A Phase II Multicenter, Open-Label Extension Study Assessing the Long-Term Efficacy and Safety of Subcutaneous ALX-0061 in Subjects With Moderate to Severe Rheumatoid Arthritis Who Have Completed One of the Preceding Phase IIb Studies With ALX-0061
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Sponsor: Ablynx, a Sanofi company

  
  
 
CLINICAL STUDY PROTOCOL 
 
ALX0061-C203 
 
 
A Phase II Multicenter, Open-Label Extension Study Assessing 
the Long-Term Efficacy and Safety of Subcutaneous ALX-0061 
in Subjects with Moderate to Severe Rheumatoid Arthritis who 
Have Completed One of the Preceding Phase IIb Studies with 
ALX-0061 
 
 
 
 
Short Title: 
An Open-Label Extension Study Assessing the 
Long-Term Efficacy and Safety of 
Subcutaneous ALX-0061 in Subjects with 
Rheumatoid Arthritis 
Study Drug: 
ALX-0061 
EudraCT n°: 
2014-003034-42 
Sponsor Protocol Code: 
ALX0061-C203 
 
Sponsor: 
Ablynx NV  
Technologiepark 21 
9052 Zwijnaarde, Belgium 
 
Contract Research Organization: 
 
 
 
 
Phase of Development: 
Phase II 
Indication: 
Rheumatoid arthritis (RA) 
Protocol Date: 
December 10, 2015 
Protocol Version: 
3.0  
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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Ablynx NV 
Clinical Trial Protocol ALX0061-C203 
 
 
Final version 3.0 
 
December 10, 2015 
CONFIDENTIAL 
Page 2/89 
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The information contained in this document, especially unpublished data, is the 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 an applicable Independent Ethics Committee (IEC)/ 
Institutional Review Board (IRB). 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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Document ID: 25_A0006_14_0210          ADMS Version Number: 3.0          Printing Date: 15/Dec/2015

Ablynx NV 
Clinical Trial Protocol ALX0061-C203 
 
 
Final version 3.0 
 
December 10, 2015 
CONFIDENTIAL 
Page 5/89 
 
 
Investigator:  
 
 
 
 
 
 
I have read Clinical Study Protocol ALX0061-C203 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 
changes to 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 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: 
 
Primary Investigator Name: 
 
 
Degree/Function: 
 
 
Site details/Address: 
 
 
 
 
 
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Ablynx NV 
Clinical Trial Protocol ALX0061-C203 
 
 
Final version 3.0 
 
December 10, 2015 
CONFIDENTIAL 
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CONTACT INFORMATION 
 
Serious adverse event (SAE) contact information and other contact details of the 
Sponsor and third parties are available in the “Investigator Site File”.  
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Ablynx NV 
Clinical Trial Protocol ALX0061-C203 
 
 
Final version 3.0 
 
December 10, 2015 
CONFIDENTIAL 
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TABLE OF CONTENTS 
 
CONFIDENTIALITY STATEMENT ......................................................................... 2 
APPROVAL OF CLINICAL STUDY PROTOCOL ........................................................ 3 
CONTACT INFORMATION .................................................................................. 6 
TABLE OF CONTENTS ....................................................................................... 7 
LIST OF ABBREVIATIONS ................................................................................. 9 
CHANGES COMPARED TO PREVIOUS VERSION(S)............................................... 12 
 
PROTOCOL SYNOPSIS ................................................................................. 14 
 
SCHEDULE OF ASSESSMENTS  ..................................................................... 20 
 
1. INTRODUCTION ..................................................................................... 22 
1.1. RHEUMATOID ARTHRITIS ...................................................................... 22 
1.1.1. Treatment of Rheumatoid Arthritis .................................................... 22 
1.1.2. Role of IL-6R in  Pathophysiology of Rheumatoid Arhtritis .................... 23 
1.2. ALX-0061 ............................................................................................ 24 
1.2.1. General Properties .......................................................................... 24 
1.2.2. Manufacture .................................................................................. 25 
1.2.3. Nonclinical Studies ......................................................................... 25 
1.2.4. Effects in Humans .......................................................................... 25 
1.2.5. Benefits and risk assessment ........................................................... 28 
 
2. OBJECTIVES ........................................................................................... 31 
 
3. STUDY DESIGN ...................................................................................... 32 
3.1. OVERALL STUDY DESIGN ....................................................................... 32 
3.1.1. Study Overview.............................................................................. 32 
3.1.2. Blinding ........................................................................................ 34 
3.2. SELECTION OF STUDY POPULATION ........................................................ 35 
3.2.1. Inclusion Criteria ............................................................................ 35 
3.2.2. Exclusion Criteria ........................................................................... 35 
3.2.3. Removal of Subjects from Therapy or Assessment .............................. 37 
3.3. TREATMENT OF SUBJECTS ..................................................................... 40 
3.3.1. Identity of Study Drug .................................................................... 40 
3.3.2. Drug Accountability ........................................................................ 40 
3.3.3. Study Drug Handling ...................................................................... 41 
3.3.4. Study Drug Injections ..................................................................... 42 
3.3.5. Prior and Concomitant Therapy ........................................................ 42 
3.3.6. Treatment Compliance .................................................................... 45 
3.3.7. Randomization ............................................................................... 45 
3.4. ASSESSMENTS ..................................................................................... 46 
3.4.1. Timing of Assessments .................................................................... 46 
3.4.2. Assessments of Efficacy .................................................................. 50 
3.4.3. Pharmacokinetic Assessments .......................................................... 57 
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3.4.4. Assessments of Safety .................................................................... 58 
3.4.5. Other Assessments ......................................................................... 62 
3.4.6. Total Blood Volume......................................................................... 63 
3.4.7. Appropriateness and Timing of Measurements ................................... 64 
3.5. ADVERSE EVENT EVALUATION AND REPORTING ....................................... 65 
3.5.1. Adverse Events .............................................................................. 65 
3.5.2. Serious Adverse Events ................................................................... 68 
3.5.3. Suspected Unexpected Serious Adverse Reactions (SUSAR) ................. 69 
3.5.4. Reporting of Adverse Events ............................................................ 70 
3.5.5. Follow-up of Adverse Events ............................................................ 70 
3.5.6. Other Reportable Information .......................................................... 71 
3.6. STATISTICS ......................................................................................... 72 
3.6.1. Study Populations .......................................................................... 72 
3.6.2. Statistical and Analytical Plan........................................................... 72 
3.6.3. Initial Characteristics of Subject Sample ............................................ 72 
3.6.4. Evaluation of Efficacy Parameters ..................................................... 72 
3.6.5. Evaluation of Pharmacokinetic Parameters ......................................... 74 
3.6.6. Evaluation of Safety Parameters ....................................................... 74 
3.6.7. Handling of Missing Data ................................................................. 75 
3.6.8. Determination of Sample Size .......................................................... 75 
3.7. DATA QUALITY ASSURANCE AND DIRECT ACCESS TO SOURCE 
DATA/DOCUMENTS ............................................................................... 76 
3.8. DATA PROTECTION ............................................................................... 77 
 
4. ETHICS .................................................................................................. 78 
4.1. ETHICS COMMITTEES AND COMPETENT AUTHORITIES .............................. 78 
4.2. ETHICAL CONDUCT OF THE STUDY ......................................................... 78 
4.3. SUBJECT INFORMATION AND CONSENT .................................................. 79 
4.4. PRIVACY .............................................................................................. 80 
 
5. DATA HANDLING AND RECORD KEEPING ............................................... 81 
5.1. DISTRIBUTION OF ACTIVITIES ............................................................... 81 
5.2. DOCUMENTATION ................................................................................. 81 
5.2.1. Case Report Form Completion .......................................................... 81 
5.2.2. Source Documentation .................................................................... 81 
5.2.3. Record Retention ............................................................................ 82 
5.2.4. Monitoring ..................................................................................... 83 
 
6. FINANCING AND INSURANCE ................................................................ 84 
 
7. PUBLICATION POLICY ........................................................................... 85 
 
8. REFERENCES .......................................................................................... 86 
 
9. APPENDIX: TENDER AND SWOLLEN JOINT COUNT ................................ 88 
 
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December 10, 2015 
CONFIDENTIAL 
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LIST OF ABBREVIATIONS 
 
AC 
Acromioclavicular  
ACR 
American College of Rheumatology 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CA 
Competent Authority 
CD20 
Cluster of differentiation 20 
CDAI 
Clinical Disease Activity Index 
CHF 
Congestive heart failure 
CL 
clearance 
CRO 
Contract research organization 
CRP 
C-reactive protein  
CTCAE 
Common Terminology Criteria for Adverse Events 
CTD 
Clinical trial directive 
CYP450 
Cytochrome P450 
DAS28 
Disease Activity Score using 28 joint counts  
DIP 
Distal interphalangeal 
DMARD 
Disease modifying antirheumatic drug 
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
(e)CRF 
(Electronic) Case report form 
ESR 
Erythrocyte sedimentation rate 
EULAR 
European League Against Rheumatism 
FACIT-fatigue 
Functional Assessment of Chronic Illness Therapy - Fatigue 
GCP 
Good Clinical Practice 
GH 
VAS Patient Global Assessment of Disease Activity 
GLP 
Good Laboratory Practice 
gp130 
Glycoprotein 130 
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
HDL 
High-density lipoprotein 
HSA 
Human serum albumin 
i.a. 
Intra-articular 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ID 
Identification  
IEC 
Independent Ethics Committee 
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December 10, 2015 
CONFIDENTIAL 
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Ig 
Immunoglobulin 
IGRA 
Interferon-gamma release assay 
IL-1 
Interleukin-1 
IL-6 
Interleukin-6 
IL-6R 
Interleukin-6 receptor 
INR 
International normalized ratio 
IP 
Interphalangeal  
IRB 
Institutional review board 
ITO 
Intention-to-observe 
i.v. 
Intravenous(ly) 
IWRS 
Interactive web response system 
LDL 
Low-density lipoprotein 
MAD 
Multiple ascending dose 
mADA 
Modified anti-drug antibody 
MCP 
metacarpophalangeal 
mIL-6R 
Membrane-bound interleukine-6 receptor 
MTP 
Metatarsophalangeal  
MTX 
Methotrexate 
nAbs 
Neutralizing antibodies 
NSAID 
Non-steroidal anti-inflammatory drug 
OLE 
Open-label extension 
PD 
Pharmacodynamic 
PIP 
Proximal interphalangeal 
PK 
Pharmacokinetic  
q2w 
Every 2 weeks 
q4w 
Every 4 weeks 
QA 
Quality Assurance 
RA 
Rheumatoid arthritis 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Sternoclavicular  
s.c. 
Subcutaneous(ly) 
SDAI 
Simplified Disease Activity Index 
SF-36 
Short Form (36) Health Survey 
sIL-6R 
Soluble Interleukin-6 receptor 
SJC 
Swollen joint count 
SLE 
Systemic lupus erythematosus 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
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TCZ 
Tocilizumab  
TEAE 
Treatment-emergent adverse event 
TJC 
Tender joint count 
TK 
Toxicokinetics 
TMJ 
Temporomandibular joint 
TNF α 
Tumor necrosis factor alpha 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
VASPA 
Visual analogue scale, patient assessment of disease activity 
VASPHA 
Visual analogue scale, physician assessment of disease activity 
VH 
Heavy chain variable region 
WHO 
World Health Organization 
WMA 
World Medical Association 
 
 
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CONFIDENTIAL 
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CHANGES COMPARED TO PREVIOUS 
VERSION(S) 
 
Version 3.0 (dated December 10, 2015) compared to Version 2.0 (dated February 17, 2015)  
Version n° and date were adapted throughout the document (incl. headers and footers). 
The table of contents was updated and the Section “Changes compared to previous version(s)” was 
completed. 
Original section 
Change/Rationale 
Approval of Clinical Study Protocol 
Due to an update of the standard operating procedure on protocol 
writing, Clinical Study Protocols are no longer signed by the Chief 
Medical Officer but by the responsible Medical Lead. 
Synopsis and Section 3.2.2. 
The exclusion criterion on laboratory abnormalities has been 
updated to ensure more consistency between the discontinuation 
criteria in the preceding Phase IIb studies with ALX-0061 
(ALX0061-C201 or ALX0061-C202) and the entry criteria of this 
open-label extension study (ALX0061-C203) and to allow 
unscheduled lab testing for study entry. 
Synopsis 
Completion of list of safety assessments. 
Schedule of Assessments 
Terms with regard to study period and study visits have been 
clarified. 
Schedule of Assessments and 
Section 3.4.4.2. 
A clarification has been added to reflect that pregnancy testing 
applies to women of childbearing potential only. 
Schedule of Assessments and 
Section 3.4.7. 
The order of assessments has been simplified. 
Schedule of Assessments, 
Sections 3.1.1., 3.3.5., 3.4.1.1., 
3.4.1.3. and 3.4.6. 
Typographical errors have been corrected. 
Section 3.1.1. 
A footnote has been added in the study design figure and a 
clarification has been added to a footnote of the figure.  
Sections 3.1.1., 3.6.4., and 3.6.6. 
It has been clarified that the term baseline mentioned in the 
analysis endpoints is referring to the baseline value of the 
preceding Phase IIb study with ALX-0061 (ALX0061-C201 or 
ALX0061-C202) the subject was enrolled in. 
Section 3.2.3.2. 
Wording has been updated for clarification purpose. 
Section 3.3.5. 
The 
use 
of 
the 
allowed 
medication 
non-steroidal 
anti-
inflammatory drugs (NSAIDs) has been further clarified and the 
prohibited medications high-potency opioid analgesics have been 
specified. 
Section 3.4.1.2. 
The number of ambulatory post-baseline visits has been 
corrected. A clarification with regard to missed visits has been 
added and the specification with regard to route of administration 
of methotrexate (MTX) has been deleted. 
Section 3.4.2.6. 
The units for providing C-reactive protein results has been 
corrected.  
Section 3.4.4.2. 
It has been specified that additional pregnancy testing is allowed 
according to local guidelines; however, this additional pregnancy 
testing is not part of and cannot replace the protocol specific 
procedures. 
Section 3.4.4.3. 
Wording has been updated with regard to options to measure 
body temperature. 
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Section 3.5.5. 
Wording with regard to follow-up of adverse events (AEs) was 
updated to clarify that all AEs will be followed until satisfactory 
outcome. 
Section 3.5.6.1. 
Information with regard to pregnancies should be reported using 
the pregnancy form (and not the pregnancy report CRF page). 
Section 3.6.4. 
No subgroup analysis by site for efficacy will be done as the 
number of patients per site is too limited. 
Section 3.6.5. 
Deletion of a redundant statement with regard to the descriptive 
statistical analysis of study drug concentrations as this will be 
performed by a vendor (under the responsibility of Ablynx NV). 
Section 3.6.6.  
Shift tables on vital signs variables according to their normal 
ranges will not be created as these are not expected to provide 
additional clinically useful information on top of the planned 
descriptive summaries on actual values and changes from 
baseline of the vital signs parameters; the latter being more 
relevant in the study population of moderate to severe 
rheumatoid arthritis (RA) patients. Medical assessment of the 
values is performed by the Investigator and during the medical 
review process. 
Section 4.3. 
Wording with regard to signing of the informed consent form 
(ICF) has been updated according to the ICH E6 guideline. 
 
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PROTOCOL SYNOPSIS 
 
 
Protocol Title: 
 
A Phase II Multicenter, Open-Label Extension Study Assessing the Long-Term 
Efficacy and Safety of Subcutaneous ALX-0061 in Subjects with Moderate to Severe 
Rheumatoid Arthritis who Have Completed One of the Preceding Phase IIb Studies 
with ALX-0061 
 
 
Protocol Short Title: 
 
An Open-Label Extension Study Assessing the Long-Term Efficacy and Safety of 
Subcutaneous ALX-0061 in Subjects with Rheumatoid Arthritis 
 
 
Study Drug: 
 
ALX-0061, a Nanobody directed towards the Interleukin-6 receptor (IL-6R) 
 
 
EudraCT n°:  
 
2014-003034-42 
 
 
Sponsor Protocol Code: 
 
ALX0061-C203 
 
 
Sponsor: 
 
Ablynx NV  
Technologiepark 21 
9052 Zwijnaarde, Belgium 
 
 
Phase of Development: 
 
Phase II 
 
 
Indication: 
 
Rheumatoid arthritis (RA) 
 
 
Objective: 
 
• To evaluate the long-term efficacy and safety of ALX-0061 administered 
subcutaneously (s.c.) to subjects with active RA. 
 
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Study Type and Treatments Administered: 
 
This is a multicenter, open-label extension (OLE) Phase II study of ALX-0061 
administered s.c. in subjects with active RA who have completed the treatment and 
assessment period of one of the preceding Phase IIb studies with ALX-0061 
(ALX0061-C201 and ALX0061-C202; placebo and ALX-0061 treatment arms only) 
and who achieved at least 20% improvement in swollen joint count (SJC) and/or 
tender joint count (TJC) (66/68 counts) at the final visit of the preceding study.  
 
Eligible subjects will receive ALX-0061 150 mg s.c. injections, beginning at Week 0 
of the OLE and every 2 weeks (q2w) thereafter, up to and including Week 102.  
Eligible subjects from Study ALX0061-C201 will also continue their MTX treatment.   
 
In the current OLE study, maintenance of response will be reassessed at the study 
visits at Weeks 12, 24, 36, 48, 60, 72, 84 and 96. Subjects who fail to maintain 
response and meet Efficacy Discontinuation Criteria (< 20% improvement in both 
SJC and TJC compared to baseline of the preceding Phase IIb study) will be 
discontinued from the OLE study. 
 
At the study visits at Weeks 0, 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96, study drug 
is to be administered s.c. at the study site. At all other time points, subjects are 
allowed to self-administer away from the clinic. Subjects unable to have injections 
administered away from the study site will be required to return to the site every 2 
weeks for administration of study drug by an authorized health professional.  
 
ALX-0061 will be supplied as a sterile liquid for s.c. injection at a volume of 1.0 mL 
in prefilled single-use syringes.  
 
 
Study Population: 
 
Subjects with active RA who have completed the 24-week (study ALX0061-C201) 
or 12-week (study ALX0061-C202) treatment and assessment period of one of the 
preceding phase IIb studies with ALX-0061, who were randomized to the placebo or 
ALX-0061 arms in the preceding studies, and who achieved at least 20% 
improvement in SJC and/or TJC (66/68 counts) at the final visit of the preceding 
study. More detailed inclusion criteria are available further below. 
 
 
Number of Subjects: 
 
Up to a maximum of approximately 501 subjects (i.e., the sum of the number of 
subjects planned to be assigned to the placebo or ALX-0061 arms in the preceding 
phase IIb studies). 
 
 
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Inclusion Criteria: 
 
The main criteria for inclusion include the following:   
• Must have been eligible for one of the preceding Phase IIb studies with 
ALX-0061 (study ALX0061-C201 or ALX0061-C202), have been randomized to 
placebo or one of the ALX-0061 arms (subjects randomized to tocilizumab [TCZ] 
in study ALX0061-C202 are not eligible), and completed the entire treatment 
and 
assessment 
period 
of 
the 
preceding 
studies 
(i.e., 
24 weeks 
for 
Study ALX0061-C201 and 12 weeks for Study ALX0061-C202). 
• Must have reached at least 20% improvement in SJC and/or TJC (66/68 counts) 
at Week 24 for subjects participating in the preceding Phase IIb ALX0061-C201 
study, or at Week 12 for subjects participating in the preceding Phase IIb 
ALX0061-C202 study. 
 
Exclusion Criteria: 
 
The main criteria for exclusion include the following:   
• Received TCZ during the previous Study ALX0061-C202. 
• Received any prohibited treatment during the previous Phase IIb studies 
(ALX0061-C201 or ALX0061-C202). 
• Diagnosis of or suspicion of a serious infection (requiring parenteral antibiotics 
and/or hospitalization) or tuberculosis (TB) during the preceding study. 
• Diagnosis of malignancy or demyelinating disease during the preceding study. 
• Any active or recurrent viral infection that based on the Investigator´s clinical 
assessment make the subject unsuitable for the study, including recurrent/ 
disseminated herpes zoster. 
• Diagnosis of congestive heart failure (CHF) class III or IV as defined by the New 
York Heart Association, unstable angina pectoris, myocardial infarction, 
cerebrovascular accident during the preceding study. 
• Abnormality in laboratory test results observed at the Week 22 Visit for subjects 
participating in the preceding Phase IIb ALX0061-C201 study, or observed at the 
Week 10 Visit 
for 
subjects 
participating 
in 
the 
preceding 
Phase IIb 
ALX0061-C202 study:  
a. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
levels ≥ 2 times the upper limit of normal (ULN). 
b. Hemoglobin levels ≤ 85 g/L (8.5 g/dL). 
c. Platelet count ≤ 75 x 109/L (75,000 cells/mm³).  
d. Absolute neutrophil count:< 1.5 x 109/L. 
e. Serum creatinine levels ≥ 1.5 mg/dL (133 µmol/L). 
f. 
Any other clinically significant abnormal laboratory result as evaluated by 
the Investigator. 
g. 
If no laboratory test results of the Week 22 Visit (for subjects participating in 
the preceding ALX0061-C201 study) or the Week 10 Visit (for subjects 
participating in the preceding ALX0061 C202 study) are available, then 
laboratory values of tests performed between Week 22 and 24 (for study 
ALX0061-C201) or Week 10 and 12 (for study ALX0061-C202) will be taken 
into account for the exclusion criteria a to e listed above. 
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A complete list of selection criteria can be found in the body of the Clinical Study 
Protocol. 
 
 
Study Drug, Comparator, Dose, Mode of Administration: 
 
• Study drug: 
- Active substance: ALX-0061 Nanobody. 
- Route and volume of administration: s.c. injections at a volume of 1.0 mL. 
 
• Placebo:  
- Not applicable. 
 
 
Study Duration: 
 
The anticipated study duration is a maximum of 114 weeks after entry into the 
OLE. The end of study is defined as the time of the last visit of the last subject 
participating in the study. 
 
• Screening period:  
Not applicable. 
 
• Treatment and assessment period: 
All eligible subjects will receive treatment from Week 0 of the OLE and up to and 
including Week 102. Subjects will return for 12 ambulatory visits planned on 
Weeks 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 and 104. Visit 1 at Week 0 will 
coincide with the last visit of the preceding study. 
 
• End of Treatment Visit (Week 104) (or Early termination Visit for subjects who 
discontinue early)/Follow-up Visit: 
- Subjects who received study drug up to and including Week 102, should 
return for the End of Treatment Visit at Week 104 and for the Follow-up Visit 
12 weeks after the last study drug administration at Week 102. 
- For subjects who will discontinue study participation for fulfilling the efficacy 
discontinuation criteria (see section 3.2.3.2) at Week 12, 24, 36, 48, 60, 72, 
84 or 96, the visit at which subjects will meet these discontinuation criteria is 
defined as the Early Termination Visit. These subjects should return for a 
Follow-up Visit 12 weeks after last study drug administration. 
- Subjects who have to discontinue early for reasons other than the efficacy 
discontinuation criteria, but are not withdrawing consent for post-treatment 
follow-up, should return for an Early Termination Visit 2 weeks after the last 
study drug administration (unless they discontinue during a study visit, in 
which case that becomes their Early Termination Visit). Subjects should also 
return for a Follow-up Visit 12 weeks after last study drug administration. 
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- Subjects who terminate study participation for reasons of lost to follow-up, 
informed consent withdrawal, or death will not have any follow-up 
assessment. 
 
 
Assessments: 
 
Efficacy evaluation: 
• The efficacy endpoints include: 
- American College of Rheumatology (ACR)20, ACR50, and ACR70 response 
over time. 
- Disease activity:  Disease Activity Score using 28 joint counts (DAS28 using 
C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]), 
Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index 
(CDAI). 
- European League Against Rheumatism (EULAR) DAS28 response (good, 
moderate, or no response). 
- Remission using disease remission parameters: DAS28, SDAI, CDAI, Boolean. 
- Health Assessment Questionnaire-Disability Index (HAQ-DI). 
- Physical and mental component scores of Short Form Health Survey (SF-36). 
- Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). 
 
Pharmacokinetics: 
• Determination of ALX-0061 serum levels.  
 
Safety:  
• Safety assessments will include: 
- Physical examinations. 
- Vital sign measurements (diastolic and systolic blood pressure, temperature, 
pulse rate). 
- Clinical laboratory assessments will include blood chemistry, hematology, 
urinalysis, coagulation and the acute phase proteins (CRP, ESR, and 
fibrinogen) as well as change from baseline in these laboratory parameters. 
- Adverse events (including serious adverse events, infections, injection site 
and hypersensitivity reactions). 
 
Immunogenicity:  
• Determination of anti-ALX-0061 antibodies (ADA) and potentially further 
characterization by modified ADA (mADA) assay and neutralizing antibody (nAb) 
assay. 
 
 
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Statistical Methods: 
 
This is an OLE study and is not set by statistical power. Subjects with active RA who 
have completed the 24-week (study ALX0061-C201) or 12-week (study ALX0061-
C202) treatment and assessment period of one of the preceding phase IIb studies 
with ALX-0061, who were randomized to the placebo or ALX-0061 arms in the 
preceding studies, and who achieved at least 20% improvement in SJC and/or TJC 
(66/68 counts) at the final visit of the preceding study, will be invited to participate 
in the extension study. Up to a maximum of approximately 501 subjects will 
participate in this OLE study. Subjects who enrolled in this OLE study will be 
included in the safety and efficacy analyses.  
 
Statistical analyses are considered descriptive. 
 
 
 
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SCHEDULE OF ASSESSMENTS A 
Study Period 
Screening/Baseline, Treatment and Assessment period (Weeks) 
Early 
Termination C 
(Weeks) 
Follow-up 
(Weeks) 
Study Visit D 
Screening/ 
Baseline B 
0  
4 
8 
12 
24 
36 
48 
60 
72 
84 
96 
104 
2 (after last 
study drug 
administration) 
12 (after last 
study drug 
dosing) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
13 
Ambulatory visit  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Written informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of entry criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug injection card dispensation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration (via interactive web 
response system [IWRS]) E 
X 
 Injections to continue every 2 weeks up to and including Week 102  
 
 
Physical examination 
X B 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs F 
X B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tuberculosis (TB) evaluation (questioning) G 
X B 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Routine clinical laboratory analyses H 
X B 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
Extended clinical laboratory analyses (including 
fasting serum lipids) I 
X B 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
Pregnancy test (urine) for females of childbearing 
potential only. 
X B 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Morning stiffness duration  
X B 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Joint assessment (66/68-joint count)  
X B 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IWRS notification of tender & swollen joint counts  
X  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Patient pain visual analogue scale (VAS) 
X B 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Health Assessment Questionnaire – Disability Index 
(HAQ-DI) 
X B 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Short Form (36) Health Survey (SF-36) 
X B 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
Functional Assessment of Chronic Illness Therapy – 
Fatigue (FACIT-Fatigue) 
X B 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
Physician and Patient global assessment of disease 
activity 
X B 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication  
X B  
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events (AEs) J 
X B 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic (PK) samples K 
X B 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Study Period 
Screening/Baseline, Treatment and Assessment period (Weeks) 
Early 
Termination C 
(Weeks) 
Follow-up 
(Weeks) 
Study Visit D 
Screening/ 
Baseline B 
0  
4 
8 
12 
24 
36 
48 
60 
72 
84 
96 
104 
2 (after last 
study drug 
administration) 
12 (after last 
study drug 
dosing) 
Immunogenicity samples K 
X B 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
A. 
All assessments are to be completed prior to the study drug administration, except for subjects who discontinue study drug injections. The order of assessments if more 
than 1 assessment is planned at the same time  should be performed according to the following principles: vital signs should be assessed prior to blood sampling; 
patient reported outcomes should occur prior to the physician’s joint evaluation, independent joint assessment should occur prior to physician’s global assessment, and 
study drug should be dosed after all other assessments have been performed. 
B. 
The Baseline Visit will coincide with the 24-week End of Treatment Visit of the preceding Study ALX0061-C201, or with the 12-week End of Treatment Visit of Study 
ALX0061-C202. The results from the End of Treatment Visit assessments for these studies do not have to be repeated at baseline for this study, and include physical 
examination, vital signs, TB evaluation (questioning), routine/extended clinical laboratory analyses (at Week 22 in Study ALX0061-C201 or at Week 10 in Study 
ALX0061-C202), pregnancy test (urine), morning stiffness duration, joint assessment (66/68-joint count), patient pain VAS, HAQ-DI, SF-36, FACIT-F, physician and 
patient global assessment, concomitant medication, AEs, PK blood samples, and  immunogenicity. 
C. 
The Early Termination Visit is to be performed 2 weeks after the last study drug dosing for subjects who discontinue from the trial for other reasons than described in the 
efficacy discontinuation criteria (see section 3.2.3.2), unless they discontinue during a study visit, in which case that becomes their Early Termination Visit. For subjects 
who will meet the efficacy discontinuation criteria at Week 12, 24, 36, 48, 60, 72, 84 or 96, the visit at which subjects will meet these discontinuation criteria is defined 
as the Early Termination Visit.  
D. All post baseline visits may occur at the indicated week ± 3 days throughout the trial. 
E. 
At the study visits at Weeks 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96, study drug is to be administered s.c. at the study site. At all other time points, subjects are 
allowed to self-administer away from the clinic. Subjects unable to have injections administered away from the study site will be required to return to the site every 2 
weeks for administration of study drug by an authorized health professional.  
F. 
Vital signs (assessment after 5 minutes in supine position) will include weight, blood pressure, pulse, and temperature. A height measurement is not required (data 
available from the preceding study). In case blood sampling is to be performed at the same visit, the vital signs assessment is to be performed prior to the blood 
sampling. 
G. If TB is suspected at any time during the study, chest x-ray and interferon-gamma release assay (IGRA) should be performed. 
H. Samples for routine clinical laboratory analyses will be collected predose, and include blood chemistry, hematology, acute phase proteins (C-reactive protein [CRP], 
erythrocyte sedimentation rate [ESR], fibrinogen) and urinalysis (urinalysis at Weeks 48 and 104). For subjects on warfarin, international normalized ratio (INR) will be 
performed at Weeks 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96, or at the Early Termination Visit.  
I. 
At the indicated visits, samples for extended clinical laboratory analyses, including fasting serum lipids on top of the routine clinical laboratory analyses, will be 
performed predose. Extended clinical laboratory samples will be taken predose after the subject has been fasting for at least 10 h.  
J. 
AEs will be recorded from the time the informed consent form is signed through the Follow-up Visit. The Investigator must follow-up on all SAEs and AEs until the events 
have subsided, returned to baseline, or the subject’s condition has stabilized in cases of permanent impairment. In case of acute or delayed severe/serious 
hypersensitivity reactions, an additional serum sample should be collected as soon as possible after the start of the event (blood volume: 5 mL). 
K. PK and immunogenicity samples will be taken predose. 
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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 RA and systemic lupus erythematosus (SLE).  
 
The currently proposed clinical study is intended to evaluate the long-term efficacy 
and safety of ALX-0061 administered s.c. to subjects with active RA.  
 
1.1. RHEUMATOID ARTHRITIS 
 
RA is a chronic systemic inflammatory autoimmune disease that affects 0.5-1% of 
the population and is 3-times more prevalent in women than in men [1]. It is 
clinically characterized by joint pain, stiffness, and swelling due to synovial 
inflammation, leading to joint damage, deformity, severe disability, and increased 
mortality. Patients may develop multiple systemic symptoms including fever, 
fatigue, anemia, and osteoporosis.  
 
1.1.1. TREATMENT OF RHEUMATOID 
ARTHRITIS 
 
The goal of therapy is to reduce inflammation, inhibit joint damage, prevent loss of 
function, decrease pain, and improve function as well as quality of life. Initial 
treatment options include disease-modifying anti-rheumatic drugs (DMARDs), non-
steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, analgesics, surgery, 
physiotherapy, and occupational therapy. 
 
The synthetic DMARDs most commonly used include methotrexate (MTX), 
sulfasalazine, leflunomide, hydroxychloroquine, cyclosporine A, and glucocorticoids. 
The therapeutic benefits of DMARDs in RA include control of signs and symptoms, 
improvement of functional status and of quality of life, and retardation of joint 
damage progression [2]. MTX, administered alone or in combination with another 
conventional DMARD, is the recommended first-line therapy for patients with RA 
[3].  
 
For patients with an inadequate response to conventional DMARDs, biological drugs 
may be indicated. These biological drugs block certain key molecules that are 
involved in the pathogenesis of the illness. These targets include tumor necrosis 
factor alpha (TNF α), selective T-cell costimulation molecule (such as cytotoxic T-
lymphocyte-associated protein 4), cluster of differentiation 20 (CD20), interleukin-1 
(IL-1), IL-6, and interleukin-6 receptor (IL-6R). The development of immune-
modulating agents has offered new treatment options for patients.  
 
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Although anti-TNF α agents and other biological DMARDs have been established as 
effective treatment options for RA, there are reasons to study the effectiveness and 
the maintenance of response of new therapeutic agents. For example, there is a 
subset of the patient population that does not achieve a clinical response, defined 
as American College of Rheumatology (ACR) 20 response, and only a small 
proportion achieve a high level ACR response (ACR50 or ACR70) [4]. Although 
therapy with biological DMARDs has been successful in the treatment of RA, certain 
patients may lose clinical response over time for various reasons such as disease 
burden, low drug serum levels, rapid clearance and immunogenicity. In addition, 
biological DMARDs have limitations with respect to safety, dosing regimen, way of 
administration, and immunogenicity. Thus there is the potential for new therapeutic 
agents to address some of these limitations and to improve the long-term 
effectiveness and safety of biological agents in treating RA. 
 
1.1.2. ROLE OF IL-6R IN  
PATHOPHYSIOLOGY OF RHEUMATOID 
ARHTRITIS 
 
IL-6 is a pleiotropic cytokine with a wide range of biological activities. The IL-6 
pathway functions through the interaction of IL-6 with its receptor IL-6R. This 
cytokine-receptor complex interacts with a third partner, the adaptor molecule 
glycoprotein 130 (gp130), responsible for signal transduction and activation of the 
cell [5]. IL-6R is present not only as a membrane bound form but also as a soluble 
form. sIL-6R can interact with IL-6 and this complex can activate gp130-positive 
cells without the presence of membrane-bound (m)IL-6R on the surface of the 
cells. This process is called trans-signaling and implies that mIL-6R negative cells 
are also susceptible to activation, with soluble IL-6R acting as an agonist [5, 6]. 
 
As IL-6 is a pleiotropic cytokine, its function is highly diverse. Many studies 
revealed that this molecule through binding to the target IL-6R and gp130 functions 
in the immune, hematopoietic, hepatic, and neural systems [7, 8]. IL-6 plays also a 
critical role in different aspects of RA such as the transition from the acute phase of 
the inflammation to the chronic irreversible status [9], stimulation of B cells to 
produce auto-antibodies, cartilage destruction [10], or anemia [11]. 
 
High concentrations of IL-6 have been documented in the serum of RA and juvenile 
RA patients [12]. Several studies have shown that sIL-6R is also elevated in both 
RA and systemic onset juvenile RA patients [13]. Analysis of the IL-6 and sIL-6R 
concentrations in synovial fluid showed that the extent of joint destruction 
correlated with increased concentrations of both ligand and receptor [12]. However, 
resident cells of the joint (chondrocytes, synoviocytes, fibroblasts, endothelial cells) 
do not express mIL-6R, indicating that high levels of sIL-6R are likely to be 
expressed by infiltrating leukocytes [13]. This indicates that sIL-6R is important in 
the chronic inflammatory setting of RA. 
 
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Based on the findings that the IL-6 pathway is important in chronic inflammatory 
diseases, drugs targeting this pathway are in development. Multiple clinical studies 
have demonstrated that treatment with IL-6 pathway inhibitors can improve 
manifestations of RA, supporting the concept that IL-6 signaling plays a key role in 
RA.   
 
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 therapeutic proteins that are 
derived from the smallest functional fragments of heavy chain only antibodies, 
which 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 host cells such as Pichia pastoris. 
 
ALX-0061 Nanobody consists of 2 humanized and sequence-optimized variable 
domains derived from heavy chain-only llama antibodies: 
• One domain (designated 20A11) binds to human IL-6R.  
• The second domain (designated ALB11) binds to human serum albumin (HSA), 
as a means to improve the PK properties of the Nanobody (half-life extension).  
 
ALX-0061 Nanobody inhibits the interaction between the IL-6 ligand and the 
receptor subunit, thereby preventing receptor signaling. ALX-0061 has a higher 
affinity for sIL-6R than for mIL-6R, and thus preferentially targets sIL-6R (the 
trans-signaling pathway). This target binding profile of ALX-0061 may result in a 
stronger engagement of the disease-driving target form (sIL-6R) [6] in a 
physiological situation with both forms (sIL-6R and mIL-6R) present. 
 
The second domain of ALX-0061 was designed to improve the PK properties of the 
Nanobody by binding to human serum albumin. Albumin is the most abundant 
protein in plasma and has a half-life of approximately 19 days in humans [14]. 
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 [14].  
 
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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 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/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 monkey. 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, a Good Laboratory 
Practice 
(GLP)-compliant 
13-week 
repeated-dose 
i.v. 
toxicity 
study, 
a 
GLP-compliant 4-week repeated dose i.v./s.c. toxicity study, and a 26-week 
repeated-dose i.v. 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. 
 
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 volunteers, has been completed. This 
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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. 
 
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 
In the MAD part of the study, all ALX-0061 treatment combinations showed rapid 
and long-lasting improvements in disease activity (as measured by ACR, EULAR, 
Disease Activity Score using 28 joint counts (DAS28) [CRP], Clinical Disease 
Activity Index (CDAI), and Boolean remission responses). There were high numbers 
of responders in all ALX-0061 treatment groups, with DAS28 remission observed in 
63% of ALX-0061-treated subjects at Week 24, and none of the ALX-0061-treated 
subjects showed worsening of disease activity during the study period. Overall, the 
efficacy profile obtained at Week 12 continued to improve during the subsequent 
12 weeks of ALX-0061 treatment. 
 
Pharmacokinetics 
The pharmacokinetics of ALX-0061 appear 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 the drug with the increase of the dose. Similar to monoclonal antibodies, 
the Nanobody has a limited volume of distribution, corresponding to the plasma 
volume. As the PK of ALX-0061 is dose-dependent due to a different contribution of 
the non-linear clearance at different serum concentrations, also the terminal half-
life (t1/2) is dose-dependent. At high concentrations, when non-linear clearance 
becomes negligible, the apparent t1/2 estimated from the linear clearance term only, 
is estimated at approximately 15 days. 
 
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. 
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• 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 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-emergent AEs 
(TEAEs) when comparing the individual ALX-0061 treatment groups, and there 
was no evidence to suggest that a 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 cerebrovascular accident occurred several days 
later and the subject died. Both events were considered remotely relateda to 
the study drug 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 treatment-emergent AEs (TEAEs) 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 
                                           
a The relationship between AEs and study medication was to be indicated as “none”, “remote”, 
“possible”, “probable” or “definite”. 
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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 ALX0061-C102 IN HEALTHY 
VOLUNTEERS 
 
Overall, a single s.c. dose of ALX-0061 in the dose range of 50 to 300 mg was safe 
and well-tolerated in a group of 70 healthy male and female subjects. The s.c. 
bioavailability of ALX-0061 was 82.3% as estimated by the population PK model.  
 
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 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.  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 CRP levels was observed following administration 
of ALX-0061. One subject in the 300 mg i.v. group showed a clinically non-
significant increase in ALT starting at 168 h post-dose up to a maximum of 150 U/L 
at 1080 h post dose. This was accompanied by a mild rise in AST and no rise in 
bilirubin. The ALT level had returned to baseline at follow-up. 
 
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. 
 
1.2.5. BENEFITS AND RISK ASSESSMENT   
 
Although a number of treatment options are available for RA, there remains a clear 
need for novel therapeutics. Many patients do not benefit optimally from the 
available small molecule and biologic drugs, leaving opportunity for differentiated 
drugs with new modes of action and an improved safety profile.  
 
Considering the importance of IL-6 in chronic inflammatory diseases, several 
companies are developing drugs that target this pathway, and multiple clinical 
studies have demonstrated that treatment with IL-6 pathway inhibitors can improve 
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manifestations of RA. ALX-0061, administered i.v. and in combination with MTX, 
has been shown to be effective in reducing signs and symptoms for the treatment 
of subjects with active RA.  
 
The current study is designed to evaluate the efficacy and safety of ALX-0061, 
administered s.c. in subjects with active RA, who have had an inadequate response 
to methotrexate (subjects from study ALX0061-C201), or who are intolerant to MTX 
or for whom continued MTX is inappropriate (subjects from study ALX0061-C202). 
Potential candidates for this study are required to have objective evidence of active 
disease.  
 
The Sponsor is studying s.c. administration in an effort to develop a route of 
administration which will offer an alternative and more convenient option for 
administration, while maintaining its clinical efficacy and safety profile. Details on 
the design of, and rationale for, the current study are available in section 3.1.1 of 
the protocol.  
 
An assessment of potential risks associated with inhibition of the IL-6 pathway, or 
inherent to the administration of therapeutic proteins, is described  below. 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 [15, 16]. 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, SAA and fibrinogen [17, 18].  
- Rapid and long-lasting decreases in CRP, 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 (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 [19].  
- 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. No TEAEs 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). 
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- In study ALX0061-C102, the results show a tendency towards a transient and 
mild decrease neutrophil count. 
 
• Increased transaminase levels (AST/ALT) in serum and increased cholesterol 
(HDL, LDL and triglycerides) levels have been reported following pharmacological 
inhibition of the IL-6 pathway [20]. With the exception of individual subjects 
showing increases beyond the normal range, there were no clinically relevant 
trends in mean liver (ALT/AST/GGT/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. 
 
• Recent data indicate that RA subjects have a generally increased rate of 
gastrointestinal (GI) perforation [21]. 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 GI 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. 
- In study ALX0061-C102, no hypersensitivity reactions were reported. 
 
• Administration of any protein therapeutic can lead to the development of ADA 
[22]. The currently available immunogenicity (ADA) results after i.v. and s.c. 
administration of ALX-0061 do not indicate meaningful 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 effects would constitute clinically meaningful risks for administration of 
ALX-0061; additional clinical studies are needed for further evaluation. In general, 
the pharmacological effects reported during Study ALX-0061-1.1/10 were reversible 
and associated with clinical response in signs and symptoms of RA. For additional 
and more detailed information regarding ALX-0061, the investigator is referred to 
the current Investigator's Brochure. 
  
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2. OBJECTIVES 
 
The objective of this study is to evaluate the long-term efficacy and safety of 
ALX-0061 administered s.c. to subjects with active RA. 
 
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3. STUDY DESIGN 
 
3.1. OVERALL STUDY DESIGN 
 
3.1.1. 
STUDY OVERVIEW 
 
This is a multicenter, open-label extension (OLE) Phase II study of ALX-0061 
administered s.c. in subjects with active RA who have completed the treatment and 
assessment period of one of the preceding Phase IIb studies with ALX-0061 
(ALX0061-C201 and ALX0061-C202; placebo and ALX-0061 treatment arms only) 
and who achieved at least 20% improvement in swollen joint count (SJC) and/or 
tender joint count (TJC) (66/68 counts) at the final visit of the preceding study. 
 
An overview of the study design is included in Figure 1. 
 
Figure 1: Overview of the design of Study ALX0061-C203 
 
 
 
a  Placebo and ALX-0061 treatment arms only 
b  Stopping criteria beginning at Week 12 and every 12 weeks of OLE for non-responders: patients with 
< 20% improvement in both TJC and SJC from baseline (of the respective initial Phase IIb study) will 
have study drug injections discontinued, and will be discontinued from the study in order to receive 
standard of care. q2w: every 2 weeks. 
 
Eligible subjects will receive ALX-0061 150 mg s.c. injections, beginning at Week 0 
of the OLE and every 2 weeks (q2w) thereafter up to and including Week 102. 
Eligible subjects from Study ALX0061-C201 will also continue their MTX treatment. 
 
The dose regimen, 150 mg s.c. every two weeks (q2w), was selected as this dose 
level is expected to be effective based on exposure-response modelling (PK-DAS28) 
of ALX-0061 using data from studies ALX-0061-1.1/10 and ALX0061-C102. 
Moreover, this regimen is covered by adequate safety margins, when comparing 
the model predicted human exposure with the observed exposure in the toxicity 
studies. 
 
In the current OLE study, maintenance of the response will be reassessed at the 
study visits at Weeks 12, 24, 36, 48, 60, 72, 84 and 96. Subjects who fail to 
maintain response and meet Efficacy Discontinuation Criteria (< 20% improvement 
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in both SJC and TJC compared to baseline of preceding study) will be discontinued 
from the OLE study. 
 
Evidence for efficacy will be obtained by analysis of the ACR20, ACR50, ACR70, 
ACR-N response rates, EULAR response, and measures of remission using the 
DAS28, the CDAI, the Simplified Disease Activity Index (SDAI), and the Boolean 
remission definition. Other RA domains, such as improvement in physical function 
and health-related quality-of-life, will be evaluated using the HAQ-DI, FACIT-fatigue 
scale, and the SF-36 questionnaires. 
 
Safety and tolerability assessments will include evaluation of AEs (including serious 
adverse events, infections, injection site and hypersensitivity reactions), laboratory 
assessment, urinalysis, vital signs, and physical examination. 
 
Additional planned assessments include determination of ALX-0061 levels in serum. 
To assess immunogenicity, the presence of ADA will be measured in serum until the 
Follow-up Visit, with potentially further characterization by modified ADA (mADA) 
and neutralizing antibody (nAb) assay. 
 
The anticipated study duration for each subject is a maximum of 114 weeks after 
entry into the OLE. Subjects who received study drug up to and including 
Week 102, should return for the End of Treatment Visit at Week 104, and for the 
Follow-up Visit 12 weeks after the last study drug administration at Week 102. The 
end of the study is defined as the time of the last visit of the last subject 
participating in the study. 
 
Study Treatment Allocation 
 
At the Week 24 (ALX0061-C201) or Week 12 (ALX0061-C202) visit of the previous 
study, informed consent will be obtained from all subjects who are deemed 
potentially eligible for the OLE study, according to the protocol-specified inclusion 
and exclusion criteria.  
 
Eligible subjects will receive ALX-0061 150 mg s.c. injections beginning at Week 0 
of the OLE and q2w thereafter up to and including Week 102.  
 
At the study visits at Weeks 0, 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96, study drug 
is to be administered s.c. at the study site. At all other time points, subjects are 
allowed to self-administer away from the clinic. Subjects unable to have injections 
administered away from the study site will be required to return to the site every 2 
weeks for administration of study drug by an authorized health professional.  
 
ALX-0061 will be supplied as a sterile liquid for s.c. injection at a volume of 1.0 mL 
in prefilled single-use syringes. More details (including information on drug 
accountability) are provided in section 3.3. 
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3.1.2. 
BLINDING 
 
As this is an OLE study, blinding is not required. 
 
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3.2. SELECTION OF STUDY 
POPULATION 
 
Up to a maximum of approximately 501 subjects (i.e., the sum of the number of 
subjects planned to be assigned to the placebo or ALX-0061 arms in the preceding 
Phase IIb studies) are planned to be included in the study.  
 
3.2.1. INCLUSION CRITERIA 
 
Each potential subject must satisfy all of the following criteria to be enrolled in the 
study: 
1. Must have been eligible for one of the preceding Phase IIb studies with 
ALX-0061 (ALX0061-C201 or ALX0061-C202), have been randomized to placebo 
or one of the ALX-0061 arms (subjects randomized to tocilizumab [TCZ] in 
Study ALX0061-C202 are not eligible) and completed the entire treatment and 
assessment 
period 
of 
the 
preceding 
studies 
(i.e., 
24 
weeks 
for 
Study ALX0061-C201 and 12 weeks for Study ALX0061-C202). 
2. Must have reached at least 20% improvement in SJC and/or TJC at Week 24 for 
subjects participating in the preceding Phase IIb ALX0061-C201 study, or at 
Week 12 for subjects participating in the preceding Phase IIb ALX0061-C202 
study. 
3. 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 (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/baseline until at least 6 months after last dosing.  
 
Male subjects must use condoms for the duration of the study and for at least 
6 months after last administration of study drug. 
4. Ability to comprehend and willingness to sign the informed consent form (ICF). 
5. An understanding of and ability and willingness to adhere to the study visit 
schedule and other protocol requirements. 
 
3.2.2. EXCLUSION CRITERIA 
 
Subjects meeting any of the following criteria may not be enrolled in the study: 
1. Received TCZ during the preceding Study ALX0061-C202. 
2. Received any prohibited treatment during the preceding Phase IIb studies 
(ALX0061-C201 or ALX0061-C202). 
3. Diagnosis of or suspicion of a serious infection (requiring parenteral antibiotics 
and/or hospitalization) or TB during the preceding study. 
4. Diagnosis of malignancy or demyelinating disease during the preceding study. 
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5. Any active or recurrent viral infection that based on the Investigator´s clinical 
assessment make the subject unsuitable for the study, including recurrent/ 
disseminated herpes zoster. 
6. Diagnosis of congestive heart failure (CHF) class III or IV as defined by the New 
York Heart Association, unstable angina pectoris, myocardial infarction, 
cerebrovascular accident during the preceding study. 
7. Planned donation of germ cells, blood, organs, or bone marrow during the 
course of the study or within 6 months thereafter. 
8. Male with female partner who is planning to become pregnant within 6 months 
after last dosing. 
9. Pregnant woman or female subjects who are breastfeeding. 
10. History of anaphylactic reaction or serious hypersensitivity reaction during the 
previous study. 
11. Anticipation that a live attenuated vaccine will be required during the study or 
within 6 months after last dosing. 
12. Abnormality in laboratory test results observed at the Week 22 Visit for 
subjects participating in the preceding Phase IIb ALX0061-C201 study, or 
observed at the Week 10 Visit for subjects participating in the preceding 
Phase IIb ALX0061-C202 study:  
a. ALT and/or AST levels ≥ 2 times the ULN. 
b. Hemoglobin levels ≤ 85 g/L (8.5 g/dL). 
c. Platelet count ≤ 75 x 109/L (75,000 cells/mm³).  
d. Absolute neutrophil count:< 1.5 x 109/L. 
e. Serum creatinine levels ≥ 1.5 mg/dL (133 µmol/L). 
f. Any other clinically significant abnormal laboratory result as evaluated by 
the Investigator. 
g. If no laboratory test results of the Week 22 Visit (for subjects participating in 
the preceding ALX0061-C201 study) or the Week 10 Visit (for subjects 
participating in the preceding ALX0061 C202 study) are available, then 
laboratory values of tests performed between Week 22 and 24 (for study 
ALX0061-C201) or Week 10 and 12 (for study ALX0061-C202) will be taken 
into account for the exclusion criteria 12a to 12e listed above. 
13. 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. SUBJECT DISCONTINUATION 
CRITERIA 
 
The subject discontinuation criteria are described below: 
 
Efficacy discontinuation criteria: 
Any subject with < 20% improvement from baseline (of the respective initial Phase 
IIb study) in both swollen and tender joint count (SJC and TJC; 66/68 counts) at 
any of the visits at Week 12, 24, 36, 48, 60, 72, 84 or 96, will discontinue from the 
trial. The visit at which subjects will meet the efficacy discontinuation criteria, is 
defined as the Early Termination Visit for these patients. Subjects who have to 
discontinue study drug but are not withdrawing consent for post-treatment follow-
up, should return for the Follow-up Visit, planned 12 weeks after the last study 
drug administration, according to section 3.4.1.3.  
 
Study drug must also be permanently discontinued if any of the following 
occurs:   
• Serious hypersensitivity reaction. 
• Following abnormalities in laboratory test results: ALT and/or AST elevations 
between > 3 and ≤5 x ULN (confirmed by repeat testing within 2-4 weeks), ALT 
or AST elevations > 5 x ULN, absolute neutrophil count < 1 x 109/L, or a platelet 
count < 50 x 103/μL.  
• Diagnosis of or suspicion of a serious infection (requiring parenteral antibiotics 
and/or hospitalization) or TB. 
• Malignancy. 
• Pregnancy or pregnancy planned within the study period  
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• Demyelinating disease. 
• The initiation of protocol-prohibited medications (see section 3.3.5). 
• CHF class III or IV as defined by the New York Heart Association, unstable 
angina pectoris, myocardial infarction, cerebrovascular accident. 
• 
In case of interruption of study drug administration for 2 consecutive doses. 
• The Investigator or the Sponsor’s medical monitor deems it is in the subject’s 
best interest. 
 
Discontinuation of study drug must be considered for subjects who develop a 
severe study drug injection-site reaction or a severe hypersensitivity reaction. 
 
Subjects who have to discontinue according to these criteria but are not 
withdrawing consent for post-treatment follow-up should return for the Early 
Termination Visit planned 2 weeks after the last study drug administration (unless 
they discontinue during a study visit, in which case that becomes their Early 
Termination Visit). Subjects should also have a Follow-up Visit planned 12 weeks 
after the last study drug administration, according to section 3.4.1.3. 
 
A description of procedures to be performed for subjects who withdraw from the 
study or study drug will be 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, 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 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 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. 
 
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 suspends or terminates 
participation in the study, the Investigator will promptly inform the Sponsor and the 
IEC/IRB and provide them with a detailed written explanation. The Investigator will 
also return all study drug, study drug containers, and other study materials to the 
Sponsor or its designee.  
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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 15 days 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. IDENTITY OF STUDY DRUG 
 
• Study drug:  
- 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 injections. ALX-0061 will be supplied as a sterile liquid for s.c. 
injection at a volume of 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 1.0 mL. 
 
The Sponsor will be providing adequate supplies of ALX-0061 for this study. 
 
3.3.2. 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. 
 
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 a description of the 
formulation and the quantity of study drug received for the study and a record of 
the materials that are dispensed, to whom and when. 
 
At all time points when the subjects are to self-administer the study drug, the 
subject will note the exact timing of dosing in the study drug injection card. At 
every next visit, subjects are required to return all study drug supplies (used and 
unused syringes) to study sites. 
 
On termination of the study, 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 on the Drug Accountability Form. All study drug supplies 
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will be returned to and destroyed by a vendor upon Sponsor approval, or will be 
locally destroyed according to site procedure upon Sponsor approval. 
 
Instructions for study drug accountability are available in the Study Drug Manual. 
 
3.3.3. STUDY DRUG HANDLING 
 
Instructions for study drug administration, handling, and storage, are available in 
the Study Drug Manual. 
 
Packaging and Labeling 
The study drug will be labeled in accordance with 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. 
 
One kit will contain 1 syringe.  
 
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 must be refrigerated at 2°C to 8°C (35.6 °F to 46.4 °F) and should be 
stored in the secondary packaging 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 Study Drug Manual.  
 
Verbal and written instructions for proper storage, handling, and administration of 
the study drug will be given to the subject, and will include instructions to contact 
the study site immediately if they experience problems with the study drug and/or 
administration. 
 
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. 
 
See the Schedule of Assessments for when clinical supplies are to be dispensed to 
the subjects. For self-injections, enough study drug until the next visit will be 
provided for the subjects to take home. All used and unused syringes should be 
returned to the site at the following clinic visit. At each visit, the site will review the 
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injection card to check whether the pre-filled syringes were used, partially used, or 
unused by the subject. 
 
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.  
 
3.3.4. STUDY DRUG INJECTIONS 
 
At the study visits at Weeks 0, 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96, study drug 
is to be administered s.c. at the study site. Subjects will remain at the site for 
60 minutes after the injection in order to assess adverse reactions. 
 
At all other time points, subjects are allowed to self-administer away from the clinic 
(after proper training in s.c. injection technique at Week 0). Subjects unable to 
have injections administered away from the study site will be required to return to 
the site every 2 weeks for administration of study drug by an authorized health 
professional.  
 
All subjects are to receive 1 injection in the abdominal region at each dosing day. 
As injections are to be performed q2w, all 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).  
 
Detailed instructions for study drug administration are available in the Study Drug 
Manual.  
 
No constraints with regard to timing of study drug administration during the day of 
dosing are to be taken into account. The exact times of medication dosing at the 
clinical site will be recorded in the (e)CRF.  
 
3.3.5. PRIOR AND CONCOMITANT THERAPY 
 
Prior and concomitant medication are documented throughout the study. 
 
During the 104-week treatment and assessment period of the study, subjects are 
not allowed to initiate DMARDs (other than MTX for subjects who completed the 
preceding Study ALX0061-C201, see below).  
 
Permitted Medication 
Subjects 
who 
completed 
the 
prior 
combination 
therapy 
study 
(Study ALX0061-C201) will receive ALX-0061 and will be recommended to continue 
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with 
MTX, 
while 
subjects 
who 
completed 
the 
prior 
monotherapy 
study 
(Study ALX0061-C202; except those who were assigned to TCZ) will receive 
ALX-0061 as monotherapy. 
 
MTX will not be considered one of the study agents and the MTX dose can be 
adjusted at the Investigator’s discretion. 
 
Commercially available MTX will be used in this study and will not be provided by 
the Sponsor. Continued supplementation with oral folic acid or oral folinic acid 
should be given at the discretion of the treating physician for patients on MTX.  
 
Subjects treated with NSAIDs (including aspirin and selective cyclooxygenase 2 
inhibitors) and other analgesics (except high-potency opioid analgesics; see 
prohibited medication) should receive the usual marketed doses approved in the 
country in which the study is being conducted, and should be on a stable dose 
whenever its possible until the Week 104 visit, or until the Early Termination Visit. 
Changes in the dose may be done at the discretion of the Investigator if he/she 
feels it is medically justified. Whenever possible, short-acting NSAIDs and other 
analgesics should not be administered within 6 hours before study assessments. 
Long-acting ones can be maintained at their usual dosing intervals before study 
assessments. 
 
Subjects treated with oral corticosteroids should receive a stable dose equivalent to 
≤ 10 mg of prednisone/day, up to and including Week 104, or until the Early 
Termination Visit. The dose of oral corticosteroid may be changed at the discretion 
of the Investigator.  
 
The number of intra-articular (i.a.) corticosteroid injections is limited to 2 injections 
over a 104-week period. The joint(s) affected by the procedure(s) will be 
considered as swollen and tender for 28 days/4 weeks in the data analyses from 
the date of the procedure onward. 
 
The use of concomitant medication will be evaluated at Weeks 0, 4, 8, and 12, and 
every 12 weeks thereafter; however, treating physicians should monitor MTX and 
other therapies in accordance with appropriate clinical guidelines. 
 
The expression of hepatic CYP450 enzymes is suppressed by IL-6. IL-6 blocking 
might therefore influence (normalize) CYP450 expression and products that are 
substrates for CYP450 enzymes (e.g., statins, warfarin, theophylline, oral 
contraceptives, calcium antagonists phenytoin, cyclosporine, benzodiazepines) 
could be metabolized faster. Subjects taking medicinal products which are 
metabolized via CYP450 3A4, should be closely monitored and their treatment 
might have to be adapted if necessary in order to maintain therapeutic efficacy. 
Subjects on warfarin will be monitored by assessment of INR (see Schedule of 
Assessments); the lipid levels will be evaluated which will be of help to monitor the 
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subjects on statins (see Schedule of Assessments). If needed, the Investigator or 
the relevant treating physician should adapt the treatment of the concerned subject 
(unscheduled visits can be planned upon the discretion of the treating physician). 
Given the long half-life of ALX-0061, the influence on the hepatic enzymes can 
persist for several weeks.  
 
Other medication (e.g., to treat AEs) may only be prescribed after consultation with 
the Investigator, unless in case of an emergency situation that does not allow 
discussion. 
 
Prohibited Medication 
The following medications are prohibited during the study (up to and including 
Week 104 or Early Termination Visit): 
• 
DMARDs (other than MTX for subjects who completed the preceding Study 
ALX0061-C201). 
• 
Intramuscular (i.m.) administration of corticosteroids for the treatment of RA. In 
this study, oral corticosteroids can be increased to 10 mg/day. For i.a. dosing 
see ”permitted medication”. 
• 
High-potency opioid analgesics, including but not limited to hydrocodone, 
metopon, oxycodone, clonitazene, hydromorphone, oxymorphone, morphine, 
fentanyl, levorphanol, buprenorphine, methadone, meperdine. 
• Use of, any biological DMARD, targeted synthetic DMARD (such as tofacitinib), or 
investigational drugs. 
• Use of any live attenuated vaccine. 
 
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 (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/baseline until at least 6 months after last dosing.  
 
No additional contraceptive method is needed in case of surgical sterilization (at 
least 3 months prior to screening/baseline), hysterectomy, a partner who has been 
vasectomized (at least 3 months prior to screening/baseline).  
 
Male subjects should use condoms for the duration of the study and for at least 
6 months after last administration of study drug. 
 
Other 
During the study, no alcohol abuse or drug abuse is allowed. 
 
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3.3.6. TREATMENT COMPLIANCE 
 
To ensure treatment compliance, study drug dosing will be supervised by the 
Investigator 
or 
his/her 
designee, 
except 
when 
study 
drug 
is 
to 
be 
self-administered. 
 
The exact times of study drug 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/administrations, will be recorded in the 
(e)CRF. 
 
Each subject will be provided with a study drug injection card to collect the date 
and time of each study drug administration. This information will be recorded on 
the card by the subject for all study drug doses administered away from clinic.  
 
The subject must bring his/her injection card to all study visits. At each visit, the 
site will review the card, record the new information in the (e)CRF, and return the 
card to the subject. Subjects will be instructed to return the completed card at their 
final visit. 
 
3.3.7. RANDOMIZATION 
 
As this is an OLE study in which all subjects will receive the same treatment 
regimen, no randomization is required. 
 
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3.4. ASSESSMENTS 
 
3.4.1. TIMING OF ASSESSMENTS 
 
Written informed consent will be obtained at the Week 24 (study ALX0061-C201) or 
Week 12 (study ALX0061-C202) visit of the preceding Phase IIb study/Week 0 visit 
of the OLE study (prior to dosing at Week 0). 
 
After informed consent has been obtained, each subject will be assigned a unique 
subject identification (ID) number. Note that through (e)CRF the subject’s previous 
subject ID number and the previous study ID will also be captured. 
 
AEs and previous/concomitant medications will be recorded from the study inclusion 
date (ICF signed) to the subject’s last visit. The AE and previous/concomitant 
medications recorded in the preceding study which are “ongoing” at the moment of 
signing the ICF for the OLE study, will also be captured in the OLE (e)CRF.  
 
3.4.1.1. ELIGIBILITY PROCEDURES 
 
At screening/baseline, which will coincide with the 24-week (Study ALX0061-C201) 
or the 12-week (ALX0061-C202) End of Treatment Visit of the preceding study, 
subjects will be screened according to the inclusion and exclusion criteria (see 
section 3.2) and will have other assessments performed as specified in the 
Schedule of Assessments. 
 
Subjects who signed an informed consent form, but do not meet the eligibility 
criteria and are not enrolled, will be designated a screen failure. Subjects who meet 
all eligibility criteria but discontinue from the study for other reasons (eg, subject 
request) will not be considered screen failures. 
 
Data of all subjects screened will be collected in the (e)CRF in order to assess the 
numbers and characteristics of the excluded subjects, and the reasons for their 
exclusion. 
  
The results from the screening/baseline procedures needed to evaluate eligibility 
must be available prior to the first administration of the study drug. Sites will use 
the central laboratory selected for the study to analyze screening/baseline samples 
and to use these reported values to determine eligibility. Note that laboratory tests 
will be conducted at the Week 22 visit for subjects participating in the preceding 
ALX0061-C201 study and at the Week 10 visit for subjects participating in the 
preceding study ALX0061-C202.  
 
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Subjects who are not eligible to participate in the OLE study should return for the 
Follow-up Visit approximately 12 weeks after the last study drug injection in the 
preceding study (ALX0061-C201 or ALX0061-C202). 
 
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. 
 
3.4.1.2. TREATMENT AND ASSESSMENT 
PERIOD 
 
Week 0 (Baseline) 
As the Baseline Visit (Week 0) coincides with the Week 24 (Study ALX0061-C201) 
or Week 12 (Study ALX0061-C202) visit of the preceding study, assessments 
planned at both visits only need to be performed once (results will be used for both 
studies). The data collected at the Week 24/Week 12 visit of the preceding study 
will be used for the statistical analysis based on all necessary parameters assessed 
at the Baseline Visit (Week 24/Week 12). 
 
Post-baseline Assessments 
Eligible subjects will receive treatment q2w from Week 0 up to and including 
Week 102. Subjects will return for 11 ambulatory post-baseline visits planned 
during the treatment and assessment period on Weeks 4, 8, 12, 24, 36, 48, 60, 72, 
84, 96, and 104.  
 
An End of Treatment Visit (or Early Termination Visit) will be performed at 
Week 104 (or within 2 weeks after the last visit for subjects who discontinue early) 
and a Follow-up Visit will be performed 12 weeks after the last study drug 
administration. Note that subjects who withdrew for reasons of lost to follow-up, 
informed consent withdrawal, or death, will not have any follow-up assessments.  
 
All assessments will be performed at the visits as indicated in the Schedule of 
Assessments. 
 
All post-baseline visits, except for the Early Termination Visit, may occur at the 
indicated week ± 3 days throughout the study versus the date of the Baseline Visit.  
 
Any subject with < 20% improvement from baseline (of the respective initial Phase 
IIb study) in both swollen and tender joint count (SJC and TJC; 66/68 counts) at 
any of the visits at Week 12, 24, 36, 48, 60, 72, 84, or 96, will discontinue from 
the trial.  
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Missed visits: 
• If a subject misses a visit but a new visit can be performed within 1 week of the 
originally planned missed visit (i.e., within 3 weeks of the previous dosing 
[including dosing in the respective initial Phase IIb study]), 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 104 weeks. 
• If a subject misses a visit and the visit can only be performed later than 3 weeks 
of the previous dosing, the site should contact the CRO. 
 
Missed self-administration date: 
• If a subject misses a self-administration time point a new injection should be 
performed as soon as the patient remembers and within 1 week of the planned 
missed self-administration time point. If later than 1 week of the missed self-
administration time point, then the CRO should be contacted. In case of 
rescheduling of missed visits, the total duration of the assessment period should 
remain 104 weeks.   
 
If a subject misses a dose of MTX on their regularly scheduled dosing date, they 
should take the forgotten dose as soon as they remember; however, if more than 
72 hours have elapsed since the missed dose, the subject should contact the 
Investigator for further dosing instructions. 
 
For all subjects, injections should not occur less than 1 week apart. The 
CRO/Sponsor should be contacted if this cannot be respected. In case of 
interruption of more than 2 consecutive administrations, the subject should be 
discontinued from the study. 
 
3.4.1.3. END OF TREATMENT VISIT AND 
FOLLOW-UP 
 
Subjects who received study drug up to and including Week 102, should return for 
the Week 104 End of Treatment Visit, and for the Follow-up Visit approximately 
12 weeks after the last study drug administration. 
 
Discontinuation of Study Drug Administration 
For subjects who discontinue study participation for fulfilling the efficacy 
discontinuation criteria (see section 3.2.3.2) at weeks 12, 24, 36, 48, 60, 72, 84 or 
96, the visit at which subjects will meet these discontinuation criteria, is defined as 
the Early Termination Visit for these subjects. These subjects and those who are 
not withdrawing consent for post-treatment follow-up should return for a Follow-up 
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Visit 12 weeks after last study drug administration to undergo the assessments as 
specified in the Schedule of Assessments. 
Subjects who discontinue early for reasons other than the efficacy discontinuation 
criteria but are not withdrawing consent for post-treatment follow-up should return 
for an Early Termination Visit 2 weeks after the last study drug administration, 
unless they discontinue during a study visit in which case that visit becomes their 
Early Termination Visit. 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 will  not return for the Early Termination 
Visit or for the 12-week Follow-up Visit.   
 
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3.4.2. 
ASSESSMENTS OF EFFICACY 
 
3.4.2.1. PHYSICIAN’S ASSESSMENT OF 
TENDER/PAINFUL AND SWOLLEN 
JOINT COUNT  
 
To be performed as part of the efficacy measurements (for more detail see 
sections 3.4.2.11 to 3.4.2.18) at visits as indicated in the Schedule of Assessments. 
 
All joints listed are used in the determination of the ACR response, where 68 joints 
are assessed for tenderness and 66 joints are assessed for swelling (see 
Appendix 9). The 28 joints indicated in the grey-shaded fields are used to 
determine the DAS28, EULAR response, CDAI, SDAI, and Boolean score. 
 
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 (i.a.) 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. 
 
An independent joint assessor (and backup independent joint assessor) will be 
designated at each study center to perform all joint assessments during the 
104-week assessment period of the study. This individual should have at least 
1 year of experience in performing joint assessments. The proposed assessors 
having less than 1 year experience will need to be approved by the Sponsor. The 
independent joint assessor will perform only the joint assessments; this individual 
will not perform or assist in any other assessments in the study. 
 
The CRO will provide training to an independent assessor from each site prior to the 
start of subject enrollment. In case the independent assessor cannot attend, the 
CRO will provide training to the Investigator who will then train the assessor. If 
possible, the independent assessor for the study should not be changed during the 
study. However, the independent assessors from each site may train additional 
assessors at the site for coverage during their absences. If more than 1 blinded 
assessor at a site performs joint assessments during the study, the names of the 
joint assessor performing the joint evaluation must be listed in the “Investigator 
Site File” and be documented in the source document at each visit. 
 
It is recommended that the independent joint assessor who performed the 
baseline joint assessments for a subject should also perform the joint 
assessments for that subject for all subsequent visits during the 104-week 
assessment period of the study.   
 
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3.4.2.2. DURATION OF MORNING STIFFNESS 
 
The average duration of morning stiffness during the previous week in minutes will 
be assessed at visits as indicated in the Schedule of Assessments. If a subject has 
stiffness that lasts the entire day, this should be recorded as 1440 minutes of 
morning stiffness. 
 
3.4.2.3. PATIENT’S ASSESSMENT OF PAIN 
(100 MM-VAS) 
 
To be performed as part of ACR response and prior to the joint count assessments 
at visits as indicated in the Schedule of Assessments. 
 
The subject will be asked “How much pain have you had because of your illness in 
the past week?” and then instructed to place a mark between 0 (“no pain”) and 
100 mm (“severe pain”) on the VAS. 
 
3.4.2.4. PATIENT’S GLOBAL ASSESSMENT OF 
DISEASE ACTIVITY (100 MM-VAS) 
 
To be performed as part of ACR response, DAS28 score, EULAR response, SDAI, 
CDAI, and Boolean remission 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 3.4.2.5).  
 
The subject will be instructed “Considering all the ways that your arthritis affects 
you, rate how you are doing on the following scale” and will be asked to place a 
mark between 0 (“very well”) and 100 mm (“very poor”) on the VAS. 
 
3.4.2.5. PHYSICIAN’S GLOBAL ASSESSMENT 
OF DISEASE ACTIVITY 
(100 MM-VAS) 
 
To be performed as part of ACR response, SDAI, and CDAI 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 3.4.2.4). 
 
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The same physician should preferably be performing the assessment at each visit 
for each subject. The physician performing the assessment of the disease activity 
cannot be the independent joint assessor as described in section 3.4.2.1. The 
results of the joint assessment will be available to the physician performing the 
assessment of the disease. 
 
The physician will make a mark between 0 (“no disease”) and 100 mm (“severe 
disease”) on the VAS to indicate the patient’s current disease activity (independent 
of the subject’s self-assessment). 
 
3.4.2.6. C-REACTIVE PROTEIN  
 
To be measured as part of ACR response, DAS28 score, SDAI, Boolean remission, 
and EULAR Response at visits as indicated in the Schedule of Assessments. 
 
The CRP concentration is to be provided in mg/dL. 
 
3.4.2.7. ERYTHROCYTE SEDIMENTATION 
RATE  
 
To be measured as part of the DAS28 score and EULAR Response at visits as 
indicated in the Schedule of Assessments. The ESR concentration is to be provided 
in mm/h. 
 
3.4.2.8. HEALTH ASSESSMENT 
QUESTIONNAIRE-DISABILITY INDEX 
 
To be performed as part of ACR Response and on its own at visits as indicated in 
the Schedule of Assessments. 
 
The HAQ-DI is a 20-question instrument which assesses the degree of difficulty the 
subject had in accomplishing tasks in 8 functional areas over the previous week 
[23]. 
 
The HAQ-DI will be provided to the subject during a visit and the subject will be 
asked to complete the questionnaire while at the study site.  
 
The HAQ-DI is composed of 20 items in 8 categories: 
• Dressing and grooming. 
• Hygiene. 
• Arising. 
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• Reach. 
• Eating. 
• Grip. 
• Walking. 
• Common daily activities. 
 
Each category has at least 2 sub-category questions. Within each category, 
subjects report the amount of difficulty they have in performing the specific sub-
category items. There are 4 response options ranging from: 
• 0 = No Difficulty. 
• 1 = With Some Difficulty. 
• 2 = With Much Difficulty. 
• 3 = Unable to Do. 
 
3.4.2.9. SF-36  
 
The SF-36 will be completed 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. 
 
3.4.2.10. FACIT-FATIGUE 
 
The FACIT-fatigue scale will be completed at visits as indicated in the Schedule of 
Assessments. 
 
The FACIT Measurement System is a collection of health-related quality of life 
questionnaires that assess multidimensional health status in people with various 
chronic illnesses, including RA. 
 
3.4.2.11. ACR RESPONSE 
 
ACR responses are presented as the numerical measurement of improvement in 
multiple disease assessment criteria. 
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ACR 20/50/70 responses are defined as below: 
• ≥ 20/50/70% improvement in tender/painful joint count (68 joints) relative to 
baseline AND 
• ≥ 20/50/70% improvement in swollen joint count (66 joints) relative to baseline 
AND 
• ≥ 20/50/70% improvement in 3 of the following 5 areas relative to baseline: 
- 
Patient’s Assessment of Pain (100 mm-VAS). 
- 
Patient’s Global Assessment of Disease Activity (100 mm-VASPA). 
- 
Physician’s Global Assessment of Disease Activity (100 mm-VASPHA). 
- 
Patient’s assessment of physical function as measured by HAQ-DI. 
- 
CRP. 
 
The ACR-N Index of Improvement [24, 25] is defined as the minimum of the 
following 3 criteria: 
• The percent improvement from baseline in TJCs. 
• The percent improvement from baseline in SJCs. 
• The median percent improvement from baseline for the following 5 assessments: 
- 
Patient’s assessment of pain (VAS). 
- 
Patient’s global assessment of disease activity (VASPA). 
- 
Physician’s global assessment of disease activity (VASPHA). 
- 
Patient’s assessment of physical function as measured by the HAQ-DI. 
- 
CRP. 
 
3.4.2.12. DAS28 SCORE USING ESR 
 
The DAS28 based on ESR is a statistically derived index combining TJC (28 joints), 
SJC (28 joints), ESR, and VASPA [26]. It is a continuous parameter and is 
determined as specified in Figure 2 [27]: 
 
Figure 2: Calculation of DAS28 (ESR) Score 
DAS28 (ESR) = ൫0.56 × ඥ𝑇𝑇𝑇28 ൯+ ൫0.28 × ඥ𝑆𝑆𝑆28൯+ (0.70 × Ln[ESR]) + (0.014 × VASPA) 
VASPA = GH 
 
The DAS28 will not be calculated on site but during the statistical analysis by the 
Biometrics-CRO. 
 
3.4.2.13. DAS28 SCORE USING CRP 
 
CRP will be used in addition to ESR in the calculation of DAS28, using the formula 
below. CRP is a more direct measure of inflammation than ESR and it is more 
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sensitive to short-term changes [28]. CRP is considered at least as valid as ESR to 
measure RA disease activity [29]. 
 
The DAS28 using CRP is a statistically derived index combining TJC (28 joints), SJC 
(28 joints), CRP (mg/L), and VASPA. The DAS28 is a continuous parameter and is 
determined as specified in Figure 3 [27]:  
 
Figure 3: Calculation of DAS28 (CRP) Score 
DAS28 (CRP) = ൫0.56 × ඥ𝑇𝑇𝑇28 ൯+ ൫0.28 × ඥ𝑆𝑆𝑆28൯+ (0.36 × Ln[CRP + 1]) + (0.014 × VASPA)
+ 0.96 
VASPA = GH 
 
The DAS28 will not be calculated on site but during the statistical analysis by the 
Biometrics-CRO. 
 
3.4.2.14. EULAR RESPONSE 
 
Comparing a subject’s DAS28 score (using CRP and ESR) relative to baseline allows 
to substantiate his/her improvement or response. The EULAR response criteria are 
defined in Table 1 [27]. 
 
The EULAR response will not be calculated on site but during the statistical analysis 
by the Biometrics-CRO. 
 
Table 1: 
EULAR Response 
Present DAS28 
Improvement in DAS28 Relative to Baseline 
 
> 1.2 
 > 0.6 and ≤ 1.2 
≤ 0.6 
≤ 3.2 
good response 
moderate response 
no response 
>3.2 and ≤ 5.1 
moderate response 
moderate response 
no response 
> 5.1 
moderate response 
no response 
no response 
 
3.4.2.15. CUT-OFF POINTS TO DEFINE 
DISEASE ACTIVITY 
 
Cut-off points for the DAS28 to define if a subject is in clinical remission or in a 
state of high, moderate, or low disease activity have been defined [27]: 
 
High disease activity 
DAS28 > 5.1 
Moderate disease activity 
3.2 < DAS28 ≤ 5.1 
Low disease activity 
2.6 ≤ DAS28 ≤ 3.2 
Remission 
DAS28 (ESR) < 2.6 
 
Cut-off points will not be calculated on site but during the statistical analysis by the 
Biometrics-CRO. 
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3.4.2.16. BOOLEAN REMISSION 
Boolean remission will be determined according to the criteria shown in Figure 4 
[30]. 
 
The Boolean remission will not be calculated on site but during the statistical 
analysis by the Biometrics-CRO. 
 
Figure 4: Calculation of Boolean Remission 
If TJC28 ≤ 1 and SJC28 ≤ 1 and VASPA (cm) ≤ 1 and CRP (mg/dL) ≤ 1 
Then remission = “yes” 
Else remission = “no” 
 
3.4.2.17. CDAI SCORE  
 
The CDAI clinical score is determined as specified in Figure 5 and Figure 6 [30, 31]. 
 
Figure 5: Calculation of CDAI Score 
CDAI = TJC28 + SJC28 + VASPA + VASPHA  
 
Figure 6: Classification of CDAI Score 
CDAI Score 
CDAI ≤ 2.8 
2.8 < CDAI ≤ 10 
10 < CDAI ≤ 22 
22 < CDAI 
Disease Activity 
remission 
low disease activity 
moderate disease 
activity 
high disease activity 
 
3.4.2.18. SDAI SCORE 
 
The SDAI clinical score is determined as specified in Figure 7 and Figure 8 [31]. 
 
The SDAI will not be calculated on site but during the statistical analysis by the 
Biometrics-CRO. 
 
Figure 7: Calculation of SDAI Score 
SDAI = TJC28 + SJC28 + VASPA + VASPHA + CRP (mg/dL) 
 
Figure 8: Classification of SDAI Score 
SDAI Score 
SDAI ≤ 3.3 
3.3 < SDAI ≤ 11.0 
11.0 < SDAI ≤ 26.0 
SDAI >26.0 
Disease Activity 
remission 
low disease activity 
moderate disease 
activity 
high disease activity 
 
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3.4.3. PHARMACOKINETIC ASSESSMENTS 
 
3.4.3.1. 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 Schedule of 
Assessments.  
 
The exact times of blood sampling will be recorded. Of note, the day and 
approximate time of administration of the last dose of study drug 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 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. 
No human DNA or RNA analysis will be performed. 
 
3.4.3.2. BIOANALYSIS 
 
Concentrations of ALX-0061 in serum will be determined by a validated ligand-
binding assay method according to bioanalytical methodology and procedures 
described in a separate Bioanalytical Analysis Plan. Results will be presented in the 
Bioanalytical Analysis Report and will be included in the Clinical Study Report. 
 
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3.4.4. ASSESSMENTS OF SAFETY 
 
Safety and tolerability assessments consist of AEs (including serious adverse 
events, infections, injection site and hypersensitivity reactions), as well as 
laboratory assessments, urinalysis, vital signs, 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 
serum sample should be collected as soon as possible after the start of the event 
(blood volume: 5 mL) to characterize the cause of hypersensitivity by 
immunogenicity testing and/or protein analysis.  
 
No human DNA or RNA analysis will be performed. 
 
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.  
 
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). 
 
3.4.4.1. ADVERSE EVENTS 
 
General information on 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, 
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. 
 
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Any abnormal test result that is determined to be an error and merely repeating an 
abnormal test does not require reporting as an AE.   
 
The Investigator will also need to indicate whether the AE is a serious infection.  
 
A “serious infection” is any infection that meets the criteria for an SAE: 
• requires hospitalization and/or  
• requires i.v. antibiotics and/or  
• resulted in death. 
 
All serious infections should be reported as SAE.  
 
3.4.4.2. LABORATORY ASSESSMENTS 
 
Blood samples for routine and extended (including fasting serum lipids) clinical 
laboratory analyses will be collected 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. Details on method, sampling and processing procedures will be 
provided in a separate Lab Manual. 
 
The following tests will be included in the routine clinical laboratory analysis: 
• Biochemistry: total bilirubin, alkaline phosphatase, gamma-glutamyltransferase, 
AST, ALT, lactate dehydrogenase, creatinine, 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, 
and mean corpuscular hemoglobin concentration. 
• Acute phase proteins: Fibrinogen, CRP, and ESR. 
• Urinalysis: erythrocytes/blood, urobilinogen, ketones, glucose, protein, pH, and 
leukocytes. 
• Coagulation: activated partial prothrombin time, prothrombin time, and INR (the 
latter for subjects on warfarin only). 
 
The following additional tests will be included in the extended clinical laboratory 
analysis: 
• Biochemistry: 
total 
cholesterol, 
HDL-cholesterol, 
LDL-cholesterol, 
and 
triglycerides (i.e., fasting serum lipids).  
 
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Note that at visits when extended clinical laboratory analysis samples are planned 
to be taken, samples should be taken predose after the subject has been fasting for 
at least 10 h. 
 
In females of childbearing potential, a urine pregnancy test will be performed at the 
visits indicated in the Schedule of Assessments. Of note, additional pregnancy 
testing is allowed according to local guidelines; however, this additional pregnancy 
testing is not part of and cannot replace the protocol specific procedures. 
 
If TB is suspected at any time during the study, a chest x-ray and IGRA test should 
be performed. 
 
All samples will be analyzed by a central laboratory, except for ESR that will be 
measured via the local laboratory. 
 
Laboratory values outside the normal range will be flagged and clinical relevance 
will be assessed by the Investigator.  
 
All clinically significant laboratory findings will be recorded as AEs in the (e)CRF 
(also see section 3.4.4.1). 
 
In the event of unexplained or unexpected clinical laboratory test values, the 
test(s) will be repeated and followed up until the results have returned to the 
normal range and/or an adequate explanation for the abnormality is found.  
 
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. 
No human DNA or RNA analysis will be performed. 
 
3.4.4.3. 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: weight, blood pressure, 
pulse, and temperature (such as oral, axillar, or tympanic). 
 
To obtain the actual body weight, subjects must be weighed lightly clothed. A 
height measurement is not required (as data will be available from preceding main 
study). 
 
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Clinically relevant abnormalities occurring during the study should be recorded as 
AE in the (e)CRF.  
 
3.4.4.4. 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 system. 
• Cardiovascular system. 
• Gastrointestinal system. 
• Musculoskeletal system. 
• Central and peripheral nervous system. 
• Skin. 
• Lymph node palpation. 
• Urogenital system (kidneys). 
• 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. 
 
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3.4.5. 
OTHER ASSESSMENTS 
 
3.4.5.1. IMMUNOGENICITY 
 
To assess systemic immunogenicity of ALX-0061, blood samples of approximately 
7 mL will be collected at the time points defined in the Schedule of Assessments. 
 
Blood samples will be taken via an indwelling i.v. catheter or by direct 
venipuncture. The exact times of blood sampling will be recorded. For further 
details on sample collection, shipment, storage and processing, please refer to a 
separate Lab Manual. 
 
Anti-ALX-0061 antibodies (ADA) will be determined, potentially with further 
characterization by mADA and nAb assay. The immunogenicity data will be 
processed according to a separate analytical plan, and the results from this analysis 
will be included in the Clinical Study Report.  
 
As described previously, in case of acute or delayed severe/serious hypersensitivity 
reactions, an additional serum sample should be collected as soon as possible after 
the start of the event (blood volume: 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. 
No human DNA or RNA analysis will be performed. 
 
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3.4.6. 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 2. 
 
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 
table are provided as best estimations. 
 
The total volume of blood taken during the study will be approximately 179.5 mL. 
Table 2: 
Number and Volume of Blood Samples to be Obtained During the 
Study 
Assessments 
# samples 
Volume (mL) 
/sample 
Volume (mL) 
Pharmacokinetics 
9 
3.5 
31.5 
Routine clinical laboratory 
8 
6.5 
52 
Extended clinical laboratory safety including 
fasting lipids 
4 
6.5 
26 
Immunogenicity  
10 
7 
70 
Total 
 
 
179.5 a 
a  In case of acute or delayed severe/serious hypersensitivity reactions, an additional serum sample 
should be collected as soon as possible after the start of the event (blood volume: 5 mL) 
 
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3.4.7. 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). Of note, at Weeks 24, 48, 72, and 104 or at the Early 
termination visit, blood samples should be taken fasted for at least 10 h. 
 
For PK, immunogenicity and safety, predose samples will be obtained between 
waking up and dosing. 
 
If assessments are planned at the same time, the order of the assessments should 
be arranged according to the following principles: 
 
1. Vital signs should be assessed prior to blood sampling,  
2. Patient reported outcomes should occur prior to the physician’s joint evaluation, 
3. Independent joint assessment should occur prior to physician’s global 
assessment, and 
4. 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 or 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 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 
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observation, and by routine 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 recorded on the AE (e)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, 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. 
 
Please refer to the Common Terminology Criteria for Adverse Events (CTCAE v4.0) 
for assessment of severity of laboratory abnormalities. 
 
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. 
 
 
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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. 
 
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”. 
 
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 the study drug is to be documented using following 
categories: 
• Dose not changed. 
• Drug interrupted (will not be allowed in this study). 
• Drug withdrawn. 
• Not applicable. 
• Unknown. 
 
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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. 
• 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. 
 
All serious infections should be reported as SAE. 
 
A treatment-emergent SAE is any SAE temporally associated with the use of study 
drug, whether considered related to the study drug or not.  
 
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).  
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The Investigator will provide the initial notification by faxing 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, year of 
birth, 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.  
 
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 CRO will report expedited the following SUSARs to the IEC/IRB on behalf of the 
Sponsor: 
• 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. 
 
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SUSARs that are already present in the European Medicines Agency Eudravigilance 
database do not have to be once again reported to the CA because they have direct 
access to the Eudravigilance database. 
 
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 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. 
TEAEs are recorded from the start of study drug administration, until 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.  
 
For subjects that are considered lost to follow-up, reasonable attempts must be 
made (and documented) to obtain information on the final status of the subject. 
 
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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 
6 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 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.  
 
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., intramuscularly) 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 occurs 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: 
• Intention-to-observe (ITO) Population: All subjects who enrolled in Study 
ALX0061-C203. 
• 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. All subjects of the 
Safety Population for whom the primary PK data are considered to be sufficient 
and interpretable, will be analyzed in the PK analyses. 
 
Unless otherwise specified, the ITO Population will be used for the analysis of 
efficacy, the Safety Population for safety and immunogenicity data, while the PK 
Population will be used for analysis of the PK variables. 
 
3.6.2. STATISTICAL AND ANALYTICAL PLAN 
 
The statistical analysis plan (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 plans 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. INITIAL CHARACTERISTICS OF 
SUBJECT SAMPLE 
 
The statistical evaluation will be descriptive using standard statistical tools 
(including mean, standard deviation, median, maximum, and minimum) for 
continuous variables and counts and percentages for categorical variables. 
 
3.6.4. EVALUATION OF EFFICACY 
PARAMETERS 
 
The following efficacy analyses will be performed: 
• The proportion of subjects achieving an ACR response of 20, 50 and 70 over 
time will be summarized. 
• ACR-N index of improvement over time will be summarized. 
• The DAS28 (using CRP and ESR) score over time will be summarized. 
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• The proportion of subjects with DAS28 (using CRP and ESR) response over time 
will be summarized. 
• The proportion of subjects with EULAR response over time will be summarized. 
• The change from baseline (absolute change) in disease activity over time will be 
summarized. The following disease activity scores will be used: 
- 
DAS28 (CRP and ESR) 
- 
SDAI  
- 
CDAI 
• The proportion of subjects in remission will be over time summarized, as well as 
the proportion of subjects who maintained remission at consecutive time points.  
The following disease remission definitions will be used: 
- 
DAS28 (ESR) < 2.6 
- 
SDAI ≤ 3.3 
- 
CDAI ≤ 2.8 
- 
Boolean: TJC28 ≤1, SJC28 ≤ 1, CRP ≤1 mg/dL, VASPA ≤1 (on a 0-10 scale) 
• The change from baseline (absolute change) in HAQ-DI over time will be 
summarized. 
• The proportion of HAQ-DI responders (i.e., those who have a clinically 
meaningful improvement from baseline of ≥ 0.25 [absolute change] in HAQ-DI) 
over time will be summarized.  
• The proportion of subjects with HAQ-DI ≤ 0.5, defining normal physical function, 
over time will be summarized. 
• The proportion of subjects with HAQ-DI ≤ 0.5 (normal physical function) with or 
without remission (DAS28, SDAI, CDAI, and Boolean) at Week 24, 48, 72 and 
104 will be summarized. 
• The changes from baseline (absolute change) in the physical and mental 
component scores of SF-36 at Week 24, 48, 72 and 104 will be summarized. 
• The change from baseline (absolute change) in SF-36 scales at Week 24, 48, 72 
and 104 will be summarized. 
• The change from baseline (absolute change) in FACIT-Fatigue at Week 24, 48, 
72 and 104 will be summarized. 
• The duration of morning stiffness at Week 104 will be summarized. 
 
All efficacy endpoints will be analyzed using the ITO Population. Summary statistics 
for continuous efficacy endpoints include mean (and associated 95% confidence 
interval), standard deviation, median, minimum, and maximum. For categorical 
efficacy endpoints frequency and proportion or percentage (together with 95% 
confidence interval) will be calculated. Note that baseline refers to the baseline 
value of the preceding Phase IIb study with ALX-0061 (ALX0061-C201 or ALX0061-
C202) the subject was enrolled in. 
 
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Subgroup analyses will be performed to evaluate consistency of the efficacy 
endpoints over covariates including demographics (including weight and region), 
baseline disease characteristics, and baseline and prior medications. 
 
3.6.5. EVALUATION OF PHARMACOKINETIC 
PARAMETERS 
 
The procedures for obtaining ALX-0061 serum concentrations are found in 
section 3.4.2. 
 
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.  
 
Study drug concentrations will be summarized by scheduled sampling time.  
 
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 modelling will be performed under the responsibility of Ablynx NV. Results will 
be provided in a separate Modelling and Simulation report. 
 
3.6.6. EVALUATION OF SAFETY PARAMETERS 
 
The DSMB will evaluate the safety data periodically (see section 3.4.5). 
 
The following analyses will be performed 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 safety and immunogenicity analyses will be performed using the Safety 
Population of all subjects who received at least 1 dose of study drug. In addition, 
subgroup analyses will be performed to evaluate consistency of safety over 
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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, adverse drug reactions, and 
SAEs will be tabulated 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).  
 
Abnormal findings in physical examinations will be listed. 
 
Immunogenicity will be assessed through listing of individual results by subject and 
summary tables. 
 
Note that baseline refers to the baseline value of the preceding Phase IIb study 
with ALX-0061 (ALX0061-C201 or ALX0061-C202) the subject was enrolled in. 
 
3.6.7. HANDLING OF MISSING DATA 
 
To provide more information, a multiple-analysis approach will be taken for the 
handling of missing data for efficacy endpoints in the ITO population. The following 
two analyses will be performed in case of missing values: 
• Analysis with last observation carried forward imputation of missing values (i.e., 
each missing value of a certain variable is replaced by the last available 
observed value of that variable), unless otherwise specified.  
• As-observed analysis where missing values are excluded. 
 
3.6.8. DETERMINATION OF SAMPLE SIZE 
 
This is an extension study and is not set by statistical power. Subjects who have 
completed the Week 24 (study ALX0061-C201) or Week 12 (study ALX0061-C202) 
assessment visit in one of the preceding Phase IIb studies with ALX-0061, and who 
are qualified for this study per inclusion/exclusion criteria, will be invited to 
participate in the extension study. Up to a maximum of approximately 501 subjects 
are planned to participate in this OLE study. 
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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, outlining the audit performed.  
 
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, 
i.e., to collect full date of birth and subject initials is NOT allowed. 
 
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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 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 
90 days 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 15 days, 
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. 
 
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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In the event a subject refuses to follow the instructions of the Investigator, the 
latter is released from any legal responsibility. 
 
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 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 (i.e., lay terminology). 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 
designated person) who conducted the ICF discussion. After having obtained the 
consent, a copy of the signed ICF must be given to the subject. The 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 date of birth (when allowed by 
local regulations). 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 
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) 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 who enrolls in the OLE study 
(including 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: 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 CRO 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 of the 
CRO 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 
 
Ablynx NV holds and will maintain an adequate insurance policy covering damages 
arising out of Ablynx-sponsored clinical research studies. 
 
Ablynx NV will indemnify the Investigator and hold him/her harmless for claims for 
damages arising out of the investigation in excess of those covered by his/her own 
professional liability insurance providing that the drug was administered under 
his/her or deputy’s supervision and in strict accordance with accepted medical 
practice and the study protocol. 
 
The Investigator must notify Ablynx NV immediately upon notice of any claims or 
lawsuits. 
 
Participants in this study are covered by an Insurance Policy held by Ablynx. This 
insurance covers any damage as a result of death or injury caused by participation 
in the study. The damage is considered having become apparent after notice has 
been given to the insurance company.  
 
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. The Investigator should promptly update this information if any 
relevant changes occur during this period. 
 
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. 
 
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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 
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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of the rheumatic diseases, 2009. 68(6): p. 954-60. 
30. Felson, D.T., et al., American College of Rheumatology/European League 
against Rheumatism provisional definition of remission in rheumatoid arthritis 
for clinical trials. Annals of the rheumatic diseases, 2011. 70(3): p. 404-13. 
31. Aletaha, D. and J.S. Smolen, The Simplified Disease Activity Index (SDAI) and 
Clinical Disease Activity Index (CDAI) to monitor patients in standard clinical 
care. Best practice & research. Clinical rheumatology, 2007. 21(4): p. 663-75. 
 
 
Document ID: 25_A0006_14_0210          ADMS Version Number: 3.0          Printing Date: 15/Dec/2015

Ablynx NV 
Clinical Trial Protocol ALX0061-C203 
 
 
Final version 3.0 
 
December 10, 2015 
CONFIDENTIAL 
Page 88/89 
9. APPENDIX: TENDER AND 
SWOLLEN JOINT COUNT 
 
Tender and swollen joint count (TJC 68/ SJC 66) 
Joint 
Patient Right 
Patient Left 
 
Tender 
Swollen 
Tender 
Swollen 
TMJ 
 
 
 
 
SC 
 
 
 
 
AC 
 
 
 
 
Shoulder 
 
 
 
 
Elbow 
 
 
 
 
Wrist 
 
 
 
 
MCP I 
 
 
 
 
MCP II 
 
 
 
 
MCP III 
 
 
 
 
MCP IV 
 
 
 
 
MCP V 
 
 
 
 
PIP I 
 
 
 
 
PIP II 
 
 
 
 
PIP III 
 
 
 
 
PIP IV 
 
 
 
 
PIP V 
 
 
 
 
DIP II 
 
 
 
 
DIP III 
 
 
 
 
DIP IV 
 
 
 
 
DIP V 
 
 
 
 
Hip 
 
N.A. 
 
N.A. 
Knee 
 
 
 
 
Ankle 
 
 
 
 
Subtalar 
 
 
 
 
MTP I 
 
 
 
 
MTP II 
 
 
 
 
MTP III 
 
 
 
 
MTP IV 
 
 
 
 
MTP V 
 
 
 
 
IP I 
 
 
 
 
IP II 
 
 
 
 
IP III 
 
 
 
 
IP IV 
 
 
 
 
IP V 
 
 
 
 
TOTAL (ACR) 
 
 
 
 
ACR TOTAL Tender Joint Count (for 68 joints): 
ACR TOTAL Swollen Joint Count (for 66 joints): 
TOTAL (for DAS28 score –  
shaded joints only ) 
 
 
 
 
DAS28 TOTAL Tender Joint Count (for 28 joints): 
DAS28 TOTAL Swollen Joint Count (for 28 joints): 
Document ID: 25_A0006_14_0210          ADMS Version Number: 3.0          Printing Date: 15/Dec/2015

Ablynx NV 
Clinical Trial Protocol ALX0061-C203 
 
 
Final version 3.0 
 
December 10, 2015 
CONFIDENTIAL 
Page 89/89 
AC=acromioclavicular; ACR=American College of Rheumatology; DAS28=Disease Activity Score using 28 
joint 
counts; 
DIP=distal 
interphalangeal; 
IP=interphalangeal; 
MCP=metacarpophalangeal; 
MTP=metatarsophalangeal; PIP=proximal interphalangeal; SC=sternoclavicular; SJC=swollen joint 
count; TMJ=temporomandibular joint; TJC=tender joint count 
 
Document ID: 25_A0006_14_0210          ADMS Version Number: 3.0          Printing Date: 15/Dec/2015

Signature Page 
This is a representation of an electronic record that was signed electronically in Livelink. 
This page is the manifestation of the electronic signature(s) used in compliance with the organizations 
electronic signature policies and procedures. 
 
Date: Tuesday, 15 December 2015, 10:54   Romance Daylight Time 
Meaning: Approved 
================================================
Document ID: 25_A0006_14_0210          ADMS Version Number: 3.0          Printing Date: 15/Dec/2015