteria 
10. Leukopenia (< 4000/mm3 at least once) 
in the absence of other known causes such as Felty's, drugs, and portal hypertension 
OR 
Lymphopenia (< 1000/mm3 at least once) 
in the absence of other known causes such as corticosteroids, drugs and infection 
 
11. Thrombocytopenia (<100,000/mm3) at least once 
in the absence of other known causes such as drugs, portal hypertension, and TTP 
 
 
Immunological Criteria 
1. ANA above laboratory reference range 
 
2. Anti-dsDNA above laboratory reference range, except ELISA: twice above laboratory reference 
range 
 
3. Anti-Sm 
 
4. Antiphospholipid antibody: any of the following:  
lupus anticoagulant 
false-positive RPR 
medium or high titer anticardiolipin (IgA, IgG or IgM) 
anti-β2 glycoprotein I (IgA, IgG or IgM) 
 
5. Low complement  
low C3 
low C4  
low CH50 
 
6. Direct Coombs test in the absence of hemolytic anemia 
 
Criteria are cumulative and need not be present concurrently. 
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9.3. THE NEW YORK HEART 
ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION 
 
Class 
Functional Capacity: How a patient with cardiac disease feels during physical 
activity 
I 
Patients with cardiac disease but resulting in no limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea or 
anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea or anginal 
pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. 
If any physical activity is undertaken, discomfort increases. 
 
 
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9.4. MODIFICATION OF DIET IN RENAL 
DISEASE’ (MDRD) FORMULA 
 
Estimated GFR (ml/min/1.73m2) = 186 x (Creat* / 88.4)-1.154 x (Age)-0.203 x (0.742 if 
female) x (1.210 if black) 
 
* Serum creatinine level in µmol/L 
 
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9.5. OVERVIEW OF CORTICOSTEROID 
HANDLING THROUGHOUT THE 
STUDY 
 
 
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9.6. BILAG-2004 
 
The BILAG-2004 [37-39] scoring system is based on the physician’s intention to treat. 
 
Grade 
Definition 
A 
Severe disease activity requiring any of the following treatment: 
1. Systemic high dose oral corticosteroids (equivalent to Prednisolone > 20 mg/day) 
2. Intravenous pulse corticosteroids (equivalent to pulse methylprednisolone ≥ 500 mg) 
3. Systemic 
immunomodulators 
(include 
biologicals, 
immunoglobulins 
and 
plasmapheresis)  
4. Therapeutic high dose anticoagulation in the presence of high dose corticosteroids or 
immunomodulators 
eg: warfarin with target INR 3 - 4 
B 
Moderate disease activity requiring any of the following treatment: 
1. Systemic low dose oral corticosteroids (equivalent to prednisolone ≤ 20 mg/day) 
2. Intramuscular or intra-articular or soft tissue corticosteroids injection (equivalent to 
methylprednisolone < 500 mg) 
3. Topical corticosteroids 
4. Topical immunomodulators 
5. Antimalarials or thalidomide or prasterone or acitretin 
6. Symptomatic therapy 
eg: NSAIDs for inflammatory arthritis 
C 
Mild disease 
D 
Inactive disease but previously affected 
E 
System never involved 
 
The following 9 systems are evaluated: constitutional, mucocutaneous, neuropsychiatric, 
musculoskeletal, cardiorespiratory, gastrointestinal, renal, ophthalmic and hematology. 
 
 
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For information on the BILAG2004 Index Glossary, please refer to [37]. 
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9.7. SLEDAI-2K 
 
Enter weight in SLEDAI-2K Score column if descriptor is present at the time of the visit or in 
the preceding 30 days. 
 
SLEDAI 2K 
Descriptor 
Definition 
Weight 
SCORE 
8 
 
 
Seizure 
Recent onset, exclude metabolic, infectious or drug 
causes. 
8 
 
 
Psychosis 
Altered ability to function in normal activity due to 
severe disturbance in the perception of reality.  
Include hallucinations, incoherence, marked loose 
associations, 
impoverished 
thought 
content, 
marked illogical thinking, bizarre, disorganized, or 
catatonic behavior.  Exclude uremia and drug 
causes 
8 
 
 
Organic brain 
syndrome 
Altered mental function with impaired orientation, 
memory, or other intellectual function, with rapid 
onset and fluctuating clinical features, inability to 
sustain attention to environment, plus at least 2 of 
the following:  perceptual disturbance, incoherent 
speech, 
insomnia 
or 
daytime 
drowsiness, 
or 
increased 
or 
decreased 
psychomotor 
activity.  
Exclude metabolic, infectious, or drug causes. 
8 
 
 
Visual 
disturbance 
Retinal changes of SLE.  Include cytoid bodies, 
retinal 
hemorrhages, 
serous 
exudate 
or 
hemorrhages in the choroid, or optic neuritis.  
Exclude hypertension, infection, or drug causes. 
8 
 
 
Cranial nerve 
disorder 
New onset of sensory or motor neuropathy 
involving cranial nerves. 
8 
 
 
Lupus 
headache 
 
Severe, persistent headache;  may be migrainous, 
but must be nonresponsive to narcotic analgesia. 
8 
 
 
CVA 
New onset of cerebrovascular accident(s).  Exclude 
arteriosclerosis. 
8 
 
 
Vasculitis 
Ulceration, 
gangrene, 
tender 
finger 
nodules, 
periungual infarction, splinter hemorrhages, or 
biopsy or angiogram proof of vasculitis. 
4 
 
 
Arthritis 
> 2 joints with pain and signs of inflammation (i.e., 
tenderness, swelling or effusion). 
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SLEDAI 2K 
Descriptor 
Definition 
Weight 
SCORE 
4 
 
 
Myositis 
Proximal muscle aching/weakness, associated with 
elevated 
creatine 
phosphokinase/aldolase 
or 
electromyogram changes or a biopsy showing 
myositis. 
4 
 
 
Urinary casts 
Heme-granular or red blood cell casts. 
4 
 
 
Hematuria 
>5 red blood cells/high power field.  Exclude stone, 
infection  or other cause. 
4 
 
 
Proteinuria 
>0.5 gram/24 hours 
4 
 
 
Pyuria 
>5 white blood cells/high power field.  Exclude 
infection. 
2 
 
 
Rash 
Inflammatory type rash. 
2 
 
 
Alopecia 
Abnormal, patchy or diffuse loss of hair. 
2 
 
 
Mucosal ulcers 
Oral or nasal ulcerations. 
2 
 
 
Pleurisy 
Pleuritic chest pain with pleural rub or effusion, or 
pleural thickening. 
2 
 
 
P 
Pericarditis 
Pericardial pain with at least 1 of the following:  
rub, 
effusion, 
or 
electrocardiogram 
or 
echocardiogram confirmation. 
2 
 
 
Low 
complement 
Decrease in CH50, C3, or C4 below the lower limit 
of normal for testing laboratory 
2 
 
 
Increased 
DNA binding 
Increased DNA binding by Farr assay above normal 
range for testing laboratory. 
1 
 
 
Fever 
>38o C. Exclude infectious cause. 
1 
 
 
Thrombocytop
enia 
<100,000 platelets / x109/L, exclude drug causes. 
1 
 
 
Leukopenia 
< 3,000 white blood cells / x109/L, exclude drug 
causes.  
 
 
TOTAL SCORE:   ______________ 
 
 
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9.8. CLASI 
 
 
 
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9.9. SLICC/DAMAGE SCORE 
 
Systemic Lupus International Collaborating Clinics/American College of Rheumatology 
Damage Index for Systemic Lupus Erythematosus* [44] 
 
Item 
Score 
Ocular (either eye, by clinical assessment) 
 
Any cataract ever 
1 
Retinal change or optic atrophy 
1 
 
 
Neuropsychiatric 
 
Cognitive impairment (e.g., memory deficit, difficulty with calculation, poor 
concentration, difficulty in spoken or written language, impaired performance level) 
or major psychosis 
1 
Seizures requiring therapy for 6 months 
1 
Cerebrovascular accident ever (score 2 if > 1) 
1 (2) 
Cranial or peripheral neuropathy (excluding optic) 
1 
Transverse myelitis 
1 
 
 
Renal 
 
Estimated or measured glomerular filtration rate <50% 
1 
Proteinuria ≥3.5 gm/24 hours 
1 
or 
 
End-stage renal disease (regardless of dialysis or transplantation) 
3 
 
 
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 
 
 
Cardiovascular 
 
Angina or coronary artery bypass 
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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Item 
Score 
 
 
Peripheral vascular 
 
Claudication for 6 months 
1 
Minor tissue loss (pulp space) 
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 
 
 
Gastrointestinal 
 
Infarction or resection of bowel below duodenum, spleen, liver, or gall bladder 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 
 
 
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 
 
 
Skin 
 
Scarring chronic alopecia 
1 
Extensive scarring or panniculum other than scalp and pulp space 
1 
Skin ulceration (excluding thrombosis) for >6 months 
1 
 
 
Premature gonadal failure 
1 
 
 
Diabetes (regardless of treatment) 
1 
 
 
Malignancy (exclude dysplasia) (score 2 if >1 site) 
1 (2) 
 
 
* 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 at least 
6 months apart to score 2. The same lesion cannot be scored twice. 
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