Phase 3, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study to Evaluate Efficacy and Safety of Certolizumab Pegol in Subjects With Active Axial Spondyloarthritis (axSpA) Without X-Ray Evidence of Ankylosing Spondylitis (AS) and Objective Signs of Inflammation
Phase: PHASE3
Conditions: Axial Spondyloarthritis, Nonradiographic Axial Spondyloarthritis, Nr-axSpA
Sponsor: UCB BIOSCIENCES GmbH

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 1 of 255
PROTOCOL AS0006 (C-AXSPAND) AMENDMENT 5 
PHASE 3, MULTICENTER, RANDOMIZED, 
PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY TO 
EVALUATE EFFICACY AND SAFETY OF CERTOLIZUMAB 
PEGOL IN SUBJECTS WITH ACTIVE AXIAL 
SPONDYLOARTHRITIS (AXSPA) WITHOUT X-RAY EVIDENCE 
OF ANKYLOSING SPONDYLITIS (AS) AND OBJECTIVE 
SIGNS OF INFLAMMATION 
PHASE 3 
EudraCT Number: 2015-001894-41 
IND Number: 9,869 
UCB BIOSCIENCES GmbH
Alfred-Nobel-Strasse 10
40789 Monheim
GERMANY
Protocol/Amendment number
Date
Type of 
amendment
Final Protocol
01 Jun 2015
Not applicable
Protocol Amendment 0.1 (Taiwan)
02 Sep 2015
Substantial
Protocol Amendment 1
15 Dec 2015
Substantial
Protocol Amendment 1.1 (Taiwan)
12 Jan 2016
Substantial
Protocol Amendment 2
14 Mar 2016
Substantial
Protocol Amendment 2.1 (Taiwan)
22 Apr 2016
Substantial
Protocol Amendment 3
13 Feb 2017
Substantial
Protocol Amendment 3.1 (Taiwan)
24 Mar 2017
Substantial
Protocol Amendment 3.2 (Australia)
28 Apr 2017
Substantial
Protocol Amendment 4
19 Dec 2017 
Substantial
Protocol Amendment 4.1 (Taiwan)
08 Jan 2018
Substantial
Protocol Amendment 4.2 (Australia)
08 Jan 2018
Substantial
Protocol Amendment 5
17 Dec 2018
Substantial
Confidential Material
Confidential
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB.
REDACTED 
IE
IE
Nobel
Nobe
0789 
0789
G
ber
ber
RE
COPY 
ENC
ENC
This document cannot
rotoc
oto
Proto
Proto
ot
P
n
ca
c
be
ocol A
ol 
co
co
be used
Amend
mend
d
l Ame
Ame
ed
A
u
t
d
to
ndme
ndm
to support
1.1 (Ta
1 (T
t
nt 2
t 2
o
ment 2.
ment 2
upp
en
s
any
iwan
wa
ny
i
a
marketing 
g
ark
n)
n)
m
authorization 
CES G
ES G
-Stras
Stra
Monh
Mon
ERM
ERM
a
application 
4-41
4
and 
1
any extensions
CTIV
TIV
or
EN
EN
V
variations 
NC
NC
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 2 of 255
STUDY CONTACT INFORMATION 
Sponsor 
UCB BIOSCIENCES GmbH
Alfred-Nobel-Strasse 10
40789 Monheim
GERMANY
Sponsor Study Physician 
Name:
, MD
Address:
Alfred-Nobel-Str 10
40789 Monheim
Germany
Phone:
Fax:
Clinical Project Manager 
Name:
, PhD
Address:
Alfred-Nobel-Str 10
40789 Monheim 
Germany
Phone:
Fax:
Clinical Trial Biostatistician 
Name:
, PhD
Address:
Alfred-Nobel-Str 10
40789 Monheim 
Germany 
Phone:
Fax:
REDA
bel
bel-S
EDACTED 
CT
DAC
COPY 
Y
CO
This document cannot 
d
an
be
dres
dres
used 
d
u
to
ios
os
supp
pp
stat
sta
pport any marketing 
tr 10
r 10
heim
heim
y
m
authorization 
n
, PhD
, PhD
or
0
au
application 
tio
pl
and any y extensions 
ten
e
or variations thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 3 of 255
Clinical Monitoring Contract Research Organization 
Name:
PRA Health Sciences
Address:
500 South Oak Way, 
Green Park, 
Reading, 
Berkshire RG2 6AD, 
UK
Phone:
+44 (118) 918 1000
Fax:
+44 (118) 918 1001
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions 
on
ten
or r
or variations 
v
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 4 of 255
SERIOUS ADVERSE EVENT REPORTING 
Serious Adverse Event reporting (24h) and safety related issues
Fax
Europe and Rest of the World: +32 2 386 24 21
USA and Canada: +1 800 880 6949 or +1 866 890 3175
E-Mail
DS_ICT@ucb.com
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or 
or variations 
va
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 5 of 255
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS..................................................................................................11 
1 
SUMMARY.....................................................................................................................16 
2 
INTRODUCTION ...........................................................................................................19 
2.1 
Natural history of axial spondyloarthritis ....................................................................19 
2.2 
Burden of disease in axSpA.........................................................................................20 
2.3 
Diagnosing axSpA in clinical practice.........................................................................20 
2.4 
Current management of axial spondyloarthritis...........................................................21 
2.5 
Rationale ......................................................................................................................22 
3 
STUDY OBJECTIVES....................................................................................................23 
3.1 
Primary objective.........................................................................................................23 
3.2 
Secondary objectives ...................................................................................................23 
3.3 
Other objectives ...........................................................................................................23 
4 
STUDY VARIABLES.....................................................................................................24 
4.1 
Efficacy variables.........................................................................................................24 
4.1.1 
Primary efficacy variable.....................................................................................24 
4.1.2 
Secondary efficacy variables ...............................................................................24 
4.1.3 
Other efficacy variables.......................................................................................25 
4.2 
Pharmacokinetic, exploratory biomarker, and pharmacogenomic variables...............27 
4.2.1 
Primary pharmacokinetic variables .....................................................................27 
4.2.2 
Exploratory biomarkers variables........................................................................27 
4.2.3 
Pharmacogenomic variables ................................................................................27 
4.3 
Immunological variables..............................................................................................27 
4.4 
Safety variables............................................................................................................28 
5 
STUDY DESIGN.............................................................................................................28 
5.1 
Study description .........................................................................................................28 
5.1.1 
Study periods .......................................................................................................28 
5.1.2 
Study duration per subject ...................................................................................30 
5.1.3 
Planned number of subjects and site(s) ...............................................................30 
5.1.4 
Anticipated regions and countries .......................................................................30 
5.2 
Schedule of study assessments.....................................................................................31 
5.3 
Schematic diagram.......................................................................................................48 
5.4 
Rationale for study design and selection of dose.........................................................51 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................51 
6.1 
Inclusion criteria ..........................................................................................................51 
6.2 
Exclusion criteria .........................................................................................................52 
6.3 
Withdrawal criteria ......................................................................................................55 
6.4 
Eligibility for the SFE Period ......................................................................................56 
REDACTED 
....
....
arker,
arker,
variabl
variab
s varia
s varia
b
COPY 
.....
......
.....
This document 
5.4
5.4
6
cannot 
Sche
Sche
S
be
An
An
used
dy d
y d
lanne
lanne
to 
er
dur
dur
support 
.....
...
n .....
...
riods
iods
any 
.....
....
.
marketing
ables
able
bles
bles ..
........
....
authorization 
....
......
....
, and p
and p
bles
es .
es
es
application 
.... ...
...........
........
....
.....
and 
......
....
any 
......
.....
extensions 
......
....
......
....
.....
....
or 
....
....
variations 
.20
20
2
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 6 of 255
7 
STUDY TREATMENTS.................................................................................................56 
7.1 
Description of investigational medicinal product(s)....................................................56 
7.2 
Treatment(s) to be administered ..................................................................................57 
7.2.1 
Treatment administration.....................................................................................57 
7.2.2 
Study AS0006 injection schedule........................................................................58 
7.3 
Packaging.....................................................................................................................60 
7.4 
Labeling .......................................................................................................................60 
7.5 
Handling and storage requirements .............................................................................60 
7.6 
Drug accountability......................................................................................................60 
7.7 
Procedures for monitoring subject compliance............................................................61 
7.8 
Concomitant medication(s)/treatment(s) .....................................................................61 
7.8.1 
Permitted concomitant treatments for axSpA (medications and therapies).........65 
7.8.2 
Prohibited concomitant and rescue treatments (medications and therapies) .......66 
7.8.3 
Concomitant medication(s)/treatments during the SFE Period ...........................67 
7.9 
Blinding........................................................................................................................67 
7.9.1 
Maintenance of study treatment blind .................................................................67 
7.9.2 
Breaking the treatment blind in an emergency situation .....................................68 
7.10 
Randomization and numbering of subjects..................................................................69 
7.10.1 
Interactive Response System ...............................................................................69 
7.10.2 
Randomization.....................................................................................................69 
8 
STUDY PROCEDURES BY VISIT ...............................................................................70 
8.1 
Screening visit (Week -6 to Day -1) ............................................................................70 
8.2 
Baseline visit (Week 0)................................................................................................71 
8.3 
Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 
44, 46, 48, and 50 (all visits ±3 days relative to Baseline) ..........................................72 
8.4 
Every 4 weeks (± 3 days) during home injection period from Week 14 to Week 46 
(Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46) ............................................................74 
8.5 
Week 52/WD (±3 days) ...............................................................................................74 
8.6 
SFE Period (Week 52 to Week 156)............................................................................75 
8.7 
FU visit (8 weeks after the Week 52/WD visit [±3 days]) ..........................................76 
8.8 
Unscheduled visits .......................................................................................................76 
8.9 
Alternative visit schedules after subject discontinuation of the double-blind study 
treatment ......................................................................................................................77 
9 
ASSESSMENT OF EFFICACY......................................................................................78 
9.1 
Assessment of efficacy variables.................................................................................79 
9.1.1 
ASDAS ................................................................................................................79 
9.1.2 
ASAS20, 40, ASAS 5/6 response, and ASAS partial remission.........................79 
9.1.3 
ASAS-NSAID score ............................................................................................80 
9.1.4 
ASQoL.................................................................................................................81 
REDACTED 
ct
......
......
......
.....
ISIT
SIT
Day
Da
COPY 
ergenc
ergen
s.....
This document 
9
9
cannot 
Uns
ns
Alt
Alt
be 
visi
sche
sch
used
riod (
od (
sit (8
it (8
to
WD (
D (
W
support
3 day
3 day
 22, 26
22, 2
(±3
(±
any 
2, 
2,
visits
visit
marketing 
..
y y -1)
1)
.......
....
, 14, 
14
authorization 
......
......
......
....
...........
....
application 
P
.......
.....
........
....
y situ
y situ
and
ns a
s a
Perio
erio
any
d the
d th
and 
and
extensions 
.........
......
...
......
....
her
her
or 
......
variations 
60
60
60
6
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 7 of 255
9.1.5 
BASDAI ..............................................................................................................81 
9.1.6 
BASFI..................................................................................................................82 
9.1.7 
BASMI.................................................................................................................82 
9.1.8 
Enthesitis (MASES).............................................................................................82 
9.1.9 
Extra-articular assessments..................................................................................83 
9.1.10 
Health status (EQ-5D) .........................................................................................83 
9.1.11 
MOS Sleep Scale .................................................................................................83 
9.1.12 
MRI assessments .................................................................................................83 
9.1.13 
PGADA (NRS) ....................................................................................................84 
9.1.14 
PhGADA..............................................................................................................84 
9.1.15 
Productivity measures (Work Productivity Survey)............................................84 
9.1.16 
Resources utilization............................................................................................85 
9.1.17 
SF-36....................................................................................................................85 
9.1.18 
Spinal mobility.....................................................................................................85 
9.1.19 
Swollen and tender joint counts (44 joints evaluation)........................................85 
9.1.20 
Total and nocturnal spinal pain NRS...................................................................86 
10 ASSESSMENT OF PHARMACOKINETICS, EXPLORATORY BIOMARKERS, 
AND PHARMACOGENOMICS VARIABLES.............................................................86 
11 ASSESSMENT OF IMMUNOGENICITY VARIABLES .............................................87 
12 ASSESSMENT OF SAFETY..........................................................................................87 
12.1 
Adverse events.............................................................................................................88 
12.1.1 
Definition of adverse event..................................................................................88 
12.1.2 
Procedures for reporting and recording adverse events.......................................88 
12.1.3 
Description of adverse events..............................................................................88 
12.1.4 
Follow up of adverse events ................................................................................89 
12.1.5 
Rule for repetition of an adverse event................................................................89 
12.1.6 
Pregnancy ............................................................................................................89 
12.1.7 
Overdose of investigational medicinal product ...................................................90 
12.1.8 
Safety signal detection.........................................................................................90 
12.2 
Serious adverse events .................................................................................................90 
12.2.1 
Definition of serious adverse event .....................................................................90 
12.2.2 
Procedures for reporting serious adverse events .................................................92 
12.2.3 
Follow up of serious adverse events....................................................................92 
12.3 
Adverse events of interest............................................................................................92 
12.4 
Immediate reporting of adverse events........................................................................93 
12.5 
Laboratory measurements............................................................................................93 
12.6 
Other safety measurements..........................................................................................95 
12.6.1 
Pregnancy testing.................................................................................................95 
REDACTED
TY V
TY V
......
....
......
......
vent
vent
COPY 
, EXP
, EXP
LES
LES
This document 
12
12
12.
12
cannot 
.2.2
2.2
2 2
2 2
be 
ous
us
D
used
afety s
fety s
s ad
s a
to
ose 
ose 
support
etition
tition
y .....
...
of
any 
erse e
erse 
marketing 
.......
....
g and r
g and
se eve
e ev
authorization 
......
......
ARIA
ARIA
......
......
....
....
application 
..
on)
n).....
........
....
LORA
LORA
and 
.......
.....
any 
.....
....
..
extensions 
......
....
......
...
......
....
or 
......
variations 
83
83
83
8
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 8 of 255
12.6.2 
Physical assessments ...........................................................................................95 
12.6.3 
Assessment and management of TB and TB risk factors....................................96 
12.6.3.1 
Tuberculosis assessments..........................................................................98 
12.6.3.2 
Chest x-ray ................................................................................................98 
12.6.3.3 
QuantiFERON or Elispot testing...............................................................98 
12.6.3.4 
Tuberculosis questionnaire........................................................................98 
12.6.3.5 
Tuberculosis management.........................................................................99 
12.6.4 
Vital signs ..........................................................................................................100 
13 STUDY MANAGEMENT AND ADMINISTRATION...............................................100 
13.1 
Adherence to protocol................................................................................................100 
13.2 
Monitoring .................................................................................................................100 
13.2.1 
Definition of source data ...................................................................................101 
13.2.2 
Source data verification .....................................................................................101 
13.3 
Data handling.............................................................................................................101 
13.3.1 
Case report completion......................................................................................101 
13.4 
Electronic reporting outcome.....................................................................................102 
13.5 
Database entry and reconciliation..............................................................................102 
13.6 
Termination of the study............................................................................................102 
13.7 
Archiving and data retention......................................................................................103 
13.8 
Audit and inspection ..................................................................................................103 
13.9 
Good Clinical Practice ...............................................................................................104 
14 STATISTICS .................................................................................................................104 
14.1 
Definition of analysis sets..........................................................................................104 
14.2 
General statistical considerations...............................................................................104 
14.3 
Planned efficacy analyses ..........................................................................................105 
14.4 
Secondary efficacy analyses ......................................................................................106 
14.5 
Other efficacy analyses..............................................................................................107 
14.6 
Planned safety and other analyses..............................................................................108 
14.6.1 
Safety analyses...................................................................................................108 
14.6.2 
Pharmacokinetic and immunogenicity variable analysis...................................109 
14.7 
Handling of protocol deviations.................................................................................109 
14.8 
Handling of dropouts or missing data........................................................................109 
14.9 
Planned interim analysis and data monitoring...........................................................111 
14.10 Determination of sample size.....................................................................................111 
15 ETHICS AND REGULATORY REQUIREMENTS....................................................111 
15.1 
Informed consent .......................................................................................................111 
15.2 
Subject identification cards........................................................................................112 
15.3 
Institutional Review Boards and Independent Ethics Committees............................112 
REDACTED 
......
......
......
.....
......
......
COPY 
......
....
....
...
This document 
14.9
4.9
14
14
cannot
Hand
Han
H
be
Ph
Ph
d
used 
afe
af
afety a
fety a
ha
h
to
fety 
ety 
support 
ly
cy anal
y an
y analy
analy
any 
ere
yses
ses
marketing 
..
.......
.....
.......
....
ratio
rati
authorization 
......
......
......
....
.........
....
application 
..
.......
.....
........
....
......
.....
and 
.......
.....
any 
.....
....
..
extensions 
......
....
......
...
........
or 
..1
variations 
99
99
100
10
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 9 of 255
15.4 
Subject privacy...........................................................................................................113 
15.5 
Protocol amendments.................................................................................................113 
16 FINANCE, INSURANCE, AND PUBLICATION.......................................................113 
17 REFERENCES ..............................................................................................................114 
18 APPENDICES ...............................................................................................................120 
18.1 
ASAS classification criteria for axial SpA ................................................................120 
18.2 
Modified NY criteria for ankylosing spondylitis.......................................................121 
18.3 
Table of corticosteroid equivalent doses....................................................................122 
18.4 
ASQoL.......................................................................................................................123 
18.5 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).............................125 
18.6 
Bath Ankylosing Spondylitis Functional Index (BASFI)..........................................126 
18.7 
EuroQoL (EQ 5D) Questionnaire ..............................................................................128 
18.8 
MOS Sleep Scale Questionnaire................................................................................130 
18.9 
PGADA (NRS) ..........................................................................................................134 
18.10 Short-Form (SF-36) Questionnaire............................................................................135 
18.11 Total spinal pain NRS and nocturnal spinal pain NRS..............................................141 
18.12 Tuberculosis Sample Worksheet................................................................................142 
18.13 Protocol Amendment 1 ..............................................................................................143 
18.14 Protocol Amendment 2 ..............................................................................................199 
18.15 Protocol Amendment 3 ..............................................................................................207 
18.16 Protocol Amendment 4 ..............................................................................................229 
18.17 Protocol Amendment 5 ..............................................................................................244 
19 DECLARATION AND SIGNATURE OF INVESTIGATOR .....................................254 
20 SPONSOR DECLARATION ........................................................................................255 
LIST OF TABLES 
Table 5‒1: 
Schedule of study assessments – Screening through Week 52 and FU...........32 
Table 5‒2: 
Schedule of alternative study assessment with CZP - after subject 
discontinuation of the double-blind study treatment .......................................37 
Table 5‒3: 
Schedule of alternative study assessment with other treatment (including 
biologics) - after subject discontinuation of the double-blind study 
treatment ..........................................................................................................41 
Table 5‒4: 
Schedule of study assessments – additional assessments for wdt 0 visit 
required for subjects transitioning to open-label CZP .....................................44 
Table 5‒5: 
Schedule of study assessments – additional assessments for wdt 0 visit 
required for subjects transitioning to alternative treatment .............................46 
Table 5‒6: 
Schedule of study assessments - Safety Follow-Up Extension Period............47 
REDACTED 
......
......
......
.....
......
......
COPY 
......
....
.......
This document 
Tab
Tab
cannot 
‒3:3:
be used 
Sched
Sched
dis
dis
to
edul
edu
support 
ule o
le
any 
N
marketing 
..
.......
.....
ATUR
ATUR
N ....
authorization 
......
......
........
......
.....
....
application 
..
.......
.....
S......
....
....
.......
and 
.......
.....
any 
.....
....
..
extensions 
......
....
......
...
......
....
or 
..1
variations 
21
21
122
12
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 10 of 255
Table 7‒1: 
Concomitant Medications (prior to Baseline and Study Visits) ......................61 
Table 9‒1: 
Swelling and tenderness grading .....................................................................86 
Table 12‒1: Laboratory measurements up to Week 52 (including the FU visit (8 weeks 
after the Week 52/WD visit)............................................................................93 
LIST OF FIGURES 
Figure 2‒1: 
ASAS Classification Criteria for axSpA..........................................................21 
Figure 5‒1: 
Schematic diagram for subjects completing the double-blind study 
treatment ..........................................................................................................48 
Figure 5‒2: 
Schematic diagram for subjects discontinued from the double-blind study 
treatment ..........................................................................................................49 
Figure 5‒3: 
Schematic diagram for subjects completing the double-blind study 
treatment and rolling over to the SFE Period...................................................50 
Figure 7‒1: 
Injection schedule through Week 52................................................................58 
Figure 7‒2: 
Injection schedule for the SFE Period .............................................................59 
REDACTED COPY 
....
...
This document cannot be used to support any marketing authorization application 
..
.......
.....
.......
...
and
blin
blin
.....
any 
.....
...
nd
nd
extensions 
......
....
blind
blind
or 
....
variations 
21
21
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 11 of 255
LIST OF ABBREVIATIONS 
ABA
abatacept
ACR
American College of Rheumatology
ADA
adalimumab
ADAb
anti-drug antibody (also called anti-CZP antibody)
AE 
adverse event
AESI
adverse event of special interest
ANCOVA
analysis of covariance
Anti-CZP Ab 
anti-CZP antibody 
Apo
apolipoprotein
AS
ankylosing spondylitis
ASAS
Assessment of SpondyloArthritis International Society 
ASAS20, 40
Assessment of SpondyloArthritis International Society 20%, 40% 
response criteria
ASAS5/6
Assessment of SpondyloArthritis International Society 20% 
improvement in 5 of 6 domains
ASDAS
Ankylosing Spondylitis Disease Activity Score
ASDAS-CII
Ankylosing Spondylitis Disease Activity Score clinically important 
improvement
ASDAS-HD
Ankylosing Spondylitis Disease Activity Score high disease activity
ASDAS-ID
Ankylosing Spondylitis Disease Activity Score inactive disease
ASDAS-LD
Ankylosing Spondylitis Disease Activity Score low disease
ASDAS-MI
Ankylosing Spondylitis Disease Activity Score major improvement
ASDAS-vHD
Ankylosing Spondylitis Disease Activity Score very high disease activity
ASQoL
Ankylosing Spondylitis Quality of Life
ASspiMRI-a
Ankylosing spine MRI acuity
AU
anterior uveitis
axSpA
axial spondyloarthritis 
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMI
Bath Ankylosing Spondylitis Metrology Index
BMO
bone marrow oedema
BMP
bone morphogenetic protein
BOCF
Baseline observation carried forward
CDMS
clinical data monitoring system
REDACTED
itis D
tis D
ndyliti
ndyliti
ng Spo
ng Spo
COPY
hritis
hriti
mains
main
Dis
Di
This document 
B
cannot 
SDAI
DA
BAS
BAS
be used to support
Anky
Ank
A
any
kylosi
kylos
marketing 
ondyl
ndy
g Spond
Spon
sing Sp
sing S
authorization 
sease A
ease 
s Dise
Dise
ylit
li
application
tional 
tional
Interna
ntern
and
al Soc
l Soc
any extensions or variations thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 12 of 255
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
COX-2
cyclooxygenase 2
CPM
Clinical Project Manager
CPMP
Committee for Proprietary Medicinal Products
CRF
case report form
CRO
Contract Research Organization
CRP
C-reactive protein
CSF-1
colony-stimulating factor-1
CZP
certolizumab pegol
Dhh
Dessert hedgehog
DKK1
Dickkopf-related protein 1
DMARD
disease-modifying antirheumatic drug
DS
Drug Safety
ECG
electrocardiogram
eCRF
electronic Case Report Form
ePRO
electronic patient reported outcome
EQ-5D
EuroQoL Health Status Questionnaire (5 dimensions)
ES
Enrolled Set
ETN
etanercept
EU
European Union
FAS
Full Analysis Set
FU
Follow-Up
GCP
Good Clinical Practice
GM-CSF
granulocyte macrophage colony-stimulating factor
GMP
Good Manufacturing Practice
GOL
golimumab
HbA1c
Hemoglobin A1c
HCQ
hydroxychloroquine
HIV
human immunodeficiency virus
HLA-B27
human leukocyte antigen B27 
HRQoL
health-related quality of life
ia
intra-articular
IB
Investigator Brochure
REDACTED 
eported
eporte
th Stat
h Sta
etet
COPY 
Form
Form
This document 
H
cannot 
A1c
1c
HCQ
HCQ
be used to support 
Follo
oll
Go
G
any
Anal
Ana
ow
marketing 
an Unio
n Uni
lyl
authorization 
d outc
d outc
tus Qu
us Qu
application and any extensions or variations thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 13 of 255
IBD
inflammatory bowel disease 
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IFX
infliximab
IGRA
Interferon-Gamma Release Assay
Ihh
Indian hedgehog
IL
interleukin
IMP
investigational medicinal product
IP
interphalangeal
IRB
Institutional Review Board
iv
Intravenous(ly)
IXRS
interactive response system
LOCF
last observation carried forward
LTB
latent tuberculosis
M-CSF
Macrophage colony-stimulating factors
MAR
missing at random
MASES
Maastricht Ankylosis Spondylitis Enthesitis Score
MCID
minimal clinically important difference
MCMC
Markov Chain Monte Carlo
MCP
metacarpophalangeal
MCS
Mental Component Summary
MedDRA®
Medical Dictionary for Regulatory Activities®
MI
multiple imputation
MMP-3
matrix metalloproteinase-3
MMRM
mixed model for repeated measures
MOS
Medical Outcomes Study
MRI
magnetic resonance imaging
mNY
Modified New York (criteria)
MTX
methotrexate
nr-axSpA
nonradiographic axSpA
NRS
Numerical Rating Scale
NSAID
nonsteroidal anti-inflammatory drug
NTMB
nontuberculous mycobacteria
NYHA
New York Heart Association
REDACTED 
sis Spo
sis Sp
ally im
lly im
hain M
hain M
h
COPY
ating 
ating
This document 
n
cannot 
Y
MTX
MTX
be used to support
mult
mult
ma
m
any
ical D
ical 
tip
ti
marketing 
Mon
on
halange
alang
Compo
Comp
D
authorization 
ondyli
ondyli
mporta
porta
nte 
nte
application 
factors
actors
and any extensions or variations thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 14 of 255
OMERACT
Outcome Measures in Rheumatology Clinical Trials
PCS
Physical Component Summary
PFS
prefilled syringe
PhGADA
Physician’s Global Assessment of Disease Activity
PGADA
Patient’s Global Assessment of Disease Activity
PIP
Proximal IP
PK
pharmacokinetics
PPS
Per Protocol Set
prn
as needed
PsA
psoriatic arthritis 
Q2W
every 2 weeks (every other week)
Q12W
every 12 weeks
QoL
Quality of Life
RA
rheumatoid arthritis
RDC
remote data capture
RS
Randomized Set
SAA
Spondylitis Association of America
SAARD
slow-acting antirheumatic drug
SAE
serious adverse event
SAP
Statistical Analysis Plan
sc
subcutaneous(ly)
sCSF1r
soluble colony-stimulating factor-1 receptor
SD
standard deviation
SF-36
Short-Form 36-Item Health Survey
SFE
Safety Follow-Up Extension 
SFE-FAS
Safety Follow-Up Full Analysis Set
SFE-SS
Safety Follow-Up Extension Safety Set
Shh
Sonic hedgehog
SI
sacroiliac
SIJ
sacroiliac joint injection
SOP
standard operating procedure
SpA
spondyloarthritis
SPARCC
Spondyloarthritis Research Consortium of Canada
SPARTAN
Spondyloarthritis Research and Treatment Network
REDACTED 
ation o
ation o
tirheum
irheu
erse e
erse e
A
COPY 
This document 
S
cannot 
SI
be used to support 
stand
tan
Sh
S
any
ble co
ble c
da
d
marketing 
ve
ve
nalysis
nalys
neous(l
eous(
ol
authorization 
of Am
f Am
matic 
matic 
entnt
application and any extensions or variations thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 15 of 255
SPC
Summary of Product Characteristics
SS
Safety Set
SSCM
Single Safety Case Management
SSZ
sulfasalazine
STIR
short-tau-inversion recovery
TEAE
treatment-emergent adverse event
TB
tuberculosis
TGF
transforming growth factor
TNF
tumor necrosis factor
TNFi
tumor necrosis factor-alpha inhibitor
ULN
upper limit of normal (for CRP the ULN defined as the upper limit of 
normal value indicative for inflammatory disease)
USA
United States of America
VAS
visual analog scale
VEGF
vascular endothelial growth factor
VU
vertebral units
WBC
white blood cell
WD
Withdrawal
wdt
withdrawal treatment
WISP
wingless-related mouse mammary tumor virus integration site protein 
(WNT1)-inducible signaling pathway proteins
WNT1
wingless-related mouse mammary tumor virus integration site protein
WPS
Work Productivity Survey
reatm
reatm
elat
elat
COPY 
facto
fac
This document cannot be used to support any 
rk Pro
rk Pr
marketing 
ted mou
ed mo
nducibl
ducib
s-rela
rel
authorization 
entnt
application and 
se)e)
any
 the u
the 
extensions or variations thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 16 of 255
1 
SUMMARY 
The C-axSpAnd study (AS0006) is a randomized, double-blind, parallel-group, placebo-
controlled study, consisting of 52 weeks of treatment with certolizumab pegol (CZP) and a 
Follow-Up (FU) Period of 8 weeks after the Week 52 Visit. The study population is subjects 
with active axial spondyloarthritis (axSpA) without x-ray evidence of ankylosing spondylitis 
(AS), but either with sacroiliitis on magnetic resonance imaging (MRI) or C-reactive protein 
(CRP) levels indicative of inflammatory disease or both, who have had an inadequate response 
to, have a contraindication to, or are intolerant to nonsteroidal anti-inflammatory drugs 
(NSAIDs). 
The study population will be subjects (≥18 years), with a documented diagnosis of adult-onset 
axSpA and who meet the Assessment of SpondyloArthritis International Society ([ASAS], 
Sieper et al, 2009) criteria for axSpA, who have had back pain of at least 12 months’ symptom 
duration, and with active disease defined by a Bath Ankylosing Spondylitis Disease Activity 
Index (BASDAI) ≥4, and spinal pain ≥4 on a 0 to 10 Numerical Rating Scale (NRS). At 
Baseline, evidence of inflammatory disease will be confirmed either by presence of sacroiliitis 
on MRI (according to ASAS/Outcome Measures in Rheumatology Clinical Trials [OMERACT] 
criteria) or by elevated CRP or by presence of both.
Additionally, subjects must have had an inadequate response to, have a contraindication to, or 
have been intolerant to at least 2 NSAIDs. Inadequate response to a NSAID is defined as lack of 
response to at least 14 days of continuous NSAID therapy at the highest tolerated dose of the 
administered NSAID. Eligible subjects will be allocated to the following double-blind study 
treatments in a 1:1 ratio:
x CZP administered subcutaneously (sc) at the dose of CZP 400mg at Weeks 0, 2, and 4 
followed by CZP 200mg every 2 weeks (every other week; Q2W) sc (starting at Week 6)
x Placebo
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site. At the Week 0, 2, 4, 6, 
and 8 visits, the administration must be done by dedicated, unblinded, and adequately trained site 
personnel. At the Week 10 and 12 visits, the subject will receive training on self-injection and
the study treatment will be self-administered under the supervision of the unblinded study 
personnel. At Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50, the study treatment administration 
should preferably be done by the unblinded study personnel, or alternatively by self-injection of 
the subject under the supervision of the unblinded study personnel. The double-blind study 
treatment will be self-injected at home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46.
The study will be placebo controlled for 52 weeks and will allow changes in background 
medications as required to control disease activity according to the judgment of the Investigator. 
Subjects whose disease activity cannot be controlled by study medication and changes in 
background therapy (including and not limited to analgesics, NSAIDs, and slow-acting 
antirheumatic drugs [SAARDs]) will be permitted to withdraw from the double-blind study drug. 
Subjects will either transition to open-label CZP treatment offered by UCB or to other treatment 
(including biologics) at the discretion of the Investigator until the assessment of the primary 
REDACTED
q
SAID
SAID
ill be a
ll be a
ly (s
ly (s
COPY 
e resp
e resp
quate
quate
This document
The 
he 
med
med
cannot
ect u
ct u
ment w
ent w
stu
stu
be
ferab
ferab
un
un
used
ent w
nt w
Week
Week
bly
bly
to 
Wee
wil
wi
support
ments w
nts w
istratio
strati
ek 10
k 10
any
s
ny 
0, 2
0, 2
marketing
sc) at t
sc) at 
weeks 
week
authorization
po
e resp
e resp
therap
therap
alloca
alloca
application
her b
er b
ogy Cl
ogy C
onse to
nse t
and
ng Sc
g Sc
by
by
any 
2 m
2 m
tis Di
tis D
ca
extensions 
of adu
of adu
ety ([A
ty ([A
mon
mon
or variations 
onse 
nse
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 17 of 255
endpoint at Week 52. At the completion of the Week 52 visit assessments, subjects on double-
blind study treatment may receive open-label CZP treatment for an additional 2 years in an open-
label, Safety Follow-Up Extension (SFE) Period. Subjects who withdrew from double-blind 
study treatment and transitioned to open-label CZP treatment are also eligible to participate in 
the SFE Period after completing the Week 52 visit assessments. Subjects on alternative 
treatments are not eligible to participate in the SFE Period.
All subjects not participating in the SFE Period after study completion at Week 52, including 
those withdrawn from the study prematurely, will have a FU visit 8 weeks after their Week 52
Visit. 
If the Investigator chooses to withdraw subjects on the other treatments (including biologics), the 
local guidelines on initiation and monitoring of the particular treatment should be followed.
The primary objective of the study is to demonstrate the efficacy of CZP administered at the dose 
of CZP 200mg Q2W, after a loading dose of CZP 400mg at Weeks 0, 2, and 4, on the signs and 
symptoms of active axSpA in subjects without x-ray evidence of AS.
The secondary objectives of the study are to assess efficacy, safety, and tolerability and to 
demonstrate the effect of CZP on health outcomes, disease activity, sacroiliac (SI) joint 
inflammation through MRI, and changes in concomitant and background medications.
Other objectives are to evaluate the effects of CZP on spinal mobility, total and nocturnal spinal 
pain (NRS), spinal inflammation, SI joint structural changes, treatment response over time, 
additional signs and symptoms of the disease, subject’s health status, acute phase reactant (CRP), 
health-related quality of life (HRQoL), work and household productivity, pharmacokinetics (PK) 
and immunogenicity, gene and protein expression and to explore the relationship between 
genomic biomarkers and disease biology, drug treatment and inflammatory and immune 
responses (for those subjects who consent to the genomics substudy). 
The primary efficacy variable is Ankylosing Spondylitis Disease Activity Score major 
improvement (ASDAS-MI) response at Week 52. The secondary efficacy variables are 
ASAS 40% (ASAS40) response at Weeks 12 and 52, change from Baseline in Bath Ankylosing 
Spondylitis Functional Index (BASFI) at Weeks 12 and 52, change from Baseline in BASDAI at 
Weeks 12 and 52, change from Baseline in SI joint Spondyloarthritis Research Consortium of 
Canada (SPARCC) score at Week 12, the number of subjects without relevant changes to 
background medication, change from Baseline in Ankylosing Spondylitis Quality of Life 
(ASQoL ) at Week 52, change from Baseline in nocturnal spinal pain (NRS) at Week 52, and the 
number of subjects with anterior uveitis (AU) or new AU flares through Week 52.
For Canada (and any other country where applicable or where requested by Regulatory 
Authorities), the primary efficacy variable is the ASAS40 response at Week 12. The secondary 
efficacy variables are ASAS40 response at Week 52, ASDAS-MI at Week 52, change from 
Baseline in BASFI at Weeks 12 and 52, change from Baseline in BASDAI at Weeks 12 and 52, 
change from Baseline in SI joint SPARCC score at Week 12, the number of subjects without 
relevant changes to background medication, change from Baseline in ASQoL at Week 52, 
change from Baseline in nocturnal spinal pain (NRS) at Week 52, and the number of subjects 
with AU or new AU flares through Week 52.
Other efficacy variables are listed in Section 4.1.3.
, subj
, sub
ork and
rk and
expres
expres
logy, 
logy, 
nse
nse
COPY 
on spi
on sp
ral ch
ral c
j
This document 
ffic
fic
Base
Bas
c
cannot
nada 
nada 
horitie
oritie
cacy
cacy
be
subj
ubj
(
used 
icat
ca
Week 5
Week 5
bjec
jec
to
sc
ation
atio
support
dex (B
ex (
nge from
ge fro
core a
ore a
any 
on
on
se at 
se at
BA
marketing 
dru
dru
ent to t
ent to 
nkylos
nkylo
nse a
nse
authorization
p
hang
hang
ect’s h
ect’s h
d hou
hou
ssion 
sion 
rug t
ug t
application 
y, a
vity, sa
ity, s
backg
backg
nal m
nal m
and 
and 
and
any
nd 4
nd 4
extensions
biolog
iolog
e follo
follo
minist
minist
4
or variations 
52
52
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 18 of 255
Pharmacokinetic, exploratory biomarker, and pharmacogenomic variables are listed in 
Section 4.2 and immunogenicity variables are listed in Section 4.3.
Safety variables to be assessed are adverse events (AEs), vital signs, physical examination, and 
measurements of laboratory parameters. In addition, subjects will be evaluated at Screening, 
Baseline, and at every 12 weeks thereafter up to Week 36 and including Week 52/Withdrawal 
(WD) (for subjects not participating in the SFE Period) for signs and symptoms of latent or 
active tuberculosis (TB) infection and risk factors for exposure to TB using the TB 
questionnaire.
Approximately 1200 subjects will be screened in order to have 300 subjects (150 subjects per 
treatment group) randomized into the study. Randomization will be stratified by presence of 
sacroiliitis on MRI and elevated CRP to ensure balanced treatment allocation across 
3 subgroups: MRI+/CRP+; MRI+/CRP-; MRI-/CRP+. 
For each subject, the study will consist of 3 periods and will last a maximum of 66 weeks: 
x Screening Period lasting up to 6 weeks
x Double-Blind, Placebo-Controlled Period for 52 weeks
x FU Period 8 weeks after the Week 52/WD visit (for subjects not participating in the SFE 
Period).
For subjects participating in the SFE Period, the study will extend up to a maximum of 
104 additional weeks.
The estimated recruitment period is up to 15 months. The first subject first visit is planned in 
Quarter 3 2015. The end of the study will be defined as the date of the last subject’s last visit, 
defined as the FU visit 8 weeks after the Week 52/WD visit for subjects not participating in the 
SFE Period, or the last visit of the SFE Period. 
 
REDACTED 
o 15 m
15 m
will be
will be
r the 
r the 
COPY 
study
study
This document cannot be used to support any marketing
Wee
Wee
E Perio
Per
authorization
y will
y will
months
month
e defin
defin
k
application 
ects no
ects n
and any
um o
um 
extensions
ec
esence
sence
oss 
oss 
of
or
ts p
ts p
variations thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 19 of 255
2 
INTRODUCTION 
2.1 
Natural history of axial spondyloarthritis 
Spondyloarthritis (SpA) is an umbrella term applied to a family of rheumatic diseases that have 
features in common with and distinct from other inflammatory arthritides, particularly 
rheumatoid arthritis (RA).  
Recently, the ASAS working group established classification criteria to distinguish 2 broad 
categories of SpA: peripheral and axial SpA (axSpA) (Rudwaleit et al, 2011; Rudwaleit, 2010; 
Rudwaleit et al, 2009b). This division is based on the body part predominantly involved in the 
inflammatory process and those areas of the body that may respond similarly well to medication. 
Therefore, peripheral SpA includes diseases affecting mainly peripheral joints, such as reactive 
arthritis and psoriatic arthritis (PsA), whereas axSpA comprises those diseases with mainly axial 
involvement (SI joints and spine), including AS and nonradiographic axSpA (nr-axSpA). 
Patients with AS have definitive evidence of structural changes in the SI joint (sacroiliitis) on 
x-ray, fulfilling the Modified New York classification criteria (mNY-positive) (van der Linden et 
al, 1984a), whereas those with nr-axSpA have no definitive structural changes on conventional 
radiographs (mNY-negative) (Rudwaleit et al, 2005; Dougados et al, 1991). 
Axial SpA is a chronic inflammatory disease that impacts a substantial proportion of the 
population. Limited evidence exists regarding the exact prevalence of axSpA; however, recent 
data suggest that the prevalence is similar to that of RA in the United States of America (USA) 
(axSpA: 0.7% to 1.4%; RA: 0.5% to 1.0%) (Reveille et al, 2012; Myasoedova et al, 2010; 
Helmick et al, 2008).  
The majority of patients with axSpA have inflammatory back pain. The disease typically
originates in the SI joints, then progresses to the spine. In the SI joints and the spine, active 
inflammation results in erosions, sclerosis, and fatty lesions. However, the most characteristic 
feature is new bone formation leading to ankylosis of the SI joints and syndesmophytes attached 
to the vertebral bodies. As a result of extended syndesmophyte formation, the spine may become 
fused over time. Objective signs of inflammation, such as enthesitis, dactylitis, peripheral 
arthritis, or uveitis; genetic features, such as the presence of human leukocyte antigen B27 
(HLA-B27); and laboratory parameters, such as elevated CRP, may also be present (Braun, 
2012; Rudwaleit et al, 2009a; Braun and Sieper, 2007). Disability in axSpA is related to both the 
degree of inflammatory activity, causing pain, stiffness, fatigue, and poor quality of sleep, and to 
the degree of bony ankylosis, causing loss of spinal mobility. 
The natural history of axSpA is characterized by a variable disease course. Over time, patients 
may develop structural damage or radiographic abnormalities involving their SI joints, and they 
may fulfill the mNY classification criteria for AS. However, the rate of development of structural 
damage varies among patients (Rudwaleit and Sieper, 2012). Some patients develop only 
unilateral sacroiliitis, and others may never develop definitive sacroiliitis on x-ray despite 
significant disease burden and other signs and symptoms of the disease, such as spinal lesions, 
uveitis, enthesitis, and peripheral arthritis. Approximately 10% of patients with nr-axSpA (25% 
if CRP levels are elevated) develop definitive evidence of sacroiliitis on x-ray within 2 years 
(Sieper and van der Heijde, 2013a). 
REDACTED
at 
Revei
Reve
have i
have 
resse
resse
COPY
pact
pac
exact 
exact 
of R
of R
This documen
dama
ama
unil
uni
cannot
ra
evelop
velop
y fulfi
fulfi
mag
ag
be
l his
l his
used
mat
mat
bony 
bony
to 
al, 
al, 
tor
tor
support
ig
ic feat
fea
atory p
atory 
, 200
20
any
ult o
ult
ns of
ns of
marketing
es to t
es to 
erosis, a
rosis,
ding to
ing to
of
of
authorization
p
RA in 
RA in
ille et 
lle et 
nflam
flam
application
ural 
ral
s et al, 
et al,
a subst
subs
preval
reval
and
posi
posi
al ch
l ch
any 
joint 
joint
ti
extensions
med
med
ch as 
h as 
with m
with m
(nr
(nr-
o
in t
in 
didi
variations 
010;
10;
thth
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 20 of 255
2.2 
Burden of disease in axSpA 
Axial SpA typically presents in patients <45 years of age, and these relatively young and 
otherwise healthy patients face a significant disease burden regardless of whether or not they 
have definitive evidence of sacroiliitis on x-ray. These patients experience substantial pain, 
prolonged, severe stiffness of joints, substantial sleep disturbances, reduced mobility and overall 
function, reduced quality of life (QoL), loss of productivity, and other disease-related symptoms 
(Huscher et al, 2006; Kobelt et al, 2006; Kobelt et al, 2004; Boonen et al, 2003; Boonen et al, 
2002; Ward, 2002). Moreover, studies have shown that the economic impact of the disease on 
society or patients can be substantial and that the costs are mainly driven by the cost associated 
with loss of work capacity (van der Heijde et al, 2013; Kobelt et al, 2006; Kobelt et al, 2004; 
Boonen et al, 2003; Ward, 2002). 
Several large observational and noninterventional cohort studies (Cuirea et al, 2013; Sieper and 
van der Heijde, 2013a) reported a similar burden of disease at study baseline across AS studies 
(captured through BASFI and BASDAI) in nonradiographic as well as radiographic axSpA 
(captured through BASDAI). A literature review of studies in both populations (Callhoff et al, 
2015) and a recent study with CZP (RAPID-AxSpA) (Landewe et al, 2014) confirmed this 
finding in the clinical study setting.
2.3 
Diagnosing axSpA in clinical practice 
The diagnosis of AS and/or axSpA should be based on clinical assessments considering typical 
signs and symptoms, but also excluding other diseases that may have similar presentations. The 
mNY classification criteria, often used to support the diagnosis of AS, excludes patients who do 
not show definitive evidence of sacroiliitis on x-ray (Rostom et al, 2010). For a definitive 
classification of AS, the mNY classification criteria require radiographic evidence of sacroiliitis 
grade ≥2 bilaterally or sacroiliitis grade 3 to 4 unilaterally PLUS at least 1 of the following 
clinical criteria: low back pain and stiffness for ≥3 months, limitation of lumbar spine motion, or 
limitation of chest expansion. These criteria were designed for classification of patients in 
clinical trials rather than for diagnostic purposes. However, they have historically been used for 
clinical diagnosis. The requirement for limitations in spinal motion and/or chest expansion has 
led to diagnoses being delayed until irreversible structural damage is documented on SI joint 
x-rays. Several publications have documented that time from symptom onset until the diagnosis 
of AS ranges from 5 years to 10 years (van der Linden et al, 1984b; Feldtkeller et al, 2003; 
Feldtkeller et al, 2000), thus demonstrating that x-ray changes lag far behind other signs and 
symptoms. 
Due to the problem of delayed disease recognition, ASAS developed new classification criteria 
for axSpA that do not require the presence of definitive sacroiliitis on x-ray, thus identifying a 
nonradiographic subpopulation (nr-axSpA) allowing for classification of all axSpA patients 
(Rudwaleit et al, 2009b; Rudwaleit et al, 2009c). These criteria establish standards that apply to 
patients with or without radiographic sacroiliitis enabling the conduct of clinical trials in patients 
with both nr-axSpA and AS. In patients with a history of chronic back pain for ≥3 months and 
age of onset <45 years, classification of axSpA can be made based on either evidence of 
sacroiliitis on radiographs or MRI plus ≥1 typical SpA feature or the presence of HLA-B27 plus 
≥2 typical SpA features (Figure 2‒1). In these criteria, sacroiliitis is defined as MRI evidence of 
SI joint inflammation or radiographic evidence of sacroiliitis meeting mNY criteria (Rostom et 
al, 2010).
REDACTED
dise
dise
upport
upport
tis on 
is on
fication
catio
ade 
ade 
COPY
pra
pr
sed on
ed on
eas
ea
This document
(Rud
Rud
pati
pat
cannot
e e
SpA th
pA th
nradiog
radio
dw
d
be 
prob
prob
used
200
200
to
5 ye
5 y
00
00
support
irere
layed 
ayed
ations h
tions
yea
ears
any
gno
gno
emen
men
marketing
n 
3 to 4
3 to 4
tiffness
ffnes
ese crite
se cri
osti
ost
authorization
n clin
clin
ses th
es th
rt the d
the d
x-ray
ray
crite
crit
application
t al, 
al,
tice
ice
nic
nic
and
opula
opula
20
20
any 
e e 
diogr
diog
ti
extensions
al, 20
l, 20
, 2013
2013
acr
acr
o
ocia
oci
00
00
variations 
e on
on 
atet
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 21 of 255
Figure 2‒1: ASAS Classification Criteria for axSpA 
ASAS=Assessment of SpondyloArthritis International Society; axSpA=axial spondyloarthritis; CRP=C-reactive 
protein; HLA-B27=human leukocyte antigen B27; mNY=modified New York; MRI=magnetic resonance imaging; 
NSAID=nonsteroidal anti-inflammatory drug; SpA=spondyloarthritis. Adapted from Rudwaleit M, et al. Ann 
Rheum Dis. 2009; 68(6):777-783 (Rudwaleit et al, 2009c). 
2.4 
Current management of axial spondyloarthritis 
There is increasing recognition of axSpA as an important clinical entity, as evidenced by the 
efforts of the American College of Rheumatology (ACR) in cooperation with the Spondylitis 
Association of America (SAA) and the Spondyloarthritis Research and Treatment Network 
(SPARTAN) to develop new treatment recommendations for axSpA including AS (see 
Appendix 18.1 for classification criteria for axSpA). To help Investigators and at the same time 
reduce the introduction of bias in the study resulting from changes in background medications, 
UCB is recommending allowed changes in background therapy. These allowed changes were
prepared by expert rheumatologists from North America and Europe and have also been aligned 
with the draft ACR/SAA/SPARTAN Recommendations for the Management of Axial 
Spondyloarthritis, including Ankylosing Spondylitis, and Children with the Enthesitis-Related 
Arthritis Form of Juvenile Idiopathic Arthritis presented at the recent ACR Nov 2014 meeting in 
Boston. Furthermore, the update of the 2006 ASAS recommendations for the use of anti-tumor 
necrosis factor (TNFs) for AS extended the recommendations to patients fulfilling the ASAS 
criteria, including patients with nr-axSpA (van der Heijde et al, 2011). 
Nonsteroidal anti-inflammatory drugs are often rapidly effective for the symptoms (pain and 
stiffness) of axSpA (Poddubnyy, 2013; Poddubnyy et al, 2012), but many patients lose 
symptomatic response and structural damage often progresses despite their use. Conventional 
disease-modifying antirheumatic drugs (DMARDs; eg, methotrexate [MTX] and sulfasalazine 
[SSZ]) have limited efficacy in axial disease, but may benefit patients with peripheral joint 
disease (Haibel et al, 2007; Braun et al, 2006; Haibel et al, 2005). Therefore, DMARDs are 
recommended only in patients with predominantly peripheral manifestations (Braun and van den 
Berg, 2011).
Patients who are intolerant of or have inadequately responded to NSAIDs, or those in whom 
NSAIDs are contraindicated, have limited treatment options. Tumor necrosis factor-alpha 
inhibitors (TNFi) (CZP, adalimumab [ADA] etanercept [ETN] infliximab [IFX]), golimumab 
OR
SpA features
• Inflammatory back pain
• Arthritis
• Enthesitis (heel)
• Uveitis
• Dactylitis
• Psoriasis
• Crohn’s/colitis
• Good response to NSAIDs
• Family history for SpA
• HLA-B27
• Elevated CRP
*Sacroiliitis on imaging
N = 649 patients with back pain
Overall
Sensitivity: 82.9%; Specificity: 84.4%
Imaging arm alone
Sensitivity: 66.2%; Specificity: 97.3%
HLA-B27 PLUS
≥2 Other SpA features
Sacroiliitis on imaging*
PLUS ≥ 1 SpA feature
Patients with back pain ≥ 3 months & age of onset < 45 years
• Active (acute) inflammation on 
MRI highly suggestive of 
sacroiliitis associated with SpA
OR
• Definitive radiographic sacroiliitis
according to mNY criteria
REDACTED
ology
ology
pondyl
ondyl
recom
recom
eria fo
eria fo
sts
COPY
spo
sp
mpor
mpor
This document
e
[SSZ
[SSZ
didi
cannot
) of
 of
tomat
omat
ease
ase
be
al an
l a
f ax
f a
used
ng pa
ng pa
ant
ant
to
NFs) 
Fs)
support
g An
An
ile Idio
le Idi
the up
the up
fo
f
any
RTA
RTA
Anky
Ank
marketing
for a
r a
tudy re
udy re
nges in
nges i
ts from
ts fro
N
authorization
rtant c
rtant c
(ACR
(ACR
loarth
oarth
mmen
mmen
axS
axS
application 
MR
ed from
ed from
ondylo
ndy
l
and
dyloar
yloar
RI=m
RI=
any 
h
extensions 
97.3%
.3%
xtension
xtension or variations thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 22 of 255
[GOL]) are the only effective and approved treatment options as of Dec 2014; IFX and GOL are 
indicated for active AS only, while CZP, ADA, and ETN are indicated for axSpA without 
radiographic evidence of AS (nr-axSpA) as an addition to the AS indication in several regions.   
At the 2014 Annual Meeting of the ACR/SPARTAN group a draft treatment guideline was 
presented for the subject suffering from both AS and nr-axSpA. These guidelines recommend the 
use of a TNFi after NSAID treatment. 
With the advent of the ASAS classification criteria for axSpA, several registration studies have 
been conducted in patients with nr-axSpA (Dougados et al, 2014), or axSpA (Landewe et al, 
2014; Sieper et al, 2013b; Sieper et al, 2013c). These studies have shown that anti-TNFs are 
effective in nr-axSpA patients, particularly in patients with objective signs of inflammation as 
defined by MRI positivity or elevated CRP. The RAPID-axSpA study, the first axSpA study to 
enroll both AS and nr-axSpA patients in the same study, showed that baseline disease activity 
and treatment effect were similar between nr-axSpA and AS subjects (Landewe et al, 2014). In 
this study, it was shown that CZP rapidly reduced the signs and symptoms of axSpA disease over 
24 weeks of Double-Blind treatment in the broad axSpA population, including the AS and the 
nr-axSpA subpopulations, and that the responses to the treatment were similar in both 
subpopulations (Landewe et al, 2014; Sieper and van der Heijde, 2013c) and maintained up to 
Week 96 (Mease et al, 2014; Sieper et al, 2014).
Based on the results of the RAPID-axSpA study, CZP received approval for the treatment of 
adult patients with severe active axSpA (comprising AS and nr-axSpA) in the European Union 
(EU) and several other countries, eg, Turkey, Argentina, Russia, Chile, Switzerland, Hong Kong, 
Dominican Republic, Ecuador, and Peru, and it was approved for the treatment of adults with 
active AS in the USA, Canada, Australia, and also Malaysia.
In accordance with the ASAS classification criteria a subject can either be classified as having 
axSpA based on imaging evidence or on clinical assessment. Recent publications showed that 
sacroiliitis on imaging via MRI is highly specific for the diagnosis of axSpA and is commonly 
used in many regions to diagnose axSpA in daily clinical practice (Rudwaleit et al, 2009a; 
Rudwaleit et al, 2009b; Rudwaleit et al, 2009c).
Because of the therapeutic response in early disease, the ASAS consensus recommendation on 
the use of TNFi in AS, updated in 2010, was extended to include the full spectrum of axSpA 
(van der Heijde et al, 2011).
2.5 
Rationale  
The RAPID-axSpA study enrolled subjects with objective signs of inflammation, and the results 
indicated that baseline disease burden was similar between the AS and nr-axSpA subpopulations 
(Landewe et al, 2014; Sieper et al, 2013b). In the RAPID-AxSpA study it was shown that CZP 
rapidly reduced the signs and symptoms of axSpA over 24 weeks of double-blind treatment in 
the broad axSpA population, including in the AS and the nr-axSpA subpopulations, and that the 
responses to the treatment were similar in both subpopulations (Landewe et al, 2014; Sieper et al, 
2013b) and maintained up to Week 96 (Mease et al, 2014; Sieper et al, 2014).
To address the unmet need for treatment options for nr-axSpA, AS0006 will be conducted 
focusing on subjects who do not meet the mNY classification criteria for AS 
(see Appendix 18.2). Data suggest that patients with objective signs of inflammation and high 
REDACTED
, Arg
, Arg
and it 
and it 
ia, and
ia, and
ficat
ficat
COPY 
CZP re
CZP re
sing A
ing A
This document
apid
pid
the b
the b
r
cannot
ed th
d th
ndewe
dewe
dly
dly
be
D-ax
ax
used 
Rati
Rati
to
al, 2
al, 2
support 
tic resp
ic res
S, upda
, upda
201
0
any
e a
e a
aleit 
aleit 
marketing
tion cr
ion c
r on clin
on cl
highly 
highl
axSp
axS
authorization
ec
AS an
AS an
entina
entina
t was a
t was a
nd also
d also
application
wer
wer
e, 2013
e, 201
ceived
eive
d
and
inclu
nclu
ere s
re s
any 
dew
dew
ms of a
ms of 
d
extensions
F
mmati
mati
axSpA
xSpA
e disea
disea
we 
we
or
s are
ar
variations 
ave 
ve
al,
al,
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 23 of 255
disease activity are likely to run a chronic disease course and unlikely to be well-managed on 
conventional therapy (Rudwaleit ACR, 2013). Furthermore, studies where anti-TNFs have been 
withdrawn in nr-axSpA patients show that patients flare quickly and hence the disease is unlikely 
to go into spontaneous remission. However, there are no long-term prospective studies to assess 
how patients meeting the ASAS classification criteria respond to conventional therapies. With 
the conduct of the 52-week blinded study period comparing CZP to placebo in combination with 
standard of care, a better understanding should be gained of how a long-term anti-TNF therapy 
compares to standard of care in patients meeting the ASAS criteria with objective signs of 
inflammation. Moreover, patients whose disease cannot be managed under the blinded study 
treatment conditions will be able to discontinue the double-blind study treatment and transition 
to either open-label CZP or other therapies.
The addition of the SFE Period will allow collection of long-term safety data from eligible 
subjects on open-label CZP for up to 2 years. In addition, MRI assessment of SI joint structural 
damage and laboratory assessment for CRP will be performed, and data from selected efficacy 
variables will be collected at the end of the SFE Period. During the SFE Period, CZP will be 
provided by the Sponsor. The treating Investigator is requested to apply routine, standard of care 
according to local standard medical practice and Investigator clinical judgment. 
Subjects enrolled into this study must have sacroiliitis on MRI as set forth by the 
ASAS/OMERACT definition; or meet the requirements for the clinical arm of the ASAS 
classification criteria for axSpA (MRI-negative nr-axSpA) and have elevated CRP levels, as 
there is good evidence to suggest that CRP is a predictor of response to anti-TNF therapy in 
axSpA. 
3 
STUDY OBJECTIVES 
3.1 
Primary objective 
The primary objective of the study is to demonstrate the efficacy of CZP 200mg Q2W on the 
signs and symptoms of subjects with active axSpA without x-ray evidence of AS.
3.2 
Secondary objectives 
The secondary objectives of the study are to assess efficacy, safety, and tolerability and to 
demonstrate the effect of CZP on: 
x Health outcomes
x Disease activity
x SI joint inflammation through MRI
x Changes in concomitant and background medications
3.3 
Other objectives 
The other objectives of the study are to assess the effect of CZP on the following: 
x Spinal mobility
x Total spinal pain (NRS)
x Spinal inflammation 
REDACTED
a pre
a pr
VES
VES
e
COPY
ents 
ents 
nr-axS
axS
red
red
This document 
3.3
3.3
T
cannot
oint 
int 
Chang
Chan
be 
ac
inin
used 
mes
me
ctivit
tivi
to 
es
support 
y o
y 
es of th
s of t
t of CZ
of C
any 
obje
obje
marketing 
is to de
s to d
with ac
ith a
authorization
SpA)
pA)
dictor 
ctor 
application
p
nical j
nical 
RI as s
RI as 
for the 
or the
) an
) an
and
FE P
E P
pply r
ply r
any
rom s
om 
Peri
Per
extensions 
tran
rom el
om el
f SI jo
SI j
or
nsit
nsi
variations 
y
dy 
dy 
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 24 of 255
x SI joint structural changes
x Treatment response over time 
x Additional signs and symptoms of the disease
 Morning stiffness 
 Fatigue 
 Extra-articular manifestations of axSpA 
 Sleep
 Physical function
x Subject’s health status
x Acute phase reactant (CRP)
x HRQoL
x Work and household productivity
x PK and immunogenicity
x Gene and protein expression and to explore the relationship between genomic biomarkers 
and disease biology, drug treatment and inflammatory and immune responses (for those 
subjects who consent to the genomics substudy).
4 
STUDY VARIABLES 
4.1 
Efficacy variables 
4.1.1 
Primary efficacy variable 
x ASDAS-MI at Week 52
The primary efficacy variable for Canada (and any other country where applicable or where 
requested by Regulatory Authorities) is the ASAS40 response at Week 12.
4.1.2 
Secondary efficacy variables 
The secondary efficacy variables are as follows:
x ASAS40 response at Weeks 12 and 52
x Change from Baseline in BASFI at Weeks 12 and 52
x Change from Baseline in BASDAI at Weeks 12 and 52
x Change from Baseline in SI joint SPARCC score at Week 12
x Number of subjects without relevant changes to background medication
x Change from Baseline in ASQoL at Week 52
x Change from Baseline in ASQoL at timepoints other than Week 52
x Change from Baseline in nocturnal spinal pain (NRS) at Week 52
REDACTED
bstudy
bstud
S
es
COPY 
 relati
relat
mma
mma
This document
C
x
cannot 
nge 
ge
Chang
hang
Ch
Ch
be 
e fro
e fro
used 
fic
fic
respon
espo
o
cacy
cacy
support
Autho
utho
ndary 
dary
any 
for C
for C
marketing 
ariable
ariabl
authorization
atory 
atory 
y).
y).
application 
onship
nshi
and any extensions or variations thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 25 of 255
x Number of subjects with AU or new AU flares through Week 52 
For Canada (and any other country where applicable or where requested by Regulatory 
Authorities), the secondary efficacy variables are:
x ASAS40 response at Week 52
x ASDAS-MI at Week 52 
x Change from Baseline in BASFI at Weeks 12 and 52
x Change from Baseline in BASDAI at Weeks 12 and 52
x Change from Baseline in SI joint SPARCC score at Week 12
x Number of subjects without relevant changes to background medication
x Change from Baseline in ASQoL at Week 52
x Change from Baseline in ASQoL at timepoints other than Week 52
x Change from Baseline in nocturnal spinal pain (NRS) at Week 52
x Number of subjects with AU or new AU flares through Week 52 
4.1.3 
Other efficacy variables 
The following variables will be analyzed at scheduled time points through Week 52 and at Week 
156 for selected variables:
x ASAS 20% response criteria (ASAS20), ASAS40, ASAS 20% improvement in 5 of 6 
domains (ASAS5/6), and ASAS partial remission response 
x Change from Baseline in individual ASAS components: 
 Patient’s Global Assessment of Disease Activity (PGADA)
 Total spinal pain (NRS) 
 BASFI
 Average of Questions 5 and 6 of the BASDAI concerning morning stiffness
 Change from Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) lateral 
spine flexion
 CRP
x Change from Baseline in BASDAI and individual Questions 1, 2, 3, and 4
x Change from Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS)
x Change from Baseline in BASMI linear
x ASDAS disease activity (Ankylosing Spondylitis Disease Activity Score inactive disease 
[ASDAS-ID], Ankylosing Spondylitis Disease Activity Score low disease [ASDAS-LD; 
Machado et al, 2018], Ankylosing Spondylitis Disease Activity Score high disease activity 
[ASDAS-HD], Ankylosing Spondylitis Disease Activity Score very high disease activity 
REDACTED 
20), A
20), A
artial r
artial r
dual
dual
COPY 
duled
duled
This document 
x
cannot 
hange 
ange 
Cha
Cha
be 
P
used
om
om
lexion
exion
to
m B
m B
support 
uestion
estion
any marketing 
l ASAS
ASA
nt of D
of D
authorization
d time
d tim
ASAS4
SAS4
remis
emis
application 
52
52
eek 52
eek 52
e p
and 
2
any extensions or variations thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 26 of 255
[ASDAS-vHD]) and clinical improvement (Ankylosing Spondylitis Disease Activity Score 
clinically important improvement [ASDAS-CII], ASDAS-MI)
x BASDAI 50 response
x Change from Baseline in Fatigue (NRS) (from BASDAI)
x Change from Baseline in sacroiliitis grading to Week 52 for structural damage
x Change from Baseline in SI joint SPARCC score at Week 52 and Week 156 and ankylosing 
spine MRI acuity (ASspiMRI-a) in the Berlin modification at Week 12 and Week 52
x Proportion of subjects with SI joint SPARCC score <2 at Week 12, Week 52, and Week 156
x Change from Baseline in ASAS-NSAID score
x Number of AU flares 
x Number of inflammatory bowel disease (IBD) exacerbations
x Number of psoriasis exacerbations 
x Work Productivity Survey (WPS) 
x Change from Baseline in the Sleep Problems Index II domains of the Medical Outcomes 
Study (MOS) Sleep scale
x Change from Baseline in enthesitis (Maastricht Ankylosis Spondylitis Enthesitis Score 
[MASES])
x Change from Baseline in swollen and tender joint counts (44 joint count)
x Change from Baseline in Physician’s Global Assessment of Disease Activity (PhGADA)
x Change from Baseline in the Short-Form 36-Item Health Survey (SF-36), Physical 
Component Summary (PCS), and Mental Component Summary (MCS)
x Change from Baseline in the SF-36 domains:
 Role Physical
 Bodily Pain
 General Health
 Vitality
 Social Functioning
 Role Emotional
 Mental Health
x Health status as assessed by the EuroQoL Health Status Questionnaire (5 dimensions) 
(EQ-5D) domains, visual analog scale (VAS) actual score and change from Baseline in VAS 
score
x Resources utilization: concomitant medical procedures, health care provider consultations not 
foreseen by the protocol, hospitalizations/emergency room visits
REDACTED
rich
rich
nd ten
nd ten
ian’s
ian’s
COPY 
x I
x 
ht A
ht
This document cannot
Soci
Soci

R
be
ality
ity
used
Heal
Hea
y
to 
ltl
support any 
he SF
he SF
marketing
s Glob
s Glo
ortrt-For
Fo
and M
and M
authorization 
Ankyl
Ankyl
nder jo
der jo
b
application 
omain
omain
and any extensions
d We
W
or 
ee
ee
variations 
sing 
ng 
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 27 of 255
4.2 
Pharmacokinetic, exploratory biomarker, and 
pharmacogenomic variables 
4.2.1 
Primary pharmacokinetic variables 
Certolizumab pegol plasma concentrations will be measured at Baseline and Weeks 1, 2, 4, 12,
24, 36, 52, and at the FU visit (8 weeks after the Week 52/WD visit). 
These plasma samples may be used additionally for analyses of CZP and its constituent moieties 
using alternative methods.
4.2.2 
Other biomarker variables 
Selected samples collected for measurement of CZP plasma concentration may be used 
additionally for analyses of candidate exploratory biomarkers and cytokines, where appropriate. 
The biomarkers to be analyzed may include, but will not be limited to the following:
Matrix metalloproteinase-3 (MMP-3), bone morphogenetic protein (BMP)-2,-4 and -7,
wingless-related mouse mammary tumor virus integration site protein (WNT1), WNT1-inducible
signaling pathway proteins (WISP), gremlin, dickkopf-related protein 1 (DKK1), sclerostin, 
hedgehog proteins (Sonic hedgehog [Shh], Indian hedgehog [Ihh], Dessert hedgehog [Dhh]), 
collagen turnover/cleavage products, collagen type X, vascular endothelial growth factor 
(VEGF), citrullinated vimentin fragments, cytokines: interleukin 13 (IL13), interleukin 17A and
F (IL17 A and IL17 F), interleukin 23 (IL23), interleukin 34 (IL34), transforming growth factor 
(TGF) β, macrophage colony-stimulating factors (M-CSF), granulocyte macrophage 
colony-stimulating factor (GM-CSF), colony-stimulating factor-1 (CSF-1), and soluble CSF-1
receptor (sCSF1r) levels.
4.2.3 
Other pharmacogenomic variables 
For individuals consenting to the genomics substudy, blood samples will be drawn for possible 
genetic/epigenetic, genomic, proteomic, and metabolomics analysis at Baseline and Week 12.
Additional samples will be collected for genomics, proteomics, and metabolomics analysis only, 
at Weeks 4 and 52/WD. 
Collection of the samples will enable the exploratory evaluation of biomarkers relative to disease 
activity, drug treatment, and inflammatory and immune response processes. The nature and 
format of these tentative analyses will be determined when the results of the main study are made 
available. The samples will be stored at -80°C at the central biorepository for up to 20 years.
4.3 
Other immunological variables 
Anti-CZP antibody/anti-drug antibody (anti-CZP Ab/ADAb) concentrations will be assessed at 
Baseline and Weeks 1, 2, 4, 12, 24, 36, 52/WD, and the FU visit (8 weeks after the Week 52/WD 
visit). In addition, the anti-CZP Ab concentrations will be assessed in subjects who withdraw 
from study drug and transition to open-label CZP. 
Determination of ADAb will be done using a validated screening, confirmation and titration 
ADAb bridging assay, with potential further characterization by a neutralizing antibody assay. 
The immunogenicity data will be processed according to dedicated Bioanalytical Analysis plans.
ors (
rs 
ny-stim
stim
enom
enom
COPY
: inte
: int
erleuk
erleuk
(M
(M
This document 
isit
sit
from
from
D
cannot
ZP an
P an
eline a
ine a
t). In
). In
be 
t
used
ampl
mp
Ot
Ot
to
tativ
ativ
lel
support 
s will e
will 
nt, and 
t, and
ve a
ve
any 
ctct
marketing 
mic 
ic
omics s
omics
omic, a
mic, 
ted fo
ed f
authorization
kin 3
n 3
-CSF
CSF
mulati
mulati
c va
va
application 
tein
h], De
h], De
lar end
ar end
rleukin
leuki
34 (
34
and
n (WN
(W
in 1 
n 1 
any 
P)
P)-2,2,-4
WNT
N
extensions 
used 
used 
here a
ere a
llowin
owin
or variations 
ties
ties
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 28 of 255
4.4 
Safety variables 
4.4.1 
Secondary safety variables 
Assessment time points for safety variables are specified in Table 5‒1 and Table 5‒6. The 
secondary safety variables are as follows:
x Incidence of treatment-emergent adverse events (TEAEs)
x Incidence of serious adverse events (SAEs)
x Adverse events leading to withdrawal from investigational medicinal product (IMP)
4.4.2 
Other safety variables 
Other safety variables are assessed as specified in Table 5‒1 and Table 5‒6, and are as follows:
x Change from Baseline in vital signs (blood pressure, temperature, and pulse rate)
x Change from Baseline in clinical laboratory values (hematology, biochemistry, and 
urinalysis)
Physical examination findings considered clinically significant changes since the physical 
examination completed at the Screening Visit will be recorded as AEs.
5 
STUDY DESIGN 
5.1 
Study description 
Study AS0006 is a 52-week, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled clinical study to evaluate the efficacy and safety of CZP in adult subjects with
active axSpA without x-ray evidence of AS and with objective signs of inflammation (sacroiliitis 
on MRI and/or elevated CRP) and who have had an inadequate response to, have a 
contraindication to, or are intolerant to NSAIDs. At the completion of the Week 52 visit 
assessments, eligible subjects may receive open-label CZP treatment for an additional 2 years in 
an open-label, SFE Period.
5.1.1 
Study periods 
The study includes 3 periods. An injection schedule is provided in Section 7.2.2.
Period 1 (Screening Period): 1 day to 6 weeks before Baseline: 
Prior to any study activities, subjects will be asked to read and sign the Informed Consent form 
for the conduct of the study. A separate informed consent form will also be obtained from 
subjects consenting to the use of their blood samples in a substudy for possible 
genetic/epigenetic, genomic, proteomic, and metabolite analysis.
Laboratory data (hematology, urine, and biochemistry tests) will be obtained, and treatment of 
latent tuberculosis (LTB) will be initiated when necessary. Subjects must undergo a TB test and 
complete a TB questionnaire. The BASDAI, BASMI, and spinal mobility assessments will be 
performed. Concomitant medications permitted during the study should remain stable for at least 
4 weeks prior to Baseline at Week 0.
Sacroiliac-joint x-ray (not older than 12 months before Baseline and verified by central reading 
during the Screening Period) must prove that the subject belongs to the mNY-negative axSpA 
REDACTED 
andom
andom
luate t
luate t
e of A
e of A
who
who
COPY 
This document
Labo
abo
late
late
canno
 con
con
tic/epi
ic/epi
ora
or
be
duct
duct
nse
ns
used 
ng
tudy a
udy a
t o
t
to
g Pe
g P
support
riods
ods
periods
eriod
any 
s
marketing 
AS a
S a
have h
have 
to NSA
o N
y recei
y rece
authorization 
mized
mized
the ef
he ef
and
and
application
change
chang
ed as A
ed as A
and 
oc
oc
any 
chem
hem
extensions 
are a
are a
lse r
se r
or variations thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 29 of 255
subpopulation, ie, does not have sacroiliitis grade ≥2 bilaterally or grade 3 to 4 unilaterally. 
Potentially eligible axSpA subjects without suitable SI-joint x-ray must undergo the x-ray with 
central reading within the Screening Period. Sacroiliac-joint x-rays (read centrally) will allow 
discrimination of subjects with AS and without definitive evidence for sacroiliitis on x-ray 
(mNY negative-axSpA). Subjects with AS (mNY-positive) must be excluded from further 
participation in this study.
Confirmed mNY-negative axSpA subjects must undergo an MRI later during the Screening 
Period for central reading with results from the central reading available by no later than at the 
Baseline visit. 
Additionally, the subjects must get a further measurement of CRP 3 to 5 days before Baseline 
(Week 0).  
Period 2 (Double-Blind Period): Week 0 to Week 52, placebo-controlled. 
Eligible subjects will be allocated to the following double-blind study treatments in a 1:1 ratio:
x CZP administered at the dose of 400mg at Weeks 0, 2, and 4 followed by 200mg Q2W 
(starting at Week 6 up to and including Week 50)
x Placebo
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site. At the Week 0, 2, 4, 6, 
and 8 visits, the administration must be done by dedicated, unblinded, and adequately trained site 
personnel. At the Week 10 and 12 visits, the subject will receive training on self-injection and 
the study treatment will be self-administered under the supervision of the unblinded study 
personnel. At Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50, the study treatment administration 
should preferably be done by the unblinded study personnel, or alternatively by self-injection of 
the subject under the supervision of the unblinded study personnel. The double-blind study 
treatment will be self-injected at home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46. 
Concomitant medications permitted during the study should remain stable for at least 4 weeks 
prior to the Weeks 12, 24, and 52/WD assessments.
Alternative schedules 
Subjects who discontinue the double-blind study treatment and enter open-label treatment with 
CZP will be assessed 2 and 4 weeks after open-label CZP treatment has been initiated and every 
12 weeks thereafter. Alternatively, subjects who discontinue the double-blind study treatment 
and receive other treatment (including biologics) will be assessed every 12 weeks after initiation 
of the other treatment. The alternative schedules for open-label CZP and other treatment can be 
found in Table 5‒2 and Table 5‒3, respectively. In either alternative schedule, assessments 
should be conducted until as close as possible to Week 52 (within ±4 weeks), where Week 52 is 
relative to the original randomization at Week 0. Subjects will then be invited to the Week 52
assessment visit.
Period 3 (Follow-Up Period):
All subjects not participating in the SFE Period after Week 52, including those withdrawn from 
the study prematurely, will have a FU visit 8 weeks after the Week 52/WD visit.
Safety Follow-Up Extension (SFE) Period: Week 52 to Week 156, open-label.
REDACTED
by d
by d
he sub
he sub
tered 
tered 
32, 36
32, 36
blin
blin
COPY
16, 20
16, 2
ed sc 
ed sc
d
This document 
hou
ou
relat
relat
a
cannot
other 
ther 
d in
d in T
uld 
uld
be
e oth
e oth
t
used
essed
ssed
eafte
eafte
to
ntin
ntin
d
support 
and 
nd 
nue
nu
any
mitted
itte
d 52/
52
marketing 
6, 4
, 4
nded st
ded s
the unb
he u
home a
ome 
d d
d
authorization
at th
at th
edicate
dicate
bject w
ect w
under
under
40, 
40,
application 
0, 24, 2
, 24,
e
and 
lowed
owed
any
atmen
atme
extensions
e Bas
 Bas
or variations 
t the 
the
thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 30 of 255
At the completion of the Week 52 visit assessments, subjects on double-blind study treatment 
may receive open-label CZP treatment for an additional 2 years. Subjects who withdrew from 
double-blind study treatment and transitioned to open-label CZP treatment are also eligible to 
participate in the SFE Period after completing the Week 52 visit assessments. Subjects on 
alternative treatments are not eligible to participate in the SFE Period. 
Eligible subjects are allowed to roll-over to the SFE-Period up to 3 months after completion of 
the Week 52 assessments.
In order to maintain the blind for subjects completing double-blind treatment, their study 
treatment will be administered sc at the study site by unblinded, dedicated study personnel on 
Weeks 52, 54, and 56. Subjects who withdrew from double-blind study treatment and 
transitioned to open-label CZP treatment do not need to visit the site at Week 54 and Week 56, 
and should continue their open-label CZP treatment regimen.
For the remainder of the SFE Period, CZP can be administered at the site by dedicated study 
personnel, or by self-injection of the subject under the supervision of the dedicated study 
personnel, or subjects may self-administer their study treatment Q2W at home. 
Starting at Week 64, all subjects are to visit the site approximately every 12 weeks (±2 weeks) 
for assessments. 
The last dosing visit will be at Week 154. The final study assessments are performed at 
Week 156/SFE-WD.
5.1.2 
Study duration per subject 
For each subject, the first 3 periods of the study will last a maximum of 66 weeks, as follows:
x Up to 6 weeks in the Screening Period
x 52 weeks in the Double-Blind Period
x A FU visit 8 weeks after the Week 52/WD visit (for subjects not participating in the SFE 
Period).
For subjects participating in the SFE Period, the study will extend up to a maximum of 
104 additional weeks.
The estimated recruitment period is up to 15 months. The first subject first visit is planned in 
Quarter 3 of 2015. The end of the study will be defined as the date of the last subject’s last visit, 
defined as the FU visit 8 weeks after the Week 52/WD visit for subjects not participating in the 
SFE Period, or the last visit of the SFE Period  
5.1.3 
Planned number of subjects and site(s) 
Approximately 1200 subjects are expected to enter the Screening Period in order to have 
300 subjects randomized into the Double-Blind Period. The end of the study will be defined as 
the date of last subject last FU visit. It is planned to enroll the subjects at approximately 
120 sites.
5.1.4 
Anticipated regions and countries 
The study will be conducted in North America, Australia, Europe, Asia, and other regions as 
appropriate.
REDACTED 
ect
ect
he stud
he stu
Period
Period
COPY 
l study
l stud
This document
Appr
ppr
300
300
th
cannot 
od
od
prox
rox
be 
e
d, or 
d, or
used
015. T
15. T
FU 
FU
to
uitm
uitm
support
g in the
in th
men
any marketing 
d
riod
riod
Week 
Week
authorization 
y
dy wi
y wi
application 
elyly eve
ev
y asses
asse
and 
he e 
W at h
W at h
any
by 
by d
dedi
ded
extensions 
nn
nd d 
and W
and W
de
d
or
nel o
el 
variations thereof. 

UCB
17 December 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 31 of 255
5.2 
Schedule of study assessments 
The Schedule of assessments is shown in Table 5‒1 for subjects who complete 52 weeks of 
treatment on either CZP 200mg Q2W or placebo.
In order to optimize the treatment the Investigator may adjust the background medication in 
accordance with the specifications described in Table 7‒1.
At any time during the study course, but preferably not before Week 12, the Investigator may 
discontinue the double-blind study treatment and start open-label treatment with either CZP 
(which will be provided free of charge by UCB) or an alternative drug (eg, other treatment 
[including biologics]). Table 5‒2 shows the schedule of assessments for subjects receiving 
open-label treatment with CZP and Table 5‒3 shows the schedule of assessments for subjects 
receiving an alternative treatment (not CZP).
Table 5‒6 shows the schedule of assessments for subjects participating in the SFE Period.
COPY 
This document cannot be used to support any marketing authorization application and any 
he e
extensions
eivin
ivin
for sub
or su
e SF
SF
or 
nt 
nt 
ng
ng
variations 
P 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 32 of 255
Table 5‒1: 
Schedule of study assessments – Screening through Week 52 and FU  
Visit #
Scr 
Scr 
day -5
to -3
1/
B
L
2
3
4
5
6
7
8
9
H
1
0
1
1
H
1
2
1
3
H
1
4
15
H
1
6
17
H
1
8
1
9
H
2
0
2
1
H
2
2
23
H
2
4
2
5
H
26
2
7
28
Week
Protocol 
Activity
-6 weeks 
to -1 day 
0 
1 2 
4 
6 
8 
1
0
 
1
2 
1
4 
/
H 
1
6 
1
8 
/
H 
2
0 
2
2 
/
H 
2
4 
26 
/H 
2
8 
30 
/H 
3
2 
3
4 
/
H 
3
6 
3
8 
/
H 
4
0 
42 
/
H 
4
4 
4
6 
/
H 
48 
5
0 
52
/
W
D
F
U
b 
Inclusion/ 
Exclusion 
criteria 
X 
X 
X 
Informed 
consenta
X 
Demographic 
data 
X 
Medical history 
and procedure 
history (incl. 
axSpA history)
X 
Vital signsc
X 
X 
 
X X 
X X X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/ 
urine/ 
biochemistryd
X 
Xe 
X X 
X 
X 
X 
X 
Xe 
X 
HBsAg/ 
antibodies to 
hepatitis C/HIV/ 
HLA-B27/
CKD-EPI 
Xf 
CRP
Xg 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
testingh
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
PEi
X 
X 
 
X X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
Extra-articular 
assessments
X 
 
X 
X 
 
 
X 
 
 
X 
X 
X 
REDACTED 
E ACTED
X
ED
RE
R
COPY 
Y
COPY
C
This document 
nt cannot 
X
no
no
nn
be 
be
be
be
be
be used 
X
d
ed
us d to 
X
o support 
s p ort any y
an marketing 
X
ng
tin
m rke n
authorization 
i n
io
aut ori ati
a
application 
ion
pli ati
plplplp
and 
an
any 
H
a y
any
a
extensions
2
io s 
6
3
8
ioioio
e te
io
or 
23
2
H
o variations 
on
3
va
va
va
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 33 of 255
Table 5‒1: 
Schedule of study assessments – Screening through Week 52 and FU  
Visit #
Scr 
Scr 
day -5
to -3
1/
B
L
2
3
4
5
6
7
8
9
H
1
0
1
1
H
1
2
1
3
H
1
4
15
H
1
6
17
H
1
8
1
9
H
2
0
2
1
H
2
2
23
H
2
4
2
5
H
26
2
7
28
Week
Protocol 
Activity
-6 weeks 
to -1 day 
0 
1 2 
4 
6 
8 
1
0
 
1
2 
1
4 
/
H 
1
6 
1
8 
/
H 
2
0 
2
2 
/
H 
2
4 
26 
/H 
2
8 
30 
/H 
3
2 
3
4 
/
H 
3
6 
3
8 
/
H 
4
0 
42 
/
H 
4
4 
4
6 
/
H 
48 
5
0 
52
/
W
D
F
U
b 
Chest x-rayj
X 
X 
TB testk
X 
X 
TB 
questionnaire 
X 
X 
X 
X 
X 
X 
Sacroiliac joint 
x-rayl
X 
X 
MRIm
X 
X 
X 
BASMI & spinal 
mobilityn
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BASDAI
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BASFI
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36
X 
X 
X 
X 
X 
X 
X 
ASQoL
X 
X X X 
X 
X 
X 
X 
X 
MOS Sleep 
Scale
X 
X 
X 
X 
X 
X 
EQ-5D
X 
X 
X 
X 
X 
X 
X 
MASES
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Total and 
nocturnal spinal 
pain
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Swollen and 
tender joint 
counts
X 
X 
X 
X 
X 
X 
REDACTED 
ED
ED
ED
ACTED
X
DA
RE A
RE
RE
RE
R
COPY 
Y
COPY
CO
CO
CO
This document t cannot 
X
t
c nn
be 
be
b
used 
d
X
d
us d to 
X
o 
t
support 
ort
po
s p o
su
s
any 
X
n
X
ny
an marketing 
g
X
ng
ng
ke ng
ke
ke
m rke
X
ma
m
authorization 
n
on
ati n
X
za
ut ori
ut
ut
ut
aut
application 
on
pli ati
pli
pli
pli
pli
and 
nd
an
any 
H
a y
any
a
extensions
2
io s 
6
3
8
ioioio
e te
io
or 
23
2
H
o variations 
on
3
va
va
va
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 34 of 255
Table 5‒1: 
Schedule of study assessments – Screening through Week 52 and FU  
Visit #
Scr 
Scr 
day -5
to -3
1/
B
L
2
3
4
5
6
7
8
9
H
1
0
1
1
H
1
2
1
3
H
1
4
15
H
1
6
17
H
1
8
1
9
H
2
0
2
1
H
2
2
23
H
2
4
2
5
H
26
2
7
28
Week
Protocol 
Activity
-6 weeks 
to -1 day 
0 
1 2 
4 
6 
8 
1
0
 
1
2 
1
4 
/
H 
1
6 
1
8 
/
H 
2
0 
2
2 
/
H 
2
4 
26 
/H 
2
8 
30 
/H 
3
2 
3
4 
/
H 
3
6 
3
8 
/
H 
4
0 
42 
/
H 
4
4 
4
6 
/
H 
48 
5
0 
52
/
W
D
F
U
b 
PhGADA 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PGADA
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Productivity
X 
X 
X 
X 
X 
X 
X 
Resources 
utilizationo
X 
X 
X 
X 
X 
X 
X 
CZP plasma 
concentration/ 
anti-CZP Abs / 
Biomarker
X 
X X X 
X 
X 
X 
X 
X 
Genetics/epigene
tics
X 
X 
Gene expression 
and proteomics
X 
X 
 
X 
X 
Prior and 
Concomitant 
medication
X 
X 
X X X 
X X X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs
X 
X X X 
X X X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IXRSp
X 
X 
 
X X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
administration 
scq
X 
X X 
X X X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject training 
on self-injectionr
X 
X 
Abs=antibodies; AE=adverse event; Apo=Apolipoprotein; AsQoL=Ankylosing Spondylitis Quality of Life; BASDAI=Bath Ankylosing Spondylitis Disease 
Activity Index; BASFI=Bath Ankylosing Spondylitis Functional Index; axSpA=axial spondyloarthritis; BASMI=Bath Ankylosing Spondylitis Metrology Index; 
REDACTED 
ACTED
AC
AC
AC
RE AC
R
COPY 
X
PY
OP
COP
This document 
=Bath
Bath
cannot 
nn
rse eve
se eve
th A
th
nn
nn
be 
e
be
be
be
be used 
X
us d to 
X
X
to support 
ort
X
X
X
ort
ort
ort
p ort
sup
X
upp
s p
any 
X
an marketing 
ng
ing
ng
m rke ng
X
X
ma
m
authorization 
X
t ori ati n
t
uth
th
aut
application 
on
ati
ca
pli a
ap
and 
X
n
X
nd
an
any 
H
a y
any
a
extensions
2
io s 
6
3
8
ioioio
e te
io
or 
23
2
H
o variations 
on
3
va
va
va
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 35 of 255
Table 5‒1: 
Schedule of study assessments – Screening through Week 52 and FU  
Visit #
Scr 
Scr 
day -5
to -3
1/
B
L
2
3
4
5
6
7
8
9
H
1
0
1
1
H
1
2
1
3
H
1
4
15
H
1
6
17
H
1
8
1
9
H
2
0
2
1
H
2
2
23
H
2
4
2
5
H
26
2
7
28
Week
Protocol 
Activity
-6 weeks 
to -1 day 
0 
1 2 
4 
6 
8 
1
0
 
1
2 
1
4 
/
H 
1
6 
1
8 
/
H 
2
0 
2
2 
/
H 
2
4 
26 
/H 
2
8 
30 
/H 
3
2 
3
4 
/
H 
3
6 
3
8 
/
H 
4
0 
42 
/
H 
4
4 
4
6 
/
H 
48 
5
0 
52
/
W
D
F
U
b 
BL=Baseline; CKD-EPI=Chronic Kidney Epidemiology Collaboration; CRP=C-reactive protein; CZP=certolizumab pegol; EQ̻5D=EuroQoL Health Status 
Questionnaire (5 dimensions); FU=Follow-Up; H=home; HbA1c=glycated hemoglobin; HBsAg=Hepatitis B surface antigen; HIV=human immunodeficiency 
virus; HLA-B27=Human Leukocyte Antigen-B27; IGRA=Interferon-Gamma Release Assay; IXRS=Interactive Response System; MASES=Maastricht 
Ankylosis Spondylitis Enthesitis Score; MOS=Medical Outcomes Study; MRI=magnetic resonance imaging; PE=physical exam; PhGADA=Physician’s Global 
Assessment of Disease Activity; PGADA=Patient’s Global Assessment of Disease Activity; sc=subcutaneously; Scr=Screening; SF̻36=Short̻Form 36̻item 
Health Survey; SFE=safety Follow-up Extension; SI=sacroiliac; TB=tuberculosis; WD=Withdrawal 
Note: All weeks are ±3 days compared to Baseline. 
Note: At the completion of the Week 52 Visit, subjects may receive open-label CZP treatment for an additional 2 years in the SFE Period
a Informed consent: Prior to any study activities, subjects will be asked to read and sign the informed consent form for the conduct of the study. A separate 
informed consent form will also be obtained from subjects consenting to the use of their blood samples in a substudy for possible genetic/epigenetic, genomic, 
proteomic, and metabolite analysis.
b FU: 8 weeks after Week 52/WD visit for subjects not participating in the SFE Period. 
c Pulse rate, systolic and diastolic blood pressures, temperature, and respiration rate are to be measured at Screening and Baseline, thereafter pulse rate, systolic 
and diastolic blood pressures, temperature are to be measured at all on-site visits. If a subject experiences an AE, respiration rate will be measured in addition.
d Subjects will be encouraged to be in fasting condition at Baseline and at Week 52/WD or at the time the subject shifts to alternative treatment, for Apo A1, 
ApoB, and lipoprotein(a) assessments.
e HbA1c will be measured at Baseline and Week 52/WD. 
f Testing to rule out HBsAg, antibodies to hepatitis C, and HIV will be performed. In addition, testing for HLA-B27 and abnormalities for estimated glomerular 
filtration rate as measured by CKD-EPI are to be performed.
g One retest of CRP is mandatory during the Screening Period within 3 to 5 days before the Baseline visit in order to meet the inclusion criteria.
h Pregnancy testing must be carried out for women of childbearing potential: A serum test will be performed at the Screening visit and FU, and urine testing 
(dipstick) at Baseline and Week 52/WD.
i Includes evaluation of signs and symptoms of active TB and risk factors for exposure to TB. Weight is to be measured at Screening, Week 24, and at 
completion at Week 52/WD. Height will be measured at the Baseline visit only.
j A chest x-ray must be done at Screening unless a chest x-ray (or computed tomography of the chest) has been done within 3 months prior to the Screening 
visit. The chest x-ray will be repeated at Week 52/WD visit only if the TB test was confirmed positive or any further evidence is suggestive of potential TB 
infection (eg, exposure).
k TB test: IGRA test (QuantiFERON test [or Elispot test when the QuantiFERON indicated is not available]). The TB test will be repeated at Week 52 (or at 
WD visit if medically indicated) for subjects with previously negative TB test result. Subjects who tested positive for TB should be encouraged to complete a 
FU visit (8 weeks after the Week 52/WD visit for subjects not participating in the SFE Period) and follow-up information of suspected and confirmed TB cases 
REDACTED
ad and
ad an
 the us
 the us
in the 
in the
nd resp
nd resp
all
al
COPY
D=W
D=W
CZP tr
ZP tr
This document
er the
r the
cannot 
FERO
ERO
dicate
icate
W
be
eni
ated a
ated 
used 
ms o
s o
will be m
ll be m
ing u
ng u
to 
of a
of a
support 
forme
orm
ing Per
ng Pe
en of ch
n of ch
any 
d HIV w
HIV 
med
marketing 
piratio
irati
on
on-site
site
e and at
and 
authorization
reatme
eatme
sign th
sign th
se of th
e of th
SFE P
SFE P
ioi
application 
=Intera
nter
ce imag
e ima
=subcu
=subcu
thdrawa
hdraw
and
rtoliz
oliz
tis B s
is B s
rac
any 
H
a y
izum
zum
any extensions
2
io s 
6
3
8
ioioio
e te
io
or 
23
2
H
o variations 
on
3
va
va
va
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 36 of 255
Table 5‒1: 
Schedule of study assessments – Screening through Week 52 and FU  
Visit #
Scr 
Scr 
day -5
to -3
1/
B
L
2
3
4
5
6
7
8
9
H
1
0
1
1
H
1
2
1
3
H
1
4
15
H
1
6
17
H
1
8
1
9
H
2
0
2
1
H
2
2
23
H
2
4
2
5
H
26
2
7
28
Week
Protocol 
Activity
-6 weeks 
to -1 day 
0 
1 2 
4 
6 
8 
1
0
 
1
2 
1
4 
/
H 
1
6 
1
8 
/
H 
2
0 
2
2 
/
H 
2
4 
26 
/H 
2
8 
30 
/H 
3
2 
3
4 
/
H 
3
6 
3
8 
/
H 
4
0 
42 
/
H 
4
4 
4
6 
/
H 
48 
5
0 
52
/
W
D
F
U
b 
should be provided to UCB at least after 3, 9, and 12 months of the start date of anti-TB treatment.
l Sacroiliac joint x-rays will be performed at Screening and Week 52/WD for all subjects. An SI joint x-ray will be performed ≤12 months prior to the Baseline 
visit.
m Magnetic resonance imaging of the spine and SI joints to be performed at Screening and at the Week 12 and at the Week 52/WD visits if MRI was performed 
more than 12 weeks prior to WD visit.
n Occiput to wall distance; chest expansion; and BASMI, which includes modified Schober test, lateral spinal flexion, cervical rotation, tragus to wall distance, 
and maximal intermalleolar distance.
o Resource utilization includes: concomitant medical procedures, health care provider consultations not foreseen by the protocol, hospitalizations/emergency 
room visits.
p Contact IXRS to register the visit and obtain next kit number, where applicable.
q At on-site visit days (Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the double-blind study treatments will be administered sc at the 
study site. At the Week 0, 2, 4, 6, and 8 visits, the administration must be done by dedicated, unblinded, and adequately trained site personnel. At the Week 10
and 12 visits, the subject will receive training on self-injection and the study treatment will be self-administered under the supervision of the unblinded study 
personnel. At Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50, the study treatment administration should preferably be done by the unblinded study personnel, 
or alternatively by self-injection of the subject under the supervision of the unblinded study personnel. The double-blind study treatment will be self-injected at 
home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46. From Week 52 onwards, after completion of all onsite assessments and procedures, the subject may
receive open-label CZP at the discretion of the Investigator.
r All subjects will receive training for self-injection at the study site on Weeks 10 and 12. During the training at the Weeks 10 and 12 visits, the double-blind 
study treatment will be self-administered under the supervision of the unblinded study personnel.
REDACTED 
licable
icable
, 40, 4
, 40, 4
ust be 
ust be 
nd the 
nd the 
he s
he s
COPY
hobe
hob
vider c
vider 
This document cannot be used to support 
uperv
perv
any
stud
study y
rvisio
vis
marketing 
stud
tud
tudy tre
udy tre
ion of t
on of 
Week 52 
eek 52
authorization
consu
consu
4, 48, 
4, 48, 
done b
done b
dy t
dy
application 
Week 12
eek 12
est, late
est, la
t
and 
ray 
ray wi
wi
any 
H
a y
any extensions
2
io s 
6
3
8
ioioio
e te
io
or 
23
2
H
o variations 
on
3
va
va
va
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 37 of 255
Table 5‒2: 
Schedule of alternative study assessment with CZP - after subject discontinuation of the 
double-blind study treatment 
Visit #
1
wdt
2
wdt
3
wdt
4
wdt
5
wdt
Week
Protocol 
Activity
0 
2
4 
6H 
8H
10H 
12 
14H 
16H 
18H 
20H 
22H 
24 and 
Q12W 
 
52/WD
a
FUa
Vital signsb 
X
X
X
X
X
Continue W24 assessments every 12 weeks until as close as possible to W52/WD of the 
original visit schedule. Subject will then be invited to the final assessment visit at 
W52/WDg
X
X
Hematology/ 
urine/biochemis
try 
Xc,d
X
X
Xd
X
CRP
X
X
X
X
X
Pregnancy 
testinge
X
X
X
PEf
X
X
X
X
X
X
Extra-articular 
assessments
X
X
X
TB testh
X
TB 
questionnaire
X
X
X
X
BASMI & 
Spinal mobilityi
X
X
X
X
X
BASDAI
X
X
X
X
X
BASFI 
X
X
X
X
X
SF-36
X
X
X
X
AsQoL
X
X
X
X
MOS Sleep 
Scale
X
X
X
X
EQ-5D
X
X
X
X
MASES
X
X
X
X
REDACTED 
D
CT
AC
ED
COPY 
PY
CO
This document 
nt cannot 
ot
an
an
an
an
an
be 
be used 
d
us
to
to 
to support t
por
pp
s
any 
a
marketing 
g
X
tin
m
X
m
authorization 
ati
ori
ori
ori
ori
ori
a
application 
on
ca
pp
ap
and 
nd any 
ny
any
ny
ny
ny extensions 
sio
22H
22H
s
or 
5
or variations 
on
n of t
n of t
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 38 of 255
Table 5‒2: 
Schedule of alternative study assessment with CZP - after subject discontinuation of the 
double-blind study treatment 
Visit #
1
wdt
2
wdt
3
wdt
4
wdt
5
wdt
Week
Protocol 
Activity
0 
2
4 
6H 
8H
10H 
12 
14H 
16H 
18H 
20H 
22H 
24 and 
Q12W 
 
52/WD
a
FUa
Total and 
nocturnal spinal 
pain
X
X
X
X
X
Swollen and 
tender joint 
counts
X
X
X
X
X
Patient’s Global 
assessment
X
X
X
X
X
Investigator’s 
AS assessment
X
X
X
X
X
CZP plasma 
concentration/ 
anti-CZP Abs/ 
Biomarker 
X
X
X
X
X
X
Gene expression 
and proteomicsj
X
Telephone 
contactk
X
X
X
Prior and 
Concomitant 
medication
X
X
X
X
X
X
X
AEs
X
X
X
X
X
X
X
IXRS
X
X
X
X
X
X
X
CZP 
administration 
sc 
Xl
Xl
Xl
X
X
X
X
X
X
X
X
X
Xm
REDACTED 
ED
AC
AC
AC
AC
A
COPY 
PY
CO
This document 
en cannot 
X
Xl
ot
an
be 
be
be
be
be
be used 
se
to 
to support t
por
up
any 
a
marketing 
m
g
ma
m
authorization 
at
ori
th
application 
on
on
on
on
ap
on
ap
ap
ap
ap
and any 
ny
any
ny
ny
ny extensions 
sio
22H
22H
s
or 
5
or variations 
on
n of t
n of t
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 39 of 255
Table 5‒2: 
Schedule of alternative study assessment with CZP - after subject discontinuation of the 
double-blind study treatment 
Visit #
1
wdt
2
wdt
3
wdt
4
wdt
5
wdt
Week
Protocol 
Activity
0 
2
4 
6H 
8H
10H 
12 
14H 
16H 
18H 
20H 
22H 
24 and 
Q12W 
 
52/WD
a
FUa
Abs=antibodies; AE=adverse event; AS=ankylosing spondylitis; AsQoL=Ankylosing Spondylitis Quality of Life; BASDAI=Bath Ankylosing Spondylitis 
Disease Activity Index; BASFI=Bath Ankylosing Spondylitis Functional Index; BASMI=Bath Ankylosing Spondylitis Metrology Index; CRP=C̻reactive 
protein; CZP=certolizumab pegol; EQ-5D=EuroQoL Health Status Questionnaire (5 dimensions); FU= Follow-Up; H=home, no site visit; HbA1c=glycated 
hemoglobin; IGRA=Interferon-Gamma Release Assay; IXRS=Interactive Response System; MASES=Maastricht Ankylosis Spondylitis Enthesitis Score; 
MOS=Medical Outcomes Study; PE=physical exam; Q2W=every 2 weeks; Q12W=every 12 weeks; sc=subcutaneously; SF̻36=Short̻Form 36̻item Health 
Survey; SFE=Safety Follow-up Extension; W=Week; WD=Withdrawal; wdt=withdrawal treatment
Note: If a subject switches from open-label CZP to other treatment (including biologics), the subject must follow the assessment schedule (Table 5‒3) for other 
treatment (including biologics)
Note: All weeks are ±3 days compared to Baseline. Week 0 of the alternative schedule starts 2 weeks after the last dose of the double-blind study treatment.
Note: At the completion of the Week 52 visit, subjects who transitioned to open-label CZP treatment after withdrawal from the Double-Blind Period are eligible 
to participate in the SFE Period.
a FU: 8 weeks after Week 52/WD visit for subjects not participating in the SFE Period.
b Pulse rate, systolic and diastolic blood pressures, temperature, and respiration rate are to be measured at wdt Week 0 thereafter pulse rate, systolic and diastolic 
blood pressures, temperature are to be measured at all on-site visits. If a subject experiences an AE, respiration rate will be measured in addition. 
c Subjects will be encouraged to be in fasting condition at the time the subject shifts to alternative treatment, for Apo A1, ApoB, and lipoprotein(a) assessments.
d HbA1c will be measured at wdt Week 0 and Week 52/WD.
e Pregnancy testing must be carried out for women of childbearing potential and will be a serum test at the FU visit and a urine test (dipstick) at wdt Week 0 
(prior to initiation of open-label CZP) and Week 52/WD visit.
f Includes evaluation of signs and symptoms of active TB and risk factors for exposure to TB. Weight is to be measured at wdt Week 0, Week 24, and at 
completion at Week 52/WD. 
g If the last Q12W assessment for a subject who discontinues study treatment is ≤4 weeks before the final assessments visit at Week 52/WD, the assessment 
should be cancelled and the subject should instead be invited to undergo the final assessments visit at Week 52 (the Week 52/WD visit is to be scheduled 
52 weeks [±3 days] after Baseline).
h TB test: IGRA test (QuantiFERON test [or Elispot test when the QuantiFERON test is indicated but not available]). The TB test will be repeated at Week 52 
(or at WD visit if medically indicated) for subjects with previously negative TB test result.
i Occiput to wall distance; chest expansion; and BASMI, which includes modified Schober test, lateral spinal flexion, cervical rotation, tragus to wall distance, 
and maximal intermalleolar distance.
j A separate informed consent will be obtained prior to gene expression and proteomic assessments, if applicable.
k A telephone contact will be made with the subject every 4 weeks after the on-site visit (ie, at Weeks 8H, 16H, 22H, and every 4 weeks after Week 24 until 
Week 52/WD visit).
REDACTED
sched
sche
open
open
in the 
in the
nd resp
nd resp
its
its
COPY
wal t
wal 
ogics), 
gics
d
This document cannot
stanc
anc
nt will 
t will 
be ma
be m
be
ed
pansi
pans
used 
t [or E
[or E
d) for 
) for
to 
nste
support 
TB a
B a
disconti
iscont
tead b
ead
any 
ari
ar
visit.
visit.
and
an
marketing 
pirati
rati
. If a sub
If a su
e the sub
the s
ring p
ing
authorization 
th
ule sta
le sta
label C
bel C
SFE P
SFE P
ion
io
application 
U= Fo
= Fo
SES=Ma
ES=M
eeks; sc
eeks; s
eatment
atmen
he subj
e sub
and 
of L
f L
ng Spo
ng Spo
oll
oll
any 
ny
Life; 
Life
any
ny
ny extensions 
sio
22H
22H
s
or 
5
or variations 
on
n of t
n of t
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 40 of 255
Table 5‒2: 
Schedule of alternative study assessment with CZP - after subject discontinuation of the 
double-blind study treatment 
Visit #
1
wdt
2
wdt
3
wdt
4
wdt
5
wdt
Week
Protocol 
Activity
0 
2
4 
6H 
8H
10H 
12 
14H 
16H 
18H 
20H 
22H 
24 and 
Q12W 
 
52/WD
a
FUa
l Loading dose of CZP 400mg at Weeks 0, 2, and 4 must be administered by dedicated site staff.
m CZP administration will be continued Q2W. 
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any 
ny
any
ny
ny extensions 
sio
22H
22H
s
or 
5
or variations 
on
n of t
n of t
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 41 of 255
Table 5‒3: 
Schedule of alternative study assessment with other treatment (including biologics) - after 
subject discontinuation of the double-blind study treatment 
Visit #
1 
wdt 
2
wdt
3
wdt
Week
Protocol Activity
0 
12 
24 and Q12W 
Continue W24 assessments every 12 weeks until as close as possible to W52/WD of the 
original visit schedule. Subject will then be invited to the final assessment visit at 
W52/WD ±4 weeks.d 
52/WD 
FUa 
Hematology/urine/biochemistry
Xb,c 
 
 
 
CRP
X 
X 
X 
X 
Pregnancy testingg
X
X
X
PE
X 
 
X 
BASDAI
X 
X 
 
X 
BASFI 
X 
X 
 
X 
Total and nocturnal spinal pain
X 
X 
 
X 
Swollen and tender joint counts
X 
Patient’s Global assessment
X 
X 
 
X 
Investigator’s AS assessment
X 
X 
 
X 
CZP plasma concentration/anti-CZP Abs/ 
Biomarker
X 
X 
 
X 
Prior and Concomitant medication
X
X
X
X
X
AEs
X 
X 
X 
X 
X 
IXRSe
X 
X 
X 
X 
X 
Other treatment administration
Xf 
Follow the regimen of the particular 
alternative treatment. Telephone contact 
to be performed on the discretion of the 
Investigator 
 
 
REDACTED 
X
TED
AC
ED
ED
ED
ED
ED
COPY 
PY
PY
PY
PY
PY
C
This document cannot be 
e use
used 
se
to support 
X
X
or
up
any 
an marketing 
tin
ke
m
authorization 
oioioion
tio
iza
X
tho
a
application 
tio
lic
ap
and 
d
nd
an
any
W52/W
52/W
nt vis
t vis
extensions 
sit a
sit
s
xte
or 
or variations 
on
cs) 
cs) -
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 42 of 255
Table 5‒3: 
Schedule of alternative study assessment with other treatment (including biologics) - after 
subject discontinuation of the double-blind study treatment 
Visit #
1 
wdt 
2
wdt
3
wdt
Week
Protocol Activity
0 
12 
24 and Q12W 
Contin
ue W24 
assess
52/WD 
FUa 
Abs=antibodies; AE=adverse event; Abs=antibodies; AE=adverse event; BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; BASFI=Bath 
Ankylosing Spondylitis Functional Index; CRP=C̻reactive protein; CZP=certolizumab pegol; eCRF=electronic case report form; FU= Follow-Up; H=home, no 
site visit; IXRS=Interactive Response System; PE=physical exam; Q12W=every 12 weeks; W=Week; WD=Withdrawal, wdt=withdrawal treatment
Note: All weeks are ±3 days compared to Baseline. Week 0 of the alternative schedule starts 2 weeks after the last dose of the double-blind study treatment.
Note: Local guidelines on initiation and monitoring of the particular treatment should be followed.
a FU: 8 weeks after Week 52/WD visit.
b Subjects will be encouraged to be in fasting condition at the time the subject shifts to alternative treatment, for Apo A1, ApoB, and lipoprotein(a) assessments.
c HbA1c will be measured at wdt Week 0.
d If the last Q12W assessment for a subject who discontinues study treatment is ≤4 weeks before the final assessments visit at Week 52/WD, the assessment 
should be cancelled and the subject should instead be invited to undergo the final assessments visit at Week 52/WD (the Week 52/WD visit is to be scheduled 
52 weeks [±3 days] after Baseline).
e For registration of visit only. Interactive Response System won't assign any open treatment medication.
f Follow the regimen of the particular alternative treatment. Arrange for additional site visits for administration and record the treatment in the Concomitant 
Medication eCRF as appropriate.
g Pregnancy testing must be carried out for women of childbearing potential and will be a serum test at the FU visit and a urine test (dipstick) at wdt Week 0 and 
Week 52/WD visit.
REDACTED
e fina
e fina
gn any 
n any 
for ad
for ad
po
p
COPY
o alte
o alt
≤4 we
≤4 we
l
This document cannot be used to support any marketing 
otential a
ential 
authorization
eks be
eks be
assessm
ssessm
open tr
open t
ditiona
ditiona
application 
after
fte
native tr
ative 
f
and
troni
on
WD=W
D=W
r t
any
tis Di
tis D
nic c
ic
y extensions 
ue W
ue
asses
asse
s
xte
e
or 
or variations 
on
cs) 
cs) -
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 43 of 255
At any time during the study course, but preferably not before Week 12, the Investigator may 
discontinue the double-blind study treatment and start open-label treatment with either CZP 
(which will be provided free of charge by UCB) or an alternative drug (eg, other treatment 
[including biologics]).
The determination by the Investigator to switch a subject from double-blind study treatment to 
either open-label CZP or other treatment will generally be done after the subject has completed 
the assessments at a given scheduled study visit. That study visit then becomes the withdrawal 
treatment (wdt) Week 0 visit of the given alternative schedule of assessments. Since many of the 
assessments required at the wdt Week 0 visit may have already been completed as part of the 
originally scheduled study visit, only those not already done at that visit should be completed. 
Table 5‒4 outlines which additional study assessments would be required at wdt Week 0 for 
subjects switching to the open-label CZP alternative schedule, and Table 5‒5 shows this 
information for subjects switching to the other treatment alternative schedule.
It may be possible that an Investigator determines that a subject should switch to the alternative 
schedule with either open-label CZP or another treatment without initiating the alternative 
treatment at the study visit when this determination is made. In this case, the subject will come 
back another day shortly thereafter to initiate the treatment and to complete all assessments 
outlined on the relevant alternative schedule of assessments (see Table 5‒4 or Table 5‒5) for the 
wdt Week 0 visit. It is important then to schedule the wdt Week 0 and the subsequent on-site 
visits accordingly in order to end up at Week 52 with the same visit date as originally planned for 
the regular double-blind study course.
REDACTED COPY 
me
m
he wd
he wd
with 
with
This document cannot be used to support any marketing authorization
dt
h the s
the s
application
his ca
his ca
d to co
d to co
s (see 
(see T
t Wee
Wee
and 
sw
s
itiatin
tiatin
any 
le.
le
witch
wit
extensions
t o
compl
ompl
Week
Week
show
how
e
or
y
of th
f th
variations 
walal
of th
of th
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 44 of 255
Table 5‒4: 
Schedule of study assessments – additional assessments for wdt 0 visit required for subjects 
transitioning to open-label CZP  
Visit #a
1/
BL 
2
3
4
5
6
7
8
9
H
10
11
H
12
13
H
14
15
H
16
17
H
18
19
H
20
21
H
22
23
H
24
25
H
26
27
Week
Protocol Activity
0 
1 
2 4 6 8 
10 
12 
14 
/H 
16 
18 
/H 
20 
22 
/H 
24 
26 
/H 
28 
30 
/H 
32 
34 
/H 
36 
38 
/H 
40 
42 
/H 
44 
46 
/H 
48 
50 
Vital signs
X
X
X
X
X
X
X
X
X
Hematology/urine/ 
biochemistry
 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CRP
 
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testing
 
 
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PE
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TB questionnaire 
 
 
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BASMI & spinal 
mobility
X
X
X
X
X
X
X
X
X
X
X
X
BASDAI
X
X
X
X
X
X
X
X
X
X
X
X
BASFI
X
X
X
X
X
X
X
X
X
X
X
X
SF-36
 
 
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ASQoL
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MOS Sleep Scale
 
 
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D
 
 
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MASES
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Total and nocturnal 
spinal pain
X
X
X
X
X
X
X
X
X
X
X
X
Swollen and tender joint 
counts
 
 
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PhGADA 
X
X
X
X
X
X
X
X
X
X
X
X
PGADA
X
X
X
X
X
X
X
X
X
X
X
X
REDACTED 
D
ACTED
CTED
AC
D
E
X
AC
AC
AC
AC
E AC
RE
RED
RE
COPY
OPY 
PY
OP
X
OP
OP
OP
O
This document can
ca no
not 
ot
not
ann
nn
cann
be 
e
b
used
ed 
ed
u
X
ed
ed
ed
u ed to
X
to
to support 
port
portrt
X
uppo
ppo
po
up
X
u
su
any 
X
y
X
a
marketing
X
g 
g
X
tin
rke
X
ar
m r
m
thorization 
n
ation
ation
a
n
th
X
zati
ati
ati
th
za
auth
auth
th
th
th
th
a
application 
atio
ati
X
n
io
X
at
pli
X
plplplpl
a
and
X
nd any
any
an
X
ny
an extensions 
21
21
H
io
/H
36
36
sioio
xte
io
e
or 
or
or
or
or variations 
on
d for s
for s
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 45 of 255
Table 5‒4: 
Schedule of study assessments – additional assessments for wdt 0 visit required for subjects 
transitioning to open-label CZP  
Visit #a
1/
BL 
2
3
4
5
6
7
8
9
H
10
11
H
12
13
H
14
15
H
16
17
H
18
19
H
20
21
H
22
23
H
24
25
H
26
27
Week
Protocol Activity
0 
1 
2 4 6 8 
10 
12 
14 
/H 
16 
18 
/H 
20 
22 
/H 
24 
26 
/H 
28 
30 
/H 
32 
34 
/H 
36 
38 
/H 
40 
42 
/H 
44 
46 
/H 
48 
50 
CZP plasma 
concentration/anti-CZP 
Abs/Biomarker
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IXRS
 
X
X
X
X
X
X
X
X
X
Study drug 
administration sc
 
Abs=antibodies; ASQoL=Ankylosing Spondylitis Quality of Life; BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; BASFI=Bath Ankylosing 
Spondylitis Functional Index; BASMI=Bath Ankylosing Spondylitis Metrology Index; BL=Baseline; CRP=C reactive protein; CZP=certolizumab pegol; 
EQ̻5D=EuroQoL Health Status Questionnaire (5 dimensions); H=home; IXRS=Interactive Response System; MASES=Maastricht Ankylosis Spondylitis 
Enthesitis Score; MOS=Medical Outcomes Study; PE=physical exam; PhGADA=Physician’s Global Assessment of Disease Activity; PGADA=Patient’s Global 
Assessment of Disease Activity; sc=subcutaneously; SF̻36=Short̻Form 36̻item Health Survey; TB=tuberculosis; wdt=withdrawal treatment 
a
Additional assessments to be performed correspond to the assessments to be performed at wdt Week 0. 
REDACTED
RS=In
RS=I
GADA
GADA
m 36
m 36̻
sments
sment
COPY
nkylos
nkylos
Index; 
ndex;
nt
Y
PY 
This document cannot be used to support any marketing authorization
BL=B
BL=
eractiv
ractiv
=Phys
Phys
item H
tem H
to be 
to be 
application 
tio
ti
X
io
ppli
plicatio
icatio
tioio
pli
io
ng Spo
ng Spo
Ba
pp
and 
nd
an
any
X
ny extensions 
21
21
H
io
/H
36
36
sioio
xte
io
e
or 
or
or
or
or variations 
on
d for s
for s
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 46 of 255
Table 5‒5: 
Schedule of study assessments – additional assessments for wdt 0 visit required for subjects 
transitioning to alternative treatment  
Visit #a
1/
BL 
2
3
4
5
6
7
8
9
H
10
11
H
12
13
H
14
15
H
16
17
H
18
19
H
20
21
H
22
23
H
24
25
H
26
27
Week
Protocol Activity
0 
1 2 4 6 8 
10 
12 
14 
/H 
16 
18 
/H 
20 
22 
/H 
24 
26 
/H 
28 
30 
/H 
32 
34 
/H 
36 
38 
/H 
40 
42 
/H 
44 
46 
/H 
48 
50 
Hematology/urine/ 
biochemistry
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRP
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PE
 
X 
X 
X 
X
X
X 
 
X
X
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
BASDAI
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BASFI
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total and nocturnal 
spinal pain
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PhGADA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PGADA
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IXRS
X 
X 
X 
X 
X 
X 
X 
X 
X 
BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; BASFI=Bath Ankylosing Spondylitis Functional Index; BL=Baseline; CRP=C reactive protein; 
H=home; IXRS=Interactive Response System; MOS=Medical Outcomes Study; PE=physical exam; PhGADA=Physician’s Global Assessment of Disease 
Activity; PGADA=Patient’s Global Assessment of Disease Activity; sc=subcutaneously; wdt=withdrawal treatment 
a
Additional assessments to be performed correspond to the assessments to be performed at wdt Week 0.
REDACTED 
TE
TED
ACTE
ACTE
TE
TE
A TE
X
DAC
AC
AC
DA
X
ED
R
COPY 
Y
OPY
OPY
O Y
X
COP
CO
This document cannot be used to support any
the as
the a
marketing
ing
ng 
tin
ASFI=B
ASFI=
Outcome
utcom
tivity;
ivity
tin
tinin
aut
auth
X
thorization 
n
ization
atio
X
n
iz
on
X
riziziziza
t
riz
th
aut
a
application 
X
n
ati
plicat
plicat
at
at
at
p
at
X
pplplpl
pp
a
and 
X
and
nd
nd
an
any 
X
an extensions 
21
H
sio
H
36
36
sisio
sio
xt
sio
e
or 
or
o variations 
on
d for s
for s
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 47 of 255
Table 5‒6: 
Schedule of study assessments - Safety Follow-Up Extension Period 
Visit #
29 
30 
31 
32
33
34
35
36
37
38
39
40
Overall Study Week/SFE Week
Protocol Activity
52/0a
54/2 
56/4 
64/12 
76/24 
88/36 
100/48 
112/60 
124/72 
136/84 
148/96 
156/104/SFE-
WD 
Informed consentb
X
 
 
CRP 
 
 
X
BASDAI
 
 
X
BASFI
 
 
X
ASQoL
 
 
X
Total and nocturnal spinal pain
 
 
X
PGADA
 
 
X
MRI SI joints
 
 
X
AEs
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
IXRSc
X 
X 
X 
X 
X 
X 
X
X 
X
X 
X
X
Study drug loading dose 
administration scd
X
X
X
 
 
 
 
 
 
 
 
Study drug dispensatione
X
X
X
X
X
X
X
X
X
AEs=adverse events; ASQoL=Ankylosing Spondylitis Quality of Life; BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; BASFI= Bath 
Ankylosing Spondylitis Functional Index; CRP=C-reactive protein; CZP=certolizumab pegol; FU=Follow-Up; IXRS=Interactive Response System; 
MRI=magnetic resonance imaging; PGADA=Patient’s Global Assessment of Disease Activity; sc=subcutaneously; SFE=Safety Follow-Up Extension; 
SI=sacroiliac; WD=Withdrawal 
a Assessments performed at the Week 52 Visit for subjects who completed the previous Double-Blind Period are in Table 5‒1; Assessments performed at the 
Week 52 Visit for subjects who transitioned to open-label CZP treatment after withdrawal from the Double-Blind Period are in Table 5‒2.
b A separate informed consent form will be obtained from subjects consenting to participate in the SFE Period.
c Contact IXRS to register the visit and obtain next kit number, where applicable, or to indicate that the subject has completed the SFE Period or withdrawn from 
the study.
d At Weeks 52, 54, and 56, study treatment administration should be performed at the site by unblinded study personnel in order to keep the blind (see 
Section 7.2.1).
e Starting at Week 52 for subjects completing open-label CZP treatment and the Week 52 Visit, dispense the assigned study medication to the subject for use at 
home, as appropriate.
REDACTED 
D
X
D
X
CT
DA
DA
DA
D
COPY 
Y
CO
C
This document cannot 
tre
tr
ubjects
bjects
be 
eatm
eatm
used
e obt
ob
obtain
obtain
to 
to o
to o
btai
btai
support 
Glob
Glo
or subje
r subje
open
op
any 
y o
y 
e prote
e prot
bal
ba
ma
of Li
of L
marketing 
eti
X
ke
ma
authorization 
n
X
at
or
ho
au
application 
n
io
at
pp
and 
nd any 
ny
ny
ny
ny
ny extensions 
1
o
ns
ex
or 
38
38
o variations 
on
va
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 48 of 255
5.3 
Schematic diagram 
Figure 5‒1: Schematic diagram for subjects completing the double-blind study treatment 
ASDAS-MI=Ankylosing Spondylitis Disease Activity Score major improvement; axSpA=axial spondyloarthritis; BL=Baseline; CRP=C-reactive protein; 
CZP=certolizumab pegol; FU=Follow-Up; mNY=modified New York criteria; MRI= magnetic resonance imaging; N=number of subjects; PI=Principal 
Investigator; Q2W=every 2 weeks (every other week); SCR=Screening; TNFi=tumor necrosis factor-alpha inhibitor; WD=withdrawal
N=150
N=150
CZP 200mg Q2W
Placebo
Double Blind
:HHN%/)
SCR
axSpA Subjects 
mNY-negative
MRI+ / CRP+
MRI+ / CRP-
MRI- / CRP+
ASDAS-MI
Week 52/WD
FU
Week 12
x
CZP administered at the dose of 400mg at Weeks 0, 2, and 4 followed by 200mg Q2W (starting 
at Week 6 up to and including Week 50).
x
Adjust background medication at any time upon discretion of the PI, but preferably not before 
Week 12 and within 4 weeks prior to Weeks 24 and 52. 
x
At the discretion of the Investigator or the subject, the subject may be withdrawn from the 
study treatment at any time. In any case, the Investigator should encourage the subject to 
perform the remaining study visits according to the appropriate alternative Schedule of Study 
Assessments and the scheduled visit window. 
x
At the discretion of the Investigator, the subject may be treated further with CZP or other TNFi 
after the study medication was discontinued.
Week 24
Week 6
CZP 400mg
D
ACTED 
D
ACTED
DAC
AC
REDA
e dose
e dose
d
COP
OPY
OPY 
C
This document 
; F
;
ery 2
ry 2
cannot 
ondyli
ondyli
FU=F
FU=F
t
ot be
a
used 
e
At th
At th
af
to
ssme
ssm
support 
ion o
on o
tment
ment a
m the re
the r
any
n 4 
n 4
of t
of
marketing 
e of 4
of 4
ding W
ing W
medicati
edicat
4 we
4 w
tion 
thorizatio
tio
thorizat
P
uth
th
aut
40
40
application 
applicatio
applicatio
applicat
ZP 200
P 200
an
and
and 
y
any extensions 
ex
e
or variations 
on thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 49 of 255
Figure 5‒2: Schematic diagram for subjects discontinued from the double-blind study treatment 
Scenario A: The subject initiates treatment with CZP for treatment to be supplied to discontinued subjects
W0/BL
W52/WD
randomized treatment (CZP or PBO)
Open-label treatment with CZP
SCR
Loading 
dose
200 mg Q2W (open)
FU
 
At the discretion of the PI the double-blind study treatment is 
discontinued and treatment with CZP is initiated. The new treatment 
shall continue through to Week 52 of the regular visit schedule.
Scenario B: The subject initiates treatment with other treatments (including biologics)
W0/BL
W52/WD
randomized treatment (CZP or PBO)
open other treatment  
SCR
other treatments (including biologics) (open)
FU
At the discretion of the PI the double-blind study treatment is 
discontinued and treatment with other treatments (including biologics) 
is initiated. The new treatment shall continue through to Week 52 of the 
regular visit schedule.
BL=Baseline; CZP=certolizumab pegol; FU=Follow-Up; PBO=placebo; PI=Principal Investigator; Q2W=every 2 weeks (every other week); SCR=Screening; 
W=week; WD=withdrawal
REDACTED
ar visi
ar vis
ments (
ments 
COPY 
atment
atment
new 
new 
This document 
walal
cannot 
zumab
umab
l
be
d. Th
d. Th
used
etion
tion
and t
and t
to 
n
supportrt 
port
port
po
any
any 
ot
marketing 
other tr
other 
ma
authorization
treatm
reatm
t sched
t sched
(inclu
(inclu
applicatioion 
tio
is s 
and 
and any 
a
extensions 
D
e
or variations 
on
ent
ent
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 50 of 255
Figure 5‒3: Schematic diagram for subjects completing the double-blind study treatment and rolling over to the 
SFE Period  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 W0/BL 
 
 
 W52/SFE-W0 
 
 
 W156/SFE-
W104/SFE-WD 
 
 randomized treatment (CZP or PBO) 
 
 
 
 
 
 
 
 
SCR 
Double-Blind Period 
 
 
Open-Label SFE Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BL=Baseline; CZP=certolizumab pegol; FU=Follow-Up; SFE=Safety Extension; PBO=placebo; SCR=Screening; SFE=safety Follow-Up Extension; W=week; 
WD=withdrawal
Note: Subjects who complete either double-blind treatment or open-label CZP-treatment and all assessments at Week 52 are eligible to roll-over to the SFE 
Period. Subjects who complete alternative treatment must finish the study at Week 52 and be scheduled for the final FU visit (8 weeks after the Week 52 Visit).
REDACTED 
Extens
Exten
COPY 
This document cannot be used to support any marketing 
n-label 
label
h the stu
the st
authorization 
sion; P
on; P
application 
at
at
at
and 
d
any 
an extensions or variations 
on
rollin
rollin
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 51 of 255
5.4 
Rationale for study design and selection of dose 
The current study will evaluate nr-axSpA subjects receiving either CZP or placebo in 
combination with standard of care for a duration of 52 weeks. This is a unique study design to 
achieve an understanding of the natural history of nr-axSpA and to support the assumption that 
treatment with a TNFi is necessary in this group of subjects. The lack of a mandatory escape arm 
for placebo subjects is balanced by the ability of the Investigators to modify background 
medications (NSAIDs, corticosteroids, analgesics, and SAARDs) during the course of the study. 
If the Investigator determines that a subject should be treated with other medicines (including 
biologics), the study medication will be discontinued and subjects will be asked to continue to 
come to the office for study visits to track their response to other treatments. If the Investigator 
choses to withdraw subjects on the other therapy, the local guidelines on initiation and 
monitoring of the particular treatment should be followed.
In accordance with prescribing information for CZP, 3 loading doses of 400mg Q2W should be 
administered upon initiation of therapy. Thus all subjects who withdraw from double-blind 
treatment prior to Week 52 and transition to open-label CZP within the AS0006 study will 
receive this loading dose prior to the maintenance dose of 200mg Q2W. It is recognized that 
some subjects would have been on active CZP prior to transition to open-label CZP. However, 
this dosing approach is justified in all transitioning subjects as there will be no change in benefit-
risk due to administration of loading dose and the blinding will be maintained in the study, 
preserving the data integrity.
The enrollment criteria will result in the following subgroups based on MRI and CRP:
x MRI+/CRP+
x MRI+/CRP-
x MRI-/CRP+
This 3-level MRI/CRP classification variable will be used as a stratification factor in the 
randomization to ensure balance across these subgroups. Taken together, these 3 subgroups 
encompass the nr-axSpA subject population that would benefit most from anti-TNF therapy and 
who have the most limited treatment options.  
6 
SELECTION AND WITHDRAWAL OF SUBJECTS 
6.1 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met:
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
Informed Consent form is signed and dated by the subject or legal representative. The 
2. Subject/legal representative is considered reliable and capable of adhering to the protocol 
(eg, able to understand and complete questionnaires), visit schedule, or medication intake 
according to the judgment of the Investigator.
3. Subject is at least 18 years old at the Screening visit.
REDACTED 
follow
follow
COPY
o t
subje
subje
e blin
e blin
This document
I
2.2
cannot
ligib
gib
An In
An In
nf
be 
l
used
SEL
EL
In
In
to 
LE
LE
support 
alanc
lanc
A subje
A sub
mited 
mited
any
catio
catio
ce
ce
marketing authorization
nding
nding
wing su
wing su
application 
hin th
n th
mg Q2
mg Q
sition t
ition 
cts as t
ts as
w
and
f 4
f 4
raw f
aw f
he
he
any 
400m
400m
extensions
ontin
ontin
he Inve
e Inve
ation a
ion a
or
udin
udi
variations 
m
study
study
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 52 of 255
4. Female subjects must be either postmenopausal for at least 1 year, surgically incapable of 
childbearing, or effectively practicing an acceptable method of contraception (either 
oral/parenteral/implantable hormonal contraceptives, intrauterine device, or barrier and 
spermicide). Abstinence only is not an acceptable method. Subjects must agree to use 
adequate contraception during the study and for at least 10 weeks (or [for participating 
countries of the EU – 5 months in accordance with the Summary of Product Characteristics, 
SPC] longer if required by local regulations) after the last dose of study treatment. Male 
subjects must agree to ensure they or their female partner(s) use adequate contraception 
during the study and for at least 10 weeks (or [for participating countries of the 
EU - 5 months in accordance with the SPC] longer if required by local regulations) after their 
last dose of study treatment.
5. Subjects must have a documented diagnosis of adult-onset axSpA and meet the ASAS 
criteria for axSpA (not including family history and good response to NSAIDs; see 
Appendix 18.1).
6. Subjects must have had back pain for at least 12 months before Screening.
7. Subjects must NOT have sacroiliitis defined by mNY criteria (see Appendix18.2) (bilateral 
≥Grade 2; unilateral ≥Grade 3) on SI joint x-rays (based on central reading of x-rays, within 
the last 12 months from Baseline).
8. Subjects must have active disease as defined by each of the following at Screening and 
Baseline:
 BASDAI score ≥4
 Spinal pain ≥4 on a 0 to 10 NRS (from BASDAI item 2)
9. Subjects must have a combination of current evidence of sacroiliitis on the screening MRI as 
defined by ASAS/OMERACT scoring confirmed via central reading (MRI+) and CRP either 
>upper limit of normal (ULN) or ≤ULN (for CRP the ULN is defined as the ULN indicative 
for inflammatory disease) at Baseline (CRP+ or CRP-), or no evidence of sacroiliitis on the 
screening MRI (MRI-) and CRP >ULN (CRP+) as follows:
 MRI+/CRP+
 MRI+/CRP-
 MRI-/CRP+
10. Subjects must have had an inadequate response to, have a contraindication to, or have been 
intolerant to at least 2 NSAIDs. Inadequate response to an NSAID is defined as lack of 
response to at least 14 days of continuous NSAID therapy at the highest tolerated dose of the 
administered NSAID.
6.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria is met:
1. Subject has previously participated in this study or subject has previously been assigned to 
treatment in a study of the medication under investigation in this study.
REDACTED 
d b
NRS (
NRS (
COPY 
ba
b
by e
by e
This document
a
6
cannot
ects
ects
ntolera
olera
resp
resp
be 
/
s m
s m
used 
RP-
CRP
CRP
to support
e) )
) and 
) and
any
N) o
N) 
at Ba
at Ba
marketing 
(from
from
n of cu
n of c
scorin
scori
or ≤
or
authorization 
each o
ach o
m
application 
e S
ria (see
ia (se
d on cen
on ce
and 
Scree
cree
any
NSA
NSA
extensions
ns) af
ns) a
eet the
et the
AI
AI
or variations 
,
n
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 53 of 255
2. Subject has participated in another study of an investigational medicinal product (IMP) (or a 
medical device) within the previous 3 months (or 5 half-lives, whichever is greater) or is 
currently participating in another study of an IMP (or a medical device). 
3. Subject has history of chronic alcohol abuse or drug abuse within the last year.
4. Subject has any medical or psychiatric condition that, in the opinion of the Investigator, 
could jeopardize or would compromise the subject’s ability to participate in this study.
5. Subject has a known hypersensitivity to any components of the IMP or comparative drugs as 
stated in this protocol.
Axial SpA-disease-related exclusions
6. Subjects must not have AS or any other inflammatory arthritis (eg, RA, systemic lupus 
erythematosus, or sarcoidosis).
7. Subject must not have fibromyalgia.
8. Subjects must not have a secondary, noninflammatory condition (eg, osteoarthritis) that in 
the Investigator’s opinion is symptomatic enough to interfere with evaluation of the effect of 
study drug on the subject’s primary diagnosis of axSpA.
Prior medications exclusions
9. Subjects must not have used the following medications in the manner as detailed by the 
exclusion criteria in the following table (see Table 7‒1).
Previous clinical studies and previous biological therapy exclusions
10. Subjects must not have received any nonbiological therapy for axSpA not listed in Table 7‒1
within or outside a clinical study in the 3 months or within 5 half-lives prior to the Baseline 
visit (whichever is longer).
11. Subjects must not have received any experimental biological agents (defined as those agents 
unlicensed for use in axSpA in Europe or the USA).
12. Subjects must not have received previous treatment with a PEGylated compound that 
resulted in a severe hypersensitivity reaction or an anaphylactic reaction.
13. Subjects may not have been exposed to more than 1 TNFi prior to the Baseline visit and may 
not be a primary failure to any TNFi therapy (defined as no response within the first 
12 weeks of treatment with the TNFi).
Medical History Exclusions
14. Female subjects who are breastfeeding, pregnant or plan to become pregnant during the study 
or within 3 months following the final dose of the investigational product.
15. Subjects with a history of chronic or recurrent infections (more than 3 episodes requiring 
antibiotics or antivirals during the preceding year), recent serious or life–threatening 
infection within the 6 months prior to the Baseline visit (including hospitalization for any 
infection in the last 6 months or any current sign or symptom that may indicate an infection).
REDACTED 
ing me
ng me
ble (se
le (se
reviou
reviou
COPY 
axSp
axS
This document
14.
14. F
cannot
week
week
Medi
Med
be
a pri
a pri
k
used 
ev
ev
may n
may n
o
vere
vere
support 
rec
ec
axSpA
axSp
have
have
h
any 
ceive
ceiv
marketing
us b
s b
any non
any no
dy in th
y in t
authorization 
edicat
dicat
ee Tab
Tab
bio
bio
application
tion (e
ion (
fere wi
ere w
A.
and any extensions 
ystem
ystem
or 
u
variations 
ugs 
ugs 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 54 of 255
16. Subjects with a history of herpes zoster infection within 6 months prior to the Baseline visit.
17. Subjects with known TB infection, at high risk of acquiring TB infection, or LTB infection 
are excluded. 
a. Known TB infection whether present or past is defined as:
i)
Active TB infection or clinical signs and symptoms suspicious for TB (pulmonary or 
extra-pulmonary)
ii) History of active TB infection involving any organ system or findings in other organ 
systems consistent with TB infection
iii) Any evidence by radiography or other imaging modalities consistent with previously 
active TB infection that is not reported in the subject’s medical history.
b. High risk of acquiring TB infection is defined as:
i)
Known exposure to another person with active TB infection within the 3 months prior 
to Screening
ii) Time spent in a healthcare delivery setting or institution where individuals infected 
with TB are housed and where the risk of transmission of infection is high.
c. Latent TB infection (unless appropriate prophylaxis is initiated prior to study treatment and 
continued to completion of prophylaxis). Please refer to Section 12.6.3 for further details and 
instructions.
18. Subjects with concurrent acute or chronic viral hepatitis B or C or with human 
immunodeficiency virus (HIV) infection.
19. Subjects with history of or current active infection with Histoplasma, Coccidiodes, 
Paracoccidioides, Pneumocystis, nontuberculous mycobacteria (NTMB), Blastomyces, or 
Aspergillus.
20. Subjects must not have a history of an infected joint prosthesis at any time.
21. Subjects receiving any live (includes attenuated) vaccination within the 8 weeks prior to 
Baseline (eg, inactivated influenza and pneumococcal vaccines are allowed but nasal 
influenza vaccination is not permitted).
22. Subjects who in the Investigator’s opinion have a high risk of infection (eg, subjects with leg 
ulcers, indwelling urinary catheter, persistent or recurrent chest infections, and subjects who 
are permanently bedridden or wheelchair bound).
23. Subjects with a history of a lymphoproliferative disorder including lymphoma or current 
signs and symptoms suggestive of lymphoproliferative disease.
24. Concurrent malignancy or a history of malignancy (subjects with less than 3 excised basal 
cell carcinomas or with cervical carcinoma in situ successfully surgically treated more than 
5 years prior to Screening may be included).
25. Subjects with Class III or IV congestive heart failure as per the New York Heart Association 
(NYHA) 1964 criteria.
REDACTED 
lea
lea
hronic 
hronic
nfectio
nfectio
t
COPY 
ran
ra
ylaxis
ylaxi
ase r
ase r
This document
s
24
24
cannot
perm
erm
Subje
ubje
sig
sig
be
indw
indw
ma
ma
used 
who in
ho in
we
we
to
nati
nati
support 
a h
ny live
ny liv
tivated
ivated
on
any 
histor
histor
marketing 
on
active 
active 
s, nontu
 non
authorization 
s isis
refer t
efer t
viral 
viral 
n
application 
ution w
tion 
mission
ission
s init
ini
and
on w
n w
any 
with
it
extensions 
with p
with p
story.
tory.
or
er o
er o
variations 
or r 
org
org
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 55 of 255
26. Subjects with a history of, or suspected, demyelinating disease of the central nervous system 
(eg, multiple sclerosis or optic neuritis).
27. Subjects having had major surgery (including joint surgery) within 8 weeks prior to 
Screening, or having planned surgery within 6 months after entering the study.
28. Subjects with a current or recent history, as determined by the Investigator, of severe, 
progressive, and/or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, 
cardiac, or neurological disease. 
29. Subjects with significant laboratory abnormalities, including but not limited to: 
 liver function tests >2.0xULN
 estimated Glomerular Filtration Rate as measured by Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI; Levey et al, 2009) <60mL/min/1.73m2
 white blood cell ([WBC] <3.0x109/L).
30. Subjects with any other condition which, in the Investigator’s judgment, would make the 
subject unsuitable for inclusion in the study.
6.3 
Withdrawal criteria  
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care.
Subjects should be withdrawn from the study if any of the following events occur:
1. Subject develops an illness that would interfere with his/her continued participation.
2. Subject is noncompliant with the study procedures or medications in the opinion of the 
Investigator.
3. Subject withdraws his/her consent.
4. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test (see Section 12.1.6 for more information regarding pregnancies).
5. The Sponsor or a regulatory agency requests withdrawal of the subject.
6. Subject’s subsequent TB test was confirmed positive or any further evidence is suggestive of 
potential TB infection (eg, exposure). Refer to Section 12.6.3 for further details and 
instructions.
Subjects should be withdrawn from the study-treatment if,
7. The Investigator decides to initiate an alternative treatment due to an unsatisfactory response 
to the study treatment, or
8. Subjects take any of the prohibited medications in Table 7‒1 and Section 7.8.2
If a subject is withdrawn from the double-blind study treatment, the Investigator should 
encourage the subject to continue participation in the study in accordance with the appropriate 
alternative schedule of study assessments (Table 5‒2 or Table 5‒3). The treatment that the 
subject receives following withdrawal of study medication is at the discretion of the Investigator, 
REDACTED 
udy if 
udy if 
ould in
ould 
e stu
e stu
COPY 
ny tim
ny tim
This document
tot
8
cannot
cts sho
s sho
The 
The 
be
tions
on
used
bseq
seq
TB inf
TB in
s
to 
que
que
support 
f a a
6 for 
for
regula
regul
any 
n
preg
pre
marketing 
udy pr
udy pr
nsent.
sent
authorization
me, w
e, w
f any o
any o
nterfe
terfe
application
judg
ud
with
with
and 
dgm
dgm
any
/mi
/m
extensions 
Disea
Disea
min/
in/
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 56 of 255
with open-label CZP available as a treatment option according to the local requirement mandated 
in the region. UCB will provide this medication free of charge. Alternatively, the Investigator 
may treat the subject with other treatments (including biologics) as deemed appropriate by local 
regulations. If the Investigator chooses to withdraw subjects on the other therapy, the local 
guidelines on initiation and monitoring of the particular treatment should be followed.
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject from the double-blind study treatment in advance. The reason for discontinuation of 
the double-blind study treatment must be recorded in the case report form (CRF) as appropriate.
Although the subject may be withdrawn from the double-blind study treatment at any time, every 
effort should be made to retain the subject in the study and encourage compliance of the subject 
with the scheduled study visits. For subjects who fail to return to study visit(s) or are considered 
lost to follow up, the Investigator should specifically communicate (at least 1 phone call and 
1 written message to the subject), and document his/her effort (date and summary of the phone 
call and copy of the written message in the source documents). In case the attempts to direct 
contact the subject fail, the Investigator is encouraged to gain information about the wellbeing of 
the subject at the end of the regular visit schedule (Week 52/WD) from other sources in 
compliance with local regulations. All results of observations and communication with the 
subject, including and not limited to the relevant information on his/her wellbeing, must be 
recorded in the source documents.  
If a subject is withdrawn from the study, the narrative description of the reason(s) for removing 
the subject must be recorded in the source documents. The CRF must document the primary 
reason for withdrawal.
Subjects withdrawn from the study will not be replaced.  
6.4 
Eligibility for the SFE Period 
To be eligible to participate in the SFE Period, subjects on double-blind study treatment and 
subjects who withdrew from double-blind study treatment and transitioned to open-label CZP 
treatment must complete all of the Week 52 visit assessments. Subjects on alternative treatments 
are not eligible to participate in the SFE Period. 
Eligible subjects are allowed to roll-over to the SFE-Period up to 3 months after completion of 
the Week 52 assessments.
Prior to initiating the SFE assessments, all subjects will be asked to read and sign a separate 
informed consent form.
Questions concerning the eligibility of a subject to continue participation in the study should be 
made in consultation with the Medical Monitor.
7 
STUDY TREATMENTS 
7.1 
Description of investigational medicinal product(s) 
The IMP (double-blind study treatment: CZP or placebo), will be supplied under the 
responsibility of the UCB Clinical Supply Unit. The frequency at which IMP will be supplied to 
each individual center will be adapted to the recruitment capacity of that center and to the expiry 
date of the IMP and will be managed by the interactive response system (IXRS).
REDACTED
narra
narra
docum
docum
will n
will n
COPY
orma
orm
ati
This document 
a
7
cannot 
c
tions c
ons 
de in
e in
be
at
onse
onse
used 
essm
ssm
ting 
ing 
to 
e al
e al
me
me
support 
ll of 
l of
cipate i
pate 
allow
llow
any
double
doubl
f th
f t
marketing 
not be
ot b
SFE 
SFE
 SFE
SFE
authorization 
ive de
ve de
ments
ments
be
application
rm
D) from
D) fro
s and c
s and 
ion on 
on on
and
e the
the
matio
atio
any
umm
umm
e at
e a
extensions
y tim
tim
e of th
of th
or are
or ar
1 pho
pho
or 
opr
op
variations 
al
on of 
n of 
priat
priat
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 57 of 255
Drug supplies will consist of the following:
Certolizumab pegol is supplied as a sterile, clear, colorless to slightly yellow liquid solution with 
a pH of approximately 4.7 in 1mL single use glass prefilled syringe (PFS) with a 25G ½ inch 
thin wall needle for sc injection. Each syringe contains an extractable volume of 1mL at a 
concentration of 200mg/mL of CZP in 10mM sodium acetate buffer and 125mM sodium 
chloride as a tonicity agent.
Placebo is supplied in a PFS with a 25G ½ inch thin wall needle, containing an injectable volume 
of 1mL 0.9% saline for single use.
Due to the difference in presentation and viscosity between CZP and placebo, special precautions 
will be taken in order to ensure maintained blinding of the study (unblinded/blinded site 
personnel and monitors).
7.2 
Treatment(s) to be administered 
Treatments to be administered are as described in Section 5.1.
7.2.1 
Treatment administration 
A pharmacy manual will be provided to each site containing instructions regarding drug 
preparation and dosing. The injection schedule through Week 52 is presented in Figure 7‒1. The 
injection schedule for the SFE Period is presented in Figure 7‒2.
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site. At the Week 0, 2, 4, 6, 
and 8 visits, the administration must be done by dedicated, unblinded, and adequately trained site 
personnel. At the Week 10 and 12 visits, the subject will receive training on self-injection and 
the study treatment will be self-administered under the supervision of the unblinded study 
personnel. At Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50, the study treatment administration 
should preferably be done by the unblinded study personnel, or alternatively by self-injection of 
the subject under the supervision of the unblinded study personnel. The double-blind study 
treatment will be self-injected at home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46.
Injections should be administered with a minimum of 10 days between the CZP 200mg Q2W 
injections.
During the SFE Period, CZP will be administered sc by dedicated unblinded study personnel at 
the study site on Weeks 52, 54, and 56 for subjects completing double-blind treatment in order to 
maintain the blind. Subjects who complete the Week 52 Visit on placebo treatment will receive 
loading doses of CZP 400mg at these visits. Subjects who complete the Week 52 Visit on CZP 
treatment will receive 1 injection of CZP 200mg and 1 injection of placebo at these visits to 
continue their previous CZP treatment regimen.
Subjects who withdrew from double-blind study treatment and transitioned to open-label CZP 
treatment do not need to visit the site at Week 54 and Week 56, and should continue their 
open-label CZP treatment regimen.
For the remainder of the SFE Period, CZP can be administered at the site by dedicated study 
personnel, or by self-injection of the subject under the supervision of the dedicated study 
personnel, or subjects may self-administer their study treatment Q2W at home. 
REDACTED
0, 12
0, 12
ministe
iniste
 done 
done 
isits, t
isits, t
nis
ni
COPY
ugh W
ugh W
d in
d in Fi
F
This document
onti
onti
Su
Su
cannot
g dose
dose
tment 
ment
tinu
inu
be
he bl
he bl
used
Peri
Peri
on W
on W
to support
ted a
ed 
dminist
mini
any
on of
on o
at h
at
marketing
the s
he 
stered 
stered 
, 32, 36
32, 3
unblin
unbli
f t
authorization
igur
gur
, 16, 2
, 16, 2
ered sc
red sc
e by de
by d
su
su
application 
instru
instru
Week 52
eek 5
rere 7
and any extensions 
ial pre
ial pre
nded si
ded s
or variations 
volum
volum
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 58 of 255
7.2.2 
Study AS0006 injection schedule 
Figure 7‒1: Injection schedule through Week 52 
CZP=Certolizumab pegol; H=home
REDA
DACTED COPY 
This 
al
document cannot be used to support any marketing auth
uthorization application and any extensions or 
or variations 
on thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 59 of 255
Figure 7‒2: Injection schedule for the SFE Period   
CZP=Certolizumab pegol; FU=follow-up; H=home; SFE=Safety Follow-Up Extension; W=week
* Subjects who complete either double-blind treatment or open-label CZP-treatment and all assessments at Week 52 are eligible to roll-over to the SFE Period. 
Subjects who complete alternative treatment must finish the study at Week 52 and be scheduled for the final FU visit (8 weeks after the Week 52 Visit).
** Subjects rolling over from open-label CZP-treatment to the SFE Period can self-administer their study medication at home from Weeks 2 to 10.
*** Subjects will complete the study assessments at Week 52 according to the protocol and be invited for the final FU visit 8 weeks after Week 52.
W50 
H
H
H
H
H
H
H
H
H
week
and before
SFE-W 0
2
4
6 - 10
12
14-22
24
26-34
36
38-46
48
50-58
60
62-70
72
74-82
84
86-94
96
98-102
104
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
○
○
○
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
according to the 
assigned treatment regimen
CZP        
200 mg
Placebo
●
○
Safety Follow-up Extension
Double-blinded
●
●
W52*
open other 
treatment
***
●
open CZP 
200 mg
● **
RED
Follo
Follo
EDACTED 
PY 
Y
COPY
This 
al
document cannot be used to support any
2 acc
2 ac
marketing
w-Up 
Up
CZP
CZP-t
dy at W
dy at W
SFE Pe
SFE P
cor
c
au
authorization application 
licatio
lic
lic tio
tion
tio
lic
pp
ap
and
and
a
any y
a y
an
an
a
xtensions 
sions
exte
●
●
s ns
ns
ns
ns
s
en
en
xte
xte
or
or 
-8
-8
r
o variations 
on
82
82
ar
ar
ari
va
va
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 60 of 255
7.3 
Packaging 
Certolizumab pegol and placebo are packaged and labeled according to Good Manufacturing 
Practice (GMP) guidelines and applicable laws or regulations. They are suitably packaged in 
such a way as to protect the IMP from deterioration during transport and storage.
7.4 
Labeling 
Clinical drug supplies will be labeled in accordance with the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and GMP and will include any 
locally required statements. If necessary, labels will be translated into the local language. Details 
on Labeling will be provided in the Pharmacy manual.
7.5 
Handling and storage requirements 
The Investigator (or designee) is responsible for the safe and proper storage of IMP at the site. 
The IMP stored by the Investigator is to be kept in a secured area with limited access. The IMP 
containers should be stored at 2 to 8°C and protected from light. Additional information 
regarding the receipt of the drug and return handling will be specified in the Pharmacy Manual.
Appropriate storage conditions must be ensured by a controlled temperature and by completing a 
temperature log in accordance with local requirements but at least once per working day with 
minimum and maximum temperatures reached over the time interval.
In case an out of range temperature is noted, it must be immediately communicated to the 
Sponsor’ designee in accordance with the Pharmacy Manual.
The Investigator (or designee) will instruct the subject to store the IMP following the instructions 
on the label.
Detailed information on handling and storage of IMP will be given in the Pharmacy Manual.
7.6 
Drug accountability 
A drug accountability form will be used to record IMP dispensing and return information during 
the course of the study. Details of any drug lost (due to breakage or wastage), not used, disposed 
of at the study site, or returned must also be recorded on the appropriate forms. All supplies and 
pharmacy documentation must be made available throughout the study for UCB (or designee) to 
review.
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers) and unused IMP containers must be reconciled and returned to UCB (or designee), 
preferably in their original packaging. Instructions on how to use and store the IMP will be 
provided. Investigational medicinal product intended for the study cannot be used for any other 
purpose than that described in this protocol. 
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned or destroyed.
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee.
The Investigator must ensure that the IMP is used only in accordance with the protocol.
REDACTED
arma
arma
uct the
ct the
d st
d s
COPY
the t
the 
must b
ust b
This document 
The 
The 
co
co
cannot 
ly i
y i
ded. In
ed. I
pose 
pose 
be 
and
and
in th
in th
used 
nd/or 
d/or 
nd un
d un
to support 
ails
ail
turned 
urned
tion mu
ion m
any
l be 
l be
s of 
s o
marketing 
storage
orage
bility
bility
us
authorization
be imm
be im
cy Ma
cy Ma
e subje
subj
application 
d tempe
temp
t least o
least
me int
me in
and
tion
on
d in t
d in t
any
mited 
ited
nal i
nal
extensions 
of IM
f IM
o
. D
. D
variations 
ude an
de an
Det
Det
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 61 of 255
All study drug documentation (eg, shipping receipts, drug accountability logs, IXRS 
randomization materials) must be maintained and accessed by unblinded, trained site personnel 
only. Designated, unblinded site personnel must be appropriately trained and licensed (per 
country guidelines) to administer injections. Each site will be required to have a written blinding 
plan in place signed by the Principal Investigator, which will detail the site’s steps for ensuring 
that the double-blind nature of the study is maintained from Week 0 to Week 52/WD. 
7.7 
Procedures for monitoring subject compliance 
Drug accountability must be recorded on the drug accountability form. 
If a subject is found to be persistently noncompliant (missing 3 or more doses over any period of 
52 weeks), the subject will be withdrawn from the study. A subject will be withdrawn from the 
study if 3 consecutive doses were missed prior to the primary endpoint assessment. No missing 
doses are allowed in the first 12 weeks of the study. Doses of IMP that were missed due to a 
reasonable interfering AE that does not allow administration of an anti-TNF due to safety 
reasons will not be considered for the evaluation of subject compliance. Evaluation of the 
reasonability of the AE must be discussed immediately with the Medical Monitor.
7.8 
Concomitant medication(s)/treatment(s) 
For any subject taking any medication, including over the counter products, nutraceuticals, or 
herbal medications at Screening or at any time during the course of the study, an accurate record 
must be kept in the clinic chart (source documentation) and the CRF. This record should include
the name of the drug, the dose, the date(s) of administration, and the indication for use.
Changes in the concomitant medication to treat the burden of the predominantly existing disease 
of the nr-axSpA symptoms is allowed during the Placebo-Controlled Period of the study under 
the conditions listed below. A change in the first 12 weeks of the study should be avoided.  
Table 7‒1: 
Concomitant Medications (prior to Baseline and Study Visits) 
Drug class
Dose 
Exclusion criteria
Study Visits
Analgesics 
(including, but not 
limited to 
acetaminophen, 
paracetamol, opiates, 
or combinations 
thereof)
Up to 
maximum 
approved dose 
Any change in stable dose regimen is 
excluded in the 14 days prior to the 
Baseline visit. 
Any ad hoc (prn) use of 
analgesics is not 
permitted within 
24 hours prior to any 
post-Screening visit. 
An increase or addition 
in opiates or a 
combination with 
opiates is not 
recommended between 
Week 0 and Week 12 or 
within 4 weeks prior to 
the Week 24 or 
Week 52 visits. 
REDACTED
f admi
f adm
to trea
o trea
d durin
durin
ge in 
ge in 
COPY 
r th
r t
ing th
ing th
tation
tation
This document 
um
cannot be used 
ates,
tes,
s s 
to 
to support 
o
aximum
ximu
appro
appro
any 
a
marketing
n the f
 the f
dicati
dicat
m
authorization
he
n) an
n) an
inistra
nistra
at the 
t the 
g the
g the
application 
(s)
(s)
counter
ounte
 cour
cour
d
and
e. E
. E
dical 
ical 
any
NF du
NF d
Eval
Eva
extensions
ny p
y p
awn fr
wn fr
ment. N
ment. N
misse
miss
or 
per
variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 62 of 255
Table 7‒1: 
Concomitant Medications (prior to Baseline and Study Visits) 
Drug class
Dose 
Exclusion criteria
Study Visits
NSAIDs (including 
COX-2 inhibitors)
Up to 
maximum 
approved dose 
regimen 
Any change in stable dose regimen is 
excluded in the 14 days prior to the 
Baseline visit. 
Any ad hoc (prn) use of 
NSAIDs is not 
permitted within 
24 hours prior to any 
post-Screening visit. 
Changes in NSAID 
doses should be avoided 
between Week 0 and 
Week 12 or within 
4 weeks prior to the 
Week 24 or Week 52
visits. 
Oral corticosteroids
Maximum 
allowed 
≤10mg daily 
total 
prednisone 
equivalenta 
Any change in stable dose used for 
axSpA in the 28 days prior to the 
Baseline visit. 
If a taper of oral corticosteroids is 
planned this should be completed 
14 days prior to Baseline visit. 
Maximum allowed 
≤10mg daily total 
prednisone equivalenta 
Changes in dose or 
initiation of 
corticosteroids 
(including tapers) 
should be avoided 
between Week 0 and 
Week 12 or within 
4 weeks prior to the 
Week 24 or Week 52
visits. 
Corticosteroids (im)
Any dose 
Use in the 28 days prior to the 
Baseline visit. 
Corticosteroids (im) 
must not be used during 
the study. 
Corticosteroids (ia)
Up to 
maximum 
approved dose 
Use in the 28 days prior to the 
Baseline visit. 
SIJ corticosteroid (ia) 
injections are not 
allowed during the 
study. 
Peripheral joint 
injections are permitted.
REDACTED 
R
COPY
ould b
ould 
r to Ba
r to B
This document cannot 
ot be used to
a
to
to suppo
Up to 
p to 
maxim
maxi
ort 
or any marketing 
a
U
ar
ma
authorization
aseli
seli
application 
the
he
steroids
teroid
e comp
e com
line
ine
and 
or 
d any
visi
vis
a
extensions 
d b
Week 
Week
12 or 
2 or 
weeks p
eeks 
Week 
eek 
or 
AID
AI
be av
e a
variations 
sit.t.
ID 
ID
on thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 63 of 255
Table 7‒1: 
Concomitant Medications (prior to Baseline and Study Visits) 
Drug class
Dose 
Exclusion criteria
Study Visits
Corticosteroids (iv)
Up to 
maximum 
approved dose 
Use in the 28 days prior to the 
Baseline visit. 
Doses of corticosteroids 
(iv) may be used during 
the study for acute 
illnesses as long as the 
dose is not given within 
1 week prior to 
Week 12, Week 24, or 
Week 52 and the 
underlying disease does 
not present a 
contraindication to the 
subject remaining in the 
study. Indications might 
include dermatitis, 
gastroenteritis, asthma 
exacerbation, and 
pneumonia. 
Hyaluronic acid (ia)
Any dose  
Use in the 28 days prior to the 
Baseline visit.  
Used in knee as needed 
after Week 12 visit. 
SAARDsb:
SSZ and/or HCQ 
and/or MTX and/or 
LFN and/or AZA
Maximum 
allowed: 
SSZ ≤3g daily 
HCQ ≤400mg 
daily  
MTX ≤25mg 
weekly 
AZA 
≤150mg/day 
LFN 
≤20mg/day  
SAARD initiated and or any change 
in the dose regimen in the 28 days 
prior to the Baseline visit. 
 
Changes in SAARD 
doses should not be 
made between Week 0
and Week 12 or within 
4 weeks prior to 
Week 24 or Week 52
visit. 
SAARD dose reduction 
to manage intolerance 
or safety issues is 
allowed at any time 
during the study at the 
Investigator’s 
discretion. 
SAARDs:
cyclosporine, 
cyclophosphamide, 
mycophenolic acid, 
apremilast
Up to 
maximum 
approved dose 
Use within 28 days prior to the 
Baseline visit 
Changes in SAARD 
doses or initiation of a 
new SAARD should be 
avoided between 
Week 0 and Week 12 or 
within 4 weeks prior to 
Week 24 or Week 52
visit 
REDACTED 
D initi
D initi
he dos
he dos
prior to
prior to
D
R
COPY 
days p
days p
it.
it.
Y
C
This document 
yco
yc
aprem
aprem
um
cannot
orine
orine
ophosp
phosp
coph
oph
be used 
us
to 
≤
to support
0mg/d
mg/d
LFN 
FN 
≤20m
≤20
any marketing 
ma
authorization 
pr
iated a
ated a
e regim
e regi
o the B
the B
tio
application 
ior to 
or to
p
and any
subj
sub
stu
s
a
extensions
ee
and th
nd th
ying d
ing d
presen
presen
ontrai
ntrai
j
or
ek 24
2
variations 
e
within
within
on thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 64 of 255
Table 7‒1: 
Concomitant Medications (prior to Baseline and Study Visits) 
Drug class
Dose 
Exclusion criteria
Study Visits
Anti-TNF therapies
IFX
ADA
ETN
GOL
CZP
Any dose 
Only 1 previous biologic is allowed.
For IFX, ADA, and GOL, any use 
within the 3 months prior to the 
Baseline visit. 
For ETN, use within the 28 days 
prior to the Baseline visit. 
For CZP any exposure history. 
If biologic therapy is 
required the subject 
must be discontinued 
from study medication 
and should conduct the 
remaining visits 
according to Figure 5‒2. 
Other rheumatologic 
therapies:
ABA
rituximab
anti-IL17 
tocilizumab
ustekinumab
tofacitinib
biosimilars to any 
approved biologic
Any dose 
Any exposure history. 
If other rheumatologic 
therapies are required 
the subject should be 
discontinued from study 
medication and should 
conduct the remaining 
visits according to 
Figure 5‒2. 
Osteoporosis 
medications:
eg,
risedronate
alendronate 
ibandronate
denosumab
cathepsin K inhibitor
cinacalcet
calcitonin
Up to 
maximum 
approved dose 
All stable osteoporosis medications 
are permitted except for 
bisphosphonates (iv). 
If the treatment is 
initiated during the 
study, the subject should 
be discontinued from 
study medication and 
should conduct the 
remaining visits 
according to Figure 5‒2. 
Osteoporosis 
medications with the 
exception of 
bisphosphonates (iv) are 
allowed without 
restriction.  
Bisphosphonates (iv) 
are not permitted any 
time within the study.   
REDACTED 
able os
ble os
permi
permi
bispho
bispho
D
R
COPY 
This document cannot 
an
be used to 
to support any marketing 
ma
authorization 
steopo
eopo
itted ex
tted e
sphon
phon
ati
application and any
e
disc
dis
m
a
extensions 
F
er rheu
r rheu
rapies
apies
e sub
e sub
on or
igur
igu
variations 
n n 
t the
the 
on thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 65 of 255
Table 7‒1: 
Concomitant Medications (prior to Baseline and Study Visits) 
Drug class
Dose 
Exclusion criteria
Study Visits
Intravenous 
bisphophonates:
zoledronic acid
ibandronate
pamidronate
Any dose 
Zoledronic acid: any use within the 
3 years prior to randomization 
Ibandronate or pamidronate: any use 
within the past 2 years. 
If iv bisphosphonate 
treatment is initiated 
during the study, the 
subject should be 
discontinued from study 
medication and should 
conduct the remaining 
visits according to 
Figure 5‒2. 
ABA=abatacept; ADA=adalimumab; axSpA=axial spondyloarthritis; AZA=azathioprine; COX-2=cyclooxygenase 
2; CZP=certolizumab pegol; DMARD=disease-modifying antirheumatic drug; ETN=etanercept; GOL=golimumab; 
HCQ=hydroxychloroquine; IFX=infliximab; ia=intra-articular; IL=interleukin; im=intramuscular; iv=intravenous; 
LFN=leflunomide; MTX=methotrexate; NSAID=nonsteroidal anti-inflammatory drug; RA=rheumatoid arthritis; 
SAARD=slow-acting antirheumatic drug; SIJ=sacroiliac joint injection; SSZ=sulfasalazine; TNF=tumor necrosis 
factor
a A table of corticosteroid equivalent doses can be found in Appendix 18.3.
b Throughout the text, we refer to compounds such as SSZ and MTX as SAARDs. These medications are also 
commonly referred to as DMARDs, but since there is no evidence that they are in fact disease-modifying in axSpA 
(unlike in RA), we have opted for the more appropriate SAARD terminology.
7.8.1 
Permitted concomitant treatments for axSpA (medications and 
therapies) 
The Investigator must make decisions regarding changes in background medications based upon 
the subject’s response to previous therapy, medical history and the physician’s judgment as to 
how to manage the axSpA disease symptoms. If possible, the following treatment 
recommendations for modifying background medications should be considered: 
x NSAIDs including cyclooxygenase-2 (COX-2) inhibitors: ad hoc as needed (prn) should not 
be used 24 hours of any post-Screening study visit. As subjects should be on stable dose of 
background medication at study entry, a change in the first 12 weeks of the study should be 
avoided. Changes in dose and type of NSAID should not be made within 4 weeks prior to 
Week 24 and 52 visits.
x Modify the SAARD if needed to treat peripheral symptoms. 
x Specific SAARDs only (SSZ and/or hydroxychloroquine [HCQ] and/or MTX): maximum 
SSZ ≤3g daily; HCQ ≤400mg daily; MTX ≤25mg weekly allowed. As subjects should be on 
stable dose of background medication at study entry, a change in the first 12 weeks of the 
study should be avoided. Changes in SAARDs doses should not be made within 4 weeks 
before Week 24 or Week 52 visit.
x Stable doses of analgesics (including, but not limited to acetaminophen, paracetamol, 
NSAIDs, opiates, or combinations thereof) will be permitted except that ad hoc prn usage is 
prohibited within 14 days of Baseline and no ad hoc use prior to any post-Screening visit. As 
subjects should be on stable dose of background medication at study entry, a change in the 
first 12 weeks of the study should be avoided. An initiation of a new chronic opiate or a 
REDACTED 
atm
atm
egardi
egard
erapy, 
erapy,
ymp
ymp
COPY 
ence
enc
ARD t
ARD t
men
me
This document
b
x
cannot 
≤3g
≤3
ble d
ble d
study
study
b
be 
 SA
SA
3g d
3g d
used
SAA
AA
AA
AA
to 
v
AR
AR
support
n at s
n at s
n dose 
dose
visits.
isits.
any 
ge
ge
ost
ost-Sc
S
stut
marketing 
, m
ptoms.
ptoms
kgroun
kgrou
enase
enas
authorization 
nts fo
nts fo
ing ch
ng ch
medi
medi
application 
AARD
AARD
at they 
at they
rminol
mino
and 
ug; R
g; 
fasalaz
salaz
any
muscu
musc
RA=
RA
extensions
rem
ording
rding
5‒2
X-2=c
2=c
cept; 
ept; 
en
or
main
mai
variations 
study
study
houl
houl
on thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 66 of 255
combination with opiates is not recommended between Week 0 and Week 12 or within 
weeks 4 of the Week 24 or Week 52 visits. 
x Add or modify the corticosteroids (see Section 7.8.2 for prohibited corticosteroids):
 Oral (maximum allowed daily total prednisone equivalent dose of ≤10mg). Oral 
corticosteroid tapers of 14 days prior to Baseline are allowed as long as the maximum 
daily dose is ≤10mg. Changes in dose or initiation of corticosteroids (including tapers) 
should be avoided between Week 0 and Week 12 or within 4 weeks prior to Week 24 or 
Week 52 visits.
 Corticosteroids administered intravenously (iv) will be permitted for the purposes of 
stress dosing for a surgical procedure under general or spinal anesthesia. Further they 
may be used during the study for acute illnesses as long as the dose is not given within a 
week of an assessment (Week 12, 24 or 52) and the underlying disease does not present a 
contraindication to the subject remaining in the trial. Indications might include dermatitis, 
gastroenteritis, asthma exacerbation, and pneumonia.
x Other treatments (including biologics): If the subject requires the start of other treatments 
(including biologics) at the discretion of the Investigator, the subject must be withdrawn from 
the blinded study medication. Every effort should be made to retain the subject in the study 
and encourage attendance at future study visits.
x The Investigator should refrain from making major changes in background medication 
between Week 0 and Week 12, as much as possible. Major changes in background
medications within 4 weeks of Week 24 or Week 52 should be avoided.
Depending on the subject’s response to previous therapy, the Investigator may also reduce the 
assigned background medication. This change should not be made between Week 0 and 
Week 12. Major changes in background medications should be avoided within 4 weeks prior to 
Week 24 or Week 52. 
If the Investigator discontinues the double-blind study treatment and initiates therapy with CZP, 
UCB will supply the subject with the CZP. If the decision is made to start a different treatment 
(including biologics), UCB will not be supplying the medication. 
7.8.2 
Prohibited concomitant and rescue treatments (medications and 
therapies) 
Prior medication exclusions and washout periods are listed in Section 6.2. In addition, use of the 
following concomitant medications is prohibited during the study, except where indicated:
x Corticosteroids (administered iv/intra-articular [ia]) are permitted only as described in 
Section 7.8.1. Intramuscular and sacroliliac joint injection (SIJ) ia corticosteroids are not 
permitted. 
x Hyaluronic acid is permitted for the use in the knee after Week 12.
x Biologicals (TNFi: IFX, ADA, ETN, GOL, abatacept (ABA), commercially available CZP), 
anti-CD20, tocilizumab, ustekimumab, also any other biological response modifiers are 
excluded.
x All iv bisphosphonates are excluded.
g g
as pos
as po
24 or 
4 or 
to pre
to pre
his c
his c
COPY 
majo
majo
This document
p
x
cannot 
ortico
ortico
Sect
Sect
be
conc
conc
used
hera
era
ion e
on e
to 
hib
rap
rap
support
ct wi
t w
CB wi
CB w
bited
bited
any
s the 
s the
with
with
marketing
ev
change
hang
und me
nd m
d
authorization
or cha
or cha
ssible
ssible
Week
Week
vious
ious
application
the s
he 
he subj
e sub
ade to r
de to 
and 
sta
st
any
might
migh
extensions
poses
oses
Further
urthe
not giv
ot giv
se do
e do
or 
s o
variations 
4 or 
or 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 67 of 255
If the subject requires any of the medications specified in this section, the subject must be 
discontinued from the study treatment prior to the initiation of these medications. Before starting 
these therapies the Investigator should contact the Study Physician.
If the subject is discontinued from study treatment in order to initiate other treatments (including 
biologics), the subject will be encouraged to return to the site for future study visits to continue 
to collect data important for study integrity.
If the subject initiates therapy with CZP, UCB will supply the subject with CZP. If the decision 
is made to start a different therapy, UCB will not supply such medication.
Subjects must not participate in any other clinical study for any indication or receive any 
unauthorized medication during the study period.
The administration of live vaccines is not recommended for subjects treated with TNFi. Live 
vaccines should not be administered 8 weeks prior to Baseline. If immunization with a live 
organism based vaccine is considered during the study, the clinician is urged to carefully weigh 
the risks versus benefits of immunization. If the subject is going to proceed with live organism 
based immunization, the subject must be withdrawn from the study prior to administration of the 
vaccine. Such vaccines must be recorded in the respective section of concomitant module of the 
CRF.
7.8.3 
Concomitant medication(s)/treatments during the SFE Period 
At the completion of the Week 52 visit assessments, subjects on double-blind study treatment 
may receive open-label CZP treatment for an additional 2 years during the SFE Period. During 
this time, CZP will be provided by the Sponsor. Concomitant medication usage during the SFE 
Period is at the discretion of the Investigator.
7.9 
Blinding 
Due to differences in presentation and viscosity between CZP and placebo, special precautions 
will be taken in order to ensure blinding during the Double-Blind Period of the study. The 
subject will receive the IMP throughout the study duration for each single administration in a 
sealed box with PFS containing either CZP 200mg or placebo. Packaging and labeling will be 
done in a way to ensure that the provided box including the PFS will not provide any information 
about the assigned treatment (CZP 200mg or placebo). Administration of the IMP will be done 
according to the schedule of study assessments (Table 5‒1) either on-site by appropriately 
trained unblinded study personnel or at home by the subject him/herself. Pharmacokinetic and 
antibody data will be provided only after the study is unblinded.
7.9.1 
Maintenance of study treatment blind 
All subject treatment details will be allocated and maintained by the IXRS.
The study will be double-blind and placebo-controlled for 52 weeks. No study team member 
involved in the clinical conduct will have access to the randomization schedule until after 
database lock and unblinding. 
If the Investigator decides to discontinue the double-blind study treatment and initiate open-label 
treatment with CZP or other treatment (including biologics), efforts will be made to ensure that 
the blinding of the previously assigned double-blind study treatment will be maintained. 
Therefore, if the open-label treatment with CZP is chosen by the Investigator, the 3 loading doses 
REDACTED 
men
men
n addi
n add
ponsor
ponso
tigator
tigator
COPY 
eatme
atme
nts, 
nts
This document 
The 
The 
inin
cannot 
subje
subje
be
ata w
a w
used 
sch
ch
ded stu
ed stu
wil
wil
to
re
hedu
hed
support
aining
ning
e that th
that 
atmen
atme
any 
blili
hroug
hroug
g e
marketing 
and vis
nd vi
indin
ndi
authorization 
, subje
subje
ditiona
tiona
r. Con
r. Con
r.
application 
y p
y p
on of c
n of
nts d
nts d
and
rocee
ocee
prio
rio
any 
t
rged to
ged t
ed
extensions 
any 
any
with TN
th TN
ion w
on w
or variations 
ion
on
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 68 of 255
of CZP 400mg Q2W will be administered by dedicated study personnel without disclosing to the 
subject the use of the PFS. After the last loading dose, the subject can self-administer CZP until 
Week 52/WD of the regular visit schedule. 
For the SFE Period, in order to maintain the blind for subjects completing the Double-Blind 
Period, study treatment will be administered sc by unblinded study staff at the study site on 
Weeks 52, 54, and 56. Subjects who completed the Week 52 Visit on placebo treatment will 
receive loading doses of CZP 400mg at these visits. Subjects who completed the Week 52 Visit 
on CZP treatment will receive 1 injection of CZP 200mg and 1 injection of placebo at these 
visits to continue their previous CZP treatment regimen. 
7.9.2 
Breaking the treatment blind in an emergency situation 
All Sponsor, Investigator site, and Contract Research Organization (CRO) staff involved with the 
study will be blinded to the treatment code until the database lock ie, after completion of the 
Double-Blind Period with the following exceptions:
x Sponsor clinical study supplies coordinator, packager, and qualified person
x Pharmacy monitors that monitor unblinded pharmacy documentation
x Sponsor pharmacovigilance staff reporting SAEs to regulatory authorities
x Laboratory staff analyzing blood samples for CZP plasma concentrations and anti-CZP 
antibodies
x Site study drug administrator
The appropriate persons (Investigators, Single Safety Case Management [SSCM] - Safety 
Officer, Medical Monitor) will be provided with an individual password to access the IXRS 
menu that will enable them to unblind a subject’s double-blind treatment allocation. This 
password must be kept confidential and not shared with any other persons. The IXRS will be 
able to identify the individual who has unblinded a subject’s treatment allocation. The IXRS will 
be accessible at all times. If possible, Investigators are advised to contact the company or its 
representatives prior to unblinding the treatment allocation of subjects. 
Under normal circumstances, the blinded treatment must not be revealed. In the case of a 
medical emergency, UCB or its representatives preferably should be contacted prior to any 
unblinding. The blind should be broken only if doing so will change the decision making as to 
the subject’s treatment or clinical intervention. Any unblinding performed by the Investigator of 
the IMP must be documented and explained by the Investigator. If the blind is broken, the date, 
the reason for the breaking the blind, and person doing so must be recorded. UCB or its 
representatives must be notified immediately if the blind is broken.
In the event of an emergency, it will be possible to determine which treatment arm and dose the
subject had been allocated to by calling the IXRS. All sites will be provided with details of how 
to contact the system for code breaking at the start of the study. The Medical Monitor (or 
equivalent) should be consulted prior to unblinding, whenever possible.
For the product and study information and emergency unblinding purposes, the Sponsor will 
provide each Investigator with an appropriate quantity of clinical study subject cards. Each 
subject will be instructed to keep the card with him/her at all times. These subject cards will be 
REDACTED 
Singl
Singl
ovide
ovide
nd a
nd a
COPY 
CZP pl
CZP p
This document 
n thth
subj
subj
tot
cannot
on fo
n f
sentati
entat
he e
he e
be
ust b
st b
for
for
used 
blin
lin
reatme
eatme
be
be
to
U
nd s
nd
support
lind
ind
ances, 
ances
UCB 
UCB 
any
ssibl
ssib
nding
din
marketing 
ed w
d w
a subje
subje
and no
nd n
o has u
o has 
lel
authorization 
le Safe
e Safe
with
with
application
entati
entat
latory 
latory
asma c
sma 
and
ed pe
ed p
i
any 
er
extensions 
f invol
f invo
omple
mple
or variations 
sit 
sit 
e
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 69 of 255
written in the language of the subject. The Investigator will fill in each card with the details of 
his/her contact information (eg, Investigator stamp) and subject identifier. The card will be 
distributed to the subject at the time of informed consent.
The Clinical Project Manager (CPM) will be informed immediately via the IXRS when a code is 
broken, but will remain blinded to specific treatment information. Any unblinding of the IMP 
performed by the Investigator must be recorded in the source documents and on the Study 
Termination CRF page.
7.10 
Randomization and numbering of subjects 
7.10.1 
Interactive Response System 
An IXRS is used for subject registration as well as randomization and treatment administration. 
To enroll a subject, the Investigator must contact the IXRS and provide brief details of the 
subject to be enrolled. Each subject will be assigned a unique subject number. Enrolled subjects 
who withdraw from the study prior to randomization will retain their subject number without 
receiving a randomization number (ie, subject numbers will not be reassigned).
The IXRS will allocate kits of study medication at Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44, 48, and 50.
7.10.2 
Randomization 
Randomization will be stratified on:
x Region
x MRI/CRP classification
Subjects will be classified as MRI+/- depending on whether or not they have evidence of 
sacroiliitis on MRI at Screening based on the ASAS/OMERACT definition. Subjects will be 
classified as CRP+/- based on the CRP value obtained at the second Screening visit scheduled to 
occur 3 to 5 days prior to Baseline. Subjects will be categorized as CRP+ if their CRP value is 
above the level indicative of inflammatory disease at this visit. Otherwise, they will be 
considered CRP-. Based on these definitions, the stratification for MRI/CRP classification will 
have the following 3 levels:
x MRI+/CRP+
x MRI+/CRP-
x MRI-/CRP+
The IXRS will be designed to ensure that at least 20% of the randomized subjects belong to each 
of the 3 clinical subgroups above.
To randomize a subject, the Investigator must contact the IXRS and provide brief details of the 
subject that is to be randomized. The IXRS will automatically inform the Investigator of the 
subject’s randomization number. Each subject will be assigned a unique randomization number. 
This randomization number will be required in all communications between the Investigator (or 
his/her designee) and the IXRS regarding a particular subject. The IXRS will allocate kit 
numbers to the subjects based on the randomization list over the course of the study. 
REDACTED 
de
de
COPY 
This document 
f tht
To r
To 
cannot 
/C
/C
IXRS 
XRS 
he 3 
he 3
be 
CRP
CRP
used 
P-
to support 
f ini
on the
on the
evels:
vels:
any
ine. 
ine
nflam
nflam
marketing
ependi
pendi
ed on th
d on t
CRP v
CRP 
Su
S
authorization application 
4, 6, 8
4, 6, 8
and 
ubjbj
eassig
assig
any
ber. 
ber
ject n
ec
extensions 
admin
dmin
f detai
detai
E
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 70 of 255
Randomization numbers and kit numbers will be tracked via the IXRS and also will be required 
to be entered into the CRF. 
Randomization schedules will be generated prior to start of the study. Subjects will be allocated 
to treatment in a 1:1 ratio (CZP 200mg: placebo). 
8 
STUDY PROCEDURES BY VISIT  
Section 5.2 (Schedule of study assessments) provides a general overview of study assessments. 
A detailed listing of procedures to be undertaken at each visit is described below. 
During the first 3 periods of the study the Investigator will assess the subjects over the entire 
study period of approximately 66 weeks including a FU Period of 8 weeks after the 
Week 52/WD visit. Visit windows of ±3 days on either side of the scheduled visit are permitted; 
however, the Investigator should try to keep the subjects on the original dosing schedule. The 
window of ±3 days is relative to Baseline and is applicable for all subsequent visits. Changes to 
the dosing schedule outside of the 3-day window must be discussed with the Medical Monitor 
and may result in subject withdrawal. 
8.1 
Screening visit (Week -6 to Day -1) 
Prior to any study activities, subjects will be asked to read and sign an informed consent form 
that has been approved by an IEC/IRB and the Sponsor and which complies with regulatory 
requirements. Subjects will be given adequate time to consider any information concerning the 
study given to them by the Investigator or designee. As part of the informed consent process, 
subjects will be given the opportunity to ask the Investigator any questions regarding potential 
risks and benefits of participation in the study. 
Assessments at the Screening visit include:
x Confirm inclusion/exclusion criteria (to be performed within Weeks -6 and Day -1 and 
confirmed between Days -5 and -3 before Baseline)
x Confirm informed consent
x Demographic data (includes date of birth, gender, race/ethnicity)
x Significant past medical and procedure history and concomitant disease (includes allergy and 
any current symptoms) including axSpA history
x Vital signs (pulse rate, systolic and diastolic blood pressure, temperature, and respiratory 
rate)
x Hematology, biochemistry, and urine for clinical laboratory values (includes a serum 
pregnancy test for women of childbearing potential; testing to rule out hepatitis B surface 
antigen, antibodies to hepatitis C, and HIV; testing of CRP, HLA-B27, and abnormalities for 
estimated Glomerular Filtration Rate as measured by CKD-EPI will be performed) 
x Physical examination (including weight) 
x Chest x-ray to be done at Screening (unless a chest x-ray or computed tomography of the 
chest has been done within 3 months prior to the Screening visit)
REDACTED
gne
gne
k the I
k the I
study.
tudy.
nclude
nclude
COPY
sor a
sor 
me to c
me to 
ee.
ee
This document 
a
cannot
matol
mato
pregna
regna
ant
ant
be used 
 (puls
(puls
to
mpto
mpto
support
clude
lude
medical 
edical
om
om
any 
s
marketing 
e:
ria (to 
ria (to
d -3 be
3 b
authorization
cons
ons
 As pa
As pa
Invest
nvest
application 
nd sign
nd sig
nd whi
d wh
nside
sid
and any 
nt 
nt
the M
the M
extensions 
en
it are p
t are p
g sche
g sch
t vis
vi
or
ntir
ntir
variations 
ts.s. 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 71 of 255
x TB test: Interferon-Gamma Release Assay (IGRA) test (QuantiFERON test [or Elispot test 
when the QuantiFERON test is indicated but not available])
x TB evaluation questionnaire 
x SI joint x-ray (centrally read). An SI joint x-ray performed ≤12 months prior to the Baseline 
visit maybe used as the Baseline assessment provided that the film can be submitted and 
meets the requirements for central reading.
x MRI (spine and SI joints, centrally read)
x BASMI and spinal mobility assessments
x BASDAI
x Prior and concomitant medication
x Contact the IXRS to indicate the subject has been screened
The period between the Screening and Baseline visits should not exceed 6 weeks. The Screening 
chest x-ray should be read by a radiologist/pulmonologist and must exclude evidence of TB. The 
qualifying CRP levels from the Screening visit will be used for the inclusion criteria review at 
Baseline. 
One retest of CRP is mandatory during the Screening Period within 3 to 5 days before the 
Baseline visit in order to meet the inclusion criteria. 
One rescreen is permitted for subjects with LTB. In this event, all Screening assessments must be 
repeated. Subjects are allowed to start the IMP after at least 4 weeks of prophylactic TB 
treatment (if compliant with the local regulations on initiation of biologic therapy in subjects 
with LTB) within the Screening Period. The subject is required to complete the full prophylactic 
treatment.
8.2 
Baseline visit (Week 0) 
Subjects agreeing to participate in the study, after giving signed informed consent, will have the 
following procedures performed/recorded prior to study drug administration:
x Review of inclusion/exclusion criteria. Note: The qualifying CRP levels from the Screening 
Period 3 to 5 days before Baseline will be used for the inclusion criteria review and for 
randomization stratification. The result of the centrally read MRI and X-ray must be 
available for the inclusion criteria review.
x Vital signs (pulse rate, systolic and diastolic blood pressure, temperature, and respiration 
rate)
x Blood samples (subjects should be encouraged to be under fasting conditions, the same 
condition [fasting or not fasting] should be applied at Week 52) will be collected for 
hematology and biochemistry analyses (biochemistry assessment will include the 
measurement of apolipoprotein (Apo) A1, ApoB, lipoprotein(a), and glycated hemoglobin 
[HbA1c])
x Urine will be collected for urinalysis and for a urine pregnancy test for women of 
childbearing potential
LTB. 
LTB. 
e IMP
e IMP
regula
regul
iod. T
iod. 
COPY 
ng Pe
ng Pe
ria.
ria.
This document
B
cannot
l sig
sig
ate)e)
Blo
Blo
be 
gns
gn
used
on st
n st
for th
for th
to
ays b
ays 
support
forme
rme
on/exc
n/exc
bef
b
any 
te in t
e in 
d
marketing
The s
The s
Wee
Wee
authorization 
In thi
In thi
P after
after
ations
tions
application
st ex
t ex
the inc
the in
riod w
od w
and
eed 6
ed 6
excl
xcl
any extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 72 of 255
x Physical examination (including height and extra-articular assessments)
x TB questionnaire 
x BASMI and spinal mobility 
x BASDAI 
x BASFI 
x SF-36
x ASQoL 
x MOS Sleep Scale 
x EQ-5D
x MASES
x Total spinal pain NRS and nocturnal spinal pain NRS 
x Swollen and tender joint counts
x PGADA
x PhGADA
x Productivity measures (WPS)
x Resources utilization 
x Plasma for CZP concentration, anti-CZP antibodies, and biomarkers 
x Genetics/epigenetics, if applicable
x Gene expression and proteomics, if applicable
x Concomitant medication
x AEs
x Contact IXRS to randomize subject and to obtain kit number 
x Study drug administration (after all other visit assessments are completed and laboratory 
samples are drawn)
8.3 
Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 
36, 38, 40, 42, 44, 46, 48, and 50 (all visits ±3 days relative to 
Baseline) 
Assessments at these visits include:
x Vital signs; pulse rate, systolic and diastolic blood pressures and temperature (respiration rate 
will be assessed in addition if the subject experiences an AE) (at all on-site visits except 
Week 1)
x Blood samples will be collected for hematology, biochemistry, and CRP (Weeks 2, 4, 8, 12, 
24, and 36 only)
REDACTED 
titi-CZP
CZ
lele
COPY 
This document
Asse
Asse
x
cannot be used 
dmi
m
re draw
e draw
W
to
minis
mini
support 
random
andom
any marketing 
cs, if ap
s, if a
authorization 
P anti
anti
application and any extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 73 of 255
x CRP for the calculation of ASDAS (Weeks 16, 20, 28, 32, 40, 44, and 48)
x Urine will be collected for urinalysis (Weeks 2, 4, 8, 12, 24, and 36 only) 
x Physical examination (Weeks 2, 4, 8, 12, 16, 24, and 36), including weight at Week 24
x Extra-articular assessments (Weeks 4, 12, 24, 36, and 48 only) 
x TB questionnaire (Weeks 12, 24, and 36 only)
x MRI (spine and SI joints; Week 12 only)
x BASMI and spinal mobility (at all on-site visits except Weeks 6, 10, and 50)
x BASDAI (Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 only)
x BASFI (Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 only)
x SF-36 (Weeks 4, 12, 24, 36, and 48 only)
x ASQoL (Weeks 1, 2, 4, 12, 24, 36, and 48 only)
x MOS Sleep Scale (Weeks 4, 12, 24, 36, and 48 only)
x EQ-5D (Weeks 4, 12, 24, 36, and 48 only)
x MASES (Weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, and 48 only)
x Total spinal pain NRS and nocturnal spinal pain NRS (Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 
32, 36, 40, 44, and 48 only)
x Swollen and tender joint counts (Weeks 4, 12, 24, and 36 only)
x PhGADA (Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 only) 
x PGADA (Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 only)
x Productivity measures (WPS) (Weeks 4, 12, 24, 36, and 48 only)
x Resource utilization (Weeks 4, 12, 24, 36, and 48 only)
x Plasma for CZP concentration, anti-CZP antibodies, and biomarkers (Weeks 1, 2, 4, 12, 24, 
and 36 only)
x Genetics and epigenetics (Week 12 only), if applicable
x Gene expression and proteomics (Weeks 4 and 12), if applicable
x Concomitant medication
x AEs
x Contact IXRS to register the visit and obtain next kit number, where applicable (Weeks 2, 4, 
6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50)
x Study drug administration (after all other visit assessments are completed and laboratory 
samples are drawn) (all visits except Week 1)
x Subject training on self-injection (Weeks 10 and 12)
REDACTED
l pa
l pa
eeks 4
eeks 4
16, 2
16, 2
COPY 
and 48
nd 48
ain
ain
This document 
x
C
cannot
ncom
om
AEs
AEs
be
xpre
pre
i
used
d ep
epi
ess
ess
to support
Week
eek
ncentra
centr
any 
S) (
S) 
ks
ks 4
marketing
20, 24
20, 2
16, 20, 
6, 20
(We
(W
authorization 
n NRS
NRS
4, 12, 
, 12,
application 
only)
only)
and any extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 74 of 255
8.4 
Every 4 weeks (± 3 days) during home injection period from 
Week 14 to Week 46 (Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46) 
The following assessments are to be performed by telephone:
x Concomitant medication 
x AEs 
8.5 
Week 52/WD (±3 days) 
A subject is regarded to have completed the Double-Blind Period of the study if s/he completes 
the Week 52 assessments. Assessments at this visit include:
x Vital signs; pulse rate, systolic and diastolic blood pressure, and temperature (respiration rate 
will be assessed in addition if the subject experiences an AE) 
x Blood samples (subjects should be encouraged to be under fasting conditions, the same 
condition [fasting or not fasting] should be applied at Week 52) will be collected for 
hematology, biochemistry, and CRP (biochemistry assessment will include the measurement
of Apo A1, ApoB, lipoprotein(a), and HbA1c)
x Urine will be collected for urinalysis and for a urine pregnancy test for women of 
childbearing potential
x Physical examination (including weight)
x Extra-articular assessments
x Chest x-ray only if the TB test was confirmed positive or any further evidence is suggestive 
of potential TB infection
x TB test: IGRA test (QuantiFERON test [or Elispot test when QuantiFERON test is indicated 
but not available]) only for subjects who have not had a previously positive TB test result
x TB Questionnaire 
x SI joint x-ray
x MRI for spine and SI joints (at Week 52/WD visit if previous MRI was performed more than 
12 weeks prior to Week 52/WD visit)
x BASMI and spinal mobility
x BASDAI
x BASFI
x SF-36
x ASQoL
x EQ-5D
x MASES
x Total spinal pain NRS and nocturnal spinal pain NRS
REDACTED 
confir
confi
COPY 
This document 
S
x
cannot 
ASFI
ASFI
SF
SF
be 
AI
AI
used 
nd spi
d spi
to
to W
to W
support 
d SI jo
SI jo
We
W
any marketing 
ON test 
N tes
bjects w
jects 
authorization 
irmed 
rmed 
application 
gnancy
nanc
and
ill b
l b
will in
ill in
any
nditio
diti
be c
be c
extensions 
e (resp
(resp
o
mpl
mpl
variations 
let
l t
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 75 of 255
x Swollen and tender joint counts
x PhGADA
x PGADA
x Productivity measures (WPS)
x Resources utilization
x Plasma for CZP concentration, anti-CZP antibodies, and biomarkers 
x Gene expression and proteomics, if applicable
x Concomitant medication
x AEs
x Contact IXRS to indicate that subject has rolled over to the SFE Period or withdrawn from 
the study
8.6 
SFE Period (Week 52 to Week 156)  
All eligible subjects must complete the Week 52 visit assessments.
Eligible subjects are allowed to roll-over to the SFE-Period up to 3 months after completion of 
the Week 52 assessments.
Prior to rolling over to the SFE Period, subjects will be asked to read and sign a separate 
informed consent form.
Telephone contacts are upon the discretion of the Investigator. Starting at Week 56, and at the 
discretion of the Investigator, it is recommended to contact the subject by phone at least once in 
between the on-site visits.
Starting at Week 64, all subjects are to visit the site approximately every 12 weeks (±2 weeks) 
for assessments performed according to local standard medical practice, as needed, including:
x Document AEs (Note: any [possible] drug-related AE must be followed-up, at least by 
phone.) 
x Contact IXRS 
 to register the visit and obtain next kit number at Weeks 54 and 56 for subjects receiving 
loading doses of study drug administration at the study site 
 to register the visit and obtain next kit number for subjects receiving study drug 
administration at the study site approximately Q12W during the remainder of the study
 to indicate that the subject has withdrawn from the study, if applicable
At Week 156/SFE-WD (±1 week), all subjects are to visit the site for the following assessments:
x Blood sample for CRP
x BASDAI
x BASFI
REDACTED
cts w
cts w
etion o
etion o
comm
com
COPY
Peri
Per
il
This document 

A
cannot
to re
o re
adm
ad
be 
ding
ng
used
ster th
er th
g do
g do
to support
any 
any 
any
ordin
ordi
[p
[
marketing
mmend
mend
are to v
re to 
ng
authorization 
ill be a
l be 
of the
f the
d
application 
ments.
ents.
od up to
d up t
and any
d or 
d or
extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 76 of 255
x ASQoL
x Total and nocturnal spinal pain
x PGADA
x MRI SI joints
x AEs
x Contact IXRS to indicate that the subject has completed the SFE Period (Week 156/SFE-
WD)
8.7 
FU visit (8 weeks after the Week 52/WD visit [±3 days])  
Subjects not participating in the SFE Period will attend a FU visit 8 weeks after the 
Week 52/WD visit (±3 days). 
Assessments at this visit include:
x Vital signs; pulse rate, systolic and diastolic blood pressure, and temperature (respiration rate 
will be assessed in addition if the subject experiences an AE)
x Blood samples will be collected for hematology, biochemistry, CRP, and serum pregnancy 
test for women of childbearing potential
x Urine will be collected for urinalysis 
x Physical examination 
x Plasma for CZP concentration, anti CZP antibodies, and biomarkers 
x Concomitant medication
x AEs
x Contact IXRS to indicate that subject has completed FU
8.8 
Unscheduled visits 
It is at the Investigator’s discretion to initiate an Unscheduled Visit, if deemed necessary by the 
Investigator for the subject’s safety and well-being. At this visit, any of the following or other 
assessments at the Investigator’s discretion may be performed depending on the reason for the 
visit:
x Vital signs 
x Blood samples for hematology, biochemistry, other testing such as for TB or CRP 
x Urine for urinalysis and/or pregnancy testing (for women of childbearing potential)
x Physical examination 
x Concomitant medication
x AEs
anti C
anti C
COPY 
y, bioc
y, bio
This document 
x
cannot 
ital sig
tal si
Blo
Blo
be used
the s
he s
t the 
t the 
to
ator
ator
su
support 
te th
e th
edule
edul
r’s d
r’s
any 
that 
hat
marketing
CZP a
CZP a
authorization application 
 and te
and t
AE)
AE)
hemis
hemi
and any 
aftf
extensions 
ays]) 
ays])
fter t
ter
or variations 
FE-
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 77 of 255
x TB questionnaire 
x Contact IXRS to indicate that subject attended an unscheduled visit
8.9 
Alternative visit schedules after subject discontinuation of the 
double-blind study treatment 
Subjects who discontinue the double-blind study treatment and enter open-label treatment with 
CZP will be assessed 2 and 4 weeks after open-label CZP treatment has been initiated and every 
12 weeks thereafter. Alternatively, subjects who discontinue the double-blind study treatment 
and receive other treatment (including biologics) will be assessed every 12 weeks after initiation 
of the other treatment. The alternative schedules for open-label CZP and other treatment can be 
found in Table 5‒2 and Table 5‒3 , respectively. In either alternative schedule, assessments 
should be conducted until as close as possible to Week 52 (within ±4 weeks), where Week 52 is 
relative to the original randomization at Week 0. Subjects will then be invited to the final 
assessment visit at Week 52.
The following assessments will be performed for subjects who are treated with open-label CZP 
after discontinuation of the double-blind study treatment:
x Vital signs; pulse rate, systolic and diastolic blood pressure, and temperature (respiration rate 
will be assessed in addition if the subject experiences an AE) at wdt Weeks 0, 2, 4, 12, 24 
(and every 12 weeks [Q12W]), 52, and FU (8 weeks after Week 52 Visit)
x Blood samples will be collected for hematology, biochemistry, and CRP analyses, and urine 
will be collected for urinalysis at wdt Weeks 0, 12, 24 (and Q12W), 52 and FU (8 weeks 
after Week 52 Visit)
Note: Fasting blood samples will be collected for hematology, biochemistry, and CRP 
analyses at wdt Week 0 (biochemistry assessment will include the measurement of Apo A1, 
ApoB, lipoprotein(a), and HbA1c). At Week 52, the biochemistry assessment will include the 
measurement of HbA1c.
x Pregnancy test for women of childbearing potential at wdt Weeks 0, 52 (urine testing), and 
FU (serum testing)
x Physical examination at wdt Weeks 0, 4, 12, 24 (and Q12W), 52, and FU
x Extra-articular assessments at wdt Weeks 12, 24 (and Q12W), and 52
x TB test at wdt Week 52 only
x TB questionnaire at wdt Weeks 0, 12, 24 (and Q12W), and 52
x SF-36, AsQoL, MOS Sleep Scale, EQ-5D, and MASES at wdt Weeks 0, 12, 24 (and Q12W), 
and 52
x BASMI & spinal mobility, BASFI, total and nocturnal spinal pain, swollen and tender joint 
counts, BASDI, Patient’s Global assessment, and Investigator’s AS assessment at wdt 
Weeks 0, 4, 12, 24 (and Q12W), and 52
x Plasma for CZP concentration, anti-CZP antibodies, and for biomarkers at wdt Weeks 0, 4, 
12, 24 (and Q12W), 52, and FU
REDACTED
tolog
tolog
Weeks 
Weeks 
l be c
l be c
misi
COPY
nces
nce
weeks
week
gy
This document
a
x
canno
ques
ues
SF-36
36
and
an
be 
at w
sti
sti
sed
ar as
r a
wdt
wdt
to 
ass
ass
support 
en
tion at
ion a
any 
of ch
of ch
marketing
collec
olle
stry as
try as
1c). At
c). A
authorization 
s a
y, bioc
, bioc
 0, 12
0, 12
ect
ect
application 
re, and
re, an
an AE)
n AE
after 
fter 
and
eated
eated
any extensions
ment 
ent 
sessm
essm
where
where
d to t
d to t
o
niti
niti
variations 
ery 
ery 
ment 
nt 
iat
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 78 of 255
x Gene expression and proteomics at wdt Week 52 only
x Concomitant medication at wdt Weeks 0, 2, 4, 12, 24 (and Q12W), 52, and FU
x AEs at wdt Weeks 0, 2, 4, 12, 24 (and Q12W), 52, and FU
x IXRS (for treatment assignment) at wdt Weeks 0, 2, 4, 12, 24 (and Q12W), 52, and FU
x CZP administration at wdt Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and every 
2 weeks thereafter, until Week 52. Loading dose of CZP 400mg at Weeks 0, 2, and 4 must be 
administered by dedicated site-staff 
x Telephone contact will occur every 4 weeks after the on-site visit at the discretion of the 
investigator
The following assessments will be applied for subjects who receive an alternative study 
assessment with other treatment (including biologics) after discontinuation of the double-blind 
study treatment:
x Blood samples will be collected for hematology and biochemistry analyses, and urine will be 
collected for urinalysis at wdt Week 0. C-reactive protein analyses will be performed at wdt 
Weeks 0, 12, 52, and FU 
Note: Biochemistry assessment will include the measurement of HbA1c at wdt Week 0 
x Physical examination at wdt Week 0 and FU.
x BASDAI, BASFI, total and nocturnal spinal pain, Patient’s Global assessment, and 
Investigator’s AS assessment at wdt Weeks 0, 12, and 52
x Swollen and tender joint counts at wdt Week 52 only
x Plasma for CZP concentration, anti-CZP antibodies, and for biomarkers at wdt Weeks 0, 12, 
and FU
x Concomitant medication at wdt Weeks 0, 12, 24 (and Q12W), 52, and FU
x AEs and IXRS (for the registration of visits) at wdt Week 0, 12, 24 (and Q12W), 52, and FU
x Other treatment administration at wdt Week 0. For Week 12 and 24 (and Q12W) the regimen 
of the particular medicine should be followed. If the Investigator choses to withdraw the 
subject, the local guidelines on initiation and monitoring of the particular treatment should be 
followed.
x Telephone contact will occur every 4 weeks after the on-site visit at the discretion of the 
Investigator
9 
ASSESSMENT OF EFFICACY 
Most of these tools have been used in AS studies but early data support their use in axSpA as 
well (Barkham et al, 2009; Haibel et al, 2008).
pinal p
pinal p
Week
Week
at wdt
at wdt
COPY
meas
mea
This document 
9
M
cannot
pho
pho
nvestig
vestig
be 
one
on
used
local
ocal
to
r me
r m
support
e regi
reg
dminis
dminis
edid
any
wdt
wd
marketing
t W
ntiti-CZP
CZ
W
authorization 
pain, P
ain, 
ks 0, 1
s 0, 1
Wee
Wee
application
alyses
alyse
uremen
ureme
and 
y ana
y ana
any 
of 
of
extensions
n of 
of 
ative s
tive s
f th
f th
or 
thth
variations 
ust be
st be 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 79 of 255
9.1 
Assessment of efficacy variables 
9.1.1 
ASDAS 
The ASDAS is comprised of a number of assessments which are scored by the subject and 
physician and multiplied by a proven formula (van der Heijde et al, 2009) as listed:
0.121 x Back pain (BASDAI Q2 result, see Section 9.1.5)
0.058 x Duration of morning stiffness (BASDAI Q6 result)
0.110 x PGADA (see Section 9.1.13)
0.073 x Peripheral pain/swelling (BASDAI Q3 result)
0.579 x (natural logarithm of the (CRP [mg/L] + 1)) 
Back pain, PGADA, duration of morning stiffness, peripheral pain/swelling and fatigue are all
assessed on a numerical scale (0 to 10 units) (Lukas et al, 2009).
The variables related to ASDAS disease activity are defined as follows:
x ASDAS-Inactive Disease (ASDAS-ID): ASDAS <1.3
x ASDAS-Low Disease (ASDAS-LD): ASDAS ≥1.3, <2.1
x ASDAS-High Disease Activity (ASDAS-HD): ASDAS ≥2.1, ≤3.5
x ASDAS-very High Disease Activity (ASDAS-vHD): ASDAS >3.5
The variables related to ASDAS improvement are defined as follows:
x ASDAS-Clinically Important Improvement (ASDAS-CII): ASDAS reduction (improvement) 
of ≥1.1 relative to Baseline
x ASDAS-Major Improvement (ASDAS-MI): ASDAS reduction (improvement) of ≥2.0 
relative to Baseline
The ASDAS will be calculated at Screening, Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32 36, 
40, 44, 48, 52/WD, and Week 156/SFE-WD.
9.1.2 
ASAS20, 40, ASAS 5/6 response, and ASAS partial remission 
The ASAS20 is defined as an improvement of at least 20% and absolute improvement of at least 
1 unit on a 0 to 10 NRS in at least 3 of the 4 following domains:
x PGADA (see Section 9.1.13)
x Pain assessment (the total spinal pain NRS score)
x Function (represented by BASFI, Section 9.1.6)
x Inflammation (the mean of the BASDAI questions 5 and 6, [see Section 9.1.5] concerning 
morning stiffness intensity and duration) 
and absence of deterioration in the potential remaining domain [deterioration is defined as a 
relative worsening of at least 20% and an absolute worsening of at least 1 unit].
REDACTED 
DAS
DAS
ment a
ment a
provem
rovem
COPY 
,
 ASD
ASD
S-v
This document 
x
cannot 
ain ass
in as
Fun
Fun
be
A (s
A (s
used 
defi
ef
o 10 N
10 N
to
fine
fine
support
Week 1
eek 
20, 40
0, 4
d
any 
d at S
d at S
15
marketing 
ASDAS
SDA
authorization 
DA
vHD):
HD):
are de
are de
ment (
ent (
application 
AS ≥2
AS ≥2
and 
ws:
ws:
any extensions 
and f
nd f
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 80 of 255
The ASAS criteria for 40% improvement are defined as relative improvements of at least 40%, 
and absolute improvement of at least 2 units on a 0 to 10 NRS in at least 3 of the 4 domains and 
no worsening at all in the remaining domain.
The ASAS 5/6 response is defined as at least 20% improvement in 5 of 6 domains, including 
spinal mobility (lateral spinal flexion) and CRP as more objective measures (Brandt et al, 2004).
The ASAS partial remission response is defined as a score of ≤2 units on a 0 to 10 unit scale in 
all 4 domains listed above for ASAS20.
The ASAS variables will be calculated at Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 
52/WD, and Week 156/SFE-WD.
9.1.3 
ASAS-NSAID score 
The ASAS-NSAID score is a tool that has been developed to measure the magnitude of NSAID 
intake during clinical studies (Dougados et al, 2011). In order to calculate the ASAS-NSAID 
score, the following information will be collected:
x Has there been NSAID intake since last visit?
x NSAID name
x Average daily intake (mg)
x Days with intake
 <1 day/week
 1 to 3 days/week
 3 to 5 days/week
 ≥5 days/week
 Every day
x Starting date
x End date (or ongoing)
The general formula for calculation is as follows:
x (equivalent NSAID score) × (days of intake during period of interest) × (days per 
week)/(period of interest in days)
Each of the components of the above calculation is described below:
x Equivalent NSAID score: This is reported in terms of NSAID equivalent dose in mg/day on a 
0 to 100 scale where the diclofenac 150mg equivalent is set to 100. An NSAID equivalence 
table was developed based on a survey of ASAS members. The table including the consensus 
equivalence score for various NSAIDs can be found in the Statistical Analysis Plan (SAP).
x Days of intake during period of interest: Equivalent to the total number of days covered 
during the period that is being measured.
REDACTED COPY 
This document
0
cannot
the 
he 
Equiv
Equiv
0 t
0 t
be 
per
co
co
sed
NSA
NSA
riod
riod
to
a fo
a fo
support 
g)
g)
for c
or c
any marketing authorization application and any
the A
the
extensions 
agnitu
gnitu
A
or
44
44
variations 
4 4
4 4
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 81 of 255
x Days per week: Proportion of days per week when the NSAID is taken. This is collected in 
the categories described in the days with intake category listed above. Each category 
corresponds to a score as follows (score in parentheses):
 Every day (7/7)
 ≥5 days/week (6/7)
 3 to 5 days/week (4/7)
 1 to 3 days/week (2/7)
 <1 day/week (0.5/7)
 No NSAID intake (0)
x Period of interest in days: Refers to the number of days covered for a given NSAID. If only 
1 NSAID was taken during the period of interest, this will be the same as days of intake 
during period of interest.
Dougados et al 2011 provided the following example. If during a period of interest (between 
2 visits) of 6 months, the subject has taken piroxicam 20mg during 4 months and if during this 
4 month-period he has taken piroxicam 3 to 5 days per week the calculation is as follows:
x 100 (20mg piroxicam score) × 120 (4 months) × 4/7 (3 to 5 days/week)/180 
(6 months) = 38.1
If the subject has used 10mg piroxicam during the remaining 2 months on 2 days a week, the 
NSAID score for this period is:
x 50 (10mg piroxicam score) ×60 (2 months) × 2/7 (1 to 3 days/week)/180 (6 months) = 4.8
In this example the total score for the 6-month period is 42.9 (38.1 plus 4.8).
9.1.4 
ASQoL 
The ASQoL, a validated disease-specific 18-item questionnaire, has been developed specifically 
for measuring HRQoL in subjects with AS (Doward et al, 2003). The ASQoL has been used and 
has shown to be responsive in axSpA (Barkham et al, 2009; Haibel et al, 2008). The ASQoL 
score ranges from 0 to 18 with higher score indicating worse HRQoL. A change of 1.8 points, 
which represents 10% of the possible score range, has been used as the minimal clinically 
important difference (MCID) criteria to guide the interpretation of ASQoL score changes in 
previous trials with a TNFi (van der Heijde et al, 2009; Davis et al, 2007). A change in ASQoL 
score of 2 points (ie, 10% of the total score range) will be used as the MCID to guide the 
interpretation of ASQoL score changes (see Appendix 18.4).
The ASQoL assessments per visit are described in Table 5‒1, Table 5‒2, and Table 5‒6.
9.1.5 
BASDAI 
The most common instrument used to measure the disease activity of AS from the subject’s 
perspective is the BASDAI (Garrett et al, 1994). The BASDAI is a validated self-reported 
instrument which consists of six 10-unit horizontal NRSs to measure severity of fatigue, spinal 
and peripheral joint pain and swelling, enthesitis, and morning stiffness (both severity and 
duration, respectively) over the last week (van Tubergen et al, 2015). The final BASDAI score
ing th
ing th
(2 mo
(2 mo
COPY 
× 4/7 
× 4/7 
This document 
he 
he
9.1
9.1
cannot 
2 p
2 p
retatio
retati
e AS
AS
be
als 
ls 
poin
poin
used 
10
10
erence
rence
s wi
wi
to
to
0% 
0% 
support
subje
ubje
sive in
sive in
o 18 w
 18 w
any 
se
se-sp
sp
ect
marketing
onth
nth
6-mon
mo
authorization 
 (
he rem
e rem
hs)
hs)
application
peri
eri
ring 4 m
ing 4
k the ca
the c
(3 to 5
3 to 
and 
riod
iod
any
e as d
as 
extensions 
en N
en N
d
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 82 of 255
ranges from 0 to 10, with lower scores indicating lower disease activity. The MCID used to 
interpret scores is 10mm on a VAS or 22.5% of the Baseline score (Pavy et al, 2005). An MCID 
of 1 unit will be selected for the NRS version (see Appendix 18.5).
The BASDAI 50 is defined as an improvement of at least 50% in the BASDAI response.
The BASDAI is calculated as follows: 
Fatigue item of the BASDAI
Fatigue as a major symptom of AS can effectively be measured with single-item questions such 
as the BASDAI item (van Tubergen et al, 2002b). This item has shown moderate to good 
reliability and responsiveness (van Tubergen et al, 2002b). The same MCID will be used for the 
fatigue item of the BASDAI as for the total BASDAI score, ie, a change of 1 unit on the NRS.
The BASDAI assessments per visit are described in the schedule of study assessments Table 5‒
1, Table 5‒2, Table 5‒3, and Table 5‒6.
9.1.6 
BASFI 
The BASFI is a validated disease-specific instrument for assessing physical function (van der 
Heijde et al, 2005; Calin et al, 1994). The BASFI comprises 10 items relating to the past week. 
The NRS version will be used for the answering options of each item on a scale of 0 (“Easy”) to 
10 (“Impossible”) (van Tubergen et al, 2015 and van Tubergen et al, 2002a). The BASFI is the 
mean of the 10 scores such that the total score ranges from 0 to 10, with lower scores indicating 
better physical function. The MCID used to interpret scores is 7mm on a 0 to 100mm VAS or 
17.5% of the Baseline score (Pavy et al, 2005); an MCID of 1 unit will be used for the NRS 
version (see Appendix 18.6).
The BASFI assessments per visit are described in Table 5‒1, Table 5‒2, Table 5‒3, and Table 5‒
6.
9.1.7 
BASMI 
The BASMI characterizes the spinal mobility of subjects with AS. The BASMI is a 
disease-specific measure consisting of 5 clinical measures to reflect subject axial status: cervical 
rotation; tragus to wall distance; lateral spinal flexion; modified Schober test; intermalleolar 
distance. Each of the 5 movements is scored according to the linear BASMI definition. The mean 
of the 5 scores provides the BASMI score. The higher the BASMI score the more severe the 
subject’s limitation of movement due to their axSpA.
The BASMI assessments per visit are described in Table 5‒1 and Table 5‒2.
9.1.8 
Enthesitis (MASES) 
The MASES is an index that measures the severity (ie, intensity and extent) of enthesitis through 
the assessment of 13 entheses (bilateral costochondral 1, costochondral 7, anterior superior iliac 
spine, posterior iliac spine, iliac crest and proximal insertion of the Achilles tendon sites, and the 
REDACTED
ASFI 
ASFI
wering
wering
2015 
2015 
total sc
total s
use
us
COPY 
ment 
ment
This document 
The 
The
9
cannot 
Ea
Ea
5 sco
5 sco
ject’s
ect’s
be 
agus
gus
ach
ach
used 
act
ac
ic mea
 mea
us to
s to
o
cteri
ter
support 
I
any 
isit ar
isit a
marketing
core
or
ed to in
ed to i
et al, 20
t al, 2
authorization
for a
for a
compr
compr
g optio
optio
and v
and v
re r
re r
application
e of st
of st
and
nge o
nge o
any 
der
de
CID w
CID w
f
extensions 
em qu
m qu
erate
rat
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 83 of 255
fifth lumbar vertebral body spinous process) (Heuft-Dorenbosch et al, 2003) each scored as 0 or 
1 and then summed for a possible score of 0 to 13.
Enthesitis assessments per visit are described in Table 5‒1 and Table 5‒2.
9.1.9 
Extra-articular assessments 
The evolution of associated nonmusculoskeletal features including IBD, psoriasis and uveitis 
(including their severity) and flare rate will be assessed as described Table 5‒1 and Table 5‒2.
9.1.10 
Health status (EQ-5D) 
The EQ-5D is comprised of a 5-item health status measures and a VAS. Each of the 5 health 
states is divided into 3 levels: no problem, some or moderate problems and extreme problems 
and is scored as 1, 2, and 3, respectively. The EQ-5D VAS records the respondent’s self-rated 
health status on a vertical 20 cm scale, 0 to 100 graduated (0=worst imaginable health status, 
100=best imaginable health status) (see Appendix 18.7).
This instrument is to be completed by the subject as described in Table 5‒1 and Table 5‒2.
9.1.11 
MOS Sleep Scale 
The MOS Sleep Scale is a validated generic self-administered scale measuring specific aspects 
of sleep. The frequency with which each problem has been experienced during the previous 
4 weeks is rated on a 5-point scale ranging from “none of the time” to “all of the time,” except 
sleep quantity, which is reported in hours. All scores are transformed linearly to range from 0 to 
100, again with the exception of the sleep quantity subscale, which is scored in hours. Higher 
scores indicate more of the attribute implied by the scale name (eg, more sleep disturbance, more 
adequate sleep, and greater sleep quantity). The psychometric properties of the MOS Sleep Scale 
have been found to be satisfactory by Hayes and colleagues (Hays et al, 2005). The domains of 
interest for this study are the Sleep Disturbance and the Sleep Problems Index II domains. The 
MCID for the Sleep Problems Index II is 6 points on a 0 to 100 scale (Wells et al, 2007) (see 
Appendix 18.8).
Subjects will be asked to complete the MOS Sleep Scale as described in Table 5‒1 and
Table 5‒2.
9.1.12 
MRI assessments 
Magnetic Resonance Imaging according to the ASAS/OMERACT definition is the presence of 
bone marrow oedema (BMO) or osteitis highly suggestive of SpA that is located in the typical 
anatomical areas (subchondral or periarticular bone marrow). There must be either more than 
1 BMO lesion on 1 slice or a lesion that is present on at least 2 consecutive slices (Rudwaleit et 
al, 2009d). In practice this is very similar to the SI joint SPARCC score ≥2 definition of MRI 
that requires at least 2 BMO lesions to be present. A recent paper showed that the sensitivity and 
specificity of the ASAS/OMERACT and SI joint SPARCC score ≥2 definitions of MRI positive 
were identical (sensitivity 0.80, specificity 0.76) (Weber et al, 2014). The Berlin modification of 
the ASspiMRI-a is a scoring system with a concentration on short-tau-inversion recovery (STIR) 
sequences without other fat saturation techniques (Braun and Baraliakos, 2011; Lukas et al, 
2007; Braun and van der Heijde, 2002; Braun et al, 2003). This scoring method quantifies 
changes in 23 vertebral units (VU) of the spine (from C2 to S1). A VU is defined as the region 
between 2 virtual lines through the middle of each vertebra. Active inflammation is scored by 
REDACTED
co
uantity
uantity
ied 
ed by
by
tity). T
tity). 
y Hay
y Hay
i
COPY
s bee
be
none o
none o
ores 
ores 
This document
at
speci
speci
w
cannot
lesio
esi
009d).
09d).
t requ
requ
be
area
are
ion
ion
used
ance
nce
oedem
edem
as
as
to 
ce Im
ce I
support 
mp
m
ssess
ssess
any 
plete
plete
marketing 
yes a
yes a
sturban
turba
x II is 
II is
authorization 
of 
are tr
are tr
y subs
y subs
y the s
y the s
The p
The p
an
an
application 
d scale 
d scale
n exper
expe
f the t
the t
and 
e 5‒
any 
1
extensions 
he
he
e prob
e prob
ent’s s
nt’s s
ble hea
le he
or 
ealt
ealt
variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 84 of 255
grading the degree of BMO from 0 to 3 in 1 dimension on 1 or more consecutive slices that 
represent the highest level of inflammation in a particular VU. Total spine ASspiMRI-a score in 
the Berlin modification can range from 0 to 69. In addition to the method mentioned above, 
MRIs may be evaluated using other reading criteria.
Magnetic resonance imaging of the spine and SI joints will be performed at Screening and at the 
Week 12 and at the Week 52/WD visits if MRI was performed more than 12 weeks prior to 
Week 52/WD. A further MRI of the SI joints will be performed at Week 156/SFE-WD. 
Magnetic resonance images will be assessed centrally and scoring will be done by 2 independent 
readers, who are blinded to both the order of the scans and to the treatment group, using a 
previously reported scoring system.
9.1.13 
PGADA (NRS) 
Subjects will score their global assessment of their disease activity in response to the question 
“How active was your spondylitis on average during the last week?” using a NRS where 0 is 
“not active” and 10 is “very active” (van Tubergen et al, 2015) (see Appendix 18.9).
The PGADA assessments per visit are described in Table 5‒1, Table 5‒2, Table 5‒3, and 
Table 5‒6.
9.1.14 
PhGADA 
The Investigator will assess the overall status of the subject with respect to the axSpA signs and 
symptoms and the functional capacity of the subject using a VAS where 0 is “very good, 
asymptomatic and no limitation of normal activities” and 100 is “very poor, very severe 
symptoms which are intolerable and inability to carry out all normal activities.”
This assessment by the Investigator should be blinded.
The PhGADA will be completed as described in Table 5‒1, Table 5‒2, and Table 5‒3.
9.1.15 
Productivity measures (Work Productivity Survey) 
The WPS is an instrument used to assess productivity at work and within the home. The WPS 
has been found to be valid, reliable, and responsive to clinical changes in RA, PsA, and axSpA 
subjects (Osterhaus and Purcaru, 2014). 
Site personnel should obtain information from the subject in order to complete this survey. The 
WPS is a 9-question instrument used to assess
 One of the WPS questions concerns the 
.
 will be asked questions about the 
;
,
 on 
a 0 to 10 scale (0=no interference; 10=complete interference). In addition, all subjects regardless 
of their employment status will be asked questions 
;
 on a 0 to 10 scale (0=no interference; 10=complete interference).
The WPS assessments per visit are described in Table 5‒1.
REDACTED 
ubje
ubj
ctiviti
ctiviti
bility to
ility t
should
should
COPY 
he sub
he su
ect 
ect
This document
a 0 to
a 0 to
of
of
t anno
anno
ca
ot be
be 
b
used
tion
on
used
u
to 
ld o
n in
n in
support
 reli
reli
Purcar
Purca
obta
obt
any
d to a
d to 
iab
iab
marketing 
d b
escribe
scrib
asure
asure
authorization 
bjec
jec
using
using
ies” an
es” a
to carr
o car
be b
e b
application 
le
ect w
ct w
and 
ppe
pe
5‒
any
g a N
g a N
endix
end
extensions 
se to t
e to t
NR
NR
or 
a a 
variations 
enden
nden
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 85 of 255
9.1.16 
Resources utilization 
Study-specific questionnaires (standard CRF modules) will be used to capture data regarding 
resources utilization during the study, ie:
x Concomitant medical procedures
x Health care provider consultations not foreseen by the protocol
x Hospitalizations/emergency room visit
Site personnel should obtain information from the subject and also corroborate data with known 
AEs and SAEs in order to complete this survey as described in Table 5‒1. The recall period for 
the questionnaire will be the previous 4 weeks.
9.1.17 
SF-36 
The SF-36 (version 2, standard recall) is a 36-item generic HRQoL instrument that uses a recall 
period of 4 weeks. Items are grouped into 8 domains as follows: Physical Functioning (10 items), 
Role Physical (4 items), Bodily Pain (2 items), General Health (5 items),Vitality (4 items), Social 
Functioning (2 items), Role Emotional (3 items), Mental Health (5 items), and 1 item for 
perceived stability or change in health (Health Transition) during the last year. The concepts 
represented by these domains contribute to physical, mental, and social aspects of HRQoL.
In addition to domain scores, the PCS and MCS scores are calculated from the 8 domains 
(excluding the Health Transition item). Component scores appreciate the impact of each domain 
on physical and mental health status (Ware et al, 1994). Each of the 8 domain scores and the 
component summary scores range from 0 to 100, with a higher score indicating a better health 
status. The 2 component summary scores are standardized with a mean of 50 and a standard 
deviation (SD) of 10 in the general USA population. The MCIDs for SF-36 domains and 
component summaries are 5 and 2.5 points, respectively (Strand et al, 2005) (see 
Appendix 18.10).
The SF-36 has been used and has shown to be responsive in axSpA (Haibel et al, 2008) and is 
also validated (van Tubergen et al, 2015). The SF-36 will be administered per visit as described 
in Table 5‒1 and Table 5‒2.
9.1.18 
Spinal mobility 
In addition to the assessments performed for the BASMI, additional spinal mobility assessments 
include:
x Occiput to wall distance
x Chest expansion
Spinal mobility will be assessed as described in Table 5‒1 and Table 5‒2.
9.1.19 
Swollen and tender joint counts (44 joints evaluation) 
The following 44 joints are to be examined for swelling and tenderness by the Principal 
Investigator, another delegated physician, or an appropriately qualified medical professional 
(based on local requirements) who has had documented training on how to perform these 
assessments correctly. Preferably the same assessor should evaluate the subject at each arthritis 
assessment. 
REDACTED 
one
one
et al, 1
et al, 
0 to 10
0 to 10
ores a
ores ar
USA 
USA 
COPY 
me
me
cores 
ores
ent s
ent
This documen
Spin
pin
9.
9.
cannot 
putu
Chest e
hest e
nal
nal
be 
ut to 
ut to 
used
e ass
ass
to 
se
se
support 
en e
n e
‒2.
l mo
l mo
any
as sh
as s
et al
et a
marketing
popu
popu
points, 
points
ho
h
authorization 
are
are
scores
core
1994)
994)
00, wi
00, w
e stan
e stan
application
(5 ite
5 ite
ing the
ng th
l, and s
, and 
re cal
e ca
and 
calal
ms),V
ms),V
em
any
ment
men
l Fun
Fun
extensions
peri
per
nt t
nt t
or
kn
kn
riod
io
variations 
know
now
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 86 of 255
Upper body (4) – bilateral sternoclavicular, and acromioclavicular joints
Upper extremity (26) – bilateral shoulders, elbows, wrists (includes radiocarpal, carpal and 
carpometacarpal bones considered as a single unit), metacarpophalangeals (MCPs) I, II, III, IV, 
and V, and thumb interphalangeals (IPs), and proximal IPs (PIPs) II, III, IV, and V
Lower extremity (14) – bilateral knees, ankles, and metatarsophalangeals (I, II, III, IV, and V)
The assessment for swelling and tenderness is made on 44 joints from the above list. Artificial 
and ankylosed joints are excluded from swelling and tenderness assessments.
The assessments per visit are described in Table 5‒1 and Table 5‒2.
Table 9‒1: 
Swelling and tenderness grading 
Grade
Swelling response (44)
Tenderness response (44)
0
None
None
1
Swelling present
Tenderness present
9.1.20 
Total and nocturnal spinal pain NRS 
The pain experienced by AS subjects is adequately measured by 2 separate questions: 1) total 
pain in the spine due to AS (ie, “How much pain of your spine due to spondylitis do you have?”); 
and 2) pain in the spine at night due to AS (ie, “How much pain of your spine due to spondylitis 
do you have at night?”) (Sieper et al, 2009; van der Heijde et al, 2005; CPMP/EWP/556/95). 
Usually, a 10% difference (ie, a 1 point difference on a NRS ranging from 0 to 10) is considered 
the MCID used to interpret scores (Dworkin et al, 2008). Pain experienced by axSpA subjects 
has also been measured with this assessment (Haibel et al, 2008) and is validated (van Tubergen 
et al, 2015) (see Appendix 18.11).
The pain NRS assessments per visit are described in Table 5‒1, Table 5‒2, Table 5‒3, and 
Table 5‒6.
10 
ASSESSMENT OF PHARMACOKINETICS, EXPLORATORY 
BIOMARKERS, AND PHARMACOGENOMICS VARIABLES 
Plasma samples for the measurement of CZP concentrations will be taken at Baseline and 
Weeks 1, 2, 4, 12, 24, 36, 52/WD, and at the FU visit (8 weeks after the Week 52/WD visit). 
These plasma samples may be used additionally for analyses of CZP and its constituent moieties 
using alternative methods and the results of those analyses may be reported separately.
These plasma samples may be used for possible analyses of exploratory biomarkers which might 
include, but are not limited to: MMP-3, BMP-2, -4 and -7, WNT1, WISP, Gremlin, DKK1, 
Sclerostin, Hedgehog proteins (Shh, Ihh, Dhh), Collagen turnover/cleavage products, collagen 
type X, VEGF, citrullinated vimentin fragments, cytokines: IL13, IL17 A and F, IL23, IL34, 
(TGF-β, M-CSF, GM-CSF, CSF-1, sCSF1r levels. The results of the analyses of CZP and its 
constituent moieties from alternative methods may be reported separately.
For subjects participating in the optional substudy, blood samples will be drawn for possible 
genetics/epigenetics, genomic, proteomics and metabolomic analysis at Baseline and Week 12, 
ain o
in 
ie, “H
ie, “H
09; van
9; van
nt diff
nt dif
Dwor
Dwor
COPY 
NR
NR
ly mea
ly me
of y
of
This document
he
inclu
nclu
Sc
S
cannot
asm
sm
altern
ltern
ese p
se p
be 
4,
ma s
ma s
sed
s for t
for 
, 12,
12
to
OM
OM
support 
SSM
SSM
MAR
MAR
any
visit
vis
marketing
rkin e
rkin 
essmen
ssmen
t a
authorization
asur
sur
your s
your 
How m
ow m
an der 
n der 
erenc
renc
application
Ten
Te
atio
t
ured 
red
and 
ne
an
any 
ny extensions 
s resp
res
en
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 87 of 255
and for genomic, proteomics, and metabolomic analysis only, at Week 4 and Week 52/WD to 
enable exploratory evaluation of biomarkers relative to drug treatment, disease biology and 
inflammatory and immune response processes. 
Samples will be moved from the Central Laboratory (ACM) at the end of the study to a 
long-term storage facility - BioStorage Technologies, GmbH - and will be stored at -80°C at a 
central biorepository for up to 20 years.
11 
ASSESSMENT OF IMMUNOGENICITY VARIABLES 
Plasma samples for the measurement of anti-CZP antibodies and potentially neutralizing 
antibodies will be taken at Baseline and Weeks 1, 2, 4, 12, 24, 36, 52/WD, and the FU visit 
(8 weeks after the Week 52/WD visit). 
The sampling, handling, and shipment of samples will be performed as detailed in the Laboratory 
Manual.
12 
ASSESSMENT OF SAFETY 
Safety variables to be assessed are physical examinations, AEs, vital signs, and measurements of 
laboratory parameters. 
Adverse events will be solicited at every visit, and recorded and coded according to the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA®) criteria.
Physical examination findings will be recorded in the CRF only at Screening. Clinically 
important abnormal changes in subsequent physical examinations will be recorded as AEs at all 
visits from Baseline to the FU visit.
Clinical laboratory values (hematology, biochemistry, urinalysis) will be collected and assessed 
at Screening, Baseline, Weeks 2, 4, 8, 12, 24, 36, at the end of study completion at Week 52/WD 
visit and at the FU visit (8 weeks after the Week 52/WD visit). In addition, clinical laboratory 
values will be collected and assessed at study visits during the administration of open-label CZP 
in subjects who withdraw from the double-blind study treatment.
Furthermore, CRP will be collected and assessed either in a blinded or open manner at 
Screening, 3 to 5 days before Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 
at the end of study completion at Week 52/WD visit and at the FU visit (8 weeks after the 
Week 52/WD visit).
At Screening, all subjects will have an IGRA test (QuantiFERON® TB test or Elispot®test, when 
the QuantiFERON test indicated is not available), and a chest x-ray reading (or, if done, 
computed tomography of the chest) which must be reported consistent with standard clinical 
reporting practice by an experienced qualified TB specialist, radiologist, or a pulmonologist, who 
is specifically required to look for signs of active TB or signs of past/inactive TB infection. A 
chest x-ray will not be done at Screening if a chest x-ray (or computed tomography of the chest) 
was done within 3 months prior to the Screening visit. The official report of the imaging must
specifically indicate the absence of findings suggestive of current active TB or prior inactive TB. 
In addition to a physical examination done intermittently throughout the study, subjects will be 
evaluated at Screening, Baseline, and every 12 weeks thereafter up to Week 36 and including the 
Week 52/WD visit, for signs and symptoms of LTB or active TB infection and risk factors for 
exposure to TB using the TB questionnaire.
REDACTED
d in 
d in
physic
physic
ogy, bi
ogy, bi
8 1
8
COPY 
cord
cor
Activit
Activi
n th
n th
This document
s sp
sp
ches
ches
w
cannot
ted to
ed to
orting 
ting 
pec
pec
be
g,
FER
FER
used 
sit).
t)
all s
all s
to 
com
)
support
 colle
colle
before 
efore
mple
mple
any
m the 
m the
marketing
ioch
och
12, 24,
2, 24,
ter the 
er the
sed at
sed a
d
authorization 
iti
he CR
e CR
cal ex
al ex
chem
he
application
ital s
al 
d and c
and 
ies (M
es (M
and 
sig
sig
any extensions
U vi
U vi
ed in t
d in t
or 
g
si
variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 88 of 255
12.1 
Adverse events 
12.1.1 
Definition of adverse event 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an IMP, 
whether or not related to the IMP. 
If a surgical procedure is performed during the study participation, the underlying condition 
should be reported as the AE (eg, “appendicitis” is the AE resulting in appendectomy).
The following laboratory values and physical findings are also to be considered AEs:
x Laboratory value(s) that are out of reference range AND of clinical relevance, excluding 
Screening values
x Laboratory value(s) that change from a subject’s Baseline AND are of clinical relevance
x Pre-existing physical findings (including vital sign measurements) that worsen compared 
with Baseline AND that are “clinically important”
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
signing the informed consent form), including any Screening and FU Periods required by the 
protocol, must be reported in the CRF even if no IMP was administered but specific study
procedures were conducted. This includes all AEs not present prior to the Screening visit and all 
AEs which recurred or worsened after the Screening visit. 
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
Investigator from the subject’s history or the Baseline Period.
12.1.2 
Procedures for reporting and recording adverse events 
The subject will be given the opportunity to report AEs spontaneously. A general prompt will 
also be given at each study visit to detect AEs. For example:
“Did you notice anything unusual about your health (since your last visit)?”
In addition, the Investigator should review any self assessment procedures (eg, questionnaires) 
employed in the study.
12.1.3 
Description of adverse events 
When recording an AE, the Investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The CRF and 
source documents should be consistent. Any discrepancies between the subject’s own words on 
his/her own records (eg, diary card) and the corresponding medical terminology should be 
clarified in the source documentation.
Details for completion of the Adverse Event CRF (including judgment of relationship to study 
drug) are described in the CRF Completion Guidelines.
REDACTED 
no I
no 
ll AEs
ll AE
e Scre
e Scre
diseas
diseas
cha
cha
COPY
l AE
l AE
y Scre
y Scr
IM
IM
This document
stan
tand
so
so
cannot 
en re
en re
be
in th
in th
used 
ou
ou
he Inv
e Inv
he
h
to
u no
u no
support 
n the op
the o
study v
udy v
ti
any 
for re
or r
marketing 
se f
e f
anges c
nges 
manner
anne
story o
tory 
authorization
eeni
eni
MP was
P wa
s not p
 not p
eening
eening
for 
for
application
ments)
ments
s occur
occu
ning 
ing
and
are of
re of
)
any 
f c
f
extensions 
y).)
AEs:
AEs:
ance, 
ance, 
or
ion
ion
variations 
MP, 
P,
n
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 89 of 255
12.1.4 
Follow up of adverse events 
An AE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up. 
If an AE is still ongoing at the end of the study for a subject, follow up should be provided until 
resolution/stable level of sequelae is achieved, or until the Investigator no longer deems that it is 
clinically significant, or until the subject is lost to follow up. If no follow up is provided, the 
Investigator must provide a justification. The follow up will usually be continued for 70 days 
after the subject has discontinued his/her IMP.
12.1.5 
Rule for repetition of an adverse event 
An increase in the intensity of an AE should lead to the repetition of the AE being reported with:
x The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening”
x The AE verbatim term being the same for the first AE and AE verbatim term repeated 
including worsening, so that the repeated AE can be easily identified as the worsening of the 
first one
12.1.6 
Pregnancy 
If an Investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the Investigator must immediately notify UCB’s Drug Safety (DS) department by providing the 
completed Pregnancy Report and Outcome form (for contact details see Serious Adverse Event 
reporting information at the beginning of this protocol). The subject should be withdrawn from 
the study as soon as the pregnancy is known (by positive pregnancy test), and the following 
should be completed:
x The subject should return for an Early Withdrawal Visit.
x The subject should immediately stop the intake of the IMP. 
x A FU visit should be scheduled 8 weeks after the Week 52/WD visit.
The Investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives.
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
Investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed up using the Pregnancy Report and Outcome form upon which the Investigator has to 
report the health of the mother and of the child. Every reasonable attempt should be made to 
follow the health of the child for 30 days after birth for any significant medical issues. In certain 
circumstances, UCB may request that follow up is continued for a period longer than 30 days. If 
the subject is lost to follow up and/or refuses to give information, written documentation of 
attempts to contact the subject needs to be provided by the Investigator and filed at the site. 
UCB’s DS department is the primary contact for any questions related to the data collection for 
the pregnancy, eventual birth, and follow up.
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, the 
Investigator or designee is asked to contact the subject to request consent of the partner via the 
Partner Pregnancy Consent form that has been approved by the responsible IRB/IEC and should 
REDACTED 
s D
s 
form (
form (
f this p
this p
know
known
COPY 
ome p
ome 
Dru
Dru
This document 
rcu
c
the s
the s
atat
annot
he he
e he
w the 
the 
ums
ums
be
p us
p us
ea
ea
used
will b
ill 
The pr
The p
ini
to 
be
be
support 
he
nform 
form
eatme
eatm
any 
ele
duled
dule
marketing 
Early W
Early 
ly sto
ly st
authorization 
pre
ug Saf
g Saf
(for co
for co
protoc
protoc
n (by p
(by p
application 
ntif
egnan
gna
and
rbatim
bati
ified
fied
any
seni
sen
m
extensions 
g repo
g repo
of the 
f the 
ini
or variations 
s 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 90 of 255
be available in the Investigator site file. In case of questions about the consent process, the 
Investigator may contact the UCB/CRO contract monitor for the study. The Investigator will 
complete the Pregnancy Report and Outcome form and send it to UCB’s DS department (for 
contact details see Serious Adverse Event reporting information at the beginning of this protocol) 
only after the partner has agreed that additional information can be captured and has provided the
signed Partner Pregnancy Consent form. UCB’s DS department is also the primary contact for 
any questions related to the data collection for the partner pregnancy, eventual birth, and follow 
up.
A pregnancy becomes an SAE in the following circumstances: miscarriage, therapeutic abortion, 
and unintended pregnancy after hormonal contraceptive failure (if the hormonal contraceptive 
was correctly used), ectopic pregnancy, fetal demise, or any congenital anomaly/birth defect of 
the baby. Those SAEs must be additionally reported using the Investigator SAE report form.
Should a subject become pregnant while participating in the study, the subject may be offered the 
option to enroll in a separate observational pregnancy follow-up study sponsored by UCB and 
conducted independently from study AS0006. If the study is available locally, the AS0006 
Principal Investigator will be provided with the locally approved information about the 
observational pregnancy follow-up study to inform the subject at the time the pregnancy is
reported. Participation in this separate study will be voluntary and will not impact therapeutic 
management of the subject nor interfere with termination and follow-up procedures as described 
in study protocol AS0006.
12.1.7 
Overdose of investigational medicinal product 
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the appropriate CRF module and drug accountability forms. Any SAE or nonserious 
AE associated with excessive dosing must be followed as any other serious or nonserious AE. 
These events may be symptomatic, in that the excessive dosing results in clinical signs and 
symptoms, or the excessive intake may itself be a symptom.
12.1.8 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible.
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the DS representative.
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
signs, laboratory or ECG results) for which data will be periodically reviewed during the course 
of the study.
12.2 
Serious adverse events 
12.2.1 
Definition of serious adverse event 
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria:
x Death
REDACTED
nal m
nal m
d in th
d in th
ule an
ule an
g mu
g mu
COPY
nation
ation
This document
of th
of th
1
cannot 
opri
pr
cally q
ally q
ns, lab
s, lab
be 
p
riate
riate
used
ician
cian
perfo
perfo
to 
s/I
n o
support
udy w
dy w
ed to th
d to th
/IECs
IECs
any
dete
det
wil
marketing
ust be 
ust be
n that th
that 
may it
may 
ec
authorization 
medic
medic
he pro
e pro
d dru
dru
application
infor
nfo
at the t
at the
ry and 
y and
and fo
and f
and
p
le loc
loc
orm
orm
any 
ect
ec
onsor
onso
l
extensions
trace
race
birth d
rth d
E repo
E repo
ct m
t m
o
abo
abo
ep
variations 
w 
w 
ort
ort
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 91 of 255
x Life-threatening
Life-threatening does not include a reaction that might have caused death had it occurred in a 
more severe form.
x Significant or persistent disability/incapacity
x Congenital anomaly/birth defect (including that occurring in a fetus)
x An important medical event that, based upon appropriate medical judgment, may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the definition of serious.
Examples of important medical events may include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias that do not result in 
inpatient hospitalization, infections that require treatment with parenteral antibiotics or the 
development of drug dependency or drug abuse.
Confirmed active TB is an SAE and must be captured on an SAE report form and provided to 
the Sponsor in accordance with SAE reporting requirements. As with all SAEs, periodic 
follow-up reports should be completed as per protocol requirements until such time as the TB 
infection resolves.
x Initial inpatient hospitalization or prolongation of hospitalization
A subject admitted to a hospital, even if he/she is released on the same day, meets the criteria 
for the initial inpatient hospitalization. An emergency room visit that results in admission to 
the hospital would also qualify for the initial inpatient hospitalization criteria. However, 
emergency room visits that do not result in admission to the hospital would not qualify for 
this criteria and, instead, should be evaluated for 1 of the other criteria in the definition of 
serious (eg, life-threatening adverse experience, important medical event).
Hospitalizations for reasons not associated with the occurrence of an AE (eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner) do not qualify for reporting. For example, if a 
subject has a condition recorded on his/her medical history and later has a preplanned surgery 
for this condition, it is not appropriate to record the surgery or hospitalization as an SAE, 
since there is no AE upon which to assess the serious criteria. Please note that, if the 
pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this would then qualify as an AE and, if necessary, the seriousness of the event would need to 
be determined.
Hospitalization for diagnostic or therapeutic procedures in the absence of any associated AE 
will not be considered as an SAE, except when otherwise required by regulatory authorities. 
If a hospitalization is planned prior to the subject receiving the first dose of IMP (at Week 0),
it will not be classified as either an AE or SAE. This also applies to a scheduled elective 
surgery where no AE is present. A noncomplicated, preplanned elective surgery will not be 
considered an AE or SAE even if it involves hospitalization. However, if a hospitalization is 
unplanned or is a result of an AE, this will be considered to be an SAE.
REDACTED
e/she
e/sh
An em
An em
he init
e ini
t resul
resu
be e
be e
COPY 
n of ho
of ho
he i
he i
This document
I
cannot 
e
Hospita
ospita
will 
will 
be 
uld
rmin
rmin
sed
g cond
cond
d the
the
to
o AE
o A
support
racte
acte
on rec
on rec
it is n
it is 
E
any
for a
for 
eris
eri
marketing
lt 
evalua
evalua
rse exp
se ex
ot ass
ot as
authorization 
osp
is rele
s rele
mergen
mergen
tial inp
al in
in a
in a
application
As w
s w
uiremen
reme
spitali
pitali
and
E repo
repo
wit
wi
any 
t
extensions 
uiring
uiring
do not
o not
antibi
antibi
or variations 
dize
ize 
of the
f the
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 92 of 255
12.2.2 
Procedures for reporting serious adverse events 
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting 
section at the front of the protocol). The Investigator must forward to UCB (or its representative) 
a duly completed “Investigator SAE Report Form for Development Drug” (SAE report form) 
provided by UCB, even if the data are incomplete, or if it is obvious that more data will be 
needed in order to draw any conclusions. Information recorded on this form will be entered into 
the global safety database.
An Investigator SAE report form will be provided to the Investigator. The Investigator SAE 
Report form must be completed in English. 
It is important for the Investigator, when completing the SAE report form, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This insight 
from the Investigator is very important for UCB to consider in assessing the safety of the IMP 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner.
Additional information (eg, autopsy or laboratory reports) received by the Investigator must be 
provided within 24 hours. All documents in the local language must be accompanied by a 
translation in English, or the relevant information included in the same document must be 
summarized in the Investigator SAE report form.
The Investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the Investigator is certain that they are in no way associated with the IMP), up to 
30 days from the end of the study for each subject (which is usually the FU visit), and to also 
inform participating subjects of the need to inform the Investigator of any SAE within this 
period. Serious AEs that the Investigator thinks may be associated with the IMP must be reported 
to UCB regardless of the time between the event and the end of the study.
Upon receipt of the SAE report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the current version of 
the CZP Investigator Brochure (IB).
12.2.3 
Follow up of serious adverse events 
An SAE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up. 
Information on SAEs obtained after clinical database lock will be captured through the DS 
database without limitation of time.
12.3 
Adverse events of interest 
An AE of interest is any AE which is listed in the European Risk Management Plan, or meets 
another commitment requiring nonstandard expedited reporting, even if the AE does not fulfill 
the expedited reporting criteria of “serious,” “unexpected,” and “associated with the use of the 
drug.” Adverse events of interest include: 
x Serious infections including opportunistic infections
x Malignancies including lymphoma
REDACTED
collec
collec
hat the
at the
ach su
ach su
need to
need t
gato
gato
COPY
clude
clud
This document 
An A
An A
an
an
cannot
e wit
wi
3
be
n on
n on
thth
used 
e f
e 
t it is 
it is 
S
to
foll
foll
support
chure 
hure
w up o
w up o
any 
for
fo
t of th
t of t
(
marketing
o in
o in
or thin
or thin
een the
en th
orm, U
rm,
authorization 
t and r
t and 
ey are 
y are 
ubject 
bject
info
nfo
application 
ved by
ved b
ge mus
ge mu
d in th
d in th
and 
ry a
y a
any
he sa
he s
auth
aut
extensions 
r S
nclude
clude
stratio
tratio
f
or
SAE
AE
variations 
to
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 93 of 255
x Congestive heart failure
x Demyelinating-like disorders
x Aplastic anemia, pancytopenia, thrombocytopenia, neutropenia, and leucopenia
x Serious bleeding events
x Lupus and lupus-like illness
x Serious skin reactions (eg., Stevens Johnson Syndrome, toxic epidermal necrosis, and 
erythema multiforme)
Note : Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total 
bilirubin in the absence of ≥2xULN ALP, with no alternative explanation for the biochemical 
abnormality, must ALWAYS be reported to UCB as an AE of interest (ie, without waiting for 
any additional etiologic investigations to have been concluded). Follow-up information should 
then be reported if an alternative etiology is identified during investigation and monitoring of the 
subject.
12.4 
Immediate reporting of adverse events 
The following AEs must be reported immediately:
x SAE: AE that the Investigator classifies as serious by the above definitions regardless of 
causality
x Suspected transmission of an infectious agent via a medicinal product
x AE of interest (see Section 12.3)
12.5 
Laboratory measurements 
Hematology, biochemistry, urinalysis, and CRP samples will be taken at Screening, Baseline, 
Weeks 2, 4, 8, 12, 24, 36, 52/WD, and at the FU visit (8 weeks after the Week 52/WD visit). 
Testing to rule out hepatitis B, hepatitis C, and HIV will be performed at Screening as well as the 
HLA-B27 antigen determination. Subjects will be encouraged to be in fasting condition at 
Baseline and at Week 52/WD or at the time the subject shifts to alternative treatment, for 
Apo A1, ApoB, and lipoprotein(a) assessments.
The urinalysis will be performed with a dipstick, and in case of a positive outcome, on a clean 
catch urine sample sent to the central laboratory for analysis. 
The central laboratory will analyze and assess blood and urine samples for the following (except 
where indicated):
Table 12‒1: Laboratory measurements up to Week 52 (including the FU visit 
(8 weeks after the Week 52/WD visit) 
Hematology
Serum biochemistry
Urinalysis
Others
Red blood cells
Sodium
pH
Hemoglobin
Potassium
Protein
Hepatitis B surface 
antigen
REDACTED 
agent
agent
sure
sure
COPY 
ous by
ous by
This document 
Ta
Ta
m
cannot
indic
ndic
able
ble
be
l lab
l lab
used 
ill b
l b
mple s
mple s
to 
be p
be
support
natio
atio
2/WD o
/WD
ipopro
popro
any
hepa
hep
ion. 
on
marketing
emen
eme
is, and
s, an
, and a
and
t
authorization 
y 
t via a
via a
application 
the a
the a
and any 
inf
in
on and
n an
extensions
LN to
LN to
e bioch
bioch
thout w
hout 
nfor
for
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 94 of 255
Table 12‒1: Laboratory measurements up to Week 52 (including the FU visit 
(8 weeks after the Week 52/WD visit) 
Hematology
Serum biochemistry
Urinalysis
Others
Hematocrit
Chloride
Glucose 
Antibodies to 
hepatitis C
Platelets
Bicarbonate
Blood
Antibodies to HIV
White blood cells
Total calcium
Esterase 
HLA-B27
Neutrophils
Inorganic phosphorus
Lymphocytes
CRP
Monocytes
Creatine phosphokinasea
Eosinophils
Glucose
Microscopy (WBC, 
RBC, casts, crystals, 
bacteria) (Microscopy 
will be performed only 
when there are 
abnormalities on 
dipstick)
Basophils
Creatinine
Urine-sample to be 
collected for 
central-laboratory 
analysis only when 
there are abnormalities 
on dipstick
Uric acid
Urea
Total protein
Albumin
Alkaline phosphatase
Aspartate 
aminotransferase 
Alanine aminotransferase 
Bilirubin
Total cholesterol
HDLb
D
ED COPY
hen t
hen 
abno
abno
did
C
This document 
nt
m
cannot 
ot be used 
us
to 
to support 
rea
ea
To
To
pp
su
any 
d
a
marketing 
ma
authorization 
rma
m
ipstick
pstick
Uri
Uri
at
ho
application 
stals, 
tals
croscop
rosco
rformed
forme
here are
re ar
maliti
aliti
and 
, 
d any y
a
extensions 
ns
ten
e
or variations 
on
V
tio
v
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 95 of 255
Table 12‒1: Laboratory measurements up to Week 52 (including the FU visit 
(8 weeks after the Week 52/WD visit) 
Hematology
Serum biochemistry
Urinalysis
Others
LDLb
HbA1cc
Apo A1
ApoB
Lipoprotein(a) 
Apo=Apolipoprotein; CRP=C-reactive protein; FU=Follow-Up; HbA1c=glycated hemoglobin; HDL=high density 
lipoprotein; HIV=human immunodeficiency virus; HLA-B27=human leukocyte antigen B27; LDL= low-density 
lipoprotein; RBC=red blood cells; WBC=white blood cells; ULN=upper limit of normal 
a Creatine phosphokinase subtypes (CK-MM; CK-MB, and CK-BB) are required if the creatine phosphokinase 
measurement is >2 ULN.
b HDL and LDL are to be measured every 6 months and at the time the subject shifts to open-label CZP.
c HbA1c is to be measure at Baseline and Week 52/WD or at the time the subject shifts to open-label CZP.
For subjects participating in the SFE Period after Week 52, it is recommended that laboratory 
assessments be performed at the local laboratory at the discretion of the Investigator according to 
local standard medical practice to evaluate potential AEs. At Week 156/SFE-WD, a blood 
sample will be taken for CRP measurement and analyzed at the central laboratory.
12.6 
Other safety measurements 
12.6.1 
Pregnancy testing 
Pregnancy testing must be carried out for women of childbearing potential and will consist of 
serum testing at Screening and FU and urine testing (dipstick) at Baseline, at wdt Week 0 of the 
alternative study assessment (for subjects administering either open-label CZP or alternative 
treatment), and at Week 52/WD. 
For subjects participating in the SFE Period after Week 52, it is recommended that pregnancy 
testing be performed according to local standard medical practice.
12.6.2 
Physical assessments 
Physical examination will be performed at Screening, Baseline, Weeks 2, 4, 8, 12, 16, 24, 36, 
52/WD, and at the FU visit (8 weeks after the Week 52/WD visit for subjects not participating in 
the SFE Period). It is recommended that physical examinations be performed according to local 
standard medical practice for subjects participating in the SFE Period after Week 52,
Physical examination findings will be recorded in the CRF only at Screening. Clinically 
important abnormal changes in subsequent physical examinations will be recorded as AEs. 
Physical examinations must be documented in source documentation.
The following body systems will be examined:
x General Appearance
REDACTED
ory a
ry 
potent
potent
ent an
ent an
asure
asure
COPY 
he t
e 
Week
Wee
at t
at
This document
stand
tand
Ph
P
cannot 
ex
ex
D, and
D, and
SFE P
SFE 
d
be 
xam
xam
used 
med
med
Phy
Phy
to
at
ed ac
d a
support
nt (f
t (f
52/WD
2/W
ting i
ing i
any
FU 
FU
for s
for
marketing
eme
m
out fo
out f
an
authorization
k 52
52
the di
he di
tial A
al A
nd ana
d ana
men
men
application
red i
ed 
subject 
subject
 the
the su
su
2, it
2 it
and 
tige
ge
f norma
norma
if t
if t
any
oglob
oglob
en B2
en B
y extensions s
ns
e
or variations 
on
on
on
on
va
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 96 of 255
x Ear, nose and throat
x Eyes
x Hair and skin
x Respiratory
x Cardiovascular
x Gastrointestinal
x Musculoskeletal
x Hepatic
x Neurological (including limb reflexes)
x Mental Status
In addition, the TB signs and symptoms will be assessed at Screening, Baseline, Weeks 2, 4, 8, 
12, 16, 24, 36, completion at Week 52/WD visit and FU (8 weeks after the Week 52/WD visit for 
subjects not participating in the SFE Period).
Weight is to be measured at Screening, Week 24, and at completion at Week 52/WD. Height will 
be measured at the Baseline visit only.
12.6.3 
Assessment and management of TB and TB risk factors 
As TNFi are known to be associated with significant risk of reactivation of LTB, appropriate 
rigorous precautions are being taken within the protocol to address this (see Section 6.2
[Exclusion Criterion 16] and Section 6.3 [Withdrawal Criterion 6]).
Signs and Symptoms
The Investigator should consider all potential sites of infection when assessing for TB during the 
subject’s history and the physical examination, and other evaluations. Sites commonly infected 
by TB include: the lungs, larynx, lymph glands, pleura, gastrointestinal system, genito-urinary 
tract (including renal), bones and joints, meninges, peritoneum, pericardium, and skin. This is 
not an exhaustive list and unusual presentations and areas of involvement should always be 
considered. 
Common symptoms that the subject may present with include cough, blood in sputum, night 
sweats, lymphadenitis, joint pain/swelling, spinal deformity, headache/confusion, abdominal 
pain mimicking IBD, frequent or painful urination, scrotal mass in men and pelvic inflammatory 
disease in women as well as other symptoms, or nonspecific symptoms. This is not an exhaustive 
list and unusual presentations should always be considered.
The subject may present an absence of signs, symptoms (ie, evidence of organ-specific 
involvement), or physical findings suggestive of TB infection with a positive IGRA test (or 
2 indeterminate IGRA test results) and a chest x-ray (or other imaging) without evidence of TB 
infection. If the result of the IGRA test is indeterminate, the particular IGRA test previously 
performed may be repeated once; if positive or indeterminate on retest, the subject may not be 
randomized to study medication without further evaluation, treatment, and discussion with Study 
Physician, if LTB infection is identified. (If active TB is identified, subject must undergo 
REDACTED 
men
men
signifi
signifi
thin th
thin th
6.3
6.3 [W
[
COPY 
at 
a
nt o
nt
This document
The 
The 
inin
cannot 
micic
e in w
e in w
and u
and u
be 
pha
p
cking
ckin
used
ptoms
toms
hade
ade
to support 
ryn
y
ones an
nes a
and un
nd un
any
al ex
al e
nx, l
nx, l
marketing 
Wi
W
all pote
ll po
exa
ex
authorization 
of TB
of TB
ficant r
cant r
he
he pro
pro
Withd
ithd
application 
afte
aft
mpletio
mplet
and
g, Ba
, Ba
fter t
er
any 
se
extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 97 of 255
appropriate study-specified withdrawal procedures.) The retest must be done during the 
protocol-defined Screening window.
Note: If available, respiratory or other specimens must also be smear and culture negative for TB 
(CDC diagnosis of LTB infection [http://www.cdc.gov/TB/topic/testing/default.htm]).
Test Conversion
Tuberculosis test conversion is defined as a positive result (IGRA) for the current test but 
previous test results were negative (IGRA). All subjects with TB test conversion must 
immediately stop study drug administration. In case of a TB test conversion, the subject must be 
considered as having either a suspected new LTB or an active TB infection and be promptly 
referred to an appropriate specialist (ie, pulmonologist, infectious disease specialist) must be 
consulted for further evaluation. If test conversion indicates LTB infection, active TB, or 
nonmycobacterial TB infection then per UCB TB working instructions, TB test conversion 
(confirmed) should be classified as due to LTB infection, active TB infection, or NTMB 
infection. Additional assessments (eg, blood tests or IGRA test, chest x-rays or other imaging) 
should be performed as medically indicated.
Latent TB
In case the evaluation by the appropriate specialist indicates a new LTB infection, a prophylactic 
TB treatment (as described in Section 6.2, Exclusion Criterion 16) should be initiated and study 
medication can be continued no sooner than 4 weeks after start of prophylactic TB treatment, if it 
is deemed likely that prophylactic TB treatment is continued to completion by the Investigator.
If prophylaxis is not initiated, the subject must to be withdrawn. 
Every action should be discussed in advance with the Medical Monitor. Latent TB must be 
reported as an SAE.
Active TB/NTMB
Subjects who develop active TB or NTMB infection during the study (conversion demonstrated 
by IGRA) must be immediately discontinued from study medication, and a withdrawal visit must 
be scheduled as soon as possible, but not later than the next regular visit. The subject should be 
encouraged to keep the FU visit (8 weeks after the Week 52/WD visit for subjects not 
participating in the SFE Period). The TB must be documented as an SAE. Treatment for TB 
should be started based on local guidelines.
Note that subjects with history of or active NTMB infection are excluded from the study 
regardless of prior or current therapy.
Confirmed active TB is an SAE and an adverse event of special interest (AESI) and must be 
captured on an SAE report form and provided to the Sponsor in accordance with SAE reporting 
requirements. As with all SAEs, periodic follow-up reports should be completed as per protocol 
requirement until such time as the TB infection resolves. 
Subjects who prematurely discontinue treatment for LTB, or, in the opinion of the Investigator or 
Sponsor, are noncompliant with anti-TB therapy must discontinue further use of study 
medication and be immediately withdrawn. Once withdrawn from study treatment, subjects not
participating in the SFE Period should return for the Week 52/WD visit, complete all 
Week 52/WD assessments, and complete a FU visit (8 weeks after the Week 52/WD visit).
REDACTED
ent is
ent is
t must 
must
advan
advan
COPY 
dicic
on Cri
on Cri
eeks a
eeks 
This document
aptpt
requi
requi
rere
cannot 
s o
s 
firmed
rmed
tured
ure
be 
bjej
of p
of p
used
d bas
ba
ects
ects
to
SFE
SF
ase
se
support 
tele
possibl
ossib
e FU v
FU 
FE P
E P
any
B or 
B or
ly di
y di
marketing 
nce 
ce
r N
r N
authorization
after 
after 
contin
conti
t toto be
be
e wi
wi
application 
s a new
a ne
erion 
erion
t
and 
x-rara
any
ion, 
ion,
ays 
ays
extensions
omp
omp
st) mu
t) mu
ve TB
ve TB
est co
est co
or
mu
mu
ptl
ptl
variations 
ust
ust
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 98 of 255
12.6.3.1 
Tuberculosis assessments 
During conduct of the study the TB assessment by IGRA will be performed at Screening and 
should be repeated at Week 52/WD for all subjects not participating in the SFE Period. It is 
recommended that TB testing be performed according to local standard medical practice during 
the SFE Period. 
The test results will be reported as positive, negative, or indeterminate and must be reviewed by 
an experienced TB specialist, radiologist, or a pulmonologist. If the assessment by IGRA is 
positive or indeterminate on retest for subjects who were previously negative at Screening and 
not treated for LTB, the subject may not continue study treatment without further evaluation by a 
TB specialist, prophylactic TB treatment, and discussion with the Medical Monitor, if LTB 
infection is identified. If active TB is identified, subject must undergo appropriate study 
specified withdrawal procedures. The retest must be done during the protocol-defined Screening 
window.
12.6.3.2 
Chest x-ray 
A plain posteroanterior chest x-ray must be done at Screening unless a chest x-ray (or a 
computed tomography of the chest) has been done within 3 months prior to the Screening visit. 
The chest x-ray must be clear of signs of TB infection (previous or current) before first study 
drug administration. For subjects not participating in the SFE Period the chest x-ray will be 
repeated at Week 52/WD visit (if chest x-ray was performed more than 12 weeks prior to 
Week 52/WD visit), only if the TB test was confirmed positive or any further evidence is 
suggestive of potential TB infection (eg, exposure). It is recommended that the chest x-ray be 
repeated for subjects participating in the SFE Period, if the TB test was confirmed positive or 
any further evidence is suggestive of potential TB infection (eg, exposure). Radiographic 
findings suggestive of inactive TB or active TB may include but are not limited to: apical 
fibrosis, pleural thickening, pulmonary nodules, fibrotic scars, calcified granulomas, upper lobe 
infiltrates, cavitations and pleural effusions, calcified lung nodules, calcified hilar lymph nodes, 
and pericardial calcification.
The chest x-ray (or, if done, the computed tomography of the chest) must be negative for TB 
infection as determined by a qualified radiologist and/ or pulmonary physician. Any new 
clinically significant findings post-Baseline during physical exam or on chest x-ray must be 
documented in the source documents and CRF as an AE.
12.6.3.3 
QuantiFERON or Elispot testing 
At Screening all subjects will have an IGRA test (QuantiFERON tube test or Elispot, if 
QuantiFERON test indicated is not available). The TB test will be repeated at completion at 
Week 52/WD for subjects not participating in the SFE Period. It is recommended that TB testing 
be performed according to local standard medical practice during the SFE Period. Results of the 
tests will be reported as positive, negative, or indeterminate.
12.6.3.4 
Tuberculosis questionnaire 
The questionnaire 
” should be used as a 
source document. The questionnaire will be completed at Screening, Baseline, and every 
12 weeks thereafter including and up to Week 36 and including Week 52/WD visit. 
REDACTED
nfir
nfi
posure
posure
SFE P
SFE P
poten
potent
r act
r act
COPY
n the 
n the
 perfo
perf
irm
rm
This document 
e pe
e pe
tests
tests
cannot
FERO
ERO
ek 52/W
k 52/W
perf
erf
be
ng a
ng a
O
used 
Qua
Qua
l
to
sour
sou
support
, the
th
by a qu
by a q
finding
inding
rce
any 
he co
he c
marketing
tive T
tive T
ry nodu
ry nod
effusio
ffusi
authorization
orm
rm
med po
ed po
re). It i
). It i
Period
Period
ial TB
al TB
application 
ess 
nths pr
ths p
ous or 
ous o
SFE Pe
FE P
med 
med
and 
s a c
a c
any extensions
ua
, if LT
if LT
te stud
e stud
defin
defin
or
ation
tio
variations 
y y
and 
and 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 99 of 255
The questionnaire will assist with the identification of subjects who may require therapy for TB. 
A subject who answers “Yes” to the question “
 
 at Screening 
is excluded. A “Yes” response to any of the other questions within the questionnaire at Screening 
should trigger further careful assessment to determine if subject has LTB or active TB (see 
Exclusion Criterion 16, Section 6.2). A “Yes” response to any of the questions during the study 
should trigger further assessments to determine if the subject has either LTB or active TB 
infection (see Appendix 18.12).
Subjects with a LTB infection must receive prophylactic therapy prior to continuing study drug 
(if allowed by prophylactic therapy specific protocol).
Subjects with active TB infection must be withdrawn from the study and will have further 
assessments.
12.6.3.5 
Tuberculosis management 
For inclusion in the study, see Section 6.2 (Exclusion Criterion 16).
It is the Sponsor’s requirement that all subjects who are on LTB treatment at Baseline must 
comply with the full therapy course (see Section 6.2, Exclusion Criterion 16). 
LTB infection and active TB identified during study
During the study, subjects who develop evidence of LTB infection or active TB must 
immediately stop further administration of study medication and will be referred to an 
appropriate TB specialist (pulmonologist or infectious disease specialist) for further evaluation. 
Evidence of LTB infection is defined as subject’s IGRA test converts to positive or 
indeterminate (and confirmed indeterminate on repeat), or the subject’s questionnaire or history 
and physical indicates that TB infection or exposure may have occurred. Evidence of active TB 
includes, in addition to the aforementioned tests, signs and symptoms of organ involvement. In 
either situation, the subject should be carefully assessed by a TB specialist for active TB. 
Subjects diagnosed with active TB or LTB infection should receive appropriate TB or 
prophylaxis therapy. 
If a TB specialist excludes an active TB infection the subject can proceed with the study drug no 
earlier than 4 weeks after the start of an appropriate prophylactic therapy. 
Any presumptive diagnosis or diagnosis of a TB infection is a reportable event. Confirmed active 
TB must be reported as an SAE; confirmed LTB as AESI (please see Sections 12.2 and 12.3).
The Investigator is to complete and submit the TB follow up form provided.
The subject should be transferred to the care of his/her physician and managed according to the 
best available standard of care. Subjects identified as having converted to active TB during the 
study must be withdrawn and scheduled to return for the Week 52/WD visit as soon as possible 
but no later than the next scheduled study visit and complete all Week 52/WD visit assessments. 
The subject should be encouraged to complete a FU visit (8 weeks after the Week 52/WD visit).
If infection with NTMB is identified during the study, the same procedure as for active TB 
acquired during the study must be followed.
REDACTED
udy m
udy m
or infe
or infe
s subje
s subje
rminat
rminat
tion
tion
COPY 
udy
udy
PY
e of LT
of LT
m
This document
study
udy
but
but
cannot
ubject 
bject 
t avail
avai
y
be
igato
igato
used
e dia
e dia
eporte
porte
to 
ag
ag
support 
des an 
es an
after th
fter t
any
TB 
TB
marketing 
ate e 
n or ex
or ex
ntioned
ioned
d be ca
be c
or
authorization
LTB i
LTB i
medicat
edicat
ectious
ctiou
ect’s I
ct’s I
on 
on 
application
treatm
reat
n Crite
Crit
nf
and 
m
any extensions 
ve fur
ve fur
o
dy d
dy d
variations 
dru
dr
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 100 of 255
Subjects with LTB infection must not undergo IGRA testing. The IGRA test should be used for 
any protocol mandated monitoring.
Follow-up information of suspected and confirmed TB cases should be provided to UCB at least 
after 3, 9, and 12 months of the start date of anti-TB treatment, including hematological and 
biochemical safety parameters, x-ray evolution data, and TB diagnostic procedures used to 
follow up and confirm recovery of TB.
12.6.4 
Vital signs 
Subjects should be sitting for 5 minutes prior and during the collection of blood pressure, pulse 
rate, and respiration rate measurements. 
Vital signs, including temperature will be measured at all on-site visits including the FU visit 
(8 weeks after the Week 52/WD visit) with the exception of the Week 1 visit (respiration rate 
will be measured at Screening and Baseline only unless the subject has an AE). It is 
recommended that vital signs be measured according to local standard medical practice during 
the SFE Period. 
13 
STUDY MANAGEMENT AND ADMINISTRATION 
13.1 
Adherence to protocol 
The Investigator should not deviate from the protocol. However, the Investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
sponsor.
After implementation of such measure, the Investigator must notify the CPM of the Sponsor 
within 24 hours and follow any local regulatory requirements.
13.2 
Monitoring 
UCB (or designee) will monitor the study to meet the Sponsor’s monitoring Standard Operating 
Procedures (SOPs), ICH-GCP guideline, and applicable regulatory requirements, and to ensure 
that study initiation, conduct, and closure are adequate. Monitoring of the study may be 
delegated by UCB to a CRO or a contract monitor.
The Investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The Investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s).
The Investigator will allow UCB (or designee) to periodically review all CRFs and 
corresponding source documents (eg, hospital and laboratory records for each study participant). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of CRFs, ensure that all protocol 
requirements, applicable authorities’ regulations, and Investigator’s obligations are being 
fulfilled, and resolve any inconsistencies in the study records.
REDACTED
their
their
or noti
r noti
ure, th
ure, th
COPY 
col. H
col. H
ned by
ed b
This document
The 
The 
cor
cor
cannot 
cum
ume
ection
ction
I
be
form
form
used
r and
and
ng th
ng th
to 
o a
d h
d h
support
GCP g
CP 
nduct, 
nduct
a CR
a CR
any 
or the
or th
marketing
the In
he In
regulat
regula
authorization
y the 
y the
health
health
ificati
ficati
application 
STR
ST
oweve
wev
and 
R
any 
AE
edical
edica
extensions 
the FU
the F
(respir
espir
E). I
E). I
or
, pu
, p
variations 
puls
puls
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 101 of 255
13.2.1 
Definition of source data  
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Photocopies/printouts of electronic CRFs (eCRFs) are not 
considered acceptable source documents. Source documents are original records in which raw 
data are first recorded. These may include hospital/clinic/general practitioner records, charts, 
diaries, x-rays, laboratory results, printouts, pharmacy records, care records, ECG or other 
printouts, completed scales, or QoL questionnaires, for example. Source documents should be 
kept in a secure, limited access area.
The following data will be recorded directly in the electronic patient reported outcome (ePRO) 
Tablet on site and will not appear in a source document as defined above:
x Patient Reported Outcome questionnaires: SF-36, EQ-5D-3L, PGADA, BASDAI, BASFI, 
ASQoL, MOS Sleep Scale, Total and Nocturnal Spinal Pain Questionnaire
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the Investigator and become a permanent part of the subject’s source documents. The 
Investigator will authorize the monitor to compare the content of the printout and the data stored 
in the computer to ensure all data are consistent.
Electronic data records such as MRI records must be saved and stored as instructed by UCB (or 
designee).
13.2.2 
Source data verification 
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, subject files, recordings from automated instruments, ECG tracings, x-ray 
films, laboratory notes). All data reported on the CRF should be supported by source documents, 
unless otherwise specified in Section 13.2.1.
13.3 
Data handling 
13.3.1 
Case report completion 
This study will be using remote data capture (RDC); the Investigator is responsible for prompt 
reporting of accurate, complete, and legible data in the eCRF and in all required reports.
Serious adverse event reporting will be done using the SAE form (see Section 12.2) while also 
entering the event in the appropriate eCRF section. The safety database and the clinical database 
will be reconciled during the study and discrepancies will be corrected as needed.
The Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Access to the RDC will be given after training has been received. A training certificate will be 
provided and filed. 
Detailed instructions on the use of the RDC will be provided in the eCRF Completion 
Guidelines.
REDACTED
must 
must
ation
ation
urac
urac
COPY
he co
he co
b
This document 
ill 
ll
The
The
A
cannot
adv
adv
ring th
ng th
l be 
be 
be 
f ac
erer
used
l be us
be us
ccur
ccur
to
se r
e r
support 
n S
n S
andli
andl
rep
re
any
ta re
ta re
Secti
Sec
marketing 
cy and
cy and
th rega
h reg
es, reco
s, rec
epo
authorization 
be sav
be sav
application 
nica
ica
opies s
pies 
ect’s so
ect’s s
ntent o
ntent 
and 
ion
on
ally
ally
any
A, BA
A, B
nnair
nna
extensions 
tcome
come
A
or
uld 
uld
variations 
d be
d b
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 102 of 255
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be re-approved by the Investigator. Any change or correction 
to the eCRF after saving must be accompanied by a reason for the change.
13.4 
Electronic reporting outcome 
Compared to the paper patient questionnaires, the new electronic options have several 
advantages combining handheld devices in conjunction with online technologies in order to send 
subject self assessments directly to a central server. The collected data could then be reviewed in 
real time for monitoring of subject symptoms and compliance. The ePRO possibilities will be 
used in this study.
This study will use an electronic Site Tablet having a large screen and intuitive fingertip data 
entry to ensure all questionnaire data are captured appropriately, completely and on time. Only 
subjects’ data will be collected with the tablets; the data of both the physicians (joint counts and 
PhGADA) and WPS will be entered directly in the eCRF or collected on worksheets.
Access to the system by site personnel will be given after training has been received. A training 
certificate will be provided and filed. The Investigator should maintain a list of personnel 
authorized to enter data into the electronic ePRO device.
13.5 
Database entry and reconciliation 
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data monitoring system (CDMS). Computerized data cleaning checks 
will be used in addition to manual review to check for discrepancies and to ensure consistency of 
the data. Case Report form data are entered into the clinical database by site personnel. 
An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed.
The subject’s screening and enrollment will be recorded in the Subject Screening and Enrollment 
Log.
The Investigator will keep a list containing all subjects enrolled into the study. This list remains 
with the Investigator and is used for unambiguous identification of each subject. The list contains 
the subject identification number, full name, date informed consent signed, date of screening, 
and the hospital number or National Health Security number, if applicable.
The subject’s consent and enrollment in the study must be recorded in the subject’s medical 
record. These data should identify the study and document the dates of the subject’s 
participation.
13.6 
Termination of the study 
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity.
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
Investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
REDACTED
m (
m (
o chec
o chec
red int
ed int
be
be ma
ma
n sa
n sa
COPY 
tio
tio
e ente
e ente
(CD
(C
This document 
3.6
3.
UC
UC
cannot 
The
he
ipatio
patio
6
be 
s c
s c
ese d
ese d
used
num
num
con
con
to
catio
cati
b
support 
ep a lis
p a li
and is u
nd is 
on
on
any 
ollm
oll
marketing
aint
int
aved in
ved in
ata wil
ta wi
lmen
me
authorization
ered
ed
DMS)
DMS)
ck for 
k for 
to the
o the
ntain
tain
application 
ntai
ntai
d/lo
d/lo
and
s bee
bee
ain a
in
any
work
work
n
extensions 
ngertip
gertip
d on t
d on t
ns (jo
ns (jo
k
or variations 
nd 
nd 
ed in
d in
l be
be
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 103 of 255
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC also should be informed and provided with reason(s) for the 
termination or suspension by the Sponsor or by the Investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused study drug and other material in accordance with UCB procedures for the study.
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the Investigator, as appropriate:
x Return of all study data to the Sponsor or its representative
x Data clarification and/or resolution
x Accountability, reconciliation, and arrangements for used and unused study drugs
x Review of site study records for completeness
x Discussion/reminder on archiving responsibilities
Further details will be given in the monitoring guidelines.
13.7 
Archiving and data retention 
The Investigator will maintain adequate records for the study, including CRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data.
All essential documents are to be retained by the Investigator until 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 at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or by an agreement with UCB (CPMP/ICH/135/95, 2002 [Section 4.9.5]). The 
Investigator will contact UCB for authorization prior to the destruction of any study records or in 
the event of accidental loss or destruction of any study records. The Investigator will also notify 
UCB should he/she relocate or move the study-related files to a location other than that specified 
in the Sponsor’s study master file.
13.8 
Audit and inspection 
The Investigator will permit study-related audits mandated by UCB, after reasonable notice, and 
inspections by domestic or foreign regulatory authorities.
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
subjects enrolled have been protected, that enrolled subjects (ie, signing consent and undergoing 
study procedures) are appropriate for the study, and that all data relevant for the evaluation of the 
IMP have been processed and reported in compliance with the planned arrangements, the 
protocol, investigational site, and IRB/IEC SOPs, ICH GCP, and applicable regulatory 
requirements.
The Investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the Investigator will immediately 
inform UCB (or designee).
REDACTED 
y the I
y the 
n ICH 
ICH
in an I
in an 
evelo
evelo
COPY 
he s
e 
rug di
rug d
discon
disco
This document 
tudy
udy
IMP
IMP
p
cannot
ain pu
in pu
ects en
cts e
dy p
y p
be
by 
by 
used 
or wil
or wil
y do
do
to
dit 
dit 
support
ate or 
e or
master
maste
an
a
any 
or a
or 
destr
destr
marketing
opmen
pmen
d, howe
, how
with U
with 
auth
aut
authorization
ntinu
ntinu
Invest
nves
regio
regio
CH r
CH r
application 
dy, incl
y, in
spensi
pens
and any extensions 
drugs
rugs
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 104 of 255
13.9 
Good Clinical Practice 
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
Investigator, institution, institution staff, or designees of the Sponsor will lead to prompt action 
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study.
14 
STATISTICS 
A description of statistical methods follows and will be described in more detail in the SAP.
14.1 
Definition of analysis sets 
The Enrolled Set (ES) will consist of all subjects who have given informed consent. 
The Randomized Set (RS) will consist of all subjects randomized into the study. 
The Safety Set (SS) will consist of all subjects who have received at least 1 dose of study 
medication. 
The Full Analysis Set (FAS) will consist of all subjects in the RS who have received at least 
1 dose of study medication. 
The Per Protocol Set (PPS) will consist of subjects in the FAS without any important protocol 
deviations that may influence the validity of the primary efficacy data. The PPS may also require 
that a defined period of exposure to study medication be completed. Important protocol 
deviations will be predefined and evaluated prior to study unblinding/database lock. 
The SFE Safety Set (SFE-SS) will be defined as all subjects who continued into the SFE Period 
and who received at least 1 dose of CZP in the SFE Period.
The SFE Full Analysis Set (SFE-FAS) will be defined as all subjects in the FAS who continued 
into the SFE Period and who received at least 1 dose of CZP in the SFE Period.
14.2 
General statistical considerations 
All efficacy analyses will be performed using the FAS. The PPS will be used for a sensitivity 
analysis on the primary endpoint only. Analyses of efficacy variables in the SFE Period will be 
performed on the SFE-FAS.
The statistical analysis of the primary efficacy variable and selected secondary efficacy variables 
will account for multiplicity by using a fixed sequence testing procedure. The predefined order 
of hypothesis testing, each at a 2-sided 0.05 significance level for the comparison between 
CZP 200mg Q2W and placebo, will be performed in the sequence shown below. After the first 
test, each subsequent test is performed only if the previous test is significant in favor of CZP at 
the 2-sided 0.05 level. Note that the first test relates to the primary efficacy variable while the 
others provide the sequence testing for selected secondary efficacy variables.
1. ASDAS-MI response at Week 52 
2. ASAS40 response at Week 12 
3. Change from Baseline in BASDAI at Week 12
4. Change from Baseline in BASFI at Week 12 
REDACTED
prior t
rior 
fined a
fined 
ZP in t
ZP in
AS) w
AS)
COPY 
the
h
imary 
imary
ation 
ation
This document
other
other
1
cannot 
mg
m
ach su
ach su
2-sid
sid
be 
is t
g Q
g Q
used
alyly
or mul
r mul
test
test
to
ysis 
ysis
support 
e p
endpoin
ndpoi
FAS.
FAS
any 
t
perfo
erf
marketing 
will be
will b
d at le
d at l
ical 
ica
authorization
y
be co
be c
o stud
o stud
as all 
as all 
the SF
he SF
application 
who
wh
AS wit
AS w
effica
effica
and 
ho h
o h
any
1 do
1 do
extensions 
nt.t.
dy.y.
or variations 
P.
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 105 of 255
5. ASAS40 response at Week 52
6. Change from Baseline in BASDAI at Week 52
7. Change from Baseline in BASFI at Week 52
8. Change from Baseline in SI joint SPARCC score at Week 12
9. Change from Baseline in ASQoL at Week 52
10. Change from Baseline in nocturnal spinal pain (NRS) at Week 52
11. Number of subjects with AU or new AU flares through Week 52
Hierarchical testing of efficacy variables for Canada (and any other country where applicable or 
where requested by Regulatory Authorities):  
1. ASAS40 response at Week 12 
2. ASDAS-MI response at Week 52  
3. Change from Baseline in BASDAI at Week 12
4. Change from Baseline in BASFI at Week 12 
5. ASAS40 response at Week 52
6. Change from Baseline in BASDAI at Week 52
7. Change from Baseline in BASFI at Week 52
8. Change from Baseline in SI joint SPARCC score at Week 12
9. Change from Baseline in ASQoL at Week 52
10. Change from Baseline in nocturnal spinal pain (NRS) at Week 52
11. Number of subjects with AU or new AU flares through Week 52
Variables evaluated over time will be summarized using imputed and observed case values. 
Further details on data summarization will be provided in the SAP.
14.3 
Planned efficacy analyses 
The primary efficacy variable measurement for this study is based on ASDAS-MI response at 
Week 52. The associated primary outcome of the study will be defined as a composite endpoint 
that is achieved if a subject fulfills the following 2 components:
1. Remain in the study and on the double-blind study treatment through 52 weeks
2. Achieve an ASDAS-MI response at 52 weeks
For simplicity, this primary efficacy variable will be referred to as ASDAS-MI response at 
Week 52. However, the composite definition as described above will apply when this endpoint is 
analyzed. The primary analysis for this endpoint will be based on logistic regression. The odds 
ratio of the ASDAS-MI responder rates at Week 52 will be estimated and tested between 
treatment groups using a logistic regression model with factors of treatment group, region, and 
MRI/CRP classification (MRI+/CRP+; MRI+/CRP-; MRI-/CRP+). If the logistic regression 
REDACTED
ek 52
ek 5
Week 5
Week 5
SPAR
SPAR
a
COPY 
2
This document
2. A
Fo
F
cannot
chie
hie
Remai
Remai
A
be
The a
he 
eve
eve
used 
fficacy
icacy
f
ass
ass
to
nne
nn
support
time w
me 
summa
umm
ed
ed
any
U or
U o
marketing 
RC
at Week
t Week
urnal sp
rnal 
authorization 
52
52
CC s
CC s
application and any extensions 
here ap
ere ap
te
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 106 of 255
model is unable to converge, then the MRI/CRP classification variable may be dropped from the 
model to facilitate convergence. The study design is likely to result in some sites with a small 
number of enrolled subjects. The use of region as a stratification variable and as a factor in the 
model is intended to combine study centers in similar geographic regions. The geographic
regions to be used will be defined in the IXRS and in the SAP. Given the composite endpoint 
definition described above, there will be no missing data for the primary endpoint, as subjects 
that discontinue the double-blind study treatment prior to Week 52 or who do not have an 
ASDAS-MI status at Week 52 are considered nonresponders to the double-blind study treatment.
As described in Section 6.3, subjects who discontinue the double-blind study treatment will not 
necessarily be withdrawn from the study. In an attempt to minimize missing data, efforts will be 
made to continue to collect safety and efficacy data on these subjects through study completion.
Sensitivity analyses will be performed to evaluate the impact of missing data on the analysis of 
the primary efficacy variable (see Section 14.8).
For Canada (and any other country where applicable or where requested by Regulatory 
Authorities), the primary efficacy variable measurement is the ASAS40 response at Week 12.
Analysis of the ASAS40 response at Week 12 will be performed as described above for 
ASDAS-MI response at Week 52. Similar to the ASADAS-MI efficacy endpoint, the ASAS40 
will be treated as a composite endpoint when it is analyzed. Specifically, subjects will need 
to: 1) achieve the relevant response (ASAS40); and 2) remain in the study and on their 
randomized double-blind study treatment through Week 12.
Subgroup analyses by age, gender, race, symptom duration, smoking history, HLA-B27 
genotype, anti-CZP Ab (ADAb) status, region, prior anti-TNF exposure, Baseline SPARCC 
score ≥5, and MRI/CRP classification (MRI+/CRP+; MRI+/CRP-; MRI-/CRP+) will be 
performed for the primary efficacy variable. Subgroup analyses will be summarized using 
descriptive statistics only.
14.4 
Secondary efficacy analyses 
The changes from Baseline in BASDAI and BASFI at Week 12 and Week 52, change from 
Baseline in ASQoL at Week 52, and change from Baseline in nocturnal spinal pain at Week 52
are specified as secondary efficacy variables. As these are continuous variables, missing data 
must be handled using a different approach from what is specified for the primary efficacy 
endpoint (a responder variable). In the current study, Investigators will be given discretion to 
discontinue the double-blind study treatment for subjects not responding in order to provide them 
with alternative therapy to treat the condition. Therefore, in many cases, missing efficacy data 
due to the double-blind study treatment discontinuation should be dependent on the observed 
efficacy scores, but independent of unobserved data. This would be consistent with a missing at 
random (MAR) assumption. However, the possibility of discontinuation due to tolerability or 
other unobserved data cannot be completely discounted. Therefore, a missing not at random 
mechanism will be used for the analysis of continuous secondary efficacy variables.
A reference-based multiple imputation (MI) procedure will be used for this analysis, which will 
impute missing data as well as data at the time points following the discontinuation of the 
double-blind study treatment for both the CZP and placebo groups. This procedure will use an 
imputation model developed based on available data from the placebo group, thereby assuming a 
placebo trajectory for missing data following study treatment discontinuation for subjects in both 
REDACTED
mptom
mptom
gion, 
gion, 
(MRI+
(MRI+
variab
variab
COPY
y
2) re
2) re
h Wee
h Wee
This documen
other
ther
mec
me
cannot
cy sco
y sco
dom (
om (
r u
r
be
tiv
doub
doub
sed
doub
doub
ve th
ve th
to
der v
der 
support
ek 52
k 52
ry effi
ry eff
g a dif
g a dif
va
any
BAS
BAS
52, a
2
marketing
ble. S
le. S
cacy a
cacy
D
authorization
ek 12
k 1
durat
durat
prior 
prior 
+/CRP
+/CRP
Su
Su
application
as de
s d
efficac
effica
Specif
Speci
main in
main i
2
and
S40 re
40 re
desc
desc
any 
by Re
by R
extensions
forts 
orts
dy com
y com
n the 
n the 
o
will
will
w
variations 
ment.
ment.
l n
l n
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 107 of 255
treatment groups (Mallinckrodt, 2013). The estimand being evaluated in this case is the 
difference in the outcome of improvement in all randomized subjects at the planned endpoint, 
attributable to the initially randomized medication. This is an effectiveness estimand of the de 
facto hypothesis which has been referred to as “estimand 6” (Mallinckrodt, 2012).
Additionally, change from Baseline in SI joint SPARCC score at Week 12 is a continuous 
secondary efficacy variable. The same MI procedure specified as the main analysis approach for 
BASDAI and BASFI will be used to account for missing SPARCC data. However, it should be 
noted that, unlike BASDAI and BASFI, SPARCC score will not be measured at any time points 
between Baseline and Week 12, meaning that those are the only 2 time points that can be 
considered in the evaluation of SPARCC score at Week 12. Comparisons between treatment 
groups will be made using an analysis of covariance (ANCOVA) model on the imputed data set. 
The model will include Baseline score, treatment group, region, and MRI/CRP classification. 
The ASAS40 response at Week 12 and Week 52 are responder secondary efficacy endpoints. 
(For Canada and any other country where applicable or where requested by Regulatory 
Authorities, the ASAS40 response at Week 12 is the primary efficacy variable; the ASAS40 
response at Week 52 and the ASDAS-MI response at Week 52 are secondary efficacy variables). 
As a responder variable, ASAS40 will be analyzed using logistic regression based on a model 
similar to the one described for the primary analysis. 
The number of subjects with new onset post-Baseline AU or new AU flares through Week 52 is 
a categorical secondary efficacy endpoint for all regions. Subjects with a new event at one or 
more visits post-Baseline will be classified as having had a flare, subjects without new events at 
all visits post-Baseline will be classified as not having had a flare. As a dichotomous outcome 
variable, treatment groups will be compared for differences using logistic regression based on a 
model similar to the one described for the primary analysis.
The comparison of CZP 200mg Q2W to placebo as described above for the ASAS40 response, 
BASDAI, and BASFI at Week 12 and Week 52, for SI joint SPARCC score at Week 12, for 
ASQoL at Week 52, nocturnal pain score at Week 52, and number of subjects with AU or new 
AU flares through Week 52 will be part of the fixed sequence testing procedure outlined in 
Section 14.2.
Additionally, sensitivity analyses will be conducted on these secondary efficacy endpoints. In 
particular, the assumptions related to missing data will be investigated further. These analyses 
are described in Section 14.8.
An additional secondary efficacy variable is the number of subjects with relevant changes to 
background medication. This variable will be based on whether or not subjects take certain 
pre-specified background medications during the course of the study and will be defined in the 
SAP. The analysis for this variable will use the same logistic regression model described for the 
primary variable. 
14.5 
Other efficacy analyses 
Double-Blind Period treatment group comparisons for CZP 200mg Q2W versus placebo will be 
performed based on the change from Baseline in other selected efficacy variables. These 
analyses will be performed using an ANCOVA model including Baseline score, treatment group, 
region, and MRI/CRP classification. The treatment differences and corresponding 95% 
REDACTED
s hav
s hav
as not 
s not 
pared 
pared 
or the
or the
COPY 
ine AU
ine A
regio
regio
This document
prim
prim
1
cannot
und
und
pecifie
ecifi
P. Th
P. Th
be
nal s
al s
d m
d m
used
Sect
Sec
sec
sec
to
mpt
mpt
i
support 
w
ity ana
ty ana
ion
i
any
pain
ai
will be
ill be
marketing
e prim
pri
W to pla
W to pl
and W
and W
n sc
n s
authorization
AU
ons. S
ons. S
ing ha
ing ha
havin
havin
for di
for di
im
im
application
e sec
se
tic regr
c reg
U or n
or n
and
y vari
var
eco
eco
any 
ffi
ff
by Re
by R
extensions
eatm
atm
mputed
puted
 class
class
ficac
ica
or 
e
me
variations 
be 
be 
points
oints
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 108 of 255
confidence intervals (CIs) will be calculated based on the adjusted means. Missing values or 
values observed after discontinuing the double-blind study treatment will be imputed using last 
observation carried forward (LOCF). The following variables will be analyzed in this manner:
x PGADA
x Morning stiffness (average of BASDAI questions 5 and 6)
x BASMI
x Total spinal pain
x SF-36, PCS, MCS, and individual domains
x Fatigue NRS
x Sleep Problems Index II domains of the MOS Sleep scale
Statistical analyses will also be done for BASDAI, BASFI, and SI joint SPARCC score for time 
points not specified in the secondary efficacy analyses, using the same analysis methods 
described in Section 14.4. Additionally, ASDAS and ASAS response variables will be analyzed 
using a logistic regression model similar to the one specified for the primary analysis at time 
points not covered in the primary and secondary efficacy analyses.
These comparisons are not part of the multiplicity-controlled testing procedure described in 
Section 14.2. The p-values reported for these analyses will not be adjusted for multiplicity and 
will be considered nominal. Exploratory statistical comparisons for CZP 200mg Q2W versus 
placebo will also be performed for WPS scores using the nonparametric bootstrap-t method. This 
will be explained in greater detail in the SAP. 
Summary statistics will be provided for other variables. Summary statistics will consist of 
frequency tables and percentages for categorical variables. Continuous variables will be 
summarized by visit (where applicable) with descriptive statistics (number of available 
observations [n], mean, median, SD, minimum and maximum). Details on the analysis of the 
other endpoints will be provided in the SAP.
14.6 
Planned safety and other analyses 
The Safety Set (SS) will be used for analysis of safety data from the Double-Blind Period as well 
as the combined Double-Blind and SFE Period (as applicable), and the SFE-SS will be used for 
analysis of safety data from the SFE Period.
14.6.1 
Safety analyses 
The frequency of all AEs during the study period will be presented for each treatment group 
separately by system organ class, high level term, and preferred term. The data will be displayed 
as number of subjects experiencing the AEs, percentage of subjects, and number of AEs. Data 
will also be corrected for exposure and reported by 100 patient-years. 
Since subjects will be permitted to change background medications and because they may also 
discontinue the double-blind study treatment and initiate a new treatment (including biologics) 
during the course of the study, special consideration will be given to how AEs are attributed to 
the double-blind study treatment. This, along with other specialized AE summaries, will be 
described in greater detail in the SAP.
REDACTED
istical
stica
cores 
cores 
e SAP
e SAP
for o
for o
COPY 
contro
contr
alyses
lyse
This document
as nu
as nu
wil
wi
cannot 
requen
equen
aratel
aratel
be used 
Do
Do
fety da
ety da
S
to
w
oubl
oub
support 
d safe
d saf
will be
ill be
any 
SD
S
ded in
ed in
marketing
other 
other
catego
catego
able) w
able)
SD, m
D,
authorization
s will
s will
 comp
 comp
using
using
P. 
application 
nse
nse
or the p
r the 
alyses.
alyses
lled te
led t
and
me ana
e an
e va
e va
any 
SPAR
PAR
alyl
extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 109 of 255
Laboratory evaluations and vital signs will be analyzed over time in the SS for observed cases 
and at the end of treatment.
14.6.2 
Pharmacokinetic and immunogenicity variable analysis 
Certolizumab pegol plasma concentrations will be tabulated and summarized by treatment group 
for each visit at which samples were taken using the geometric mean, geometric coefficient of 
variation, 95% CIs, arithmetic mean, arithmetic SD, minimum and maximum. Individual plasma 
concentrations for CZP and anti-CZP levels versus time will be produced on the same graph.
Immunogenicity will be assessed through listing of individual results by subject and summary 
table. Immunogenicity data will be correlated with PK and efficacy readout. In addition, 
immunogenicity will be correlated with possible safety findings.
14.7 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which could potentially have a 
meaningful impact on study conduct or on the primary efficacy outcome for an individual 
subject. The criteria for identifying important protocol deviations will be defined within the 
appropriate protocol-specific document. Important protocol deviations will be reviewed as part 
of the ongoing data cleaning process and all important deviations will be identified and 
documented prior to unblinding to confirm exclusion from analysis sets.
14.8 
Handling of dropouts or missing data 
For analysis purposes, the primary efficacy variable is defined as a composite endpoint in which 
it is necessary to achieve ASDAS-MI at Week 52 and to remain on randomized double-blind 
study treatment through Week 52 in order to be considered a responder (see Section 14.3).
Because this composite endpoint definition does not allow for a missing response status, no 
formal method for handling missing data is needed in the primary efficacy analysis. However, in 
order to assess the impact of various missing data assumptions on the analysis, additional 
sensitivity analyses of the primary efficacy variable will be performed as follows:
x Including observed data at Week 52: The observed data at Week 52 will be used and 
analyzed according to randomized treatment, regardless of whether or not the subject is still 
on his/her randomized double-blind study treatment at that time. Despite efforts to continue 
to collect data on all subjects (even if they discontinue the double-blind study treatment), 
there may still be subjects with missing data at Week 52. Such subjects will be considered as 
non-responders in accordance with the composite endpoint definition outlined above. The 
same logistic regression model specified for the primary analysis will be used.
x MI: The Markov Chain Monte Carlo (MCMC) method will be used to impute intermittent 
missing data. The resulting multiply imputed data sets will be monotone missing and will be 
imputed using monotone regression (assuming a MAR pattern). Note that the MI procedure 
will be done on the continuous ASDAS variable, which will be dichotomized for the logistic 
regression analysis. Ankylosing Spondylitis Disease Activity Score data collected following 
the discontinuation of double-blind study treatment will be treated as missing in the original 
data set for this sensitivity analysis.
x Tipping point analysis: In this analysis, various assumptions will be made about average 
outcomes among the subsets of subjects who prematurely discontinued double-blind study 
REDACTED
ariab
ariab
Week 5
Week 5
der to 
der to 
finition
finitio
da
da
COPY 
fro
fr
issin
issin
l
This document
im
cannot
The
The
missin
missi
imp
imp
be
ogist
ist
used 
ll be
b
nders 
ders 
tic
tic
to 
n a
be s
be s
support
rando
and
zed do
ed do
all su
all su
any 
t Wee
Wee
marketing
on d
n d
ata is ne
ta is n
s missi
miss
y effic
effi
authorization
ng d
g d
le is d
le is d
52 and
2 and
be co
be co
doe
doe
application
ations
ation
ons wi
ons w
analys
analy
dat
da
and 
me e 
ll be 
l be 
any
d po
d po
for a
for
extensions 
on, 
on, 
ot
or
ma
m
variations 
ma
ma
mary
ary
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 110 of 255
treatment. Various “delta adjustments” will be made to the assumed responses among 
missing data in each treatment arm with varying degrees of plausibility (O’Kelly, 2014). The 
goal of the tipping point analysis is to identify assumptions about the missing data under 
which the conclusions change, ie, under which there is no longer evidence of a treatment 
effect. Then, the plausibility of such assumptions would be discussed. Further details of this 
procedure will be described in the SAP.
x Observed case analysis: This analysis will only include the observed data for subjects still on 
the original double-blind study treatment. Data collected after the discontinuation of 
double-blind study treatment and all other missing data will be excluded from the analysis. 
The same logistic regression model specified for the primary efficacy analysis will be 
performed.
Sensitivity analyses of the primary efficacy variable for Canada (and any other country where 
applicable or where requested by Regulatory Authorities), ASAS40 response at Week 12, will 
mirror the approach described above for ASDAS-MI at Week 52. 
The sensitivity analyses of the secondary binary efficacy variables (ASAS40 at Week 52) will be 
as follows:
x Including observed data at Week 52: As described for the primary efficacy variable.
x MI: As described for the primary efficacy variable. Note that as ASAS40 is a composite of 
4 different variables, the MI procedure will be performed on each of these components, and 
the ASAS40 response will be derived based on the multiply imputed datasets.
x Reference-based MI: This procedure will impute missing data as well as data at the time 
points following the discontinuation of the double-blind study treatment for both the CZP 
and placebo groups. This procedure will use an imputation model developed based on data 
from the placebo group (Mallinckrodt, 2013). The estimand being evaluated in this case is 
the difference in the outcome of improvement in all randomized subjects at the planned 
endpoint, attributable to the initially randomized medication, which has been referred to as 
“estimand 6” (Mallinckrodt, 2012).
x Observed case analysis: As described for the primary efficacy variable.
For the secondary efficacy variable “number of subjects with AU or new AU flares through 
Week 52,” missing values should only occur in the unlikely case that a subject does not have any 
post-Baseline AU assessments performed. Therefore, sensitivity analyses for this variable will 
focus on analyses adjusting for exposure time at risk such as event rate, incidence rate, and 
confidence interval.
The sensitivity analyses of secondary continuous efficacy variables (the change from Baseline in 
BASDAI and BASFI at Weeks 12 and 52, and the change from Baseline in the SI joint SPARCC 
score at Week 12, change from Baseline in ASQoL at Week 52, and change from Baseline in 
nocturnal spine pain at Week 52) will be as follows:
x Including observed data at Week 52: As described for the primary efficacy variable.
x MI: As described for the primary efficacy variable.
x Observed case analysis: As described for the primary efficacy variable.
REDACTED
sed on
sed o
 will i
will
on of 
on of
dure w
dure 
COPY 
able. N
able. N
e per
e per
This document
BAS
AS
scor
sco
n
cannot 
nce i
ce i
sensi
sensi
SD
SD
be
nalys
naly
int
in
used
ng v
g v
AU a
AU a
se
se
to 
ffic
val
val
support 
od
ysis: As
sis: A
icacy
cac
any
init
ini
dt, 20
dt, 20
marketing
will u
will u
krodt, 2
rodt, 
of impr
f imp
itial
itia
authorization
N
rform
rform
n the m
n the m
imput
mpu
he do
he d
application 
(
e prim
e prim
otote th
e th
and 
ASA
ASA
any
se 
se 
extensions
ll be
l be
er cou
r cou
e atat
o
alys
aly
variations 
l on 
l on 
ysi
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 111 of 255
x LOCF
Missing data for the other efficacy variables described in Section 14.5 will be handled as 
follows:
x With imputation: Non-responder imputation for binary variables and LOCF for continuous 
variables (as described in Section 14.5)
x Observed case analysis: As described for the primary efficacy variable.
Additionally, algorithms for imputing missing or partial dates for safety evaluations will be 
detailed in the SAP.
14.9 
Planned interim analysis and data monitoring 
An interim analysis is planned after the completion of the Double-Blind Period of the last subject 
at Week 52. At this time, the database from the Double-Blind Period will be locked, the 
treatment codes will be made available to relevant UCB personnel, and an interim study report 
will be written. The Investigators and subjects will remain blind to the assigned CZP dose 
regimen of the Double-Blind Period. After the completion of the SFE Period of the last subject, 
the database will be locked, and a final study report will be written. From the Week 52 Visit 
onward, subjects will be treated with open-label CZP until the last dosing visit of the study 
(SFE Week 104).
Regular monitoring of safety data collected during clinical studies will be performed as 
described in the Safety Signal Detection in the Ongoing Clinical Trials Charter for CZP.
A specific data monitoring, steering, or evaluation committee is not planned for this study.
14.10 
Determination of sample size 
Subjects will be randomized in a 1:1 ratio to the CZP 200mg Q2W and placebo treatment 
groups. The expected responder rates for ASDAS-MI at Week 52 are 40% and 20% for CZP and 
placebo, respectively. A total sample size of 300 (150 subjects per treatment group) provides 
95% power to detect a statistically significant difference in the ASDAS-MI responder rate at 
Week 52 between CZP and placebo, using a 2-sided significance level of 0.05.
With Protocol Amendment 4, ASAS40 response at Week 12 was elevated to be the primary 
efficacy variable for Canada (and any other country where applicable or where requested by 
Regulatory Authorities); however, the study was fully enrolled at the time of this amendment. 
The expected responder rates for ASAS40 response at Week 12 are also 40% for CZP and 20% 
for placebo, which are identical to the assumed response rates cited for ASDAS-MI at Week 52. 
Therefore, the planned total sample size of 300 would provide 95% power for this variable, as 
well.
15 
ETHICS AND REGULATORY REQUIREMENTS 
15.1 
Informed consent 
Subject’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki.
REDACTED
he On
he On
evalua
valua
f sam
f sam
COPY 
ng cli
ng cli
This document 
15
15
1
cannot
ore, t
re, t
be
o, wh
o, wh
h
used
horit
orit
respo
respo
to
or C
r C
i
support
nd pla
d pla
dment 4
ment 
Cana
Can
any 
mp
mp
cally s
cally 
marketing
mpl
pl
ratio to
ratio t
tes for 
es for
ple s
ple
authorization
inical
inical
going
going
ation c
tion c
ple s
le s
application 
SFE
FE
tten. Fr
ten. F
he last 
e last
and
he ass
e ass
E P
E P
any 
e l
n inte
n int
igi
extensions 
d of th
d of t
lock
oc
or variations 
e
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 112 of 255
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the subject in both oral and written form by the Investigator (or 
designee). Each subject will have the opportunity to discuss the study and its alternatives with 
the Investigator.
Prior to participation in the study, the written Informed Consent form should be signed and 
personally dated by the subject, or his/her legal representative, and by the person who conducted 
the informed consent discussion (Investigator or designee). The subject or his/her legal 
representative must receive a copy of the signed and dated Informed Consent form. As part of 
the consent process, each subject must consent to direct access to his/her medical records for 
study-related monitoring, auditing, IRB/IEC review, and regulatory inspection. An additional 
Informed Consent form for participation in the substudy should be completed.
If the Informed Consent form is amended during the study, the Investigator (or the Sponsor, if 
applicable) must follow all applicable regulatory requirements pertaining to the approval of the 
amended Informed Consent form by the IRB/IEC and use of the amended form.
All studies conducted at centers in the USA must include the use of a Health Insurance 
Portability and Accountability Act Authorization form.
The subject may withdraw his/her consent to participate in the study at any time. A subject is 
considered as enrolled in the study when he/she has signed the Informed Consent form. A CRF 
must not be started, nor may any study specific procedure be performed for a given subject, 
without having obtained his/her written consent to participate in the study.
15.2 
Subject identification cards 
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the subject. 
The Investigator will fill in the subject identifying information and medical emergency contact 
information. The Investigator will instruct the subject to keep the card with them at all times.
15.3 
Institutional Review Boards and Independent Ethics 
Committees 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki.
The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, Informed 
Consent form, Investigator’s Brochure, Investigator’s curriculum vitae (if applicable), 
advertisement (if applicable), and all other subject-related documents to be used for the study to 
the IRB/IEC for its review and approval.
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol.
REDACTED
nt to
nt to
n card
card
nd As
nd A
a su
a su
COPY
signe
sign
rocedu
roced
o p
o p
This document
Cons
ons
adv
adv
th
cannot
ponsib
onsib
ation 
tion
nsen
sen
be
men
men
used 
tor/U
or/U
to 
cco
support 
es
es
ducted u
ucted
ordan
ordan
any
Rev
Re
marketing
ubject
ubject
ct ident
ct iden
instruc
nstru
vi
authorization
ure 
re 
partici
artici
ds
ds
sent f
ent f
application 
he stud
he stu
d the I
d the 
e be
be
and 
a Hea
a Hea
any 
o th
o t
d form
d form
extensions
dditi
dditi
or the 
r the 
the a
he
o
s fo
s fo
ioi
variations 
t of 
of 
or
or
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 113 of 255
The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol deviations, 
to eliminate immediate hazards to subjects.
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as 
allowed.
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The Investigator should provide a final report to the IRB/IEC following study
completion.
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the Sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
Investigators are to provide the Sponsor (or its representative) with evidence of such IRB/IEC 
notification.
15.4 
Subject privacy 
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned at Screening.
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
subject’s primary medical records that directly concerns this study (including, but not limited to, 
laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports for deaths 
occurring during the study).
15.5 
Protocol amendments 
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective.
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented.
16 
FINANCE, INSURANCE, AND PUBLICATION 
Insurance coverage will be handled according to local requirements.
Finance, insurance, and publication rights are addressed in the Investigator and/or CRO 
agreements, as applicable.
REDACTED 
phold 
hold 
esigne
esigne
COPY 
enta
en
This document
e ap
e ap
imp
imp
cannot 
e.
nifican
fican
appr
ppr
be
valu
alu
used 
ges m
es m
uat
ua
to
otoc
toc
support
ing a s
ng a 
udy).
dy).
co
co
any
ds t
ds 
ECG 
ECG 
marketing 
tatives 
atives
ulatory
ulator
that
tha
authorization 
the su
the su
ee) wi
e) wi
application
or or 
or or
country
ountr
ve) wit
ve) w
and 
e ap
ap
 regu
regu
any 
ppro
ppr
extensions
nve
on IRB
on IRB
no le
no le
follow
ollow
or
estig
esti
variations 
C as 
C as 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 114 of 255
17 
REFERENCES 
Barkham N, Keen HI, Coates LC, O'Connor P, Hensor E, Fraser AD, et al. Clinical and imaging 
efficacy of infliximab in HLA–B27–Positive patients with magnetic resonance imaging–
determined early sacroiliitis. Arthritis Rheum. 2009;60:946-54.
Boonen A, van der Heijde D, Landewé R, Guillemin F, Rutten-van Mölken M, Dougados M, et 
al. Work status and productivity costs due to ankylosing spondylitis: comparison of three 
European countries. Ann Rheum Dis. 2002;61:429-37.
Boonen A, van der Heijde D, Landewé R, Guillemin F, Rutten-van Mölken M, Dougados M, et 
al. Direct costs of ankylosing spondylitis and its determinants: an analysis among three European 
countries. Ann Rheum Dis. 2003;62:732-40.
Braun J. Axial spondyloarthritis: thoughts about nomenclature and treatment targets. Clin Exp 
Rheumatol. 2012;30:S132-5.
Braun J, Baraliakos X. Imaging of axial spondyloarthritis including ankylosing spondylitis. Ann
Rheum Dis. 2011;70(Suppl 1):i97-103.
Braun J, Baraliakos X, Golder W, Brandt J, Rudwaleit M, Listing J, et al. Magnetic resonance 
imaging examinations of the spine in patients with ankylosing spondylitis, before and after 
successful therapy with infliximab: evaluation of a new scoring system. Arthritis Rheum. 
2003;48:1126-36.
Brandt J, Listing J, Sieper J, Rudwaleit M, van der Heijde D, Braun J. Development and 
preselection of criteria for short term improvement after anti-TNFα treatment in ankylosing 
spondylitis. Ann Rheum Dis. 2004;63:1438-44.
Braun J, Sieper J. Ankylosing spondylitis. Lancet. 2007;369:1379-90.
Braun J, van den Berg R, Baraliakos X, Boehm H, Burgos-Vargas R, Collantes-Estevez E, et al. 
2010 update of the ASAS/EULAR recommendations for the management of ankylosing 
spondylitis. Ann Rheum Dis. 2011;70:896-904.
Braun J, van der Heijde D. Imaging and scoring in ankylosing spondylitis. Best Pract Res Clin 
Rheumatol. 2002;16:573-604.
Braun J, Zochling J, Baraliakos X, Alten R, Burmester G, Grasedyck K, et al. Efficacy of 
sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis 
and early ankylosing spondylitis: a multicentre randomised controlled trial. Ann Rheum Dis. 
2006;65:1147-53.
Calin A, Garrett S, Whitelock H, Kennedy LG, O'Hea J, Mallorie P, et al. A new approach to 
defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing 
Spondylitis Functional Index. J Rheumatol. 1994;2:2281-5.
Callhoff J, Sieper J, Weiß A, Zink A, Listing J. Efficacy of TNFα blockers in patients with 
ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann 
Rheum Dis. 2015;74:1241-8.
CPMP/EWP/556/95. Points to consider on the clinical investigation of medicinal products other 
than NSAIDS for the treatment of RA. June 2004.
REDACTED
an de
an de
rovem
ovem
1438
1438 4
dylitis
dylitis
COPY
new s
new 
This document
Spon
pon
C
cannot 
A, Ga
A, Ga
ining 
ning 
nd
be 
147
147-
used
patie
patie
ylosin
ylosin
5
to
J, Ba
J, B
en
en
support
. Ima
Ima
3-604
604
Bara
Bar
any
011;
011
agi
marketing
s. Lan
s. La
s X, Bo
X, B
R recom
R reco
;70
7
authorization 
r Heijd
r Heij
ment af
nt af
44.4.
application 
ng J, et
g J, 
ng spon
g spo
coring 
oring
and 
kyl
kyl
any 
losin
los
extensions
ree E
ee E
target
arget
o
os M
os M
Eu
E
variations 
M
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 115 of 255
Cuirea A, Scherer A, Exer P, Bernhard J, Dudler J, Beyeler B, et al. Tumor necrosis factor α 
inhibition in radiographic and nonradiographic axial spondyloarthritis: results from a large 
observational cohort. Arthritis Rheum. 2013;65:3096-106.
Davis JC Jr, Revicki D, van der Heijde DM, Rentz AM, Wong RL, Kupper H, et al. 
Health-related quality of life outcomes in patients with active ankylosing spondylitis treated with 
adalimumab: results from a randomized controlled study. Arthritis Rheum. 2007;57:1050-7.
Dougados M, Braun J, Burgos-Vargos R, Maksymowych W, Sieper J, van der Heijde D. ASAS 
recommendations for collecting, analysing and reporting NSAID intake in clinical 
trials/epidemiological studies in axial spondyloarthritis. Ann Rheum Dis. 2011;70:249-251.
Dougados M, van der Heijde D, Sieper J, Braun J, Maksymowych W, Citera G, et al. Efficacy of 
etanercept in nonradiographic axial spondyloarthritis. The symptomatic efficacy and effect on 
objective signs of inflammation of etanercept in early nonradiographic axial spondyloarthritis. 
Ann Rhuem. 2014;66:2091-102.
Dougados M, van der Linden S, Juhlin R, Huitfeld B, Amor B, Calin A, et al. The European 
Spondylarthropathy Study Group preliminary criteria for the classification of 
spondylarthropathy. Arthritis Rheum. 1991;34:1218-27.
Doward LC, Spoorenberg A, Cook SA, Whalley D, Helliwell PS, Kay LJ, et al. Development of 
the ASQL: a quality of life instrument specific to ankylosing spondylitis. Ann Rheum Dis. 
2003;62:20-6.
Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. Interpreting the 
clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT 
recommendations. J Pain. 2008;9:105-21.
Feldtkeller E, Bruckel J, Khan MA. Scientific contributions of ankylosing spondylitis patient 
advocacy groups. Curr Opin Rheumatol. 2000;12:239-47.
Feldtkeller E, Khan MA, van der Heijde D, van der Linden S, Braun J. Age at disease onset and 
diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. 
Rheumatol Int. 2003;23:61-6.
Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to 
defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease 
Activity Index. J Rheumatol. 1994;21:2286-91.
Haibel H, Brandt HC, Song IH, Brandt A, Listing J, Rudwaleit M, et al. No efficacy of 
subcutaneous methotrexate in active ankylosing spondylitis: a 16-week open-label trial. Ann 
Rheum Dis. 2007;66:419-21.
Haibel H, Rudwaleit M, Braun J, Sieper J. Six months open label trial of leflunomide in active 
ankylosing spondylitis. Ann Rheum Dis. 2005;64:124-6.
Haibel H, Rudwaleit M, Listing J, Heldmann F, Wong RL, Kupper H, et al. Efficacy of 
adalimumab in the treatment of axial spondylarthritis without radiographically defined 
sacroiliitis: results of a twelve-week randomized, double-blind, placebo-controlled trial by an 
open-label extension up to week fifty-two. Arthritis Rheum. 2008;58:1981-91.
REDACTED 
ton D,
ton D
es in c
s in c
21.
21.
Sci
Sci
COPY 
Hell
el
nkylo
nkylo
This document
aib
ai
anky
anky
H
cannot 
eo
eo
m Dis.
Dis.
bel H
bel H
be 
ran
ous m
ous m
used
Rh
Rh
ndt 
ndt 
to
atus 
us
heu
heu
support 
-6.6.
T, Kenn
Ken
s in 
s in
any 
r H
negati
negat
marketing 
ientific
entific
atol. 20
tol. 2
Heijd
Heij
authorization 
, Clee
Clee
chroni
hroni
application 
ific
fic
ell PS,
ll PS
sing sp
ing s
and
A, e
A, e
cati
cati
any 
t
extensions 
2
al. Ef
al. Ef
y and 
y and
spond
spond
or
251.
51
variations 
SAS 
AS 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 116 of 255
Hays RD, Martin SA, Sesti AM, Spritzer KL. Psychometric properties of the Medical Outcomes 
study sleep measure. Sleep Med. 2005;6:41-4.
Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh KC, et al. Estimates of the 
prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis 
Rheum. 2008;58:15-25.
Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, Landewé R, van der Tempel H, Mielants 
H, et al. Assessment of enthesitis in ankylosing spondylitis. Ann Rheum Dis. 2003;62:127-32.
Huscher D, Merkesdal S, Thiele K, Zeidler H, Schneider M, Zink A. Cost of illness in 
rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and systemic lupus erythematosus 
in Germany. Ann Rheum Dis. 2006;65:1175-83.
Kobelt G, Andlin-Sobocki P, Brophy S, Jönsson L, Calin A, Braun J. The burden of ankylosing 
spondylitis and the cost-effectiveness of treatment with infliximab (Remicade). Rheumatology 
(Oxford). 2004;43:1158-66.
Kobelt G, Andlin-Sobocki P, Maksymowych WP. Costs and quality of life of patients with 
ankylosing spondylitis in Canada. J Rheumatol. 2006;33:289-95.
Landewé R, Braun J, Deodhar A, Dougados M, Maksymowych WP, Mease PJ, et al. Efficacy of 
certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing 
spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study. Ann 
Rheum Dis. 2014;73:39-47.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604-12.
Lukas C, Braun J, van der Heijde D, Hermann KG, Rudwaleit M, Ostergaard M, et al. Scoring 
inflammatory activity of the spine by magnetic resonance imaging in ankylosing spondylitis: a 
multireader experiment. J Rheumatol. 2007;34:862-70.
Lukas C, Landewé R, Sieper J, Dougados M, Davis J, Braun J, et al. Development of an 
ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis. Ann 
Rheum Dis. 2009;68:18-24.
Machado PM, Landewé R, van der Heijde D, Assessment of SpondyloArthritis international 
Society (ASAS). Letter. Ankylosing Spondylitis Disease Activity Score (ASDAS): 2018 update 
of the nomenclature for disease activity states. Ann Rheum Dis. 2018;77:1539-40.
Mallinckrodt CH. Preventing and Treating Missing Data in Longitudinal Clinical Trials: A 
Practical Guide. New York, NY: Cambridge University Press; 2013.
Mallinckrodt CH, Lin Q, Lipkovich I, Molenberghs G. A structured approach to choosing 
estimands and estimators in longitudinal clinical trials. Pharmaceutical Statistics. 
2012;11:456-61.
Mease PJ, Fleischmann R, Wollenhaupt J, Deodhar A, Gladman D, Hoepken B, et al. Long-term 
safety and efficacy of certolizumab pegol in patients with psoriatic arthritis with and without 
prior anti-tumor necrosis factor exposure: 96-week outcomes from the RAPID-PsA trial. 
Presented at the European League Against Rheumatism (EULAR) 2014 Congress. Abstract 
#OP0077.
REDACTED 
g YL,
g YL,
on rate
n rate
 Herm
 Herm
COPY
spon
spon
domis
dom
This document
estim
stim
201
201
canno
l Gu
Gu
llinckr
linck
ma
ma
be
odt C
odt C
uid
uid
used
Le
ature 
ature 
CH
CH
to
etter
ette
support 
iviv
24.4.
wé R, 
wé R
any
Dou
Do
ity sc
ty sc
marketing 
mann
man
magne
magne
tol. 200
ol. 20
uga
ug
authorization 
sed
ed
, Castr
Cast
e. Ann
. Ann
nn
application 
ych WP
ych W
dyloarth
yloart
d pla
d pl
and 
of lif
of lif
any 
de
de
extensions
ythem
them
den of
en of
e). R
e). R
or 
ma
m
variations 
nts 
ts
2.
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 117 of 255
Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of 
rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955-2007. Arthritis 
Rheum. 2010;62:1576-82.
O’Kelly M, Ratitch B. Clinical Trials with Missing Data: A Guide for Practitioners. John Wiley
& Sons; 2014.
Osterhaus JT, Purcaru O. Discriminant validity, responsiveness and reliability of the 
arthritis-specific Work Productivity Survey assessing workplace and household productivity 
within and outside the home in patients with axial spondyloarthritis, including non-radiographic 
axial spondyloarthritis and ankylosing spondylitis; Arthritis Res Ther. 2014;16:R164.
Pavy S, Brophy S, Calin A. Establishment of the minimum clinically important difference for the 
bath ankylosing spondylitis indices: a prospective study. J Rheumatol. 2005;32:80-5.
Poddubnyy D. Axial spondyloarthritis: is there a treatment of choice? Ther Adv Musculoskelet 
Dis. 2013;5:45-54.
Poddubnyy D, Rudwaleit M, Haibel H, Listing J, Märker-Hermann E, Zeidler H, et al. Effect of 
non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial 
spondyloarthritis: results from the German Spondyloarthritis Inception Cohort. Ann Rheum Dis. 
2012;71:1616-22.
Reveille JD, Witter JP, Weisman MH. Prevalence of axial spondylarthritis in the United States: 
estimates from a cross-sectional survey. Arthritis Care Res (Hoboken). 2012;64:905-10.
Rostom S, Dougados M, Gossec L. New tools for diagnosing spondyloarthropathy. Joint Bone 
Spine. 2010;77:108-14.
Rudwaleit M. American College of Rheumatology 77th annual meeting, association of 
rheumatology health professionals. October 25th-30th 2013. San Diego, CA. 
Rudwaleit M. New approaches to diagnosis and classification of axial and peripheral 
spondyloarthritis. Curr Opin Rheumatol. 2010;22:375-80.
Rudwaleit M, Haibel H, Baraliakos X, Listing J, Mäarker-Hermann E, Zeidler H, et al. The early 
disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception 
Cohort. Arthritis Rheum. 2009a;60:717-27.
Rudwaleit M, Jurik A-G, Hermann K-GA, Landewe´ R, van der Heijde D, Baraliakos X, et al. 
Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial 
spondyloarthritis – a consensual approach by the ASAS/ OMERACT MRI Group. Ann Rheum 
Dis. 2009d; 68:1520-7.
Rudwaleit M, Khan MA, Sieper J. The challenge of diagnosis and classification in early 
ankylosing spondylitis: do we need new criteria? Arthritis Rheum. 2005;52:1000-8.
Rudwaleit M, van der Heijde D, Landewe R, Akkoc N, Brandt J, Chou CT, et al. The 
Assessment of SpondyloArthritis International Society classification criteria for peripheral 
spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis. 2011;70:25-31.
Rudwaleit M, van der Heijde D, Landewé R, Listing J, Akkoc N, Brandt J, et al. The 
development of Assessment of SpondyloArthritis international Society classification criteria for 
REDACTED 
tis 
tis 
ools fo
ools fo
Rheu
Rheu
COPY 
 of ax
of a
s Ca
Ca
This document
anky
nky
Ru
Ru
cannot
09d; 
9d; 
dwalei
walei
ylo
ylo
be
rthrit
rthri
6
used
rik A
k 
ve sac
e sac
tis
tis
to 
A
suppor
aralia
rali
ondyla
ondy
um. 20
um. 2
any 
heu
heum
iak
iak
marketing 
umato
mat
ctober 
tober
diagno
diagn
ma
m
authorization 
xial
ial
are Re
re Re
or diag
r dia
tol
application
gress
gres
nceptio
ncepti
al spo
sp
and 
E, Zei
E, Zei
i
any 
A
extensions 
fferen
feren
:80
:80-5
Adv M
dv 
or variations 
y
raphi
aphi
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 118 of 255
axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis. 
2009c;68:777-83.
Rudwaleit M, Landewé R, van der Heijde D, Listing J, Brandt J, Braun J, et al. The development 
of Assessment of SpondyloArthritis international Society classification criteria for axial 
spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty 
appraisal. Ann Rheum Dis. 2009b;68:770-6.
Rudwaleit M, Sieper J. Referral strategies for early diagnosis of axial spondyloarthritis. Nat Rev 
Rheumatol. 2012;8:262-8.
Sieper J, Kivitz A, van Tubergen A, Deodhar A, Coteur G, Woltering F, et al. Rapid 
improvements in patient-reported outcomes with certolizumab pegol in patients with axial 
spondyloarthritis, including ankylosing spondylitis: 24-Week results of RAPID-axSpA trial. 
European League Against Rheumatism (EULAR) 2013b, Congress 2013; Abstract # THU0360.
Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, Burgos-Vargas R, et al. The Assessment 
of SpondyloArthritis International Society (ASAS) handbook: a guide to assess 
spondyloarthritis. Ann Rheum Dis. 2009;68(Supple 2):ii1-ii44.
Sieper J, van der Heijde D. Review: Nonradiographic axial spondyloarthritis: new definition of 
an old disease? Arthritis Rheum. 2013a;65:543-51.
Sieper J, van der Heijde D, Dougados M, et al. Efficacy and safety of adalimumab in patients 
with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial 
(ABILITY-1). Ann Rheum Dis. 2013c;72:815-22.
Sieper J, Rudwaleit M, van der Heijde D. Long-term safety and efficacy of certolizumab pegol in
patients with axial spondyloarthritis, including ankylosing spondylitis and non-radiographic axial 
spondyloarthritis: 96-week outcomes of the RAPID-axSpA trial. Presented at the European 
League Against Rheumatism (EULAR) 2014 Congress. Abstract #SAT0351.
Strand V, Scott DL, Emery P, Kalden JR, Smolen JS, Cannon GW, et al. Physical function and 
health related quality of life: analysis of 2-year data from randomized, controlled studies of 
leflunomide, sulfasalazine, or methotrexate in patients with active rheumatoid arthritis. 
J Rheumatol. 2005;32:590-601.
van der Heijde D, Dougados M, Davis J, Weisman MH, Maksymowych W, Braun J, et al. 
Assessment in Ankylosing Spondylitis International Working Group/Spondylitis Association of 
America recommendations for conducting clinical trials in ankylosing spondylitis. Arthritis 
Rheum. 2005;52:386-94.
van der Heijde D, Purcaru O, Kavanaugh A. Economic burden of axial spondyloarthritis related 
to paid work and household productivity at baseline in the RAPID-axSpA Study: differences and 
similarities between ankylosing spondylitis and non-radiographic axial spondyloarthritis. Value 
in Health. 2013;16:A323-A636.
van der Heijde D, Schiff MH, Sieper J, Kivitz AJ, Wong RL, Kupper H, et al. Adalimumab 
effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: 
long-term results from the ATLAS trial. Ann Rheum Dis. 2009;68:922-9.
REDACTED 
res
res
15
15-22
22
D. Lon
D. Lon
includ
inclu
s of
s of
COPY 
fficacy
fficac
sults
sul
This document
simil
mil
in H
in H
cannot 
er Heij
r Heij
paid w
aid w
lal
be
05;5
05;5
used
Anky
nky
mmen
mmen
52
52
to
Dou
Dou
ylo
ylo
support
, or m
or m
590
90-60
60
ugad
uga
any 
ala
analys
naly
me
marketing 
din
din
f the R
the R
AR) 20
R) 20
lden J
den
authorization 
y an
an
ts of a 
s of a
.
ng
ng-ter
ter
ng a
ng a
application 
ondylo
ondyl
and s
nd
and
e to a
to a
any 
R, et a
R, et 
ass
extensions 
ith ax
th ax
axSp
axSp
bstrac
strac
or variations 
Rev
Rev
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 119 of 255
van der Heijde D, Sieper J, Maksymowych W, Dougados M, Burgos-Vargas R, Landewé R, et 
al. 2010 Update of the international ASAS recommendations for the use of anti-TNF agents in 
patients with axial spondyloarthritis. Ann Rheum Dis. 2011;70:905-8.
van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing 
spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 
1984a;27:361-68.
van der Linden S, Valkenburg HA, de Jongh BM, Cats A. The risk of developing ankylosing 
spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients 
with the general population. Arthritis Rheum. 1984b;27:241-9.
van Tubergen A, Black PM, Coteur G. Are patient-reported outcome instruments for ankylosing 
spondylitis fit-for-purpose for the axial spondyloarthritis patient? A Qualitative and 
Psychometric Analysis. Rheum. 2015;54:1842-51.
van Tubergen A, Coenen J, Landewé R, Spoorenberg A, Chorus A, Boonen A, et al. Assessment 
of fatigue in patients with ankylosing spondylitis: a psychometric analysis. Arthritis Rheum. 
2002b;47:8-16.
van Tubergen A, Debats I, Ryser L, Londoño J, Burgos-Vargas R, Cardiel MH, et al. Use of a 
numerical rating scale as an answer modality in ankylosing spondylitis-specific questionnaires. 
Arthritis Rheum. 2002a;47:242-8.
Ward MM. Functional disability predicts total costs in patients with ankylosing spondylitis. 
Arthritis Rheum. 2002;46:223-31.
Ware JE, Kosinski M, Keller SD. SF-36 Physical and Mental Health Summary scales: a user’s 
manual; 1994.
Weber U, Ostergaard M, Lambert RG, Pedersen SJ, Chan SM, Zubler V, et al. Candidate 
lesion-based criteria for defining a positive sacroiliac joint MRI in two cohorts of patients with 
axial spondyloarthritis. Ann Rheum Dis. 2015;74:1976-82.
Wells G, Li T, Maxwell L, MacLean R, Tugwell P. Determining the minimal clinically 
important differences in activity, fatigue, and sleep quality in patients with rheumatoid arthritis. J 
Rheumatol. 2007;34:280-9.
REDACTED 
cos
co
6 Phys
6 Phys
G
COPY 
osi
os
osts 
sts
This document cannot be used to support 
Ma
M
activity
ctivit
80
80-9.9.
any 
um
u
acLe
acLe
marketing 
, Peder
Pede
positiv
ositi
m Di
m D
authorization 
in pat
n pa
sical a
ical a
application 
as R, C
s R, C
spond
spon
and
alysis
lysis
any 
nen A
nen A
s A
extensions 
for an
or an
 and 
and 
or variations 
g
ents
ents
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 120 of 255
18 
APPENDICES  
18.1 
ASAS classification criteria for axial SpA 
ASAS classification criteria for axial SpA 
(for subjects with chronic back pain ≥3 months and age at onset <45 years)
Imaging criteria
ASAS clinical criteria for axial SpA
Sacroiliitis (MRI or radiographs*) plus ≥1 SpA 
feature
HLA-B27 plus ≥2 other SpA features
SpA features**
Inflammatory back pain***
Psoriasis
Arthritis
Crohn’s disease/ulcerative colitis
Enthesitis (heel)
HLA-B27
Uveitis
Elevated CRP
Dactylitis
CRP=C-reactive protein; MRI=magnetic resonance imaging; HLA-B27=human leukocyte antigen B27; 
NSAID=nonsteroidal anti-inflammatory drug; SpA=spondyloarthritis
* Active inflammatory lesions of sacroiliac joints with definite bone marrow oedema/osteitis suggestive of 
sacroiliitis associated with spondyloarthritis in MRI or radiographic sacroiliitis grade 2 to 4 bilaterally or 
grade 3 to 4 unilaterally according to modified NY criteria.
** Family history for SpA and Good response to NSAIDs are excluded as SpA feature criteria.
***Inflammatory back pain according to ASAS criteria for Axial SpA defined as the presence of 4 out of 5 
of the following parameters:
1) age at onset <45 years
2) insidious onset
3) improvement with exercise
4) no improvement with rest
5) pain at night (with improvement upon getting up)
REDACTED 
=sp
sp
with de
with d
MRI o
MRI o
ied NY
ed NY
ponse t
ponse t
AS
A
COP
ging; H
ging; H
pond
pon
PY 
OPY
This document cannot be used to support 
ex
ex
nt with 
t with
t (with 
(with
any 
xercis
xerc
marketing
to NS
 N
SAS cri
AS cri
authorization 
HLA
LA
dyloart
yloart
efinite 
finite
or radio
r radio
Y criter
criter
NSA
NSA
ap
A B2
B2
application 
ap
and 
ve c
any 
coli
co
extensions 
ns
ex
or 
or variations 
ari
ari
ari
ar
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 121 of 255
18.2 
Modified NY criteria for ankylosing spondylitis 
Subjects meeting the NY criteria in the context of this protocol are defined as subjects meeting 
the definite AS diagnosis according to the modified NY criteria below. 
Modified NY criteria for ankylosing spondylitis 
Diagnosis
1) Clinical criteria
a) Low back pain and stiffness for more than 3 months which improves with exercise, but is not 
relieved by rest.
b) Limitation of motion of the lumbar spine in both the sagittal and frontal planes.
c) Limitation of chest expansion relative to normal values corrected for age and sex.
2) Radiologic criterion
Sacroiliitis grade ≥2 bilaterally or sacroiliitis grade 3 to 4 unilaterally.
Grading
1) Definite ankylosing spondylitis if the radiologic criterion is associated with at least 1 clinical 
criterion
Note: A second grading of “probably ankylosing spondylitis” is part of the modified NY criteria, but it is 
not applicable for this study. It is included here for completeness. The grading will be probable ankylosing 
spondylitis if three clinical criteria are present and the radiologic criterion is present without any signs or 
symptoms satisfying the clinical criteria (other causes of sacroiliitis should be considered).
REDACTED
mp
he rad
he rad
auses o
auses o
COPY
litis” is
litis” 
pleten
lete
PY 
PY
This document cannot be used to support any marketing authorization
s par
pa
ness. T
ess. T
iologic
iologic
of sacro
f sacro
ap
art of
rt o
application 
associat
ssocia
tio
ap
and 
an
any 
an extensions 
ns
ex.x.
ns
ex
or 
otot
variations 
a
va
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 122 of 255
18.3 
Table of corticosteroid equivalent doses 
Table of corticosteroid equivalent doses 
Prednisone (reference)
10mg 
Cortisone
50mg 
Hydrocortisone 
40mg 
Prednisolone 
10mg 
Triamcinolone 
8mg 
Methylprednisolone 
8mg 
Betamethasone 
1.5mg 
Dexamethasone 
1.5mg 
Corticosteroid equivalent doses (with reference to prednisone 10mg dose) (Meikle and Tyler, 1977)
REDACTED COPY 
This document cannot be used to support any marketing authorization application and
(Meik
Meik
d any 
a
extensions 
on
en
e
or 
or variations 
ria
ar
thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 134 of 255
18.9 
PGADA (NRS) 
NRS patient global disease activity 
How active was your spondyloarthritis on average during the last week?  
Please tick the box that represents your answer ( i.e.     10          ) 
Not active
very active
0
1
2
3
4
5
6
7
8
9
10
REDACTED COPY 
This document cannot be used to support any marketing authorization application and 
nd any extensions 
ens
ensions
ons
io
or variations 
o
thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 141 of 255
18.11 
Total spinal pain NRS and nocturnal spinal pain NRS 
NRS pain
p
Please tick the box that represents your answer ( i.e. 
)
1. Total SpinePain
p
How much pain of your spine due to spondyloarthritis do you have?
o
no pain
most severe pain
2. Nocturnal SpinePain
p
How much pain of your spine due to spondyloarthritis do you have at night?
no pain
most severe pain
10
1
2
3
4
6
7
8
9
10
5
0
1
2
3
4
6
7
8
9
t
10
e
0
5
n
0
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any
m
any ext
extensions 
exten
exten
te
1
x
or 
or
or variations 
n
v
thereof. 

REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 143 of 255
18.13 
Protocol Amendment 1 
Rationale for the amendment
The substantial amendment includes several changes to clarify and/or add supporting 
information regarding the procedures and assessments, and to remove inconsistencies and errors: 
a range of sensitivity analyses, previously discussed with the regulatory authorities, to evaluate 
the impact of missing data on the analysis of the primary efficacy variable. 
Other changes included the following: the exclusion criterion regarding the upper limit of normal 
of the liver function tests for subjects who are not treated with methotrexate, the requirement for 
plasma samples to be analyzed to confirm the washout of specific prohibited medications was 
removed, and the reporting-needs of particular physician-completed assessments in the eCRFs 
were clarified. Two tables were included to assist the Investigators in identifying the assessments 
to be performed when subjects switch to alternative treatments. Inconsistencies in the laboratory 
assessments performed, the definition of study treatment, and the use of Week 52 and 
Week 52/Withdrawal (WD) visit were corrected, study personal information was updated, and 
minor editorial changes were made.
Modifications and changes
Global changes
The following changes were made throughout the protocol:
x The study contact information is updated
x Week 52 and Week 52/Early Withdrawal visits are updated to Week 52/WD visit throughout 
the protocol, as defined in the Schedule of Assessments.
x Double-blind study treatment administration during the Double-Blind Period has been 
defined consistently throughout the protocol.
x The laboratory assessments to be performed throughout the study are updated so that they are 
described consistently throughout the protocol.
x Magnetic resonance imaging (MRI) for the spine is to be performed at Week 12, along with 
the already planned sacroiliac (SI) MRI.
x “Are Patient-Reported Outcome Instruments for Ankylosing Spondylitis Fit-For-Purpose for 
the Axial Spondyloarthritis Patient? A Qualitative and Psychometric Analysis” by van 
Tubergen et al has been published and the protocol is updated to reflect the publication
x The protocol is updated to reflect that the recording of the Physician’s Global Assessment of 
Disease Activity (PhGADA), joint count, and Work Productivity Survey (WPS) will be on 
the electronic Case Report form (eCRF) only.
x For subjects who discontinue the study treatment during Study Period 2, the assessments 
completed at the scheduled visit do not need to be repeated at the withdrawal treatment (wdt) 
Week 0 visit of the alternative schedule. Therefore, 2 additional tables are added to facilitate 
the Investigators understanding of which remaining assessments are required to be 
performed, when the subject enterseither the open-label certolizumab pegol (CZP) or the 
alternative treatment schedule.
REDACTED 
awal v
awal v
edule 
edule
min
min
COPY 
e proto
e prot
This document 
th
x
cannot
e prot
prot
Diseas
Diseas
the
the
be
en e
n e
used 
Rep
Re
Spond
pond
et a
et a
to
epor
epo
support 
imagin
magi
ed sacr
d sacr
any 
o o 
ougho
ougho
marketing 
nistrati
nistrat
the pro
he pr
be p
be 
authorization
ocol
co
visits a
visits 
of As
of As
application 
ol:l:
and
mati
ati
any
Week
Week
tion 
ion
extensions
tions
ons
n the 
n the 
ng the 
ng the
ies in
es in
k
or
men
men
s w
variations 
norma
orma
entnt
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 144 of 255
x The use of the Interactive response system (IXRS) is updated to clarify that it will be used to 
register subjects attending Visit 1 without issuing any kit number.
x The current study does not analyze the samples collected data for methotrexate (MTX), 
sulfasalazine (SSZ), hydroxychloroquine (HCQ), nonsteroidal anti-inflammatory drug 
(NSAID), corticosteroids, and the washout of any prohibited medications; the text that 
describes this is deleted.
x The Safety Set (SS) definition is updated.
x Following discussion with the regulatory authorities, a range of different sensitivity analyses 
have been included to investigate the missing data assumption.
x The use of graphs for individual plasma concentrations for CZP and anti-CZP levels versus 
time analysis is included.
x Other changes made in this amendment are to provide clarification or are administrative in 
nature, including minor editorial changes to abbreviations.
Specific changes
This section displays the modifications in this amendment compared with the Final Protocol 
dated 01 Jun 2015. The changes are displayed in the order of appearance.
Change #1
Study Contact Information 
Sponsor Study Physician 
Name:
, MD
Address:
208 Bath Road
Slough 
Berkshire
UK
SL1 3WE 
Phone:
Fax:
REDACTED 
R
COPY
dmen
dme
the or
the o
This document cannot be 
be used 
se
to 
to support
Berk
erk
UK
UK
up
any 
gh 
gh 
kshi
ksh
marketing 
, M
ing
h Road
h Roa
rketi
authorization
rder 
der
application 
t comp
com
r of
r of
and any
are a
are 
extensions 
P leve
 leve
o
ana
ana
variations 
alyl
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 145 of 255
Has been changed to:
Sponsor Study Physician 
Name:
, MD
Address:
Alfred-Nobel-Str 10
40789 Monheim
Germany 
Phone: 
Fax: 
Change #2
List of abbreviations
The following abbreviations have been added:
Apo
apolipoprotein
HbA1c
Hemoglobin A1c
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MI
multiple imputation
Change #3
List of abbreviations
The following abbreviation has been deleted:
TNFα
tumor necrosis factor alpha
Change #4
Section 1 Summary, paragraphs 3, 4, 6, 7, 12, 15, and 16
Additionally, subjects must have had an inadequate response to, have a contraindication to, or 
have been intolerant to at least 2 NSAIDs. Inadequate response to a NSAID is defined as lack of 
response to at least 14 days of continuous NSAID therapy at the highest tolerated dose of the 
administered NSAID. Eligible subjects will be allocated to the following study treatments in a 
1:1 ratio:
x CZP administered subcutaneously (sc) at the dose of CZP 400mg at Weeks 0, 2, and 4 
followed by CZP 200mg every 2 weeks (every other week; Q2W) sc (starting at Week 6)
x Placebo
REDACTED 
onte C
onte C
utation
utation
COPY 
This document
av
respo
respo
ad
ad
cannot 
1 S
tional
onal
e be
e be
be 
Sum
Sum
used to support
on h
n h
tum
tu
any 
has
has
marketing authorization 
arlo
arlo
n
application and any extensions 
ns
ns
or r variations 
v
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 146 of 255
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), 
study treatments will be administered sc at the study site by dedicated, unblinded, and adequately 
trained site personnel. The study treatment will be self-injected at home at Weeks 14, 18, 22, 26, 
30, 34, 38, 42, and 46. All subjects will receive training for self-injection at the study site at 
Weeks 10 and 12. During the training at the Weeks 10 and 12 visits, the study treatment will be 
self-administered under the supervision of the dedicated unblinded study personnel.
Subjects whose disease activity cannot be controlled by study medication and changes in 
background therapy (including and not limited to analgesics, NSAIDs, and slow-acting 
antirheumatic drug [SAARDs]) will be permitted to withdraw from the double-blind study drug. 
Subjects will either transition to open-label treatment offered by UCB with the marketed product 
of CZP, after Week 52, ie, completion of all study assessments, or at the discretion of the 
Investigator and in accordance with the local regulatory requirements for a maximum duration of 
2 years or until marketing authorization is granted for CZP (if applicable), whichever comes first, 
or subjects will transition to receive other treatment (including biologics). These subjects will 
remain in the study until the assessment of the primary endpoint at Week 52.
All subjects, including those withdrawn from study treatment, will have a FU Visit 8 weeks after 
their final Week 52 visit.
The primary efficacy variable is Ankylosing Spondylitis Disease Activity Score major 
improvement (ASDAS-MI) response at Week 52. The secondary efficacy variables are 
Assessment in Axial SpondyloArthritis International Society 40% (ASAS40) response at 
Weeks 12 and 52, change from Baseline in Bath Ankylosing Spondylitis Functional Index 
(BASFI) at Weeks 12 and 52, change from Baseline in BASDAI at Weeks 12 and 52, change 
from Baseline in Sacroiliac-Spondyloarthritis Research Consortium of Canada (SI-SPARCC) 
score at Week 12, and the number of subjects without relevant changes to background 
medication.
Safety variables to be assessed are adverse events (AEs), vital signs, physical examination, and 
measurements of laboratory parameters. In addition, subjects will be evaluated at Screening, 
Baseline, and at every 12 weeks thereafter up to and including Week 36 for signs and symptoms 
of latent or active tuberculosis (TB) infection and risk factors for exposure to TB using the TB 
questionnaire.
Approximately 900 subjects will be screened in order to have 300 subjects (150 subjects per 
treatment group) randomized into the study. Randomization will be stratified by presence of 
sacroiliitis on MRI and elevated CRP to ensure balanced treatment allocation across three 
subgroups: MRI+/CRP+; MRI+/CRP-; MRI-/CRP+. For each subject, the study will last a 
maximum of 66 weeks and will consist of 3 periods: 
x Screening Period lasting up to 6 weeks
x Double-Blind, placebo-controlled Period for 52 weeks
x FU Period 8 weeks after the Week 52/Withdrawal (WD) visit.
Have been changed to:
Additionally, subjects must have had an inadequate response to, have a contraindication to, or 
have been intolerant to at least 2 NSAIDs. Inadequate response to a NSAID is defined as lack of 
Bath A
Bath A
m Bas
m Bas
rthriti
rthriti
f subj
f subj
COPY 
itis 
iti
The se
The se
onal 
onal 
This document 
x
cannot
mum o
um o
Scre
Scre
be
n
 MR
 MR
used
p) ran
ran
MR
MR
to
0 sub
su
d
support
ee
ulosis 
losis 
bje
bj
any
ame
am
ks the
ks th
(T
marketing
jects
ects
e adver
adve
mete
met
authorization
ec
Socie
Socie
Ankylo
Ankylo
seline 
seline 
is Res
s Res
s w
s w
application
l ha
ha
isease 
sease
conda
conda
and
eek 
ek 
ave
ave
any
The
The
52.
52
extensions
eted 
ted
n of th
of th
ximum
ximum
hiche
hiche
o
dy d
dy 
p
variations 
dr
dr
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 147 of 255
response to at least 14 days of continuous NSAID therapy at the highest tolerated dose of the 
administered NSAID. Eligible subjects will be allocated to the following double-blind study 
treatments in a 1:1 ratio:
x CZP administered subcutaneously (sc) at the dose of CZP 400mg at Weeks 0, 2, and 4 
followed by CZP 200mg every 2 weeks (every other week; Q2W) sc (starting at Week 6)
x Placebo
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site by dedicated, unblinded, 
and adequately trained site personnel. The double-blind study treatment will be self-injected at 
home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46. All subjects will receive training for self 
injection at the study site at Weeks 10 and 12. During the training at the Weeks 10 and 12 visits, 
the double-blind study treatment will be self administered under the supervision of the dedicated 
unblinded study personnel.
Subjects whose disease activity cannot be controlled by study medication and changes in 
background therapy (including and not limited to analgesics, NSAIDs, and slow-acting 
antirheumatic drugs [SAARDs]) will be permitted to withdraw from the double-blind study drug. 
Subjects will either transition to open-label CZP treatment offered by UCB or to other treatment 
(including biologics) at the discretion of the Investigator until the assessment of the primary 
endpoint at Week 52. At the completion of the Week 52 visit, and in accordance with the local 
regulatory requirements, CZP will be provided for a maximum duration of 2 years or until 
marketing authorization is granted for CZP (if applicable), whichever comes first.
All subjects, including those withdrawn from double-blind study treatment, will have a FU 
visit 8 weeks after their final Week 52 visit.
The primary efficacy variable is Ankylosing Spondylitis Disease Activity Score major 
improvement (ASDAS-MI) response at Week 52. The secondary efficacy variables are 
Assessment in Axial SpondyloArthritis International Society 40% (ASAS40) response at 
Weeks 12 and 52, change from Baseline in Bath Ankylosing Spondylitis Functional Index 
(BASFI) at Weeks 12 and 52, change from Baseline in BASDAI at Weeks 12 and 52, change 
from Baseline in SI-Spondyloarthritis Research Consortium of Canada (SPARCC) score at 
Week 12, and the number of subjects without relevant changes to background medication.
Safety variables to be assessed are adverse events (AEs), vital signs, physical examination, and 
measurements of laboratory parameters. In addition, subjects will be evaluated at Screening, 
Baseline, and at every 12 weeks thereafter up to and including Week 52/Withdrawal (WD) for 
signs and symptoms of latent or active tuberculosis (TB) infection and risk factors for exposure 
to TB using the TB questionnaire.
Approximately 900 subjects will be screened in order to have 300 subjects (150 subjects per 
treatment group) randomized into the study. Randomization will be stratified by presence of 
sacroiliitis on MRI and elevated CRP to ensure balanced treatment allocation across 
3 subgroups: MRI+/CRP+; MRI+/CRP-; MRI-/CRP+. For each subject, the study will last a 
maximum of 66 weeks and will consist of 3 periods: 
x Screening Period lasting up to 6 weeks
REDACTED
d for
d fo
(if ap
(if ap
n from
n from
52 vis
52 vis
COPY
gator 
gator
Week 5
Week 5
or a
r a
This document
Appr
Appr
tre
tre
cannot
nd
nd sy
sy
TB usin
B usi
be
ts
and a
and a
used
s to b
to b
s of l
of l
to 
um
support
d 52, c
52, c
pondylo
ondy
mber 
mber
any
Arth
Arth
m Bas
m Ba
h
marketing 
it.t.
ylosing
ylosin
nse a
se at W
t
thriti
hrit
authorization
52 vi
2 vi
a max
max
pplicab
plicab
m doub
m doub
application
AIDs
ID
from t
from 
ffered 
ffered
until th
until t
visit
isit
and
ation 
tion
Ds, a
s a
any 
an
extensions
injec
njec
ining f
ning 
s 10 an
10 an
ion o
on o
or
lind
lind
ctet
variations 
0), the
0), the
de
de
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 148 of 255
x Double-Blind, Placebo-Controlled Period for 52 weeks
x FU Period 8 weeks after the Week 52/Withdrawal (WD) visit.
Change #5
Section 2.2 Burden of disease in axSpA, paragraph 2
Several large observational and noninterventional cohort studies (Cuirea et al, 2013; Sieper and 
van der Heijde, 2013a) reported a similar burden of disease at study baseline across AS studies 
(captured through BASFI and BASDAI) in nonradiographic as well as radiographic axSpA 
(captured through BASDAI). A literature review of clinical studies in both populations (Callhoff 
et al, 2015) and (RAPID-AxSpA) (Landewe et al, 2014) confirmed this finding in the clinical 
study setting.
Has been changed to:
Several large observational and noninterventional cohort studies (Cuirea et al, 2013; Sieper and 
van der Heijde, 2013a) reported a similar burden of disease at study baseline across AS studies 
(captured through BASFI and BASDAI) in nonradiographic as well as radiographic axSpA 
(captured through BASDAI). A literature review of studies in both populations (Callhoff et al, 
2015) and a recent study with CZP (RAPID-AxSpA) (Landewe et al, 2014) confirmed this 
finding in the clinical study setting.
Change #6
Section 2.4 Current management of axial spondyloarthritis, paragraphs 3 and 4
Patients who are intolerant of or have inadequately responded to NSAIDs, or those in whom 
NSAIDs are contraindicated, have limited treatment options. Tumor necrosis factor alpha 
(TNFα) inhibitors (CZP, adalimumab [ADA] etanercept [ETN] infliximab [IFX]), golimumab 
[GOL]) are currently the only effective and approved treatment options as of Dec 2014; IFX and 
GOL are indicated for active AS only, while CZP, ADA, and ETN are indicated for axSpA 
without radiographic evidence of AS (nr-axSpA) as an addition to the AS indication in several 
regions.
At the 2014 Annual Meeting of the ACR/SPARTAN group a draft treatment guideline was 
presented for the subject suffering from both AS and nr-axSpA. These guidelines recommend the 
use of a TNF inhibitor after NSAID treatment.
Have been changed to:
Patients who are intolerant of or have inadequately responded to NSAIDs, or those in whom 
NSAIDs are contraindicated, have limited treatment options. Tumor necrosis factor-alpha 
inhibitors (TNFi) (CZP, adalimumab [ADA] etanercept [ETN] infliximab [IFX]), golimumab 
[GOL]) are the only effective and approved treatment options as of Dec 2014; IFX and GOL are 
indicated for active AS only, while CZP, ADA, and ETN are indicated for axSpA without 
radiographic evidence of AS (nr-axSpA) as an addition to the AS indication in several regions.   
REDACTED 
of ax
of ax
COPY
ud
ud
A) (La
A) (L
This document
Patie
atie
NSA
NS
i
cannot 
N
e been
been
ent
en
be 
r t
NF in
NF in
sed
nnual 
nual 
the s
the 
to support
ly y
tive A
ive A
evidenc
viden
any
mum
mum
effec
effec
marketing 
xial s
al s
e inade
inad
e limite
limit
mab
mab
authorization 
sp
sp
application
udy b
dy b
s well a
well
in both
in bot
ndewe
ndew
and
uirea e
irea e
ba
b
any extensions
axSp
xSp
tions (
ions 
in the
in th
or
tud
tu
pA
pA
variations 
r and 
and 
udie
die
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 149 of 255
At the 2014 Annual Meeting of the ACR/SPARTAN group a draft treatment guideline was 
presented for the subject suffering from both AS and nr-axSpA. These guidelines recommend the 
use of a TNFi after NSAID treatment.
Change #7
Section 2.5 Rationale, paragraph 2
To address the unmet need for treatment options for nr-axSpA, AS0006 will be conducted 
focusing on subjects who do not meet the mNY classification criteria for AS (see 
Appendix 18.2). Data suggest that patients with objective signs of inflammation and high disease 
activity are likely to run a chronic disease course and unlikely to be well managed on 
conventional therapy (Rudwaleit ACR 2013). Furthermore, studies where anti-TNFs have been 
withdrawn in nr axSpA patients show that patients flare quickly and hence the disease is unlikely 
to go into spontaneous remission. However, there are no long-term prospective studies to assess 
how patients meeting the ASAS classification criteria respond to conventional therapies. With 
the conduct of this 52-week study comparing CZP to placebo in combination with standard of 
care, a better understanding should be gained of how a long-term anti-TNF therapy compares to
standard of care in patients meeting the ASAS criteria with objective signs of inflammation. 
Moreover, patients whose disease cannot be managed under the blinded study treatment 
conditions will be able to discontinue the study treatment and transition to either open-label CZP 
or other therapies.
Has been changed to:
To address the unmet need for treatment options for nr-axSpA, AS0006 will be conducted 
focusing on subjects who do not meet the mNY classification criteria for AS (see 
Appendix 18.2). Data suggest that patients with objective signs of inflammation and high disease 
activity are likely to run a chronic disease course and unlikely to be well managed on 
conventional therapy (Rudwaleit ACR 2013). Furthermore, studies where anti-TNFs have been 
withdrawn in nr-axSpA patients show that patients flare quickly and hence the disease is unlikely 
to go into spontaneous remission. However, there are no long-term prospective studies to assess 
how patients meeting the ASAS classification criteria respond to conventional therapies. With 
the conduct of this 52-week study comparing CZP to placebo in combination with standard of 
care, a better understanding should be gained of how a long-term anti-TNF therapy compares to 
standard of care in patients meeting the ASAS criteria with objective signs of inflammation. 
Moreover, patients whose disease cannot be managed under the blinded study treatment 
conditions will be able to discontinue the double-blind study treatment and transition to either 
open-label CZP or other therapies.
Change #8
Section 4.1.3 Other efficacy variables
The following bullet has been added:
x Change from Baseline in sacroiliitis grading to Week 52 for structural damage
REDACTED 
ent opt
ent opt
et the
et the
COPY
ed un
ed un
eatme
eatm
This document 
Ch
Ch
cannot 
ns w
s 
label 
abel 
be
pati
ati
wil
wi
used 
ders
ers
re in p
e in p
ien
ien
to 
2
stan
stan
support
missio
issio
he ASA
e AS
-wee
wee
any 
t A
t A
nts sho
ts sh
marketing
e mN
e mN
tients w
tients 
disease
diseas
ACR
ACR
authorization
ent a
nt a
tions 
ions 
NY
NY
application 
omb
m
m anti
m ant
objectiv
bject
der the 
er the
and
and
and
venti
venti
mbin
bin
any 
h
ective
ectiv
ion
i
extensions
d high
high
d on
d on
TNF
TNF
he di
e di
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 150 of 255
Change #9
Section 4.2.3 Pharmacogenomic variables
For individuals consenting to the genomics substudy, blood samples will be drawn for possible 
genetic/epigenetic, genomic, proteomic, and metabolomics analysis at Baseline and Week 12. 
Additional samples will be collected for genomics, proteomics, and metabolomics analysis only, 
at Baseline, Weeks 4, 12, and 52. Collection of the samples will enable the exploratory 
evaluation of biomarkers relative to disease activity, drug treatment, and inflammatory and 
immune response processes. The nature and format of these tentative analyses will be determined 
when the results of the main study are made available. The samples will be stored at -80°C at the 
central biorepository for up to 20 years.
Has been changed to:
For individuals consenting to the genomics substudy, blood samples will be drawn for possible 
genetic/epigenetic, genomic, proteomic, and metabolomics analysis at Baseline and Week 12. 
Additional samples will be collected for genomics, proteomics, and metabolomics analysis only, 
at Weeks 4 and Week 52/WD. Collection of the samples will enable the exploratory evaluation 
of biomarkers relative to disease activity, drug treatment, and inflammatory and immune 
response processes. The nature and format of these tentative analyses will be determined when 
the results of the main study are made available. The samples will be stored at -80°C at the 
central biorepository for up to 20 years.
Change #10
Section 4.3 Immunological variables, paragraph 1
4.3 
Immunological variable(s) 
Anti-CZP antibody (anti-CZP Ab) concentrations will be assessed at Baseline and Weeks 1, 2, 4, 
12, 24, 36, 52, and the FU Visit (8 weeks after the Week 52/WD Visit). In addition, the anti CZP 
Ab concentrations will be assessed in subjects who withdraw from study drug and transition to 
open-label CZP. The number and percent of subjects with anti-CZP Ab concentrations above 
2.4 units/mL will be reported as follows:
Has been changed to:
4.3 
Immunological variables 
Anti-CZP antibody (anti-CZP Ab) concentrations will be assessed at Baseline and Weeks 1, 2, 4, 
12, 24, 36, 52/WD, and the FU visit (8 weeks after the Week 52/WD visit). In addition, the 
anti-CZP Ab concentrations will be assessed in subjects who withdraw from study drug and 
transition to open-label CZP. The number and percent of subjects with anti-CZP Ab 
concentrations above 2.4 units/mL will be reported as follows:
REDACTED 
es, pa
es, pa
(
COPY
e sam
e sam
This document
rans
ans
con
con
cannot
36, 5
36, 5
CZP 
CZP
siti
sit
be
antib
antib
used 
d
muno
uno
to
 to:
to:
support 
sse
s
mber an
mber a
eported
porte
any
(8 w
(8 
essed
essed
marketing 
ara
ra
s)
s)
) conce
con
we
w
authorization 
agra
agra
application 
le t
e 
nflamm
flam
analys
analy
ples w
ples w
and
metab
etab
the
the
any 
d
aselin
aselin
bol
b
extensions 
0
draw
draw
or
°C 
°C 
variations 
rmin
rmin
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 151 of 255
Change #11
Section 4.4 Safety variables, paragraphs 4 through 6
Clinical laboratory values (hematology, biochemistry, urinalysis) will be collected and assessed 
at Screening, Baseline, Weeks 2, 4, 8, 12, 24, 36, at the end of study Completion at 
Week 52/Early Withdrawal Visit and at the FU Visit (8 weeks after the Week 52/WD Visit). In 
addition, clinical laboratory values will be collected and assessed at study visits during the 
administration of open-label CZP in subjects who withdraw from the study treatment.
Furthermore, CRP will be collected and assessed either in a blinded or open manner at 
Screening, 3 to 5 days before Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 
at the end of study Completion at Week 52/Early Withdrawal Visit and at the FU Visit (8 weeks 
after the Week 52/WD Visit).
At Screening, all subjects will have an Interferon-Gamma Release Assay (IGRA) test 
(QuantiFERON® TB test or Elispot®test, when the QuantiFERON test indicated is not available), 
and a chest x-ray read (or, if done, computed tomography of the chest) which must be reported 
consistent with standard clinical reporting practice by an experienced qualified TB specialist, 
radiologist, or a pulmonologist, who is specifically required to look for signs of active TB or 
signs of past/inactive TB infection. The official report of the imaging must specifically indicate 
the absence of findings suggestive of current active TB or prior inactive TB. In addition to a 
physical examination done intermittently throughout the study, subjects will be evaluated at 
Screening, Baseline, and every 12 weeks thereafter up to and including Week 36, including the 
Completion/Early Withdrawal Visit, for signs and symptoms of latent or active TB infection and 
risk factors for exposure to TB using the TB questionnaire
Have been changed to:
Clinical laboratory values (hematology, biochemistry, urinalysis) will be collected and assessed 
at Screening, Baseline, Weeks 2, 4, 8, 12, 24, 36, at the end of study completion at Week 52/WD 
Visit and at the FU Visit (8 weeks after the Week 52/WD Visit). In addition, clinical laboratory 
values will be collected and assessed at study visits during the administration of open-label CZP 
in subjects who withdraw from the double-blind study treatment.
Furthermore, CRP will be collected and assessed either in a blinded or open manner at 
Screening, 3 to 5 days before Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 
at the end of study completion at Week 52/WD visit and at the FU visit (8 weeks after the 
Week 52/WD visit).
At Screening, all subjects will have an Interferon-Gamma Release Assay (IGRA) test 
(QuantiFERON® TB test or Elispot®test, when the QuantiFERON test indicated is not available),
and a chest x-ray read (or, if done, computed tomography of the chest) which must be reported 
consistent with standard clinical reporting practice by an experienced qualified TB specialist, 
radiologist, or a pulmonologist, who is specifically required to look for signs of active TB or 
signs of past/inactive TB infection. The official report of the imaging must specifically indicate 
the absence of findings suggestive of current active TB or prior inactive TB. In addition to a 
physical examination done intermittently throughout the study, subjects will be evaluated at 
Screening, Baseline, and every 12 weeks thereafter up to and including the Week 52/WD visit, 
REDACTED
eafte
afte
gns and
ns and
TB q
TB q
COPY
TB o
TB o
hout th
hout th
ter u
er
This document
cons
cons
rad
rad
cannot 
nin
nin
ntiFER
tiFER
a che
a ch
i
be 
ng, 
ng,
used
udy c
dy c
visit
visit
to
ays 
ays 
support
from
from
ll be co
l be c
be
b
any 
ks 
ks
ssesse
ssess
t
marketing 
gy, bioc
gy, bio
, 8, 12
8, 12
s afte
aft
authorization
he st
e st
up to 
up to 
d sym
sym
questio
uestio
application 
ced
ed
look fo
ook f
imagin
imag
r prior 
prior
stud
tud
and
t) wh
) wh
d qu
d qu
any 
GR
G
dicate
dicat
hic
hi
extensions
44, 4
4, 4
Visit (
Visit (
GRA
RA
or 
48
48
variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 152 of 255
for signs and symptoms of latent tuberculosis (LTB) or active TB infection and risk factors for 
exposure to TB using the TB questionnaire.
Change #12
Section 5.1.1 Study periods
The study includes 3 periods. An injection schedule is provided in Section 7.2.2.
Period 1 (Screening Period): 1 to 6 weeks before Baseline: 
Prior to any study activities, subjects will be asked to read and sign the Informed Consent form 
for the conduct of the study. A separate informed consent form will also be obtained from 
subjects consenting to the use of their blood samples in a substudy for possible genetic, 
genomic/epigenetic, and proteomic analysis.
Laboratory data is to be obtained to verify the doses of MTX, SSZ, hydroxychloroquine (HCQ), 
NSAIDs, and corticosteroids, if used, are stable. Laboratory data will also be collected to ensure 
the washout of any medications not permitted for use during the study has been performed, and 
to initiate latent TB treatment where necessary. Concomitant medications permitted during the 
study should remain stable for at least 4 weeks prior to Baseline.
Sacroiliac-joint x-ray (not older than 12 months before Baseline and verified by central reading 
during the Screening Period) must prove that the subject belongs to the mNY-negative axSpA 
subpopulation, ie, does not have sacroiliitis grade ≥2 bilaterally or grade 3 to 4 unilaterally. 
Potentially eligible axSpA subjects without suitable SI-joint x-ray must undergo the x-ray with 
central reading within the Screening Period. SI-joint x-rays (read centrally) will allow 
discrimination of subjects with AS and without definitive evidence for sacroiliitis on x-ray 
(mNY negative-axSpA). Subjects with AS (mNY-positive) must be excluded from further 
participation in this study.
Confirmed mNY-negative axSpA subjects must undergo an MRI later during the Screening 
Period for central reading with results from the central reading available by no later than at the 
Baseline visit. 
Additionally the subjects must get a further measurement of CRP 3 to 5 days before Baseline 
(Week 0).  
Period 2 (Double-Blind Period): Week 0 to Week 52, placebo controlled. 
Eligible subjects will be allocated to the following study treatments in a 1:1 ratio:
x CZP administered at the dose of 400mg at Weeks 0, 2, and 4 followed by 200mg Q2W 
(starting at Week 6 up to and including Week 50)
x Placebo
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), 
study treatments will be administered sc at the study site by dedicated, unblinded and adequately 
trained site personnel. The study treatment will be self-injected at home at Weeks 14, 18, 22, 26, 
30, 34, 38, 42, and 46. All subjects will receive training for self-injection at the study site on 
Weeks 10 and 12. During the training on Weeks 10 and 12 visits, the study treatment will be 
he 
grade 
grade
ut suit
ut suit
eriod. 
eriod.
and w
and w
h
COPY 
o B
efore B
fore
subj
subj
This document 
x
cannot 
u
ZP ad
ZP ad
(star
(star
be
bjec
bjec
used 
uble
ble-B
to support 
ithth
ects m
cts m
any
pA s
pA 
h resu
h resu
marketing 
withou
itho
h AS (m
AS (
sub
su
authorization 
Ba
bject b
ect b
≥2 bi
≥2 bi
itable 
table 
SI
SI-jojo
-
ou
application
study
udy
medicat
edica
eline.
line.
aselin
aselin
and
dro
ll also
also
y h
y h
any 
oxych
oxych
b
extensions
nsen
nsen
ned fro
ed fro
e gene
gene
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 153 of 255
self-administered under the supervision of the unblinded study personnel. Concomitant 
medications permitted during the study should remain stable for at least 4 weeks prior to the 
Week 12, 24, and 52 assessments.
Period 3 (Follow-Up Period):
All subjects, including those withdrawn from study treatment, will have a FU Visit 8 weeks after 
the Week 52/WD visit.
Alternative schedules  
Subjects who discontinue the study treatment and enter open-label treatment with CZP or other 
treatments (including biologics) will follow alternative schedules of assessments. Assessments
are to be continued as at Week 12 every 12 weeks until as close as possible to Week 52 (within 
±4 weeks of the originally planned Week 52 Visit) of the regular visit schedule. Subjects will 
then be invited to the final assessment visit at Week 52.
Has been changed to:
The study includes 3 periods. An injection schedule is provided in Section 7.2.2.
Period 1 (Screening Period): 1 day to 6 weeks before Baseline: 
Prior to any study activities, subjects will be asked to read and sign the Informed Consent form 
for the conduct of the study. A separate informed consent form will also be obtained from 
subjects consenting to the use of their blood samples in a substudy for possible 
genetic/epigenetic, genomic, proteomic, and metabolite analysis.
Laboratory data (hematology, urine, and biochemistry tests) will be obtained, and treatment of 
LTB will be initiated when necessary. Subjects must undergo a TB test and complete a TB 
questionnaire. Bath Ankylosing Spondylitis Disease Activity Index, BASMI, and spinal mobility 
assessments will be performed. Concomitant medications permitted during the study should 
remain stable for at least 4 weeks prior to Baseline at Week 0.
Sacroiliac-joint x-ray (not older than 12 months before Baseline and verified by central reading
during the Screening Period) must prove that the subject belongs to the mNY-negative axSpA 
subpopulation, ie, does not have sacroiliitis grade ≥2 bilaterally or grade 3 to 4 unilaterally. 
Potentially eligible axSpA subjects without suitable SI-joint x-ray must undergo the x-ray with 
central reading within the Screening Period. Sacroiliac-joint x-rays (read centrally) will allow 
discrimination of subjects with AS and without definitive evidence for sacroiliitis on x-ray 
(mNY negative-axSpA). Subjects with AS (mNY-positive) must be excluded from further 
participation in this study.
Confirmed mNY-negative axSpA subjects must undergo an MRI later during the Screening 
Period for central reading with results from the central reading available by no later than at the
Baseline visit. 
Additionally the subjects must get a further measurement of CRP 3 to 5 days before Baseline 
(Week 0).  
Period 2 (Double-Blind Period): Week 0 to Week 52, placebo controlled. 
Eligible subjects will be allocated to the following double-blind study treatments in a 1:1 ratio:
mp
metab
meta
d bioch
d bioc
y. Subj
y. Subj
ndy
ndy
COPY
o rea
re
consen
cons
ples 
ples 
This document
eriri
Base
Base
A
cannot 
tioio
irmed
rmed
iod f
od f
be 
tiv
on in
on in
used
th
of sub
of sub
ve-ax
ax
to
hin t
hin 
suppor
d) m
d) m
not hav
not ha
xSpA s
SpA
th
any
er tha
er tha
mus
mu
marketing
je
ylitis D
litis D
comitan
omita
prior t
prior
authorization 
nt 
 in a s
in a s
abolite
bolite
hemis
hemis
ects m
cts m
application 
Se
e:
and si
and s
t form
form
nd 
ectio
ectio
any extensions
ssess
sessm
eek 52
ek 5
e. Sub
. Sub
or
or ot
r o
variations 
h
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 154 of 255
x CZP administered at the dose of 400mg at Weeks 0, 2, and 4 followed by 200mg Q2W 
(starting at Week 6 up to and including Week 50)
x Placebo
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site by dedicated, unblinded 
and adequately trained site personnel. The double-blind study treatment will be self-injected at 
home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46. All subjects will receive training for self-
injection at the study site on Weeks 10 and 12. During the training on Weeks 10 and 12 visits, 
the double-blind study treatment will be self-administered under the supervision of the unblinded 
study personnel. Concomitant medications permitted during the study should remain stable for at 
least 4 weeks prior to the Weeks 12, 24, and 52/WD assessments.
Period 3 (Follow-Up Period):
All subjects, including those withdrawn from the double-blind study treatment, will have a FU 
visit 8 weeks after the Week 52/WD visit.
Alternative schedules  
Subjects who discontinue the double-blind study treatment and enter open-label treatment with 
CZP will be assessed 2 and 4 weeks after open-label CZP treatment has been initiated and every 
12 weeks thereafter. Alternatively, subjects who discontinue the double-blind study treatment 
and receive other treatment (including biologics) will be assessed every 12 weeks after initiation 
of the other treatment. The alternative schedules for open-label CZP and other treatment can be 
found in Table 5‒2 and Table 5‒3, respectively. In either alternative schedule, assessments 
should be conducted until as close as possible to Week 52 (within ±4 weeks), where Week 52 is 
relative to the original randomization at Week 0. Subjects will then be invited to the final 
assessment visit at Week 52.
Change #13
Section 5.1.2 Study duration, paragraph 2
The estimated recruitment period is up to 15 months. The first subject first visit is planned in 
Quarter 3 of 2015. A completed subject is one who completes the Week 52 Visit. UCB will offer 
continuation of open-label treatment with the marketed product of CZP, after Week 52, ie, 
completion of all study assessments, on discretion of the Investigator and in accordance with the 
local regulatory requirements, for a maximum duration of 2 years or until marketing 
authorization is granted for CZP (if applicable), whichever comes first.
Has been changed to:
The estimated recruitment period is up to 15 months. The first subject first visit is planned in 
Quarter 3 of 2015. A completed subject is one who completes the Week 52/WD visit. Subjects 
will either transition to open-label CZP treatment offered by UCB or to other treatment 
(including biologics) at the discretion of the Investigator until the assessment of the primary 
endpoint at Week 52/WD. At the completion of the Week 52/WD visit, and in accordance with 
the local regulatory requirements, CZP will be provided for a maximum duration of 2 years or 
until marketing authorization is granted for CZP (if applicable), whichever comes first.
REDACTED 
cs) w
cs) 
dules f
dules f
ctively
ctivel
possib
possi
n at W
n at W
COPY
 CZP
 CZ
discon
disco
wil
wi
This document 
Has
as
The
The
Q
cannot 
ula
ula
rizatio
izatio
s be
be
be 
of 
of 
ator
ator
used
. A
. A
f open
open
f all 
all
to
A c
A c
support 
ration, 
ation
ment p
ment 
any marketing
Week
Week
authorization
ntinu
tin
ll be a
l be a
for op
or op
ly. In e
y. In 
le to 
e to 
k
application 
nd ente
nd ent
treatm
reatm
nue
nue
and any 
tment
tmen
extensions 
e u
in stab
n stab
or
unbl
nb
variations 
elf
elf-f
sits, 
sits, 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 155 of 255
Change #14
Section 5.2 Schedule of study assessments, paragraph 3
At any time during the study course, but preferably not before Week 12, the Investigator may 
discontinue the study treatment and start open-label treatment with either CZP (which will be 
provided free of charge by UCB) or an alternative drug (eg, other treatment [including 
biologics]). Table 5‒2 shows the schedule of assessments for subjects receiving open-label 
treatment with CZP and Table 5‒3 shows the schedule of assessments for subjects receiving an 
alternative treatment (not CZP).
Has been changed to:
At any time during the study course, but preferably not before Week 12, the Investigator may 
discontinue the double-blind study treatment and start open-label treatment with either CZP 
(which will be provided free of charge by UCB) or an alternative drug (eg, other treatment 
[including biologics]). Table 5‒2 shows the schedule of assessments for subjects receiving 
open-label treatment with CZP and Table 5‒3 for subjects receiving an alternative treatment (not 
CZP).
REDACTED COPY 
This document cannot be used to support any marketing authorization application and
an alt
n al
any 
otot
subjec
subje
ter
t
extensions 
stigat
tigat
th eith
h eith
ther 
her 
or variations 
an 
an 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 156 of 255
Change #15
Section 5.2 Schedule of study assessments, Table 5–1
The following row has been added:
Table 5‒1: 
Schedule of study assessment - Study Periods 1 to 3 (Screening until FU)  
Visit #
Scr
Scr 
day -5
to -3
1/
B
L
2
3
4
5
6
7
8
9
H
1
0
1
1
H
1
2
1
3
H
1
4
15
H
1
6
17
H
1
8
1
9
H
2
0
2
1
H
2
2
23
H
2
4
2
5
H
26
2
7
28
29
Week
Protocol 
Activity
-6 weeks 
to -1 day
0
1
2
4
6
8
1
0
1
2
1
4
/
H
1
6
1
8
/
H
2
0
2
2
/
H
2
4
26
/H
2
8
30
/H
3
2
3
4
/
H
3
6
3
8
/
H
4
0
42
/
H
4
4
4
6
/
H
48
5
0
52
/
W
D
F
U
b
HBsAg/
antibodies to 
hepatitis 
C/HIV/HLA-B
27/CKD-EPI
Xf 
 
 
Change #16
Section 5.2 Schedule of study assessments, Table 5–1 (The row describing IXRS)
Table 5‒1: 
Schedule of study assessment - Study Periods 1 to 3 (Screening until FU)  
Visit #
Scr
Scr 
day -
5 to-
3
1/
B
L
2
3
4
5
6
7
8
9
H
1
0
1
1
H
1
2
1
3
H
1
4
15
H
1
6
17
H
1
8
1
9
H
2
0
2
1
H
2
2
23
H
2
4
2
5
H
26
2
7
28
29
Week
Protocol 
Activity
-6 to 
-1 
0 
1 
2
4 
6 
8 
1
0
 
1
2 
1
4 
/
H 
1
6 
1
8 
/
H 
2
0 
2
2 
/
H 
2
4 
26 
/H 
2
8 
30 
/H 
3
2 
3
4 
/
H 
3
6 
3
8 
/
H 
4
0 
42 
/
H 
4
4 
4
6 
/
H 
48 
5
0 
52
/
W
D
F
U
b
IXRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X 
REDACTED 
AC
AC
ACTED COPY 
Y
COPY
This document cannot 
n
nno
c nn
be 
b
used 
d
2
d
us d to 
o support 
6
7
t
s p ort any
Stu
Stu
a
marketing 
1 (Th
1 (T
authorization 
hori
o
ati n application 
/H
/H
li ati
pli
pli
plic
pli
and
0
3
d 
an
any 
9
H
a y extensions 
2
xte
te
te
e te
or variations 
on thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 157 of 255
Has been changed to:
Table 5‒1: 
Schedule of study assessment - Study Periods 1 to 3 (Screening until FU)  
Visit #
Scr
Scr 
day -5
to -3
1/
B
L
2
3
4
5
6
7
8
9
H
1
0
1
1
H
1
2
1
3
H
1
4
15
H
1
6
17
H
1
8
1
9
H
2
0
2
1
H
2
2
23
H
2
4
2
5
H
26
2
7
28
29
Week
Protocol 
Activity
-6 weeks 
to -1 day 
0 
1 
2
4 
6 
8 
1
0
 
1
2 
1
4 
/
H 
1
6 
1
8 
/
H 
2
0 
2
2 
/
H 
2
4 
26 
/H 
2
8 
30 
/H 
3
2 
3
4 
/
H 
3
6 
3
8 
/
H 
4
0 
42 
/
H 
4
4 
4
6 
/
H 
48 
5
0 
52
/
W
D
F
U
b
IXRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X 
REDACTED COPY 
This document cannot be used to support any marketing authorization application 
titititio
and 
an
a
any
4
/
any 
a y extensions
1
H
2
2
s
te
io s 
3
xte
te
e te
e t
or 
o variations 
on thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 158 of 255
Change #17
Section 5.1 Schedule of study assessments, Table 5-1: footnotes d to o have been reordered 
and footnotes with changes are noted.
a
Informed consent: Prior to any study activities, subjects will be asked to read and sign the 
informed consent form for the conduct of the study. A separate informed consent form will 
also be obtained from subjects consenting to the use of their blood samples in a substudy for 
possible genetic, genomic/epigenetic, and proteomic analysis.
d Testing to rule out hepatitis B surface antigen and antibodies to hepatitis C and testing for 
HLA-B27 and abnormalities for estimated Glomerular Filtration Rate as measured by 
CKD-EPI are to be performed at Screening only.
f
Pregnancy testing must be carried out for women of childbearing potential and will be serum 
testing at the Screening Visit and FU and urine testing (dipstick) at Baseline and 
Week 52/Withdrawal.
g Includes evaluation of signs and symptoms of active TB and risk factors for exposure to TB. 
Weight is to be measured at Screening, Week 24, and at Completion at Week 52/Early 
Withdrawal. Height will be measured at the Baseline Visit only.
k Magnetic resonance imaging of the spine and SI joints to be performed at Screening, 
Weeks 12 (SI only), 52, or Early Withdrawal Visit if MRI was performed more than 12 weeks 
prior to Early Withdrawal Visit.
n At on-site visit days (Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), 
study treatments will be administered sc at the study site by dedicated, unblinded and 
adequately trained site personnel. The study treatment will be self-injected at home at 
Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46. From Week 52 onwards, after completion of all 
on site assessments and procedures, the subject may receive further open-label treatment with 
CZP to be supplied to discontinued subjects or another biologics at the discretion of the 
Investigator.
o All subjects will receive training for self-injection at the study site on Weeks 10 and 12. 
During the training at the Weeks 10 and 12 visits, the study treatment will be 
self-administered under the supervision of the unblinded study personnel.
Have been changed to: 
a
Informed consent: Prior to any study activities, subjects will be asked to read and sign the 
informed consent form for the conduct of the study. A separate informed consent form will 
also be obtained from subjects consenting to the use of their blood samples in a substudy for 
possible genetic/epigenetic, genomic, proteomic, and metabolite analysis.
d Subjects will be encouraged to be in fasting condition at Baseline and at Week 52/WD or at 
the time the subject shifts to alternative treatment, for Apo A1, ApoB, and lipoprotein(a) 
assessments.
e
HbA1c will be measured at Baseline and Week 52/WD. 
REDACTED 
8, 10, 
8, 10, 
d sc
d sc atat
The s
The s
42,
42,
COPY
oints
oint
Visit if
Visit 
This document
d Su
Su
cannot 
med
e
o be ob
be ob
possib
ossib
be 
co
d co
d co
used
nged
ged
onse
onse
to 
u
d t
d
support
e trai
trai
at the W
the W
under 
nder
any 
ini
i
marketing 
stud
tu
, and 4
and 4
es, the 
s, the
nued su
nued 
authorization 
f M
12, 16
2, 16
t the s
the s
udy t
dy t
application
pletio
pletio
only.
only.
to be p
o be 
MRI 
MRI
and 
factor
factor
any 
inin
extensions 
d by 
by 
and w
nd w
ne a
ne a
or
g fo
g fo
variations 
for
or
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 159 of 255
f
Testing to rule out HBsAg, antibodies to hepatitis C, and HIV will be performed. In addition, 
testing for HLA-B27 and abnormalities for estimated glomerular filtration rate as measured by 
CKD-EPI are to be performed.
h Pregnancy testing must be carried out for women of childbearing potential: A serum test will 
be performed at the Screening visit and FU, and urine testing (dipstick) at Baseline and 
Week 52/WD.
i
Includes evaluation of signs and symptoms of active TB and risk factors for exposure to TB. 
Weight is to be measured at Screening, Week 24, and at completion at Week 52/WD. Height 
will be measured at the Baseline visit only.
m Magnetic resonance imaging of the spine and SI joints to be performed at Screening and at the 
Week 12 and at the Week 52/WD visits if MRI was performed more than 12 weeks prior to 
WD visit.
p Contact IXRS to register the visit and obtain next kit number, where applicable.
q At on-site visit days (Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site by dedicated, unblinded 
and adequately trained site personnel. The double-blind study treatment will be self-injected at 
home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46. From Week 52 onwards, after 
completion of all onsite assessments and procedures, the subject may receive open-label CZP 
at the discretion of the Investigator. 
r
All subjects will receive training for self-injection at the study site on Weeks 10 and 12. 
During the training at the Weeks 10 and 12 visits, the double-blind study treatment will be 
self-administered under the supervision of the unblinded study personnel.
REDACTED 
inject
inject
nd 12 
nd 12 
ision o
sion 
COPY 
46.6
ures, t
ures, 
This document cannot be used to support any marketing authorization 
tion at
ion a
visits
visits
of the 
f the 
application
udy s
udy 
dy trea
dy tre
om We
m W
he sub
he su
and 
2, 36,
2, 36,
i
any 
pplica
pplic
extensions 
ening a
ning 
 week
week
or variations 
TB.
B. 
Heigh
eigh
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 160 of 255
Change #18
Section 5.2 Schedule of study assessments
The following row has been added:
Table 5‒2: 
Schedule of alternative study assessment with CZP - after subject discontinuation of study 
treatment 
Visit #
wdt
2
wdt
3
wdt
5
wdt
6
wdt
Week
Protocol 
Activity
0 
2
4 
6H 
8H
10 
12 
14 H 
16H 
18 H 
20 H 
22 H 
24 and 
Q12W 
 
52/
WD 
FUa
Telephone 
contactk
 
 
 
X
 
 
 
X
 
X 
 
 
 
 
 
Change #19
Section 5.2 Schedule of study assessments
Table 5‒2: 
Schedule of alternative study assessment with CZP - after subject discontinuation of study treatment 
Visit #
1
wdt
2
wdt
3
wdt
5
wdt
6
wdt
Week
Protocol 
Activity
0 
2
4 
6 H 
8 H
10 
12 
14 H 
16H 
18 H 
20 H 
22 H 
24 and 
Q12W 
 
52/WD 
FUa
Has been changed to:
Table 5‒2: 
Schedule of alternative study assessment with CZP - after subject discontinuation of the double-blind study 
treatment 
Visit #
1
wdt
2
wdt
3
wdt
4
wdt
5
wdt
REDACTED COPY 
OP
OP
OP
OP
This document 
wd
w
en cannot 
dt
dt
no
an
be
lter
er
used 
rna
rna
to support 
1
s ppo
any y
10
any marketing 
ment w
ent w
5
w
rk
authorization application 
ca
a pli
and 
an
any extensions 
ontin
ontin
ex
ex
ex
ex
or variations 
on thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 161 of 255
Week
Protocol 
Activity
0 
2
4 
6H 
8H
10H 
12 
14H 
16H 
18H 
20H 
22H 
24 and 
Q12W 
 
52/WD 
FUa
Change #20
Section 5.2 Schedule of study assessments, Table 5–2
Table 5‒2: 
Schedule of alternative study assessment with CZP - after subject discontinuation of study treatment 
Visit #
1
wdt
2
wdt
3
wdt
5
wdt
6
wdt
Week
Protocol Activity
0 
2
4 
6 H 
8 H
10 
12 
14 H 
16H 
18 H 
20 H 
22 H 
24 and 
Q12W 
 
52/WD 
FUa
CZP administration sc 
Xi 
Xi 
Xi 
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
Continue assessments as at W24 every 12 weeks 
until as close as possible to W52 of the original 
visit schedule. Subject will then be invited to the 
final assessment visit at W52
X
X
REDACTED 
DAC ED COPY 
16
PY
X
CO
This document cannot be used 
use
to support 
u
rt any 
a
marketin
m
ing 
in
authorizati
uth
ation 
X
on
ati
application 
io
H
18 H
18
lic
p
and
disco
isco
a
any 
on
extensions or 
o variations 
on
ion
va
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 162 of 255
Has been changed to: 
Table 5‒2: 
Schedule of alternative study assessment with CZP - after subject discontinuation of the double-blind study 
treatment 
Visit #
1
wdt
2
wdt
3
wdt
4
wdt
5
wdt
Week
Protocol Activity
0
2
4
6H
8H
10H
12
14H
16H
18H
20H
22H
24 and 
Q12W
52/WD
FUa
CZP administration sc 
Xl
Xl
Xl
X
X
X
X
X
X
X
X
X
Xm
Continue assessments as at W24 every 12 weeks 
until as close as possible to W52 of the original 
visit schedule. Subject will then be invited to 
the final assessment visit at W52
 
 
REDACTED
AC ED 
ED COPY 
PY
This document cannot be used to support any y marketing 
m
in
authorization 
th
atio
application 
pp
io
and
X
d 
d any 
2H
a
extensions 
5
w
on
te
H
ex
or
the
th
variations 
on
he
he
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 163 of 255
Change #21
Section 5.2 Schedule of study assessments, Table 5‒2: footnotes have been reordered and 
footnotes with changes are noted.
Note: All weeks are ±3 days compared to Baseline. Week 0 of the alternative schedule starts 
2 weeks after the last dose of the study treatment.
d
Includes evaluation of signs and symptoms of active TB and risk factors for exposure to TB. 
Weight is to be measured at wdt Week 0, Week 24, and at completion at Week 52/Early 
Withdrawal Visit.
e
If the last Q12W assessment for a subject who discontinues study treatment is ≤4 weeks 
before the final assessments visit at Week 52, the assessment should be cancelled and the 
subject should instead be invited to undergo the final assessments visit at Week 52 (the
Week 52 Visit is to be scheduled 52 weeks (±3 days) after Baseline).
Have been changed to:
Note: All weeks are ±3 days compared to Baseline. Week 0 of the alternative schedule starts 
2 weeks after the last dose of the double-blind study treatment.
c
Subjects will be encouraged to be in fasting condition at the time the subject shifts to 
alternative treatment, for Apo A1, ApoB, and lipoprotein(a) assessments.
d HbA1c will be measured at wdt Week 0 and Week 52/WD.
f
Includes evaluation of signs and symptoms of active TB and risk factors for exposure to TB. 
Weight is to be measured at wdt Week 0, Week 24, and at completion at Week 52/WD. 
g If the last Q12W assessment for a subject who discontinues study treatment is ≤4 weeks 
before the final assessments visit at Week 52/WD, the assessment should be cancelled and the 
subject should instead be invited to undergo the final assessments visit at Week 52 (the 
Week 52/WD visit is to be scheduled 52 weeks [±3 days] after Baseline).
k A telephone contact will be made with the subject every 4 weeks after the on-site visit (ie, at 
Weeks 8H, 16H, 22H, and every 4 weeks after Week 24 until Week 52/WD visit).
m CZP administration will be continued Q2W.
Change #22
Section 5.2 Schedule of study assessments, Table 5-3: table title 
Table 5‒3: 
Schedule of alternative study assessment with other treatment 
(including biologics) - after subject discontinuation of the study 
treatment 
Has been changed to:
Table 5‒3: 
Schedule of alternative study assessment with other treatment 
(including biologics) - after subject discontinuation of the 
double-blind study treatment 
REDACTED 
W
ms 
ms of
of
ek 0, W
k 0, W
a subje
a subje
atat
COPY
on
o
poprot
popro
Week
Week
This document cannot 
5.2 
.2
e 5‒3
e 5‒
be 
2 Sc
2 Sc
used to support
be
and e
and e
n will 
n will 
any 
e mad
mad
marketing
ect w
ect w
Week 
Week 
d to und
to un
eduled
edule
authorization 
k 52/W
k 52/W
f activ
activ
Week 
Week 
wh
w
application 
alt
the tim
he tim
ein(a) 
in(a)
nd 
tern
tern
any extensions
4 wee
4 we
elled a
lled a
Week 
Week 
or variations 
TB.
B. 
y 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 164 of 255
Change #23
Additional text has been added for other treatment administration for Week 12, Week 24, and Q12W
Table 5‒3: 
Schedule of alternative study assessment with other treatment (including biologics) - 
after subject discontinuation of the double-blind study treatment 
Visit #
1
wdt
2
wdt
3
wdt
Week
Protocol Activity
0
12
24 and Q12W
Continue assessments as at W24 every 12 weeks until as close as possible to 
W52 of the original visit schedule. Subject will then be invited to the final 
assessment visit at W52 ±4 weeks. 
52/WD
FUa
Other treatment administration
Follow the regimen of the particular 
alternative treatment.
REDACTED COPY 
This document cannot 
ot be used 
d to 
t
support any marketing 
m
authorization application
ssi
io
and 
ble to
ble t
nal 
nal 
any y
any extensions
biolo
biol
ten
e
or variations 
on thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 165 of 255
Has been changed to:
Table 5‒3: 
Schedule of alternative study assessment with other treatment (including biologics) - after 
subject discontinuation of the double-blind study treatment 
Visit #
1
wdt
2
wdt
3
wdt
Week
Protocol Activity
0
12
24 and Q12W
Continue assessments as at W24 every 12 weeks until as close as possible to 
W52 of the original visit schedule. Subject will then be invited to the final 
assessment visit at W52 ±4 weeks. 
52/WD
FUa
Other treatment administration
Follow the regimen of the particular 
alternative treatment. Telephone 
contact to be performed on the 
discretion of the investigator
REDACTED COPY 
This document cannot be used 
sed to 
t
support any marketing 
m
authorization application
e as
io
and 
s poss
s pos
o the f
o the f
any extensions 
on
xt
ex
or
og
og
variations 
on
gic
gic
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 166 of 255
Change #24
Section 5.2 Schedule of study assessments, Table 5-3: footnotes have been reordered and 
changes to footnotes are noted.
Note: All weeks are ±3 days compared to Baseline. Week 0 of the alternative schedule starts 
2 weeks after the last dose of the study treatment.
b
If the last Q12W assessment for a subject who discontinues study treatment is ≤4 weeks 
before the final assessments visit at Week 52 the assessment should be cancelled and the 
subject should instead be invited to undergo the final assessments visit at Week 52/WD (the 
Week 52 visit is to be scheduled 52 weeks [±3 days] after Baseline).
Have been changed to:
Note: All weeks are ±3 days compared to Baseline. Week 0 of the alternative schedule starts 
2 weeks after the last dose of the double-blind study treatment.
b
Subjects will be encouraged to be in fasting condition at the time the subject shifts to 
alternative treatment, for Apo A1, ApoB, and lipoprotein(a) assessments.
c
HbA1c will be measured at wdt Week 0.
d
If the last Q12W assessment for a subject who discontinues study treatment is ≤4 weeks 
before the final assessments visit at Week 52/WD, the assessment should be cancelled and 
the subject should instead be invited to undergo the final assessments visit at Week 52/WD 
(the Week 52/WD visit is to be scheduled 52 weeks [±3 days] after Baseline).
Change #25
Section 5.2 Schedule of study assessments
The following paragraphs have been added:
At any time during the study course, but preferably not before Week 12, the Investigator may 
discontinue the double-blind study treatment and start open-label treatment with either CZP 
(which will be provided free of charge by UCB) or an alternative drug (eg, other treatment 
[including biologics]).
The determination by the Investigator to switch a subject from double-blind study treatment to 
either open-label CZP or other treatment will generally be done after the subject has completed 
the assessments at a given scheduled study visit. That study visit then becomes the wdt Week 0 
visit of the given alternative schedule of assessments. Since many of the assessments required at 
the wdt Week 0 visit may have already been completed as part of the originally scheduled study 
visit, only those not already done at that visit should be completed. Table 5‒4 outlines which 
additional study assessments would be required at wdt Week 0 for subjects switching to the 
open-label CZP alternative schedule, and Table 5‒5 shows this information for subjects 
switching to the other treatment alternative schedule.
It may be possible that an Investigator determines that a subject should switch to the alternative 
schedule with either open-label CZP or another treatment without initiating the alternative 
treatment at the study visit when this determination is made. In this case, the subject will come 
REDACTED
erg
d 52 w
d 52 w
COPY
scon
sco
WD, th
WD,
rgo t
go t
This document
isit,
sit,
addi
addi
o
cannot
f the g
the g
wdt W
wdt W
t, o
be
ment
ment
used
on b
on b
bel C
bel C
to 
]).)
support
ind stu
nd st
d free o
free
any 
course
ours
marketing 
sments
smen
been 
been
authorization 
he
the fin
he fin
weeks
weeks
application 
ses
inues s
nues 
e asse
asse
nd
the s
he s
ssm
ssm
any 
sub
su
extensions 
sche
sche
or
WD 
WD
variations 
e
D (th
D (th
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 167 of 255
back another day shortly thereafter to initiate the treatment and to complete all assessments 
outlined on the relevant alternative schedule of assessments (see Table 5‒4 or Table 5‒5) for the 
wdt Week 0 visit. It is important then to schedule the wdt Week 0 and the subsequent on-site 
visits accordingly in order to end up at Week 52 with the same visit date as originally planned for 
the regular double-blind study course.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 168 of 255
Change #26
Section 5.2 Schedule of study assessments
The following tables have been added:
Table 5‒4: 
Schedule of study assessments – additional assessments for wdt 0 visit required for subjects 
transitioning to open-label CZP 
Visit #a
1/
BL
2
3
4
5
6
7
8
9
H
10
11
H
12
13
H
14
15
H
16
17
H
18
19
H
20
21
H
22
23
H
24
25
H
26
27
Week
Protocol Activity
0
1 2
4 6 
8 10 
12 
14 
/H 
16 
18 
/H 
20 
22 
/H 
24 
26 
/H 
28 
30 
/H 
32 
34 
/H 
36 
38 
/H 
40 
42 
/H 
44 
46 
/H 
48 
50 
Vital signs
X
X
X
X
X
X
X
X
X
Hematology/urine/ 
biochemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CRP
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testing
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PE
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TB questionnaire 
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BASMI & spinal 
mobility
X
X
X
X
X
X
X
X
X
X
X
X
BASDAI
X
X
X
X
X
X
X
X
X
X
X
X
BASFI
X
X
X
X
X
X
X
X
X
X
X
X
SF-36
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ASQoL
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MOS Sleep Scale
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MASES
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Total and nocturnal 
spinal pain
X
X
X
X
X
X
X
X
X
X
X
X
REDACTED 
D
X
ED
CT D
X
CT
CT
ACT
X
X
DA
RED
R
COP
OPY 
PY
OP
X
O
CO
This document cann
an
annot
n
an
an ot 
ot
an
annot be
be 
e
be
b
used 
d
u
X
d
u ed
us
u
to
X X
to support t
port
portrt
X
pp
pp
pp
up
X
s
any
X
y y
a y
a
marketing 
g
arke
k
X
g
ng
ke
g
ma
mar
m
authorization 
n
ation
ation
a
n
X
at
za
X
X
hor
th
X
au
application 
/H
/H
o
licatio
catitio
li
o
X
X
lililic
a pli
and 
d
30
H
3
d
nd any 
1
ny extensions 
sit req
t req
9
ex
or variations 
on thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 169 of 255
Table 5‒4: 
Schedule of study assessments – additional assessments for wdt 0 visit required for subjects 
transitioning to open-label CZP 
Visit #a
1/
BL
2
3
4
5
6
7
8
9
H
10
11
H
12
13
H
14
15
H
16
17
H
18
19
H
20
21
H
22
23
H
24
25
H
26
27
Week
Protocol Activity
0
1 2
4 6 
8 10 
12 
14 
/H 
16 
18 
/H 
20 
22 
/H 
24 
26 
/H 
28 
30 
/H 
32 
34 
/H 
36 
38 
/H 
40 
42 
/H 
44 
46 
/H 
48 
50 
Swollen and tender joint 
counts
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PhGADA 
X
X
X
X
X
X
X
X
X
X
X
X
PGADA
X
X
X
X
X
X
X
X
X
X
X
X
CZP plasma 
concentration/anti-CZP 
Abs/Biomarker
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IXRS
X
X
X
X
X
X
X
X
X
Study drug 
administration sc
BASMI=Bath Ankylosing Spondylitis Metrology Index; CRP=C reactive protein; CZP=certolizumab pegol; EQ̻5D=EuroQoL Health Status Questionnaire 
(5 dimensions); H=home; IXRS=Interactive Response System; MASES=Maastricht Ankylosis Spondylitis Enthesitis Score; MOS=Medical Outcomes Study; 
PE=physical exam; PhGADA=Physician’s Global Assessment of Disease Activity; PGADA=Patient’s Global Assessment of Disease Activity; 
sc=subcutaneously; SF̻36=Short̻Form 36̻item Health Survey; TB=tuberculosis 
REDACTED
ACTED
TED 
D
ACT D
ctive pr
tive p
ASES=
ASES=
Dise
Dise
AC
AC
COPY
OPY 
OP
X
OP
OP
OP
OP
OP
C
This document cannot be used to support any marketing 
=Ma
Ma
ease Ac
ase Ac
B=tube
B=tub
authorization 
tion
tion
horiza
rizatio
atio
tio
h
za
rotein; 
otein
aast
aas
ho
application 
tio
ti
X
o
X
tio
a pli
o
a
and
X
nd 
d
nd
a
any 
X
ny
a
extensions 
21
H
io
H
36
36
ioion
xte
io
X
ex
or r
or variations 
on
for s
for s
v
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 170 of 255
Table 5‒5: 
Schedule of study assessments – additional assessments for wdt 0 visit required for subjects 
transitioning to alternative treatment  
Visit #a
1/
BL
2
3
4
5
6
7
8
9
H
10
11
H
12
13
H
14
15
H
16
17
H
18
19
H
20
21
H
22
23
H
24
25
H
26
27
Week
Protocol Activity
0
1
2
4
6
8
10
12
14
/H
16
18
/H
20
22
/H
24
26
/H
28
30
/H
32
34
/H
36
38
/H
40
42
/H
44
46
/H
48
50
Hematology/urine/ 
biochemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CRP
X
X
X
X
X
X
X
X
X
X
X
X
PE
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BASDAI
X
X
X
X
X
X
X
X
X
X
X
X
BASFI
X
X
X
X
X
X
X
X
X
X
X
X
Total and nocturnal 
spinal pain
X
X
X
X
X
X
X
X
X
X
X
X
PhGADA 
X
X
X
X
X
X
X
X
X
X
X
X
PGADA
X
X
X
X
X
X
X
X
X
X
X
X
CZP plasma 
concentration/ 
anti-CZP Abs/ 
Biomarker
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IXRS
X
X
X
X
X
X
X
X
X
BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; BASFI=Bath Ankylosing Spondylitis Functional Index; CRP=C reactive protein; 
CZP=certolizumab pegol; H=home; IXRS=Interactive Response System; MOS=Medical Outcomes Study; PE=physical exam; PhGADA=Physician’s Global 
Assessment of Disease Activity; PGADA=Patient’s Global Assessment of Disease Activity; sc=subcutaneously 
a
Additional assessments to be performed correspond to the assessments to be performed at wdt Week 0.
REDACTED 
ED
CTE
CTE
X
ED
ED
TED
DACT
ACT
CT
DA
X
ED
R D
COPY 
OPY
OPY
COP
OP
OP
CO
This document cannot be used to support
y I
y I
e Resp
Resp
s Globa
Glob
espond
spond
any 
ny 
ny
ndex;
ndex
ny
ny
ny marketing 
X
ar
tin
ma
ma
ma
authorization
ation
io
X
on
X
riza
za
za
riz
aut
a
X
ho
aut
au
au
au
application 
X
ti
licati
licat
X
tititio
ati
X
pplic
plic
lic
pp
X
p
ap
and
and
nd 
d
an
a
any 
X
an
a
extensions 
1
H
io
36
ioion
xt
sio
x
ex
or 
2
r
o variations 
on
for s
for s
v
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 171 of 255
Change #27
Section 5.3 Schematic diagram, Figure 5-1
CZP 400mg loading dose has been added to the figure. 
Change #28
Section 5.3 Schematic diagram, Figure 5-2
“Double-blind” and “other treatment” have been added to clarify the study treatment.
Change #29
Section 6.2 Exlcusion criteria, exclusion criterion 29, first subcriterion
29. Subjects with significant laboratory abnormalities, including but not limited to: 
 liver function tests >2.0xULN, if the subject is not treated with MTX and >ULN if 
subject is on concomitant MTX treatment
Has been changed to:
29. Subjects with significant laboratory abnormalities, including but not limited to: 
 liver function tests >2.0xULN
Change #30
Section 6.3 Withdrawal criteria, paragraphs 1 and 3
If a subject is withdrawn from study treatment, the Investigator should encourage the subject to 
continue participation in the study in accordance with the appropriate alternative schedule of 
study assessments (Table 5‒2 or Table 5‒3). The treatment that the subject receives following 
withdrawal of study medication is at the discretion of the Investigator. Open label CZP for 
treatment to be supplied to discontinued subjects will be made available as a treatment option 
according to the local requirement mandated in the region. UCB will provide this medication 
free of charge. Alternatively, the Investigator may treat the subject with other treatments 
(including biologics) as deemed appropriate by local regulations. If the Investigator choses to 
withdraw subjects on the other therapy, the local guidelines on initiation and monitoring of the 
particular treatment should be followed.
Although the subject may be withdrawn from the double-blind study treatment at any time, every 
effort should be made to retain the subject in the study and encourage compliance of the subject 
with the scheduled study visits. For subjects who fail to return to study visit(s) or are considered 
lost to follow up, the Investigator should specifically communicate (at least 1 phone call and 1 
written message to the subject), and document his/her effort (date and summary of the phone call 
and copy of the written message in the source documents). In case the attempts to direct contact 
the subject fail, the Investigator is encouraged to gain information about the wellbeing of the 
subject at the end of the regular visit schedule (Week 52) from other sources in compliance with 
local regulations. All results of observations and communication with the subject, including and 
REDACTED COPY 
ities, i
ities,
This document
effor
ffor
wit
wit
l
cannot
ar tr
r tr
hough
hough
rt
be
subje
subje
ea
ea
used
Alter
lter
ologic
logic
to
cal r
cal r
rna
rna
support
2
ication
cation
ed to d
d to d
requ
req
any
dy i
dy 
or
or T
marketing 
ragrap
agra
dy trea
dy tre
inin
authorization
incl
nc
application 
wit
wit
cludi
lud
and 
ot li
t l
ith M
th M
any 
limit
im
extensions or
ent
ent
variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 172 of 255
not limited to the relevant information on his/her wellbeing, must be recorded in the source 
documents.
Have been changed to:
If a subject is withdrawn from the double-blind study treatment, the Investigator should 
encourage the subject to continue participation in the study in accordance with the appropriate 
alternative schedule of study assessments (Table 5‒2 or Table 5‒3). The treatment that the 
subject receives following withdrawal of study medication is at the discretion of the Investigator, 
with open-label CZP available as a treatment option according to the local requirement mandated 
in the region. UCB will provide this medication free of charge. Alternatively, the Investigator 
may treat the subject with other treatments (including biologics) as deemed appropriate by local 
regulations. If the Investigator chooses to withdraw subjects on the other therapy, the local 
guidelines on initiation and monitoring of the particular treatment should be followed.
Although the subject may be withdrawn from the double-blind study treatment at any time, every 
effort should be made to retain the subject in the study and encourage compliance of the subject 
with the scheduled study visits. For subjects who fail to return to study visit(s) or are considered 
lost to follow up, the Investigator should specifically communicate (at least 1 phone call and 
1 written message to the subject), and document his/her effort (date and summary of the phone 
call and copy of the written message in the source documents). In case the attempts to direct 
contact the subject fail, the Investigator is encouraged to gain information about the wellbeing of 
the subject at the end of the regular visit schedule (Week 52/WD) from other sources in 
compliance with local regulations. All results of observations and communication with the 
subject, including and not limited to the relevant information on his/her wellbeing, must be 
recorded in the source documents.  
Change #31
Section 7.1 Description of investigational medicinal product(s), paragraph 1
The IMP will be supplied under the responsibility of the UCB Clinical Supply Unit. The 
frequency at which IMP will be supplied to each individual center will be adapted to the 
recruitment capacity of that center and to the expiry date of the IMP and will be managed by the 
interactive response system (IXRS).
Has been changed to:
The IMP (double-blind study treatment: CZP or placebo), will be supplied under the 
responsibility of the UCB Clinical Supply Unit. The frequency at which IMP will be supplied to 
each individual center will be adapted to the recruitment capacity of that center and to the expiry 
date of the IMP and will be managed by the interactive response system (IXRS).
REDACTED
s of o
s of o
elevan
levan
COPY 
cum
cu
ged to
ged to
e (W
e (W
This document 
atete
cannot
ibilit
bilit
indiv
indiv
e of 
of
be
doub
doub
t
used 
nged 
ged 
blbl
to
e sy
e sy
support 
nde
nd
will be
will b
of that 
f that 
yste
yst
any 
sti
st
er th
er t
marketing 
tigat
iga
authorization
o g
Week 5
eek 5
bserva
bserv
nt info
nt info
application
ate (at
ate (a
t (date 
(date
nts). In
ts). I
gain i
gain 
and 
com
om
dy vi
dy vi
any
ment
men
mpli
mp
extensions
sti
riate b
riate b
y, the l
the l
follow
ollow
t
or
igat
gat
variations 
gator,
ator,
andat
ndat
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 173 of 255
Change #32
Section 7.2.1 Treatment administration, paragraph 2
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), 
study treatments will be administered sc at the study site by dedicated, unblinded and adequately 
trained site personnel. The study treatment will be self-injected at home at Weeks 14, 18, 22, 26, 
30, 34, 38, 42, and 46. All subjects will receive training for self-injection at the study site on 
Weeks 10 and 12. During the training on Weeks 10 and 12 visits, the study treatment will be self 
administered under the supervision of the unblinded study personnel.
Has been changed to:
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site by dedicated, unblinded, 
and adequately trained site personnel. The double-blind study treatment will be self-injected at 
home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46. All subjects will receive training for self 
injection at the study site on Weeks 10 and 12. During the training on Weeks 10 and 12 visits, 
the double-blind study treatment will be self-administered under the supervision of the unblinded 
study personnel.
Change #33
Section 7.8 Concomitant medication(s)/treatment(s)
Table 7‒1: 
Concomitant Medications (prior to Baseline and Study Visits)
Drug class
Dose 
Exclusion criteria
Study Visits
SAARDsb:
SSZ and/or HCQ 
and/or MTX and/or 
LFN and/or AZA
Maximum 
allowed: 
SSZ ≤3g daily 
HCQ ≤400mg 
daily  
MTX ≤25mg 
weekly AZA 
≤150mg/day 
LFN 
≤20mg/day 
(see exclusion 
criteria for 
washout 
requirements) 
SAARD initiated and or any change 
in the dose regimen in the 28 days 
prior to the Baseline Visit. 
Use of LFN in the 6 months prior to 
the Baseline Visit unless a 
cholestyramine washout has been 
performed. In case of a 
cholestyramine washout, use 28 days 
prior to the Baseline Visit is 
acceptable. 
Changes in SAARD 
doses should not be 
made between Week 0
and Week 12 or within 
4 weeks prior to 
Week 24 or Week 52 
visit. 
SAARD dose reduction 
to manage intolerance 
or safety issues is 
allowed at any time 
during the study at the 
Investigator’s 
discretion. 
SAARDs:
AZA, cyclosporine, 
cyclophosphamide, 
mycophenolic acid, 
apremilast
Up to 
maximum 
approved dose 
Use within 28 days prior to the 
Baseline Visit 
Changes in SAARD 
doses or initiation of a 
new SAARD should be 
avoided between 
Week 0 and Week 12 or 
within 4 weeks prior to 
Week 24 or Week 52 
REDACTED
atme
atme
ions (
ons 
Excl
Excl
DA
R
S
R
COPY 
This document 
SA
SA
en
um
cannot be used to
≤
to support 
y
MTX ≤2
TX ≤
week
week
1
any 
ilyl
00mg
00mg
marketing 
us
y
SAARD
AAR
in th
in t
pr
ng
ma
authorization 
nt(s)
t(s)
(prio
(prio
sion 
ion
ut
application 
he s
e 
and
n We
We
sup
sup
any 
l b
ceive
ceive
ek
extensions 
48, an
48, a
cated,
ated,
be s
be s
or variations 
e self 
self 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 174 of 255
Table 7‒1: 
Concomitant Medications (prior to Baseline and Study Visits)
Drug class
Dose 
Exclusion criteria
Study Visits
visit 
Anti-TNF therapies
IFX
ADA
ETN
GOL
CZP
Any dose 
For IFX, ADA, and GOL, any use 
within the 3 months prior to the 
Baseline Visit. 
For CZP any exposure history. 
For ETN, use within the 28 days 
prior to the Baseline Visit. 
Only 1 previous biologic is allowed. 
If biologic therapy is 
required the subject 
must be discontinued 
from study medication 
and should conduct the 
remaining visits 
according to Figure 5–2. 
Has been changed to:
Table 7‒1: 
Concomitant Medications (prior to Baseline and Study Visits)
Drug class
Dose 
Exclusion criteria
Study Visits
SAARDsb:
SSZ and/or HCQ 
and/or MTX and/or 
LFN and/or AZA
Maximum 
allowed: 
SSZ ≤3g daily 
HCQ ≤400mg 
daily  
MTX ≤25mg 
weekly 
AZA 
≤150mg/day 
LFN 
≤20mg/day  
SAARD initiated and or any change 
in the dose regimen in the 28 days 
prior to the Baseline visit. 
 
Changes in SAARD 
doses should not be 
made between Week 0
and Week 12 or within 
4 weeks prior to 
Week 24 or Week 52
visit. 
SAARD dose reduction 
to manage intolerance 
or safety issues is 
allowed at any time 
during the study at the 
Investigator’s 
discretion. 
SAARDs:
cyclosporine, 
cyclophosphamide, 
mycophenolic acid, 
apremilast
Up to 
maximum 
approved dose 
Use within 28 days prior to the 
Baseline visit 
Changes in SAARD 
doses or initiation of a 
new SAARD should be 
avoided between 
Week 0 and Week 12 or 
within 4 weeks prior to 
Week 24 or Week 52
visit 
Anti-TNF therapies
IFX
ADA
ETN
GOL
CZP
Any dose 
Only 1 previous biologic is allowed.
For IFX, ADA, and GOL, any use 
within the 3 months prior to the 
Baseline visit. 
For ETN, use within the 28 days 
prior to the Baseline visit. 
For CZP any exposure history. 
If biologic therapy is 
required the subject 
must be discontinued 
from study medication 
and should conduct the 
remaining visits 
according to Figure 5–2. 
REDACTED 
R
COPY 
ine
n
This document 
IFX
FX
AD
AD
um
cann
i-TNF
TNF
nnot 
nn
be used 
d,
to 
to support 
to
aximu
xim
appro
appro
t any 
a
marketing 
ma
authorization application
chang
chang
28 day
28 day
sit.t.
and 
a
any
Study
Stud
a
extensions
to Fi
Fi
s
or 
ts 
ts 
variations 
tion
on
uct th
uct th
on thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 175 of 255
Change #34
Section 7.9.1 Maintenance of study treatment blind, paragraph 3
If the Investigator decides to discontinue the study treatment and initiate open-label treatment 
with CZP or other treatment (including biologics), efforts will be made to ensure that the 
blinding of the previously assigned study treatment will be maintained. This is to ensure that in 
case open-label treatment with CZP is chosen by the Investigator, the 3 loading doses of CZP 
400mg Q2W will be administered by dedicated study personnel without disclosing to the subject 
the use of the PFS. After the last loading dose the subject can self administer CZP until Week 52
of the regular visit schedule.
Has been changed to:
If the Investigator decides to discontinue the double-blind study treatment and initiate open-label 
treatment with CZP or other treatment (including biologics), efforts will be made to ensure that 
the blinding of the previously assigned double-blind study treatment will be maintained. 
Therefore, if the open-label treatment with CZP is chosen by the Investigator, the 3 loading 
doses of CZP 400mg Q2W will be administered by dedicated study personnel without disclosing 
to the subject the use of the PFS. After the last loading dose the subject can self administer CZP 
until Week 52/WD of the regular visit schedule.
Change #35
Section 7.10.1 Interactive Response System, paragraph 3
The IXRS will allocate kits of study medication at Week 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44, 48, and 50.
Has been changed to:
The IXRS will allocate kits of study medication at Weeks 0, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44, 48, and 50.
Change #36
Section 8.1 Screening visit (Week -6 to Day -1): bullet point item 1 and paragraph 5
x Confirm inclusion/exclusion criteria
One rescreening of subjects with latent TB who are able to complete a minimum of 4 weeks of 
TB therapy within the Screening Period is permitted. In this event, all Screening assessments 
must be repeated.
Has been changed to:
x Confirm inclusion/exclusion criteria (to be performed within Weeks -6 and Day -1 and 
confirmed between Days -5 and -3 before Baseline)
One rescreen is permitted for subjects with LTB. In this event, all Screening assessments must be 
repeated. Subjects are allowed to start the IMP after at least 4 weeks of prophylactic TB 
treatment (if compliant with the local regulations on initiation of biologic therapy in subjects 
REDACTED 
em, p
em, p
medicat
medica
COPY 
This document 
Has
Has
cannot 
ree
ree
erapy
erapy
st be 
t be
be 
enin
enin
used 
eni
ni
nclus
nclus
to 
ing
ing
support any marketing 
dy me
dy m
authorization 
parag
arag
tion a
ion a
application 
y p
y p
 subjec
subje
and
estiga
stiga
pers
pers
any 
m
be m
be m
atot
extensions 
d initia
nitia
made
made
or variations 
bject 
ject 
eek
eek 5
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 176 of 255
with LTB) within the Screening Period. The subject is required to complete the full prophylactic 
treatment.
Change #37
Section 8.2 Baseline visit (Week 0), bullet point item 3
x Blood samples will be collected for hematology and biochemistry analyses
Has been changed to:
x Blood samples (subjects should be encouraged to be under fasting conditions, the same 
condition [fasting or not fasting] should be applied at Week 52) will be collected for 
hematology and biochemistry analyses (biochemistry assessment will include the 
measurement of apolipoprotein (Apo) A1, ApoB, lipoprotein(a), and glycated hemoglobin 
[HbA1c])
Change #38
Section 8.3 Weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 
44, 46, 48, and 50 (all visits ±3 days relative to Baseline), bulleted items 5, 8, and 28. 
x Physical examination (Weeks 2, 4, 8, 12, 16, 24, and 36), including weight at Week 24 and at 
completion at Week 52/WD
x MRI (SI joints only, Week 12 only)
x Contact IXRS to obtain next kit number (Week 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 
44, 48, and 50)
Have been changed to:
x Physical examination (Weeks 2, 4, 8, 12, 16, 24, and 36), including weight at Week 24 
x MRI (spine and SI joints; Week 12 only)
x Contact IXRS to register the visit and obtain next kit number, where applicable (Weeks 2, 4, 
6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50)
Change #39
Section 8.5 Week 52/WD (±3 days)
8.5 
Completion Visit (Week 52)/Early Withdrawal (±3 days) 
Has been changed to:
8.5 
Week 52/WD (±3 days) 
REDACTED 
6, ,
numb
numb
COPY
2
aselin
aselin
24, 
24, 
This document 
.5
Ha
Ha
cannot 
on 8.5
n 8.5
be 
39
39
used 
,
to
 20
20
support
ints; W
nts; W
registe
egiste
2
any
eks 2
eks 2
marketing 
ber (W
er (
authorization 
and 3
and 3
(W
application 
4, 26, 
4, 26,
e), bu
e), bu
and any 
y
extensions
he sam
e sam
cted fo
ted fo
ude th
de th
cated
ated
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 177 of 255
Change #40
Section 8.5 Completion Visit (Week 52)/Early Withdrawal (±3 days), paragraph 1, bulleted 
items 2 and 10
Assessments at this visit include:
x Blood samples will be collected for hematology, biochemistry, and CRP
x MRI for spine and SI joints (at Week 52 Visit if previous MRI was performed more than 
12 weeks prior to Week 52 visit)
Have been changed to:
A subject is regarded to have completed the study if s/he completes the Week 52/WD. 
Assessments at this visit include:
x Blood samples (subjects should be encouraged to be under fasting conditions the same 
condition [fasting or not fasting] at Baseline should be applied at Week 52) will be collected 
for hematology, biochemistry, and CRP (biochemistry assessment will include the 
measurement of apolipoprotein (Apo) A1, ApoB, lipoprotein(a), and HbA1c)
x MRI for spine and SI joints (at Week 52/WD visit if previous MRI was performed more than 
12 weeks prior to Week 52/WD visit)
Change #41
Section 8.6 FU visit (8 weeks after the Week 52/WD visit)
8.6 
FU Visit (8 weeks after the Week 52/WD visit) 
Has been changed to:
8.6 
FU visit (8 weeks after the Week 52/WD visit [±3 days]) 
Change #42
Section 8.8 Alternative visit schedules after subject discontinuation of study treatment and 
bullet points 2, 15 and 16. New bullet points have been added for telephone contact.
8.8 Alternative Visit schedules after subject discontinuation of study treatment 
Alternative schedules for assessment for subjects who discontinue the study treatment are 
described in this section. Assessments are to be continued as at Week 24 every 12 weeks until as 
close as possible to Week 52 (within ±3 days of the originally planned Week 52 visit) of the 
original visit schedule. Subject will then be invited to the final assessment visit at Week 52.
The following assessments will be performed for subjects who are treated with open-label CZP 
after discontinuation of study treatment:
x Blood samples will be collected for hematology, biochemistry analyses, urine will be 
collected for urinalysis at wdt Weeks 0, 12, 24 (and Q12W), 52 and FU and CRP at Week 0, 
12, 24 (and Q12W), 52, and FU (8 weeks after Week 52 Visit)
REDACTED 
 Week
Wee
e We
e We
COPY 
This document
origi
rigi
Th
T
cannot 
ve 
ve
bed in
bed in
se as p
e as p
be 
e sch
e sch
used 
15 a
5 
ative 
tive 
to
ti
and
an
support 
ive vi
ve vi
any marketing
eek 
ek 
the W
the W
authorization 
k 52/W
k 52/W
k 5
k 5
application
(a), a
(a), a
vious M
vious M
and 
Wee
e
nt wil
nt wil
any
ditio
diti
ek 52
ek 52
extensions 
/WD.
WD.
on
on
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 178 of 255
x CZP administration at wdt Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 (and Q12W), 52, 
and FU. Loading dose of CZP 400mg at Weeks 0, 2 and 4 must be administered by dedicated 
site-staff 
The following assessments will be applied for subjects who receive an alternative study 
assessment with other treatment (including biologics) after discontinuation of study treatment:
x Blood samples will be collected for hematology, biochemistry, and urine will be collected for 
urinalysis at wdt Week 0, CRP analyses will be performed at wdt Weeks 0, 12, 52, and FU 
Has been changed to:
8.8 Alternative visit schedules after subject discontinuation of the double-blind 
study treatment 
The following assessments will be performed for subjects who are treated with open-label CZP 
after discontinuation of the double-blind study treatment:
x Blood samples will be collected for hematology, biochemistry, and CRP analyses, and urine 
will be collected for urinalysis at wdt Weeks 0, 12, 24 (and Q12W), 52 and FU (8 weeks 
after Week 52 visit)
Note: Fasting blood samples will be collected for hematology, biochemistry, and CRP 
analyses at wdt Week 0 (biochemistry assessment will include the measurement of 
apolipoprotein (Apo) A1, ApoB, lipoprotein(a), and HbA1c). At Week 52, the biochemistry 
assessment will include the measurement of HbA1c. 
x CZP administration at wdt Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and every 
2 weeks thereafter, until Week 52. Loading dose of CZP 400mg at Weeks 0, 2, and 4 must be 
administered by dedicated site-staff
x Telephone contact will occur every 4 weeks after the on-site visit at the discretion of the 
Investigator
The following assessments will be applied for subjects who receive an alternative study 
assessment with other treatment (including biologics) after discontinuation of the double-blind 
study treatment:
x Blood samples will be collected for hematology and biochemistry analyses, and urine will be 
collected for urinalysis at wdt Week 0. C-reactive protein analyses will be performed at wdt 
Weeks 0, 12, 52, and FU 
Note: Biochemistry assessment will include the measurement of HbA1c at wdt Week 0
x Telephone contact will occur every 4 weeks after the on-site visit at the discretion of the 
Investigator
Change #43
Section 9.1.2 ASAS20, 40, ASAS 5/6 response, and ASAS partial remission, bulleted item 2
x Pain assessment (the average of total and nocturnal spinal pain NRS scores)
REDACTED
(
of H
of H
2, 4, 6
2, 4, 6
 Load
 Loa
taff
taff
COPY 
hem
he
ent wi
ent w
a), an
a), a
b
This document 
I
cannot 
B
Teleph
eleph
Inv
Inv
be 
Bioc
Bioc
used
r urin
urin
12, 5
12, 5
to
will
wil
support
atmen
men
l be
l b
any 
ll be 
ll be
nt
marketing 
ery 4 w
ry 4 
authorization
nd Hb
nd H
bA1c.
A1c
6, 8, 1
6, 8, 1
ing d
ng d
application 
2W
2W
tology
olog
ll inclu
l incl
bA
and
nd CR
d CR
W), 
W),
any 
RP
R
extensions 
uble
uble
ith op
th op
or variations 
for 
or 
FU 
U 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 179 of 255
Has been changed to:
x Pain assessment (the total spinal pain NRS score)
Change #44
Section 9.1.3 ASAS-NSAID score, bulleted item 10
x Days per week: Number of days per week when the NSAID is taken. This is collected in the 
categories described in the days with intake category listed above. Each category corresponds 
to a score as follows (score in parentheses):
 Every day (7)
 ≥5 days/week (6)
 3 to 5 days/week (4)
 1 to 3 days/week (2)
 <1 day/week (0.5)
 No NSAID intake (0)
Has been changed to: 
x Days per week: Proportion of days per week when the NSAID is taken. This is collected in 
the categories described in the days with intake category listed above. Each category 
corresponds to a score as follows (score in parentheses):
 Every day (7/7)
 ≥5 days/week (6/7)
 3 to 5 days/week (4/7)
 1 to 3 days/week (2/7)
 <1 day/week (0.5/7)
 No NSAID intake (0)
Change #45
Section 9.1.4 ASQoL, addition of Table 5-2 to paragraph 2
REDACTED
eek w
eek w
th inta
th inta
core in
core in
COPY 
h
This document cannot
n 9.1.
n 9.1.
be 
45
used to
inta
inta
support 
7)
7)
5/7)
5/7)
take 
ake
any marketing authorization 
hen th
hen th
ake ca
ke ca
n pare
n pare
application and any extensions or
resp
res
variations 
n the
n the
spo
spo
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 180 of 255
Change #46
Section 9.1.5 BASDAI, paragraph 5
The BASDAI assessments per visit are described in the schedule of study assessments Table 5-1.
Has been changed to:
The BASDAI assessments per visit are described in the schedule of study assessments Table 5-1,
Table 5‒2, and Table 5‒3.
Change #47
Section 9.1.6 BASFI, paragraph 2
The BASFI assessments per visit are described in Table 5‒1.
Has been changed to:
The BASFI assessments per visit are described in Table 5‒1, Table 5‒2, and Table 5‒3.
Change #48
Section 9.1.7 BASMI, paragraph 2
The BASMI assessments per visit are described in Table 5‒1.
Has been changed to:
The BASMI assessments per visit are described in Table 5‒1 and Table 5‒2.
Change #49
Section 9.1.8 Enthesitis (MASES), paragraph 2
Enthesitis assessments per visit are described in Table 5‒1.
Has been changed to:
Enthesitis assessments per visit are described in Table 5‒1 and Table 5‒2.
Change #50
Section 9.1.9 Extra-articular assessments
The evolution of associated nonmusculoskeletal features including inflammatory bowel disease, 
psoriasis and uveitis (including their severity) and flare rate will be assessed as described 
Table 5‒1.
Has been changed to:
The evolution of associated nonmusculoskeletal features including inflammatory bowel disease, 
psoriasis and uveitis (including their severity) and flare rate will be assessed as described 
Table 5‒1 and Table 5‒2.
REDACTED
ed in
ed in
e descr
e desc
COPY 
This document
The 
he 
pso
pso
T
cannot 
#5
#5
on 9.
n 9.
ev
ev
be 
50
50
used 
me
me
o
ents 
ents
support
visit
visi
o:
any
SES)
SES
t
marketing 
rib
authorization 
Table
able
ibed 
bed 
application and 
5‒2
‒2 a
any extensions or variations 
1,
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 181 of 255
Change #51
Section 9.1.10 Health status (EQ-5D), paragraph 2
This instrument is to be completed by the subject as described in Table 5‒1.
Has been changed to:
This instrument is to be completed by the subject as described in Table 5‒1 and Table 5‒2.
Change #52
Section 9.1.11 MOS Sleep Scale, paragraph 2
Subjects will be asked to complete the MOS Sleep Scale as described in Table 5‒1.
Has been changed to:
Subjects will be asked to complete the MOS Sleep Scale as described in Table 5‒1 and 
Table 5-2.
Change #53
Section 9.1.12 MRI assessments
Magnetic Resonance Imaging according to the ASAS/Omeract definition is the presence of bone 
marrow oedema (BMO) or osteitis highly suggestive of SpA that is located in the typical 
anatomical areas (subchodral or periarticular bone marrow). There must be either more than
1 BMO lesion on 1 slice or a lesion that is present on at least two consecutive slices (Rudwaleit 
et al, 2009d). In practice this is very similar to the SPARCC SIJ ≥2 definition of MRI that 
requires at least 2 BMO lesions to be present. A recent paper showed that the sensitivity and 
specificity of the ASAS/Omeract and SPARCC SIJ score ≥2 definitions of MRI positive were 
identical (sensitivity 0.80, specificity 0.76) (Weber et al, 2014). The Berlin modification of the 
ASspiMRI-a is a scoring system with a concentration on short-tau-inversion recovery (STIR) 
sequences without other fat saturation techniques (Braun and Baraliakos, 2011, Lukas et al, 
2007; Braun and van der Heijde, and 2002; Braun et al, 2003). This scoring method quantifies 
changes in 23 vertebral units (VU) of the spine (from C2 to S1). A VU is defined as the region 
between 2 virtual lines through the middle of each vertebra. Active inflammation is scored by 
grading the degree of BMO from 0 to 3 in 1 dimension on 1 or more consecutive slices that 
represent the highest level of inflammation in a particular VU. Total spine ASspiMRI-a score in 
the Berlin modification can range from 0 to 69. In addition to the method mentioned above, 
MRIs may be evaluated using other reading criteria.
Magnetic resonance imaging of the spine and SI joints will be performed at Screening, Week 12 
(SI only), 52, or Withdrawal Visit if MRI was performed more than 12 weeks prior to Early 
Withdrawal. MRIs will be assessed centrally and scoring will be done by 2 independent readers, 
who are blinded to both the order of the scans and to the treatment group, using a previously 
reported scoring system.
e AS
e AS
sugges
sugge
cular 
cular 
hat is 
hat is
sim
sim
COPY 
SA
SA
This document
Mag
Mag
(SI
(SI
cannot
rlin m
in m
Is may
s may
be
he hi
he h
used
al lin
l lin
egree
gree
to
bral
bra
support 
yste
ste
fat satu
fat sa
der He
der He
al u
al u
any
ificit
ifici
em w
m
marketing 
pr
pr
milar to
milar to
e prese
pres
and SP
and S
ty
t
authorization 
AS/Om
AS/Om
stive 
tive 
bone 
bone 
rese
rese
application and 
in T
any 
Tabl
Tab
extensions 
5‒1
5‒1
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 182 of 255
Has been changed to:
Magnetic Resonance Imaging according to the ASAS/Omeract definition is the presence of bone 
marrow oedema (BMO) or osteitis highly suggestive of SpA that is located in the typical 
anatomical areas (subchondral or periarticular bone marrow). There must be either more than 
1 BMO lesion on 1 slice or a lesion that is present on at least 2 consecutive slices (Rudwaleit et 
al, 2009d). In practice this is very similar to the SPARCC SIJ ≥2 definition of MRI that requires 
at least 2 BMO lesions to be present. A recent paper showed that the sensitivity and specificity of 
the ASAS/Omeract and SPARCC SIJ score ≥2 definitions of MRI positive were identical 
(sensitivity 0.80, specificity 0.76) (Weber et al, 2014). The Berlin modification of the 
ASspiMRI-a is a scoring system with a concentration on short-tau-inversion recovery (STIR) 
sequences without other fat saturation techniques (Braun and Baraliakos, 2011; Lukas et al, 
2007; Braun and van der Heijde, 2002; Braun et al, 2003). This scoring method quantifies 
changes in 23 vertebral units (VU) of the spine (from C2 to S1). A VU is defined as the region 
between 2 virtual lines through the middle of each vertebra. Active inflammation is scored by 
grading the degree of BMO from 0 to 3 in 1 dimension on 1 or more consecutive slices that 
represent the highest level of inflammation in a particular VU. Total spine ASspiMRI-a score in
the Berlin modification can range from 0 to 69. In addition to the method mentioned above, 
MRIs may be evaluated using other reading criteria.
Magnetic resonance imaging of the spine and SI joints will be performed at Screening and at the 
Week 12 and at the Week 52/WD visits if MRI was performed more than 12 weeks prior to 
Week 52/WD. Magnetic resonance images will be assessed centrally and scoring will be done by 
2 independent readers, who are blinded to both the order of the scans and to the treatment group, 
using a previously reported scoring system.
Change #54
Section 9.1.13 PGADA (NRS), paragraph 2
The PGADA assessments per visit are described in Table 5‒1.
Has been changed to:
The PGADA assessments per visit are described in Table 5‒1, Table 5‒2, and Table 5‒3.
Change #55
Section 9.1.14 PhGADA, paragraph 3
The PhGADA will be completed as described in Table 5‒1.
Has been changed to:
The PhGADA will be completed as described in Table 5‒1, Table 5‒2, and Table 5‒3.
REDACTED
ll be
ll b
both th
both th
em.
em.
COPY
nts w
nts w
was pe
was pe
e a
e a
This document
Has 
Has 
T
canno
9.1.
9.1.
 PhGA
PhGA
be 
1
used to support 
ments p
ents 
any 
visit 
visit
marketing 
paragr
arag
authorization
erfor
rfor
assess
ssess
he ord
he ord
application
e meth
e met
ill be p
ll be p
rme
rm
and
ons
ns
spin
spin
any
mmati
mmat
secu
sec
extensions
y (ST
y (ST
ukas e
kas e
d quan
d quan
fined 
ned 
i
or 
TI
TI
variations 
y of 
y of 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 183 of 255
Change #56
Section 9.1.17 SF-36, paragraph 3
The SF-36 has been used and has shown to be responsive in axSpA (Haibel et al, 2008) and also 
validating in van Tubergen et al. (Manuscript validating the response has been submitted to 
Rheumatology). The SF-36 will be administered per visit as described in Table 5‒1.
Has been changed to:
The SF-36 has been used and has shown to be responsive in axSpA (Haibel et al, 2008) and is 
also validated (van Tubergen et al, 2015). The SF-36 will be administered per visit as described 
in Table 5‒1 and Table 5-2.
Change #57
Section 9.1.18 Spinal mobility, paragraph 2
Spinal mobility will be assessed as described in Table 5‒1.
Has been changed to:
Spinal mobility will be assessed as described in Table 5‒1 and Table 5‒2.
Change #58
Section 9.1.19 Swollen and tender joint counts (44 joints evaluation), paragraph 1
The following 44 joints are to be examined for swelling and tenderness by the Principal 
Investigator, another delegated physician, or an appropriately qualified medical professional 
(based on local requirements) who has had documented training on how to perform these 
assessments correctly. Preferably the same assessor should evaluate the subject at each arthritis 
assessment. The individual with this delegated duty must be listed on Form 1572.
Has been changed to:
The following 44 joints are to be examined for swelling and tenderness by the Principal 
Investigator, another delegated physician, or an appropriately qualified medical professional 
(based on local requirements) who has had documented training on how to perform these 
assessments correctly. Preferably the same assessor should evaluate the subject at each arthritis 
assessment.
Change #59
Section 9.1.19 Swollen and tender joint counts (44 joints evaluation), paragraph 6
The assessments per visit are described in Table 5‒1.
Has been changed to:
The assessments per visit are described in Table 5‒1 and Table 5‒2.
REDACTED 
t coun
t coun
amined
mine
icia
icia
COPY 
5‒
5
This document 
ha
ha
Sec
Sec
annot 
ange
ange
be 
t.t
used
requ
equ
orrec
orrec
to
er d
er d
uirir
support 
ts are t
s are 
dele
dele
any
h thi
h th
marketing 
d f
d f
an, or a
n, or 
has had
as had
the sam
the sa
isi
authorization 
nts (4
nts (4
for s
for s
application 
and 
nd Ta
T
and any extensions or
escri
scr
variations 
d is
d is
ib
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 184 of 255
Change #60
Section 9.1.20 Total and nocturnal spinal pain NRS, paragraph 2
The pain NRS assessments per visit are described in Table 5‒1.
Has been changed to:
The pain NRS assessments per visit are described in Table 5‒1, Table 5‒2, and Table 5‒3.
Change #61
Section 12.5 Laboratory measurements, Table 12–1
Apoliproproteins and lipoprotein(a) have been added to Table12-1 and a repeat of “others” 
has been removed from the “others” column
Change #62
Section 12.6.1 Pregnancy testing
Pregnancy testing must be carried out for women of childbearing potential and will consist of 
serum testing at Screening and FU and urine testing (dipstick) at Baseline and 
Week 52/Withdrawal FU.
Has been changed to:
Pregnancy testing must be carried out for women of childbearing potential and will consist of 
serum testing at Screening and FU and urine testing (dipstick) at Baseline, at wdt Week 0 of the 
alternative study assessment (for subjects administering either open-label CZP or alternative 
treatment), and at Week 52/WD.
Change #63
Section 12.6.3 Assessment and management of TB and TB risk factors, paragraph 13
Subjects who prematurely discontinue treatment for latent TB, or, in the opinion of the 
Investigator or Sponsor, are noncompliant with anti-TB therapy must discontinue further use of 
study medication and be immediately withdrawn. Once withdrawn from study treatment, 
subjects should return for the Study Completion/Withdrawal Visit, complete all Early 
Withdrawal assessments, and complete a FU Visit (8 weeks after the Week 52/WD-visit).
Has been changed to:
Subjects who prematurely discontinue treatment for LTB, or, in the opinion of the Investigator or 
Sponsor, are noncompliant with anti-TB therapy must discontinue further use of study 
medication and be immediately withdrawn. Once withdrawn from study treatment, subjects 
should return for the Week 52/WD visit, complete all Week 52/WD assessments, and complete a 
FU visit (8 weeks after the Week 52/WD visit).
REDACTED 
or wom
or wom
nd urin
nd uri
bjec
bjec
COPY 
hil
hi
g (dip
g (dip
This document
Subj
Subj
Sp
canno
awal
wal
s been
been
be
ould
ould
l a
l a
used
pon
on
ion an
on a
d r
d r
to 
atur
tu
nso
nso
support 
ment an
ent a
urely
rely
any marketing 
ne 
ne
cts adm
ts adm
authorization 
p
men o
men o
e tes
tes
application 
earing 
aring
stick) 
tick)
and any extensions 
repeat
epeat
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 185 of 255
Change #64
Section 12.6.3.2 Chest x-ray, paragraph 1
A plain posteroanterior chest x-ray (or, if done, computed axial tomography of the chest) must be 
done within 3 months prior to the Screening Visit. The chest x-ray must be clear of signs of TB 
infection (previous or current) before first study drug administration. The chest x-ray will be 
repeated at Completion Week 52/Withdrawal Visit (if chest x-ray was performed more than 
12 weeks prior to Early Withdrawal Visit), only if the TB test was confirmed positive or any 
further evidence is suggestive of potential TB infection (eg, exposure). Radiographic findings 
suggestive of inactive TB or active TB may include but are not limited to: apical fibrosis, pleural 
thickening, pulmonary nodules, fibrotic scars, calcified granulomas, upper lobe infiltrates, 
cavitations and pleural effusions, calcified lung nodules, calcified hilar lymph nodes, and 
pericardial calcification.
Has been changed to:
A plain posteroanterior chest x-ray (or, if done, computed axial tomography of the chest) must be 
done within 3 months prior to the Screening visit. The chest x-ray must be clear of signs of TB 
infection (previous or current) before first study drug administration. The chest x-ray will be 
repeated at Week 52/WD visit (if chest x-ray was performed more than 12 weeks prior to 
Week 52/WD visit), only if the TB test was confirmed positive or any further evidence is 
suggestive of potential TB infection (eg, exposure). Radiographic findings suggestive of inactive 
TB or active TB may include but are not limited to: apical fibrosis, pleural thickening, 
pulmonary nodules, fibrotic scars, calcified granulomas, upper lobe infiltrates, cavitations and 
pleural effusions, calcified lung nodules, calcified hilar lymph nodes, and pericardial 
calcification.
Change #65
Section 12.6.3.4 Tuberculosis questionnaire, paragraph 1
The questionnaire “
” should be used as a 
source document. The questionnaire will be completed at Screening, Baseline, and every 
12 weeks thereafter including and up to Week 36 and at Completion at Week 52/Early 
Withdrawal Visit. The questionnaire will assist with the identification of subjects who may 
require therapy for TB. A subject who answers “Yes” to the question “
 
at Screening is excluded. A “Yes” response to any of the other questions within the
questionnaire at Screening should trigger further careful assessment to determine if subject has 
latent or active TB (see Exclusion Criterion 16, Section 6.2). A “Yes” response to any of the 
questions during the study should trigger further assessments to determine if the subject has 
either latent TB or active TB infection (see Appendix 18.12).
Has been changed to:
The questionnaire 
” should be used as a 
source document. The questionnaire will be completed at Screening, Baseline, and every 
12 weeks thereafter including and up to Week 36 and including Week 52/WD visit. The 
REDACTED
ed to
ed t
granu
granu
 calci
calci
COPY
ed po
ed p
e). Ra
e). Ra
to:
to:
This document
ques
ques
eith
eit
cannot 
at 
at
onnai
onna
nt or 
nt or 
i
o be
t Sc
t Sc
be used 
. T
y for T
for T
us
o
The 
The
suppo
questio
uesti
ncludi
clud
t
ort any
que
que
a
marketing 
est
authorization
adio
dio
apica
apica
uloma
loma
ified h
fied h
application 
mu
mu
ation. T
tion.
more 
more
sitive o
sitive
ogra
ogra
and
graph
grap
must 
ust
any 
hy
h
extensions
sis
ltrates
ltrate
odes, a
des, a
or
s, pl
, p
variations 
y
ngs 
ngs 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 186 of 255
questionnaire will assist with the identification of subjects who may require therapy for TB. A 
subject who answers “Yes” to the question 
 
 at Screening 
is excluded. A “Yes” response to any of the other questions within the questionnaire at Screening 
should trigger further careful assessment to determine if subject has LTB or active TB (see 
Exclusion Criterion 16, Section 6.2). A “Yes” response to any of the questions during the study 
should trigger further assessments to determine if the subject has either LTB or active TB 
infection (see Appendix 18.12).
Change #66
Section 12.6.3.5 Tuberculosis management, paragraph 6
The subject should be transferred to the care of his/her physician and managed according to the 
best available standard of care. Subjects identified as having converted to active TB during the 
study must be withdrawn and scheduled to return for the Withdrawal Visit as soon as possible 
but no later than the next scheduled study visit and complete all Early Withdrawal Visit 
assessments.
Has been changed to:
The subject should be transferred to the care of his/her physician and managed according to the 
best available standard of care. Subjects identified as having converted to active TB during the 
study must be withdrawn and scheduled to return for the Week 52/WD visit as soon as possible 
but no later than the next scheduled study visit and complete all Week 52/WD visit assessments. 
Change #67
Section 13.2.1 Definition of source data, paragraph 2 and bulleted items 1 and 2
The following data will be recorded directly in the PC Tablet on site and will not appear in a 
source document as defined above:
x Patient outcome questionnaires: SF-36, EQ-5D-3L, OMERACT flare questionnaire, 
PGADA, WPS-RA and the socio-professional status
x Investigator’s assessments: PhGADA and the swollen and tender joint counts
Have been changed to:
The following data will be recorded directly in the electronic patient reported outcome (ePRO) 
Tablet on site and will not appear in a source document as defined above:
x Patient Reported Outcome questionnaires: SF-36, EQ-5D-3L, PGADA, BASDAI, BASFI, 
ASQoL, MOS Sleep Scale, Total and Nocturnal Spinal Pain Questionnaire
REDACTED 
fied
fied
return 
return 
y visit
y visit
COPY 
s/her p
s/her
d as
d a
This document
x
P
cannot
llowin
lowi
let on
et on
be
n cha
n cha
used
r’s as
’s as
an
an
to 
RA
RA
support
d ab
ab
uestion
estio
A an
A an
any
orded
orde
bov
bov
marketing 
rce dat
ce da
d
authorization 
phy
phy
s havi
havi
for th
for th
t and c
and 
application 
arly
rly
hysic
ysic
and
Visi
Visi
ly W
y W
any 
ge
o activ
 acti
t a
t
extensions 
ed ac
d ac
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 187 of 255
Change #68
Section 13.3.1 Case report completion, paragraph 2
The following paragraph has been deleted:
The study will also use an electronic device (Site Tablet) to capture the PhGADA and joint 
counts (see Section 13.4).
Change #69
Section 13.4 Electronic reporting outcome, paragraph 2
This study will use an electronic Site Tablet having a large screen and intuitive fingertip data 
entry to ensure all questionnaire data are captured appropriately, completely and on time. Not 
only subjects’ data will be collected with the tablets, physicians’ data (joint counts and 
PhGADA) will be entered directly.
Has been changed to:
This study will use an electronic Site Tablet having a large screen and intuitive fingertip data 
entry to ensure all questionnaire data are captured appropriately, completely and on time. Only 
subjects’ data will be collected with the tablets; the data of both the physicians (joint counts and 
PhGADA) and WPS will be entered directly in the eCRF or collected on worksheets.
Change #70
Section 13.5.1 Subject Screening and Enrollment log/Subject Identification Code list
Heading 13.5.1 has been deleted.
Change #71
Section 14.1 Definition of analysis sets, paragraph 3
The Safety Set (SS) will consist of all subjects in the RS who have received at least 1 dose of 
study medication.
Has been changed to:
The Safety Set (SS) will consist of all subjects who have received at least 1 dose of study 
medication.
Change #72
Section 14.2 General statistical considerations, paragraph 2
The statistical analysis of the primary efficacy variable and selected secondary efficacy variables 
will account for multiplicity by using a fixed sequence testing procedure. The predefined order 
of hypothesis testing, each at a 2-sided 0.05 significance level for the comparison between CZP 
200mg Q2W and placebo, will be performed in the sequence shown below. After the first test, 
REDACTED 
nd En
nd En
COPY
data o
data 
he eCR
he eC
This document 
Cha
Cha
cannot 
y
tion.
ion.
be
Set 
Set
used 
anged
nged
to support 
of ana
of ana
will co
ill co
any marketing
nro
ro
authorization
RF o
RF o
ollm
oll
application 
een and
en an
tely, co
ely, c
of both
f both
or
or
and any
t co
co
extensions 
fingert
nger
and on
nd on
oun
oun
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 188 of 255
each subsequent test is performed only if the previous test is significant in favor of CZP at the 
2-sided 0.05 level. Note that the first test relates to the primary efficacy variable while the others 
provide the sequence testing for secondary efficacy variables.
Has been changed to
The statistical analysis of the primary efficacy variable and selected secondary efficacy variables 
will account for multiplicity by using a fixed sequence testing procedure. The predefined order 
of hypothesis testing, each at a 2-sided 0.05 significance level for the comparison between CZP 
200mg Q2W and placebo, will be performed in the sequence shown below. After the first test, 
each subsequent test is performed only if the previous test is significant in favor of CZP at the 
2-sided 0.05 level. Note that the first test relates to the primary efficacy variable while the others 
provide the sequence testing for selected secondary efficacy variables.
Change #73
Section 14.3 Planned efficacy analyses
The primary efficacy variable measurement for this study is based on ASDAS-MI response at 
Week 52. The associated primary outcome of the study will be defined as a composite endpoint 
that is achieved if a subject fulfills the following 2 components:
1. Remain in the study and on study treatment through 52 weeks
2. Achieve an ASDAS-MI response at 52 weeks
For simplicity, this primary efficacy variable will be referred to as ASDAS-MI response at 
Week 52. However, the composite definition as described above will apply when this endpoint is 
analyzed. The primary analysis for this endpoint will be based on logistic regression. The odds 
ratio of the ASDAS-MI responder rates at Week 52 will be estimated and tested between 
treatment groups using a logistic regression model with factors of treatment group, region, and 
MRI/CRP classification (MRI+/CRP+; MRI+/CRP-; MRI-/CRP+). If the logistic regression 
model is unable to converge, then MRI/CRP classification may be dropped from the model to 
facilitate convergence. The study design is likely to result in some sites with a small number of 
enrolled subjects. The use of region as a stratification variable and as a factor in the model is 
intended to combine study centers in similar geographic regions. The geographic regions to be 
used will be defined in the IXRS and in the SAP. Given the composite endpoint definition 
described above, there will be no missing data for the primary endpoint, as subjects that 
discontinue study treatment prior to Week 52 or who do not have an ASDAS-MI status at 
Week 52 are considered nonresponders to study treatment.
As described in Section 6.3, subjects who discontinue study treatment will not necessarily be 
withdrawn from the study. In an attempt to minimize missing data, efforts will be made to 
continue to collect safety and efficacy data on these subjects through study completion. An 
alternative analysis for ASDAS-MI at Week 52 will be performed in which the observed data at 
Week 52 will be used, regardless of whether or not the subject is still on his/her randomized 
study treatment at that time. Despite efforts to continue to collect data on all subjects (even if 
they discontinue study treatment), there may still be subjects with missing data at Week 52. Such 
subjects will be considered as nonresponders in accordance with the composite endpoint 
REDACTED
weeks
week
iable w
iable 
efinitio
efinitio
his e
his e
COPY
ompo
omp
throu
throu
This document
withd
with
con
con
cannot
2 are
2 are
descri
escr
dr
d
be
e stu
e stu
used
ned 
ed
ve, th
ve, th
d
to
e st
e st
d in
d i
support 
e, t t
he stud
he stu
use of
use o
tudy
tud
any
/CR
/CR
then 
hen 
marketing
on
endpo
endpo
tes at W
es at 
regress
egres
RP+
RP
authorization
ugh 5
ugh 5
s
will b
will b
n as 
n as 
application 
ed on 
ed on
be defin
be def
nents:
nents
2
and any extensions
ZP 
hile th
hile th
or
at t
at t
variations 
CZP 
ZP 
test,
test,
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 189 of 255
definition outlined above. The same logistic regression model specified for the primary analysis 
will be used.
Subgroup analyses by age, gender, race, symptom duration, smoking history, HLA-B27 
genotype, anti-CZP Ab status, region, prior anti-TNF exposure, and MRI/CRP classification 
(MRI+/CRP+; MRI+/CRP-; MRI-/CRP+) will be performed for the primary variable.
Has been changed to:
The primary efficacy variable measurement for this study is based on ASDAS-MI response at 
Week 52. The associated primary outcome of the study will be defined as a composite endpoint 
that is achieved if a subject fulfills the following 2 components:
1. Remain in the study and on the double-blind study treatment through 52 weeks 
2. Achieve an ASDAS-MI response at 52 weeks
For simplicity, this primary efficacy variable will be referred to as ASDAS-MI response at 
Week 52. However, the composite definition as described above will apply when this endpoint is 
analyzed. The primary analysis for this endpoint will be based on logistic regression. The odds 
ratio of the ASDAS-MI responder rates at Week 52 will be estimated and tested between 
treatment groups using a logistic regression model with factors of treatment group, region, and 
MRI/CRP classification (MRI+/CRP+; MRI+/CRP-; MRI-/CRP+). If the logistic regression 
model is unable to converge, then the MRI/CRP classification variable may be dropped from the 
model to facilitate convergence. The study design is likely to result in some sites with a small 
number of enrolled subjects. The use of region as a stratification variable and as a factor in the 
model is intended to combine study centers in similar geographic regions. The geographic 
regions to be used will be defined in the IXRS and in the SAP. Given the composite endpoint 
definition described above, there will be no missing data for the primary endpoint, as subjects 
that discontinue the double-blind study treatment prior to Week 52 or who do not have an 
ASDAS MI status at Week 52 are considered nonresponders to the double-blind study treatment.
As described in Section 6.3, subjects who discontinue the double-blind study treatment will not 
necessarily be withdrawn from the study. In an attempt to minimize missing data, efforts will be 
made to continue to collect safety and efficacy data on these subjects through study completion. 
Sensitivity analyses will be performed to evaluate the impact of missing data on the analysis of 
the primary efficacy variable (see Section 14.8).
Subgroup analyses by age, gender, race, symptom duration, smoking history, HLA-B27 
genotype, anti-CZP Ab status, region, prior anti-TNF exposure, and MRI/CRP classification 
(MRI+/CRP+; MRI+/CRP-; MRI-/CRP+) will be performed for the primary efficacy variable. 
Subgroup analyses will be summarized using descriptive statistics only.
Change #74
Section 14.4 Secondary efficacy analyses
The changes from Baseline in BASDAI and BASFI at Week 12 and Week 52 are specified as 
secondary efficacy variables. As these are continuous variables, missing data must be handled 
using a different approach from what is specified for the primary efficacy endpoint (a responder 
variable). 
REDACTED 
ign
ign
ion
ion as 
as
ers in 
ers in 
he IXR
he IXR
ll be 
ll be 
COPY
 MR
MR
classif
classi
n is 
n is
This document 
Ch
Ch
cannot 
CRP
RP
roup a
oup a
be 
ntiti
RP+;
RP+;
used 
yses b
yses b
i CZ
CZ
to
y va
y va
support 
rom
om
ect safe
ct sa
will be p
ill be 
aria
ar
any
bject
bjec
m the
m th
marketing
no m
no m
dy treat
dy trea
consid
consid
tst
authorization 
fica
ca
likely
likely
a stra
a stra
simila
simil
RS an
RS an
application 
og
mated 
mated
ors of tr
rs of t
/CRP
/CRP
ation
atio
nd
appl
appl
gisti
gisti
any
AS
AS-M
ly w
ly
extensions 
eks
ks
or
ndp
ndp
variations 
e at 
at 
poi
poi
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 190 of 255
Investigators will be given discretion to discontinue study treatment for subjects not responding 
in order to provide them with alternative therapy to treat the condition. Therefore, in many cases,
missing efficacy data due to study treatment discontinuation should be dependent on the 
observed efficacy scores, but independent of unobserved data. This would be consistent with a 
missing at random pattern of missingness. However, the possibility of discontinuation due to 
tolerability or other unobserved data cannot be completely discounted. Therefore, a missing not 
at random mechanism will be considered as the primary analysis method of continuous 
secondary efficacy variables, where reference-based imputation methods will be used. 
This approach will impute missing data as well as data at time points following discontinuation 
of study treatment for both the CZP and placebo groups using an imputation model developed 
based on data from the placebo group (Mallinckrodt, 2013). The estimand being evaluated in this 
case is a de-facto estimand that has been described as the difference in outcome improvement in 
all randomized subjects at the planned endpoint attributable to the initially randomized 
medication (Mallinckrodt, 2012). This reference-based imputation procedure will be described in 
greater detail in the SAP. The final model to be used on the imputed data will be an analysis of 
covariance (ANCOVA) model where response is the change from Baseline, with Baseline score 
as a fixed-effect covariate and treatment group, region, and MRI/CRP classification as fixed 
effect categorical factors. 
Additionally, change from Baseline in SI joint SPARCC score at Week 12 is a continuous 
secondary efficacy variable. As with BASDAI and BASFI, a reference-based imputation 
approach will be used to account for missing data. However, it should be noted that, unlike 
BASDAI and BASFI, SPARCC score will not be measured at any time points between Baseline 
and Week 12, meaning that those are the only 2 time points that can be considered in the 
evaluation of SPARCC score at Week 12. Therefore, Week 12 represents the only time point at 
which the placebo treatment effect can be evaluated for the imputation procedure. Comparisons 
between treatment groups will be made using an ANCOVA on the imputed data set. The model 
will include Baseline score, treatment group, region, and MRI/CRP classification. 
The ASAS40 response at Week 12 and Week 52 are responder secondary efficacy endpoints. As
a responder variable, ASAS40 will be analyzed using logistic regression based on a model 
similar to the one described for the primary analysis. As with the primary efficacy endpoint, the 
ASAS40 will be treated as a composite endpoint when it is analyzed. Specifically, subjects will 
need to 1) achieve the relevant response (ASAS40) and 2) remain in the study and on their 
randomized study treatment through the time point being analyzed (Week 12 or Week 52).
The comparison of CZP 200mg Q2W to placebo as described above for the ASAS40 response, 
BASDAI, and BASFI at Week 12 and Week 52 and for SI joint SPARCC score at Week 12 will 
be part of the fixed sequence testing procedure outlined in Section 14.2.
Additionally, sensitivity analyses will be conducted on these secondary efficacy endpoints. In 
particular, the assumptions related to missing data will be investigated further. These analyses 
are described in Section 14.8.
An additional secondary efficacy variable is the number of subjects with relevant changes to
background medication. This variable will be based on whether or not subjects take certain 
pre-specified background medications during the course of the study and will be defined in the 
REDACTED
data.
data
not be
not be
e only
e only
k 12. T
k 12. 
an b
an b
COPY
RCC 
RCC
nd BA
nd BA
a H
a H
This document
Addi
Addi
part
par
canno
AI, an
I, an
art of t
rt of t
diti
iti
be
ariso
ariso
and
and
used
e t
udy tre
dy tr
on
on
to
the r
the 
suppor
S40 
S40 
ibed fo
bed f
ed as 
ed as
any
k 12 
k 12
0 wi
w
marketing
Th
be eva
be eva
ade usin
de us
ment gr
ent g
authorization
ASFI
SFI
Howe
Howe
e mea
 mea
y 2 tim
2 tim
here
here
application
I/CRP
/CRP
score a
score 
I a
I
and
ata 
ta 
aseli
asel
any
ure w
ure 
wil
wi
extensions
devel
evel
evalua
valua
e impr
e impr
andom
ndom
o
nuat
nua
lol
variations 
atio
ati
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 191 of 255
SAP. The analysis for this variable will use the same logistic regression model described for the 
primary variable.
Has been changed to:
The changes from Baseline in BASDAI and BASFI at Week 12 and Week 52 are specified as 
secondary efficacy variables. As these are continuous variables, missing data must be handled 
using a different approach from what is specified for the primary efficacy endpoint (a responder 
variable). In the current study, Investigators will be given discretion to discontinue the double 
blind study treatment for subjects not responding in order to provide them with alternative 
therapy to treat the condition. Therefore, in many cases, missing efficacy data due to the 
double-blind study treatment discontinuation should be dependent on the observed efficacy 
scores, but independent of unobserved data. This would be consistent with a missing at random 
(MAR) assumption. However, the possibility of discontinuation due to tolerability or other 
unobserved data cannot be completely discounted. Therefore, a missing not at random 
mechanism will be used for the analysis of continuous secondary efficacy variables.
A reference-based multiple imputation (MI) procedure will be used for this analysis, which will 
impute missing data as well as data at the time points following the discontinuation of the 
double-blind study treatment for both the CZP and placebo groups. This procedure will use an 
imputation model developed based on available data from the placebo group, thereby assuming a 
placebo trajectory for missing data following study treatment discontinuation for subjects in both 
treatment groups (Mallinckrodt, 2013). The estimand being evaluated in this case is the 
difference in the outcome of improvement in all randomized subjects at the planned endpoint, 
attributable to the initially randomized medication. This is an effectiveness estimand of the de 
facto hypothesis which has been referred to as “estimand 6” (Mallinckrodt, 2012).
Additionally, change from Baseline in SI joint SPARCC score at Week 12 is a continuous 
secondary efficacy variable. The same MI procedure specified as the main analysis approach for 
BASDAI and BASFI will be used to account for missing SPARCC data. However, it should be 
noted that, unlike BASDAI and BASFI, SPARCC score will not be measured at any time points 
between Baseline and Week 12, meaning that those are the only 2 time points that can be 
considered in the evaluation of SPARCC score at Week 12. Comparisons between treatment 
groups will be made using an ANCOVA model on the imputed data set. The model will include 
Baseline score, treatment group, region, and MRI/CRP classification.  
The ASAS40 response at Week 12 and Week 52 are responder secondary efficacy endpoints. As 
a responder variable, ASAS40 will be analyzed using logistic regression based on a model 
similar to the one described for the primary analysis. As with the primary efficacy endpoint, the 
ASAS40 will be treated as a composite endpoint when it is analyzed. Specifically, subjects will 
need to 1) achieve the relevant response (ASAS40) and 2) remain in the study and on their 
randomized double-blind study treatment through the time point being analyzed (Week 12 or 
Week 52).
The comparison of CZP 200mg Q2W to placebo as described above for the ASAS40 response, 
BASDAI, and BASFI at Week 12 and Week 52 and for SI joint SPARCC score at Week 12 will 
be part of the fixed sequence testing procedure outlined in Section 14.2.
REDACTED
n all ra
n all r
edicati
dicati
ed to a
ed to a
in S
in S
COPY 
from
fro
y treat
y treat
mand
mand
This document 
ando
nd
We
We
cannot
40 wi
0 wi
d to 1)
d to 1
dom
dom
be
va
he o
he o
used
espon
pon
ariab
ariab
to 
tme
m
support
ion of 
on of
sing an
ing a
ment g
ent
any
BA
BA
2, me
2, m
S
marketing
SI join
I join
me MI p
e MI 
to acco
o ac
ASF
AS
authorization
tm
d bein
bein
andom
andom
ion. T
ion. T
as “es
as “es
application
the di
he d
oups. T
oups. 
the pla
he pl
ment d
ment d
and 
for th
or th
any 
ata
y vari
y var
extensions
he
effica
effica
sing a
ing a
bility o
ility 
at ra
t ra
or variations 
r r 
le
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 192 of 255
Additionally, sensitivity analyses will be conducted on these secondary efficacy endpoints. In 
particular, the assumptions related to missing data will be investigated further. These analyses 
are described in Section 14.8.
An additional secondary efficacy variable is the number of subjects with relevant changes to 
background medication. This variable will be based on whether or not subjects take certain 
pre-specified background medications during the course of the study and will be defined in the 
SAP. The analysis for this variable will use the same logistic regression model described for the 
primary variable.
Change #75
Section 14.5 Other efficacy analyses, paragraph 1
Treatment group comparisons for CZP 200mg Q2W vs placebo will be performed based on the 
change from Baseline in other selected efficacy variables. These analyses will be performed 
using an ANCOVA model including Baseline score, treatment group, region, and MRI/CRP 
classification. The treatment differences and corresponding 95% confidence intervals will be 
calculated based on the adjusted means. Missing values or values observed after discontinuing 
study treatment will be imputed using last observation carried forward (LOCF). The following 
variables will be analyzed in this manner:
Has been changed to:
Treatment group comparisons for CZP 200mg Q2W versus placebo will be performed based on 
the change from Baseline in other selected efficacy variables. These analyses will be performed 
using an ANCOVA model including Baseline score, treatment group, region, and MRI/CRP 
classification. The treatment differences and corresponding 95% confidence intervals will be 
calculated based on the adjusted means. Missing values or values observed after discontinuing 
the double-blind study treatment will be imputed using last observation carried forward (LOCF). 
The following variables will be analyzed in this manner:
Change #76
Section 14.6.1 Safety analyses, paragraph 2
Since subjects will be permitted to change background medications and because they may also 
discontinue study treatment and initiate a new treatment (including biologics) during the course 
of the study, special consideration will be given to how AEs are attributed to study treatment. 
This, along with other specialized AE summaries, will be described in greater detail in the SAP.
Has been changed to:
Since subjects will be permitted to change background medications and because they may also 
discontinue the double-blind study treatment and initiate a new treatment (including biologics) 
during the course of the study, special consideration will be given to how AEs are attributed to 
the double-blind study treatment. This, along with other specialized AE summaries, will be 
described in greater detail in the SAP.
REDACTED 
0mg Q
0mg Q
ted eff
ted ef
Basel
Base
nces
nces
COPY 
n ca
c
This document
Has 
Has 
Sin
Sin
canno
tudy
udy
along
along
b
be
e stu
e stu
y s
y s
used 
fe
s will 
will
ud
to
ety 
ety 
support any
e ana
an
marketing 
linin
s and c
and 
ans. M
ns. M
will be
will b
alyl
authorization 
Q2W v
2W v
fficacy
ficacy
ne sc
ne s
application
confi
conf
ues ob
ues ob
ied for
ed fo
and 
ses
es
p, regi
, reg
fid
fid
any
rform
rfor
s wil
s wil
extensions 
rm
rm
or variations 
the
he
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 193 of 255
Change #77
Section 14.6.2 Pharmacokinetic and immunogenicity variable analysis, paragraph 1
Certolizumab pegol plasma concentrations will be tabulated and summarized by treatment group 
(overall and by anti-CZP Ab level - above or below 2.4 units/mL within each treatment group) 
for each visit at which samples were taken using the geometric mean, geometric coefficient of 
variation, 95% confidence intervals (CIs), arithmetic mean, arithmetic SD, minimum and 
maximum, geomean plasma concentration time curves with their 95% CI will be plotted overall 
and by anti CZP Ab status.
Has been changed to:
Certolizumab pegol plasma concentrations will be tabulated and summarized by treatment group 
(overall and by anti-CZP Ab level - above or below 2.4 units/mL within each treatment group) 
for each visit at which samples were taken using the geometric mean, geometric coefficient of 
variation, 95% confidence intervals (CIs), arithmetic mean, arithmetic SD, minimum and 
maximum, geomean plasma concentration time curves with their 95% CI will be plotted overall 
and by anti CZP Ab status. Individual plasma concentrations for CZP and anti-CZP levels versus 
time will be produced on the same graph.
Change #78
Section 14.8 Handling of dropouts or missing data
For analysis purposes, the primary efficacy variable is defined as a composite endpoint in which 
it is necessary to achieve ASDAS-MI at Week 52 and to remain on randomized study treatment 
through Week 52 in order to be considered a responder (see Section 14.3). Because this 
composite endpoint definition does not allow for a missing response status, no formal method for 
handling missing data is needed in the primary analysis. An additional analysis (also described in 
Section 14.3) will be performed in which all observed data at Week 52 are used, including data 
collected for subjects who may have discontinued study treatment without being withdrawn from 
the study.
Analyses of other binary efficacy variables will be treated in the same way as the primary 
efficacy variable. That is, a subject will be considered a responder only if the response is 
achieved and if the subject is still on his/her randomized study treatment at the time when the 
variable is evaluated. For ASAS40 response at Week 12 and Week 52 (secondary efficacy 
endpoints included in the fixed sequence statistical testing procedure), an additional analysis 
based on all collected data (as described above for the primary endpoint) will be performed. 
To account for missing data and data following discontinuation of study treatment for continuous 
secondary efficacy variables (change from Baseline in BASDAI and BASFI at Week 12 and 
Week 52 and change from Baseline in SI joint SPARCC score at Week 12), the analysis method 
that will be used when considering statistical significance in the fixed sequence testing procedure 
will be referenced-based imputation where an ANCOVA model is used on the multiply imputed 
data (see Section 14.4).
Other analyses of continuous secondary efficacy data will be implemented to evaluate sensitivity 
of results to the method of handling missing data and will include the following:
REDACTED
ng d
ng d
cy var
cy var
at We
at We
sidere
sidere
COPY 
This document
secon
econ
We
We
cannot
n all
n all
accou
accou
nd
be
inclu
inclu
used
the s
he s
aluate
aluate
d
to
That 
hat
su
su
support 
ary effi
ry eff
t is, 
t is
any 
in
y hav
y hav
marketing 
ed a r
d a 
ot allow
t allo
the pri
he pr
n whi
n wh
authorization 
ata
ta
riable 
riable 
ek 52
ek 52
re
application 
CZP
ZP
and
% CI 
CI 
P an
P an
any 
etet
D, min
D, mi
w
extensions 
treatm
reatm
treatm
reatm
tric 
ric 
or variations 
erall
rall 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 194 of 255
x ANCOVA based on all observed data (including from subjects who discontinued study 
treatment but continued in the study) where any remaining missing data is imputed using 
reference-based imputation methods
x mixed model for repeated measures (MMRM) with Baseline score as a fixed effect covariate 
and treatment group, region, MRI/CRP classification, and visits as fixed effect categorical 
factors, and Baseline by visit and treatment group by visit as interaction terms (where data 
following study treatment discontinuation are treated as missing)
x LOCF
x Baseline observation carried forward (BOCF)
Additionally, “tipping point” sensitivity analyses will be conducted. These analyses will vary 
assumptions about average outcomes among the subjects in the CZP treatment group who 
discontinue study treatment early through a series of delta adjustments (O’Kelly, 2014). These 
assumptions may be severe and will include the possibility that subjects with missing data in the 
CZP treatment group had worse outcomes than dropouts on the placebo arm. Such adjustments 
to the assumptions may be performed until a statistically significant result in favor of CZP is no 
longer observed. The plausibility of the assumptions leading to that change would then be 
considered. Further details on all of these sensitivity analyses will be provided in the SAP.
Descriptive summaries based on observed case data will also be prepared. 
Additionally, algorithms for imputing missing or partial dates for safety evaluations will be 
detailed in the SAP.
Has been changed to:
For analysis purposes, the primary efficacy variable is defined as a composite endpoint in which 
it is necessary to achieve ASDAS-MI at Week 52 and to remain on randomized double-blind 
study treatment through Week 52 in order to be considered a responder (see Section 14.3).
Because this composite endpoint definition does not allow for a missing response status, no 
formal method for handling missing data is needed in the primary efficacy analysis. However, in 
order to assess the impact of various missing data assumptions on the analysis, additional 
sensitivity analyses of the primary efficacy variable will be performed as follows:
x Including observed data at Week 52: The observed data at Week 52 will be used and 
analyzed according to randomized treatment, regardless of whether or not the subject is still 
on his/her randomized double-blind study treatment at that time. Despite efforts to continue 
to collect data on all subjects (even if they discontinue the double-blind study treatment), 
there may still be subjects with missing data at Week 52. Such subjects will be considered as 
non-responders in accordance with the composite endpoint definition outlined above. The 
same logistic regression model specified for the primary analysis will be used.
x MI: The MCMC method will be used to impute intermittent missing data. The resulting 
multiply imputed data sets will be monotone missing and will be imputed using monotone 
regression (assuming a MAR pattern). Note that the MI procedure will be done on the 
continuous ASDAS variable, which will be dichotomized for the logistic regression analysis. 
Ankylosing Spondylitis Disease Activity Score data collected following the discontinuation 
REDACTED
or p
or 
ffica
ffica
COPY 
ta will
a will
pa
pa
This document
s
x
cannot
re ma
e ma
non
on-rer
sam
sam
be
ect d
ect d
used
cordi
ordi
rand
rand
to
rved
ved
support
of va
of va
the pri
he p
d d
d d
any 
t d
t d
missing
issin
marketing
acy va
acy v
at We
at W
in orde
n ord
defin
defi
authorization 
l a
artial d
rtial d
application
nt re
t r
 that ch
that c
es will 
s will
also b
also b
and
ebo ar
bo a
resu
res
any
Kel
Ke
with m
with 
extensions 
yses w
ses w
nt grou
t grou
elly
lly
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 195 of 255
of double-blind study treatment will be treated as missing in the original data set for this 
sensitivity analysis.
x Tipping point analysis: In this analysis, various assumptions will be made about average 
outcomes among the subsets of subjects who prematurely discontinued double-blind study 
treatment. Various “delta adjustments” will be made to the assumed responses among 
missing data in each treatment arm with varying degrees of plausibility (O’Kelly, 2014). The 
goal of the tipping point analysis is to identify assumptions about the missing data under 
which the conclusions change, ie, under which there is no longer evidence of a treatment 
effect. Then, the plausibility of such assumptions would be discussed. Further details of this 
procedure will be described in the SAP.
x Observed case analysis: This analysis will only include the observed data for subjects still on 
the original double-blind study treatment. Data collected after the discontinuation of 
double-blind study treatment and all other missing data will be excluded from the analysis. 
The same logistic regression model specified for the primary efficacy analysis will be 
performed.
The sensitivity analyses of the secondary binary efficacy variables (ASAS40 at Weeks 12 and 
52) will be as follows:
x Including observed data at Week 52: As described for the primary efficacy variable.
x MI: As described for the primary efficacy variable. Note that as ASAS40 is a composite of 
4 different variables, the MI procedure will be performed on each of these components, and 
the ASAS40 response will be derived based on the multiply imputed datasets.
x Reference-based MI: This procedure will impute missing data as well as data at the time 
points following the discontinuation of the double-blind study treatment for both the CZP 
and placebo groups. This procedure will use an imputation model developed based on data 
from the placebo group (Mallinckrodt, 2013). The estimand being evaluated in this case is 
the difference in the outcome of improvement in all randomized subjects at the planned 
endpoint, attributable to the initially randomized medication, which has been referred to as 
“estimand 6” (Mallinckrodt, 2012).
x Observed case analysis: As described for the primary efficacy variable.
The sensitivity analyses of secondary continuous efficacy variables (the change from Baseline in 
BASDAI and BASFI at Weeks 12 and 52 and the change from Baseline in the SI joint SPARCC 
score at Week 12) will be as follows:
x Including observed data at Week 52: As described for the primary efficacy variable.
x MI: As described for the primary efficacy variable.
x Observed case analysis: As described for the primary efficacy variable.
x LOCF
Missing data for the other efficacy variables described in Section 14.5 will be handled as 
follows:
REDACTED
ar
will
will be
be
based
based
ure w
ure w
tion 
tion 
COPY
ed fo
ed fo
riabl
riabl
This document 
x
cannot
cludin
udin
MI: 
MI: 
be
eek 
eek 
used
naly
aly
BASF
BAS
12
12
to 
lyse
yse
support
thth
ckrodt
krod
alysis:
lysis
any
e o
e o
he ini
e ini
marketing
wil
n of the
of th
ure wil
re wi
inckrod
nckro
of i
of
authorization
le. No
e. No
 perfo
perfo
d on th
d on th
ll im
l im
application
es (A
es (A
r the pr
the p
and 
y
any
d fr
d f
y anal
anal
extensions 
r subje
subje
inuati
nuati
from
from
or
of
of
variations 
ent 
nt 
f th
f t
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 196 of 255
x With imputation: Non-responder imputation for binary variables and LOCF for continuous 
variables (as described in Section 14.5)
x Observed case analysis: As described for the primary efficacy variable.
Additionally, algorithms for imputing missing or partial dates for safety evaluations will be 
detailed in the SAP.
Change #79
Section 14.10 Determination of sample size
Subjects will be randomized in a 1:1 ratio to the CZP 200mg Q2W and placebo treatment 
groups. The expected response rates for ASDAS-MI at Week 52 are 40% and 20% for CZP and 
placebo, respectively. A total sample size of 300 (150 subjects per treatment group) provides 
95% power to detect a statistically significant difference in the ASDAS-MI response rate at 
Week 52 between CZP and placebo, using a 2-sided significance level of 0.05.
Has been changed to:
Subjects will be randomized in a 1:1 ratio to the CZP 200mg Q2W and placebo treatment 
groups. The expected responder rates for ASDAS-MI at Week 52 are 40% and 20% for CZP and
placebo, respectively. A total sample size of 300 (150 subjects per treatment group) provides 
95% power to detect a statistically significant difference in the ASDAS-MI responder rate at 
Week 52 between CZP and placebo, using a 2-sided significance level of 0.05.
REDACTED 
diff
diff
a 2
a 2-sid
sid
COPY
I at 
at
(150 su
150 
ffere
fer
This document cannot be used to support any marketing authorization 
subj
ub
ence in
nce i
ded sig
ed si
application 
Q2W 
Q2W
Week 52
eek 5
bject
ject
and
el of 
l of 
any 
MI res
MI re
0 0
0
extensions 
reatm
eatm
20% f
0% f
grou
grou
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 197 of 255
Change #80
Section 17 References
Callhoff J, Sieper J, Weiß A, Zink A, Listing J. Efficacy of TNFα blockers in patients with 
ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann 
Rheum Dis. 2015;
Has been changed to:
Callhoff J, Sieper J, Weiß A, Zink A, Listing J. Efficacy of TNFα blockers in patients with 
ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann 
Rheum Dis. 2015;74:1241-8.
Change #81
Section 17 References
Dougados M, van der Heijde D, Sieper J, et al. Efficacy of etanercept in nonradiographic axial 
spondyloarthritis. The Symptomatic Efficacy and Effect on Objective Signs of Inflammation of 
Etanercept in Early Nonradiographic Axial Spondyloarthritis. Ann Rhuem. 2014;66:2091-102.
Has been changed to:
Dougados M, van der Heijde D, Sieper J, Braun J, Maksymowych W, Citera G, et al. Efficacy of 
etanercept in nonradiographic axial spondyloarthritis. The symptomatic efficacy and effect on 
objective signs of inflammation of etanercept in early nonradiographic axial spondyloarthritis. 
Ann Rhuem. 2014;66:2091-102.
Change #82
Section 17 References
van Tubergen A, Black PM, Coteur G. Are Patient-Reported Outcome Instruments for 
Ankylosing Spondylitis Fit-For-Purpose for the Axial Spondyloarthritis Patient? A Qualitative 
and Psychometric Analysis. Rheum. In press
Has been changed to:
van Tubergen A, Black PM, Coteur G. Are Patient-Reported Outcome Instruments for 
Ankylosing Spondylitis Fit-For-Purpose for the Axial Spondyloarthritis Patient? A Qualitative 
and Psychometric Analysis. Rheum. 2015;54:1842-51.
Change #83
Section 17 References
Weber U, Ostergaard M, Lambert RG, Pedersen SJ, Chan SM, Zubler V, et al. Candidate 
lesion- based criteria for defining a positive sacroiliac joint MRI in two cohorts of patients with 
axial spondyloarthritis. Ann Rheum Dis. 2014-205408. Doi: 10.1136/annrheumdis-2014-205408,
REDACTED
oarthr
oarthr
cept in
ept in
COPY 
J, Ma
J, M
This document
Chan
Cha
S
cannot
ychom
chom
be
g Sp
g Sp
used 
ed 
d 
A, B
A, B
to
 to:
to:
support 
, C
Fitit-For
Fo
alysis. 
alysis.
any 
Coteu
Cote
marketing authorization
Maksym
aksym
itis. T
itis. T
n early
n early
application
p
ective 
ective
. Ann R
. Ann 
and 
pt in n
t in 
any extensions or 
nn
nn
variations 
h
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 198 of 255
Has been changed to:
Weber U, Ostergaard M, Lambert RG, Pedersen SJ, Chan SM, Zubler V, et al. Candidate lesion
based criteria for defining a positive sacroiliac joint MRI in two cohorts of patients with axial 
spondyloarthritis. Ann Rheum Dis. 2015;74:1976-82.
Change #84
Section 18.1 ASAS classification criteria for axial SpA, footnote 3 (number 1)
1) age at onset <40 years
Has been changed to:
1) age at onset <45 years
Change #85
Sections 18.9 PGADA (NRS) and 18.11 Total spinal pain NRS and nocturnal spinal pain 
NRS; “Spondylitis” has been changed to “Spondyloarthritis”.
REDACTED COPY 
This document cannot be used to support any marketing authorization application
S and
S an
tis”.
is”.
and 
d
any extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 199 of 255
18.14 
Protocol Amendment 2 
Rationale for the amendment
This substantial amendment includes changes to clarify some of the study procedures, as well as 
to update Inclusion Criteria 5 and 6 concerning the Assessment of SpondyloArthritis 
International Society (ASAS) criteria, and to increase the number of participating sites and 
screened subjects. The rationale for the changes is as follows:
x Inclusion Criterion 5 about subjects having a documented diagnosis of adult-onset axial 
spondyloarthritis (axSpA) as defined by the specified ASAS criteria has been updated in 
order to:  i.) clarify that the ASAS criteria are classification criteria and are not intended to be 
used as diagnosis criteria and to avoid any misinterpretation, and ii.) remove the part “with at 
least 12 months symptom duration before Screening” since this part has been added to the 
updated Inclusion Criterion 6. 
x Inclusion Criterion 6 about subjects having evidence of inflammatory back pain as defined 
by the ASAS criteria has been updated to specify that subjects must have had back pain for at 
least 12 months before Screening. The reason is that the requirements for objective signs and 
symptoms of inflammation are clearly defined in Inclusion Criterion 9. The initial Inclusion 
Criterion 6 was therefore a repetition of this requirement. The updated version stresses the 
importance of having back pain as the lead symptom for axSpA for at least 12 months to 
ensure that the pain is chronic in nature.
x The number of participating sites and the number of screened subjects have been increased 
from 95 to 120 and from 900 to 1200, respectively, in order to adjust for a higher screening 
failure rate, which was actually exceeding the expected rate of 67%.
x Other changes included the following:
 Text about chest x-ray at Screening has been updated to clarify that the chest x-ray must 
be done at Screening unless a chest x-ray (or a computed tomography of the chest) has 
been done within 3 months prior to the Screening visit.
 Text about study treatment administration at on-site visits has been updated to clarify at 
which visits the subcutaneous (sc) injections will be administered by dedicated, 
unblinded, and adequately trained site personnel or by self-injection of the subject under 
the supervision of the unblinded study personnel.
 Study contact information for Clinical Trial Biostatistician has been updated.
 Minor editorial changes have been made.
Modifications and changes
Global changes
The following changes were made:
x The study contact information for Clinical Trial Biostatistician has been updated.
x Inclusion Criteria 5 and 6 have been updated.
REDACTED
e num
e num
respe
respe
ceedin
ceedin
owin
owin
COPY
ptom 
ptom
This document
Glob
Glob
T
canno
Mino
Min
difica
difica
be 
y c
y
nor
nor
sed
rvisi
visi
cont
con
to
and 
and
ion
ion
support
treatm
reatm
e subcu
subc
d ade
d ad
any
nths 
nths
marketing 
ng:g:
reenin
eenin
ss a ch
s a c
authorization 
mber of
ber of
ectivel
ective
ng the 
g the
application
reme
em
Criteri
Criter
t. The u
 The
for axS
for ax
and
y
ust ha
ust h
men
men
any 
y back
y bac
extensions
ntend
tend
he par
e pa
en add
en add
or
d in
d i
de
d
variations 
l
in
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 200 of 255
x The number of participating sites and screened subjects has been increased from 95 to 120 
and from 900 to 1200, respectively.
x Text about chest x-ray at Screening has been updated throughout the protocol to clarify that 
the chest x-ray must be done at Screening unless a chest x-ray (or a computed tomography of 
the chest) has been done within 3 months prior to the Screening visit.
x Text about study treatment administration at on-site visits has been updated to clarify at 
which visits the sc injections will be administered by dedicated, unblinded, and adequately 
trained site personnel or by self-injection of the subject under the supervision of the 
unblinded study personnel.
x Other changes made in this amendment are to provide clarification or are administrative in 
nature, including minor editorial changes to abbreviations.
Specific changes
This section displays the modifications in this amendment compared with the Final Protocol 
Amendment 1 dated 15 Dec 2015. The changes are displayed in order of appearance.
Change #1
Study Contact Information 
Clinical Trial Biostatistician 
Name:
, MS
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617
United States 
Phone:
Fax:
Has been changed to:
Clinical Trial Biostatistician 
Name:
, MS
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617
United States of America
Phone:
Fax:
REDACTED 
S
D
porate
porate
C 2761
C 2761
CT
COPY 
This document cannot 
an
be
dres
dres
used 
d
u
to 
os
os
t
support 
stat
sta
t any 
keting 
17
ke
marke
authorization 
ati
e Drive
Driv
hor
application 
rder
de
and
with
with
er o
r o
any 
th
extensions 
inistra
nistr
or variations 
ely 
ly 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 201 of 255
Change #2
Section 1 Summary, paragraph 2
The study population will be subjects (≥18 years), with a documented diagnosis of adult-onset 
axSpA as meeting the Assessment of SpondyloArthritis International Society ([ASAS], Sieper et 
al, 2009) criteria of at least 12 months’ symptom duration, and with active disease defined by a 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4, and spinal pain ≥4 on a 
0 to 10 Numerical Rating Scale (NRS). At Baseline, evidence of inflammatory disease will be 
confirmed either by presence of sacroiliitis on MRI (according to ASAS/Outcome Measures in 
Rheumatology Clinical Trials [OMERACT] criteria) or by elevated CRP or by presence of both.
Has been changed to:
The study population will be subjects (≥18 years), with a documented diagnosis of adult-onset 
axSpA and who meet the Assessment of SpondyloArthritis International Society ([ASAS], 
Sieper et al, 2009) criteria for axSpA, who have had back pain of at least 12 months’ symptom 
duration, and with active disease defined by a Bath Ankylosing Spondylitis Disease Activity 
Index (BASDAI) ≥4, and spinal pain ≥4 on a 0 to 10 Numerical Rating Scale (NRS). At 
Baseline, evidence of inflammatory disease will be confirmed either by presence of sacroiliitis 
on MRI (according to ASAS/Outcome Measures in Rheumatology Clinical Trials [OMERACT] 
criteria) or by elevated CRP or by presence of both.
Change #3
Section 1 Summary, paragraph 4
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site by dedicated, unblinded, 
and adequately trained site personnel. The double-blind study treatment will be self-injected at 
home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46. All subjects will receive training for self 
injection at the study site at Weeks 10 and 12. During the training at the Weeks 10 and 12 visits, 
the double-blind study treatment will be self administered under the supervision of the dedicated 
unblinded study personnel.
Has been changed to:
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site. At the Week 0, 2, 4, 6, 
and 8 visits, the administration must be done by dedicated, unblinded, and adequately trained site
personnel. At the Week 10 and 12 visits, the subject will receive training on self-injection and 
the study treatment will be self-administered under the supervision of the unblinded study 
personnel. At Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50, the study treatment administration 
should preferably be done by the unblinded study personnel, or alternatively by self-injection of 
the subject under the supervision of the unblinded study personnel. The double-blind study 
treatment will be self-injected at home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46.
REDACTED 
6, 8, 
6, 8, 
e adm
e adm
COPY 
This document
shou
hou
the
the
cannot 
l. A
. 
udy tre
dy tre
sonne
onne
uldld
be 
th
At t
At t
used
ys
y
tudy tr
udy t
he ad
he a
to
s (at
s (a
support 
t W
any 
k
ent wi
ent w
marketing 
minis
mini
The do
The d
34, 38,
4, 38
ks 10 
10
authorization 
10, 12
10, 12
st
application 
atin
tin
either b
ther 
tology 
tology
and
dylit
dylit
ing 
ng
any 
cici
12 m
12 m
isi
extensions 
ce 
sis of a
s of a
iety 
ety 
or
of b
of 
variations 
be
es in
es in
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 202 of 255
Change #4
Section 1 Summary, paragraph 16, first sentence
Approximately 900 subjects will be screened in order to have 300 subjects (150 subjects per 
treatment group) randomized into the study.
Has been changed to:
Approximately 1200 subjects will be screened in order to have 300 subjects (150 subjects per 
treatment group) randomized into the study.
Change #5
Section 4.4 Safety variables, paragraph 6
At Screening, all subjects will have an Interferon-Gamma Release Assay (IGRA) test 
(QuantiFERON® TB test or Elispot®test, when the QuantiFERON test indicated is not available), 
and a chest x-ray read (or, if done, computed tomography of the chest) which must be reported 
consistent with standard clinical reporting practice by an experienced qualified TB specialist, 
radiologist, or a pulmonologist, who is specifically required to look for signs of active TB or 
signs of past/inactive TB infection. The official report of the imaging must specifically indicate 
the absence of findings suggestive of current active TB or prior inactive TB. In addition to a 
physical examination done intermittently throughout the study, subjects will be evaluated at 
Screening, Baseline, and every 12 weeks thereafter up to and including the Week 52/WD visit, 
for signs and symptoms of latent tuberculosis (LTB) or active TB infection and risk factors for 
exposure to TB using the TB questionnaire. 
Has been changed to:
At Screening, all subjects will have an Interferon-Gamma Release Assay (IGRA) test 
(QuantiFERON® TB test or Elispot®test, when the QuantiFERON test indicated is not available), 
and a chest x-ray reading (or, if done, computed tomography of the chest) which must be 
reported consistent with standard clinical reporting practice by an experienced qualified TB 
specialist, radiologist, or a pulmonologist, who is specifically required to look for signs of active 
TB or signs of past/inactive TB infection. A chest x-ray will not be done at Screening if a chest 
x-ray (or computed tomography of the chest) was done within 3 months prior to the Screening 
visit. The official report of the imaging must specifically indicate the absence of findings 
suggestive of current active TB or prior inactive TB. In addition to a physical examination done 
intermittently throughout the study, subjects will be evaluated at Screening, Baseline, and every 
12 weeks thereafter up to Week 36 and including the Week 52/WD visit, for signs and symptoms 
of latent tuberculosis (LTB) or active TB infection and risk factors for exposure to TB using the 
TB questionnaire. 
Change #6
Section 5.1.1 Study periods, Period 2, paragraph 2
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site by dedicated, unblinded 
and adequately trained site personnel. The double-blind study treatment will be self-injected at 
home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46. All subjects will receive training for 
REDACTED
aft
is (LT
s (LT
re.
re.
n
COPY
TB o
TB 
out the
ut th
ter u
er u
This document 
Cha
Ch
cannot 
 thth
nt tub
nt tub
quest
quest
be 
ly t
y
here
here
used
re
urren
urren
thro
thro
to
epor
epo
suppor
pulm
pulm
tive TB
ive T
omogr
mogr
t
any
ard cl
ard c
mo
mo
marketing 
Interfe
nterfe
test, w
test, 
one, c
one, 
i
authorization 
e s
up to a
p to a
TB) or 
B) or 
application
ook fo
ook fo
imagin
imagi
prior in
prior 
study
tudy
and
) wh
wh
d qua
d qu
any
dicate
dicat
hich
hic
extensions 
GRA) 
RA)
or variations 
r 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 203 of 255
self-injection at the study site on Weeks 10 and 12. During the training on Weeks 10 and 12 
visits, the double-blind study treatment will be self-administered under the supervision of the 
unblinded study personnel. Concomitant medications permitted during the study should remain 
stable for at least 4 weeks prior to the Weeks 12, 24, and 52/WD assessments.
Has been changed to:
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site. At the Week 0, 2, 4, 6, 
and 8 visits, the administration must be done by dedicated, unblinded, and adequately trained site 
personnel. At the Week 10 and 12 visits, the subject will receive training on self-injection and 
the study treatment will be self-administered under the supervision of the unblinded study 
personnel. At Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50, the study treatment administration 
should preferably be done by the unblinded study personnel, or alternatively by self-injection of 
the subject under the supervision of the unblinded study personnel. The double-blind study 
treatment will be self-injected at home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46. 
Concomitant medications permitted during the study should remain stable for at least 4 weeks 
prior to the Weeks 12, 24, and 52/WD assessments.
Change #7
Section 5.1.3 Planned number of subjects and site(s)
Approximately 900 subjects are expected to enter the Screening Period in order to have 
300 subjects randomized into the Double-Blind Period. The end of the study will be defined as 
the date of last subject last FU visit. It is planned to enroll the subjects at approximately 95 sites.
Has been changed to:
Approximately 1200 subjects are expected to enter the Screening Period in order to have 
300 subjects randomized into the Double-Blind Period. The end of the study will be defined as 
the date of last subject last FU visit. It is planned to enroll the subjects at approximately 
120 sites.
Change #8
Section 5.2 Schedule of study assessments - Study Periods 1 to 3 (Screening until FU), 
Table 5-1: footnote j
j Screening chest x-ray (or computed tomography of the chest) must have occurred within 3 
months prior to Screening visit and will be repeated at Week 52/WD visit only if the TB test 
was confirmed positive or any further evidence is suggestive of potential TB infection (eg, 
exposure).
Has been changed to:
j A chest x-ray must be done at Screening unless a chest x-ray (or computed tomography of the 
chest) has been done within 3 months prior to the Screening visit. The chest x-ray will be 
repeated at Week 52/WD visit only if the TB test was confirmed positive or any further 
evidence is suggestive of potential TB infection (eg, exposure).
REDACTED 
nter
nter
lind P
lind P
plann
plann
COPY 
te(s)
te(s)
r the
r th
This document
Has 
Has 
j
cannot
p
confir
onfir
posur
posur
be
ch
rior 
rior 
used
note
ote
hest x
hest 
to 
ule o
le 
e j
e j
support 
 of s
of
any 
sis
marketing 
ected to
cted t
Double
ouble
it. It 
it. It
authorization 
e Scre
e Scr
Period
eriod
ned to 
ed to 
application and
stable
able
any 
ubl
ub
8, 42,
8, 42
f
extensions
tio
d study
d stud
nt adm
nt adm
by self
y sel
blele-b
or
on a
n a
variations 
he
he
6, , 
ned s
ed s
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 204 of 255
Change #9
Section 5.2 Schedule of study assessments - Study Periods 1 to 3 (Screening until FU), 
Table 5-1: footnote q
q At on-site visit days (Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site by dedicated, unblinded 
and adequately trained site personnel. The double-blind study treatment will be self-injected at 
home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46. From Week 52 onwards, after completion 
of all onsite assessments and procedures, the subject may receive open-label CZP at the 
discretion of the Investigator.  
Has been changed to:
q At on-site visit days (Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site. At the Week 0, 2, 4, 6, 
and 8 visits, the administration must be done by dedicated, unblinded, and adequately trained 
site personnel. At the Week 10 and 12 visits, the subject will receive training on self-injection 
and the study treatment will be self-administered under the supervision of the unblinded study 
personnel. At Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50, the study treatment 
administration should preferably be done by the unblinded study personnel, or alternatively by 
self-injection of the subject under the supervision of the unblinded study personnel. The 
double-blind study treatment will be self-injected at home at Weeks 14, 18, 22, 26, 30, 34, 38, 
42, and 46. From Week 52 onwards, after completion of all onsite assessments and procedures, 
the subject may receive open-label CZP at the discretion of the Investigator.
Change #10
Section 6.1 Inclusion criteria, Inclusion Criteria 5 and 6
5. Subjects must have a documented diagnosis of adult-onset axSpA as defined by the specified 
ASAS criteria (not including family history and good response to NSAIDs; see 
Appendix 18.1) with at least 12 months symptom duration before Screening.
6. Subjects must have evidence of inflammatory back pain as defined by the ASAS criteria.
Have been changed to:
5. Subjects must have a documented diagnosis of adult-onset axSpA and meet the ASAS 
criteria for axSpA (not including family history and good response to NSAIDs; see 
Appendix 18.1).
6. Subjects must have had back pain for at least 12 months before Screening.
Change #11
Section 7.2.1 Treatment administration, paragraph 2
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site by dedicated, unblinded, 
and adequately trained site personnel. The double-blind study treatment will be self-injected at 
home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46. All subjects will receive training for 
self-injection at the study site on Weeks 10 and 12. During the training on Weeks 10 and 12 
mp
mp
the di
the d
usio
usio
COPY
f the
f th
d at ho
at h
pleti
leti
This document 
ha
ha
Sec
Sec
cannot
bjects
ects
ange
ange
be 
dix
used 
t ha
h
axSp
axSp
18
18
to
have
have
support
videnc
denc
to:
o:
any
st 12
st 12
marketing
on Cri
on Cr
ed diag
d dia
family
amil
authorization 
om
ion of
on of
iscreti
screti
application
vis
, the st
the s
study p
study 
unblind
unblin
me at
me a
and
e trai
trai
sion
sion
any
nd ad
nd a
inin
in
extensions 
4, 48, 
, 48,
he W
he W
or variations 
at 
at 
etion
etion
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 205 of 255
visits, the double-blind study treatment will be self-administered under the supervision of the 
unblinded study personnel.
Has been changed to:
At on-site visit days (at Weeks 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 50), the 
double-blind study treatments will be administered sc at the study site. $WWKH:HHN
DQGYLVLWVWKHDGPLQLVWUDWLRQPXVWEHGRQHE\GHGLFDWHGXQEOLQGHGDQG
DGHTXDWHO\WUDLQHGVLWHSHUVRQQHO$WWKH:HHNDQGYLVLWVWKHVXEMHFW
ZLOOUHFHLYHWUDLQLQJRQVHOILQMHFWLRQDQGWKHVWXG\WUHDWPHQWZLOOEHVHOI
DGPLQLVWHUHGXQGHUWKHVXSHUYLVLRQRIWKHXQEOLQGHGVWXG\SHUVRQQHO At Weeks 
16, 20, 24, 28, 32, 36, 40, 44, 48, and 50, the study treatment administration should preferably be 
done by the unblinded study personnel, or alternatively by self-injection of the subject under the 
supervision of the unblinded study personnel. The double-blind study treatment will be self-
injected at home at Weeks 14, 18, 22, 26, 30, 34, 38, 42, and 46.
Change #12
Section 8.1 Screening visit (Week -6 to Day -1), bullet 8
x Chest x-ray (must occur within 3 months prior to Screening visit)
Has been changed to:
x Chest x-ray to be done at Screening (unless a chest x-ray or computed tomography of the 
chest has been done within 3 months prior to the Screening visit)
Change #13
Section 12.6.3.2 Chest x-ray
A plain posteroanterior chest x-ray (or, if done, computed axial tomography of the chest) must be 
done within 3 months prior to the Screening visit. The chest x-ray must be clear of signs of TB 
infection (previous or current) before first study drug administration. The chest x-ray will be 
repeated at Week 52/WD visit (if chest x-ray was performed more than 12 weeks prior to 
Week 52/WD visit), only if the TB test was confirmed positive or any further evidence is 
suggestive of potential TB infection (eg, exposure). Radiographic findings suggestive of inactive 
TB or active TB may include but are not limited to: apical fibrosis, pleural thickening, 
pulmonary nodules, fibrotic scars, calcified granulomas, upper lobe infiltrates, cavitations and 
pleural effusions, calcified lung nodules, calcified hilar lymph nodes, and pericardial 
calcification.
The chest x-ray (or, if done, Computed Axial Tomography of the Chest) must be negative for TB 
infection as determined by a qualified radiologist and/ or pulmonary physician. Any new 
clinically significant findings post-Baseline during physical exam or on chest x-ray must be
documented in the source documents and CRF as an AE.
Has been changed to:
A plain posteroanterior chest x-ray must be done at Screening unless a chest x-ray (or a 
computed tomography of the chest) has been done within 3 months prior to the Screening visit.
The chest x-ray must be clear of signs of TB infection (previous or current) before first study 
REDACTED
ss a
ss a c
rior to
rior to
COPY 
Scrc
h
This document
infec
nfec
clin
clin
d
cannot
ation
tion
chest
chest
ctiti
be
usion
usio
n
used
may
ma
dules
dules
to
tial 
tial
ay i
ay i
support
nt)t)
 visit 
visit 
nly if t
nly if 
al TB
l TB
any
he S
he S
) befo
befo
marketing 
y (or, i
y (or, 
Scr
Sc
authorization 
hest x
est x
o the S
the S
application 
ning vi
ing v
and any extensions
At 
At 
ld pref
d pre
subje
subje
ent w
ent w
or 
V
W
variations 
QG
HFW
HFW
VHO
VHO
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 206 of 255
drug administration. The chest x-ray will be repeated at Week 52/WD visit (if chest x-ray was 
performed more than 12 weeks prior to Week 52/WD visit), only if the TB test was confirmed 
positive or any further evidence is suggestive of potential TB infection (eg, exposure). 
Radiographic findings suggestive of inactive TB or active TB may include but are not limited to: 
apical fibrosis, pleural thickening, pulmonary nodules, fibrotic scars, calcified granulomas, upper 
lobe infiltrates, cavitations and pleural effusions, calcified lung nodules, calcified hilar lymph 
nodes, and pericardial calcification.
The chest x-ray (or, if done, the computed tomography of the chest) must be negative for TB 
infection as determined by a qualified radiologist and/ or pulmonary physician. Any new 
clinically significant findings post-Baseline during physical exam or on chest x-ray must be 
documented in the source documents and CRF as an AE.
COPY 
This document cannot be used to support any marketing authorization application and any extensions
must 
must
or 
b
variations 
TB
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 207 of 255
18.15 
Protocol Amendment 3 
Rationale for the amendment
This substantial amendment includes changes to clarify the study details regarding the additional 
2 years of long-term, open-label CZP treatment that will be provided to eligible subjects at the 
completion of the Week 52 visit. This period of the study has been named the Safety-Follow Up 
Extension (SFE) Period and the protocol has been updated throughout accordingly (eg, a new 
Schedule of Study Assessments has been added and eligibility criteria, guidance for study drug 
administration and concomitant medication usage have been updated).
Additional changes include:
x allowing female subjects who become pregnant while participating in the AS0006 study the 
option to enroll in a separate, observational, pregnancy follow-up study sponsored by UCB.
x removal of the 40% cap on IXRS randomization to each of the 3 clinical subgroups for 
MRI/CRP classifications: (MRI+/CRP+, MRI+/CRP-, or MRI-/CRP+) in order to reflect the 
real world situation. 
x to clarify that cases of potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting 
≥2xULN total bilirubin in the absence of ≥2xULN ALP, with no alternative explanation for 
the biochemical abnormality, must ALWAYS be reported to UCB as an AE of interest 
(ie, without waiting for any additional etiologic investigations to have been concluded).
x minor typographical errors have been corrected throughout the protocol. Additional specific 
changes are listed below.
Modifications and changes
Global changes
The following changes were made throughout the protocol:
Specific changes
Change #1
The study acronym (C-AXSPAND) was added to the title page.
Change #2
The fax number for SAE reporting in the USA and Canada has been updated.
Serious Adverse Event reporting (24h) and safety related issues
Fax
Europe and Rest of the World: +32 2 386 24 21
USA and Canada: +1 800 880 6949 or +1 866 890 3175
E-Mail
DS_ICT@ucb.com
REDACTED
rrecte
rrecte
COPY
e rep
e rep
gic inv
gic inv
This document 
me
cannot
x
ot 
ot be 
S
e used 
ber fo
er f
u
to support 
AXSP
AXS
any marketing 
throug
throu
authorization
vesti
esti
d thro
d thro
application 
ULN AL
LN A
with n
with 
orted to
rted t
iga
iga
and 
RP+
P+
any
cal su
al s
+) in
+) i
extensions 
S0006 
0006 
ponsor
onso
or variations 
rug
ug
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 208 of 255
Change #3
List of abbreviations
The following terms were revised or added:
ICH
International Council for Harmonisation
SFE
Safety Follow-Up Extension
SFE-SS
Safety Follow-Up Extension-Safety Set
Change #4
Section 1 Summary
Paragraph 1, first sentence:
AS0006 is a randomized, double-blind, parallel-group, placebo-controlled study, consisting of 
52 weeks of treatment with certolizumab pegol (CZP) and a Follow-Up (FU) Period of 8 weeks 
after the Week 52 visit.
Has been changed to:
The C-axSpAnd study (AS0006) is a randomized, double-blind, parallel-group, placebo-
controlled study, consisting of 52 weeks of treatment with certolizumab pegol (CZP) and a 
Follow-Up (FU) Period of 8 weeks after the Week 52 visit.
And paragraphs 6 and 7:
Subjects whose disease activity cannot be controlled by study medication and changes in 
background therapy (including and not limited to analgesics, NSAIDs, and slow-acting 
antirheumatic drugs [SAARDs]) will be permitted to withdraw from the double-blind study drug. 
Subjects will either transition to open-label CZP treatment offered by UCB or to other treatment 
(including biologics) at the discretion of the Investigator until the assessment of the primary 
endpoint at Week 52. At the completion of the Week 52 visit, and in accordance with the local 
regulatory requirements, CZP will be provided for a maximum duration of 2 years or until 
marketing authorization is granted for CZP (if applicable), whichever comes first.  
All subjects, including those withdrawn from double-blind study treatment, will have a FU visit 
8 weeks after their final Week 52 visit. 
Have been changed to:
Subjects whose disease activity cannot be controlled by study medication and changes in 
background therapy (including and not limited to analgesics, NSAIDs, and slow-acting 
antirheumatic drugs [SAARDs]) will be permitted to withdraw from the double-blind study drug.
Subjects will either transition to open-label CZP treatment offered by UCB or to other treatment 
(including biologics) at the discretion of the Investigator until the assessment of the primary 
endpoint at Week 52. At the completion of the Week 52 visit assessments, subjects on double-
blind study treatment may receive open-label CZP treatment for an additional 2 years in an open-
label, Safety Follow-Up Extension (SFE) Period. Subjects who withdrew from double-blind 
study treatment and transitioned to open-label CZP treatment are also eligible to participate in 
the SFE Period after completing the Week 52 visit assessments. Subjects on alternative 
treatments are not eligible to participate in the SFE Period.
REDACTED 
e cont
e cont
t limit
t limit
ll be p
l be 
COPY
nt wit
nt wi
k 52 v
52 
This document 
ubjbj
(incl
(incl
en
en
cannot
ound
und
heum
heum
bject
ject
be
hose
hos
t
used 
anged
nged
to
fina
fina
support
s gran
gran
g those
 those
al W
al
any 
mpl
mp
will b
will 
t
marketing
perm
perm
label C
label
ion of t
on of
pletio
leti
authorization 
visit
isi
trolled
rolled
ted to
ed to
i
application 
ind, pa
nd, p
h certol
certo
it
and any 
stu
stu
FU) P
FU) 
extensions 
udy
udy
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 209 of 255
All subjects not participating in the SFE Period after study completion at Week 52, including 
those withdrawn from the study prematurely, will have a FU visit 8 weeks after their Week 52
visit. 
And paragraphs 15, 16, and 17:
Safety variables to be assessed are adverse events (AEs), vital signs, physical examination, and 
measurements of laboratory parameters. In addition, subjects will be evaluated at Screening, 
Baseline, and at every 12 weeks thereafter up to Week 36 and including Week 52/Withdrawal 
(WD) for signs and symptoms of latent or active tuberculosis (TB) infection and risk factors for 
exposure to TB using the TB questionnaire.
Approximately 1200 subjects will be screened in order to have 300 subjects (150 subjects per 
treatment group) randomized into the study. Randomization will be stratified by presence of 
sacroiliitis on MRI and elevated CRP to ensure balanced treatment allocation across 
3 subgroups: MRI+/CRP+; MRI+/CRP-; MRI-/CRP+. For each subject, the study will last a 
maximum of 66 weeks and will consist of 3 periods: 
x Screening Period lasting up to 6 weeks
x Double-Blind, Placebo-Controlled Period for 52 weeks
x FU Period 8 weeks after the Week 52/WD visit.
The estimated recruitment period is up to 15 months. The first subject first visit is planned in 
Quarter 3 2015. A completed subject is one who completes the Week 52 visit. 
Have been changed to:
Safety variables to be assessed are adverse events (AEs), vital signs, physical examination, and 
measurements of laboratory parameters. In addition, subjects will be evaluated at Screening, 
Baseline, and at every 12 weeks thereafter up to Week 36 and including Week 52/Withdrawal 
(WD) (for subjects not participating in the SFE Period) for signs and symptoms of latent or 
active tuberculosis (TB) infection and risk factors for exposure to TB using the TB 
questionnaire.
Approximately 1200 subjects will be screened in order to have 300 subjects (150 subjects per 
treatment group) randomized into the study. Randomization will be stratified by presence of 
sacroiliitis on MRI and elevated CRP to ensure balanced treatment allocation across 
3 subgroups: MRI+/CRP+; MRI+/CRP-; MRI-/CRP+. 
For each subject, the study will consist of 3 periods and will last a maximum of 66 weeks: 
x Screening Period lasting up to 6 weeks
x Double-Blind, Placebo-Controlled Period for 52 weeks
x FU Period 8 weeks after the Week 52/WD visit (for subjects not participating in the SFE 
Period).
For subjects participating in the SFE Period, the study will extend up to a maximum of 
104 additional weeks.
The estimated recruitment period is up to 15 months. The first subject first visit is planned in 
Quarter 3 2015. The end of the study will be defined as the date of the last subject’s last visit, 
who c
who c
dverse
dverse
ters
ters
COPY 
nths. 
nths. 
This document 
x
cannot 
reenin
reenin
Dou
Dou
be
ubjec
ubje
used 
RI I
MRI+/
RI+/
t
to
d
and
and
support 
ubjects 
bjects
domiz
omiz
any
on a
on a
marketing 
e ev
e
s. In ad
In ad
reafter 
eafter
ng
ng in t
in 
and
authorization
The 
The 
omple
omple
even
ven
application 
fi
and any
he stu
he st
extensions 
subjec
ubjec
y y pres
pres
n acro
acro
t
or variations 
al
rs fo
rs fo
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 210 of 255
defined as the FU visit 8 weeks after the Week 52/WD visit for subjects not participating in the 
SFE Period, or the last visit of the SFE Period. 
Change #5
Section 2.5 Rationale 
Paragraph 2:
To address the unmet need for treatment options for nr-axSpA, AS0006 will be conducted 
focusing on subjects who do not meet the mNY classification criteria for AS 
(see Appendix 18.2). Data suggest that patients with objective signs of inflammation and high 
disease activity are likely to run a chronic disease course and unlikely to be well managed on 
conventional therapy (Rudwaleit ACR 2013). Furthermore, studies where anti-TNFs have been 
withdrawn in nr-axSpA patients show that patients flare quickly and hence the disease is unlikely 
to go into spontaneous remission. However, there are no long-term prospective studies to assess 
how patients meeting the ASAS classification criteria respond to conventional therapies. With 
the conduct of this 52-week study comparing CZP to placebo in combination with standard of 
care, a better understanding should be gained of how a long-term anti-TNF therapy compares to 
standard of care in patients meeting the ASAS criteria with objective signs of inflammation. 
Moreover, patients whose disease cannot be managed under the blinded study treatment 
conditions will be able to discontinue the double-blind study treatment and transition to either 
open-label CZP or other therapies.
Has been changed to:
To address the unmet need for treatment options for nr-axSpA, AS0006 will be conducted 
focusing on subjects who do not meet the mNY classification criteria for AS 
(see Appendix 18.2). Data suggest that patients with objective signs of inflammation and high 
disease activity are likely to run a chronic disease course and unlikely to be well managed on 
conventional therapy (Rudwaleit ACR 2013). Furthermore, studies where anti-TNFs have been 
withdrawn in nr-axSpA patients show that patients flare quickly and hence the disease is unlikely 
to go into spontaneous remission. However, there are no long-term prospective studies to assess 
how patients meeting the ASAS classification criteria respond to conventional therapies. With 
the conduct of the 52-week blinded study period comparing CZP to placebo in combination with 
standard of care, a better understanding should be gained of how a long-term anti-TNF therapy 
compares to standard of care in patients meeting the ASAS criteria with objective signs of 
inflammation. Moreover, patients whose disease cannot be managed under the blinded study 
treatment conditions will be able to discontinue the double-blind study treatment and transition 
to either open-label CZP or other therapies.
And a new 3rd paragraph has been added: 
The addition of the SFE Period will allow collection of long-term safety data from eligible 
subjects on open-label CZP for up to 2 years. During the SFE Period, CZP will be provided by 
the Sponsor. The treating investigator is requested to apply routine, standard of care according to 
local standard medical practice and investigator clinical judgment. 
REDACTED 
option
optio
the m
the m
hat p
hat p
COPY
nd st
nd s
This document
The 
The 
sub
sub
cannot
ope
ope
a ne
a ne
be 
ond
nd
pen
pen
used 
darar
More
More
diti
diti
to 
ett
rd o
rd o
support
ASAS
ASA
week bl
eek b
tter u
ter u
any 
sh
sh
ion. H
ion. H
S
marketing
patien
patien
onic di
onic d
ACR 20
CR 2
how 
how
authorization 
ns for
ns for
NY c
NY c
t
application 
ntnt
ective s
ctive
the bli
the bl
udy tre
dy tr
and
bininatat
ti-TN
T
any 
tiviv
tional
iona
tioi
extensions
anaged
nage
NFs h
Fs h
e disea
disea
ve s
ve s
or
d hi
d hi
variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 211 of 255
Change #6
Section 5.1
Study description
Paragraph 1: 
Study AS0006 is a 52-week, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled clinical study to evaluate the efficacy and safety of CZP in adult subjects with
active axSpA without x-ray evidence of AS and with objective signs of inflammation (sacroiliitis 
on MRI and/or elevated CRP) and who have had an inadequate response to, have a 
contraindication to, or are intolerant to NSAIDs. 
Has been changed to:
Study AS0006 is a 52-week, multicenter, randomized, double-blind, parallel-group, 
placebo-controlled clinical study to evaluate the efficacy and safety of CZP in adult subjects with
active axSpA without x-ray evidence of AS and with objective signs of inflammation (sacroiliitis 
on MRI and/or elevated CRP) and who have had an inadequate response to, have a 
contraindication to, or are intolerant to NSAIDs. At the completion of the Week 52 visit 
assessments, eligible subjects may receive open-label CZP treatment for an additional 2 years in 
an open-label, SFE Period. 
Change #7
Section 5.1.1 Study periods
The subsection describing the Follow-Up Period (Period 3):
Period 3 (Follow-Up Period):
All subjects, including those withdrawn from the double-blind study treatment, will have a FU 
visit 8 weeks after the Week 52/WD visit.
Has been changed to:
Period 3 (Follow-Up Period):
All subjects not participating in the SFE Period after Week 52, including those withdrawn from 
the study prematurely, will have a FU visit 8 weeks after the Week 52/WD visit.
And a new subsection describing the SFE Period has been added:
Safety Follow-Up Extension (SFE) Period: Week 52 to Week 156, open-label. 
At the completion of the Week 52 visit assessments, subjects on double-blind study treatment 
may receive open-label CZP treatment for an additional 2 years. Subjects who withdrew from 
double-blind study treatment and transitioned to open-label CZP treatment are also eligible to 
participate in the SFE Period after completing the Week 52 visit assessments. Subjects on 
alternative treatments are not eligible to participate in the SFE Period. 
Eligible subjects are allowed to roll-over to the SFE-Period up to 3 months after completion of 
the Week 52 assessments.
In order to maintain the blind for subjects completing double-blind treatment, their study 
treatment will be administered sc at the study site by unblinded, dedicated study personnel on 
Weeks 52, 54, and 56. Subjects who withdrew from double-blind study treatment and 
REDACTED 
Perio
Perio
awn fr
awn fr
viv
COPY 
This document 
arti
rt
alter
alter
cannot
ceive
eive
le-bli
bli
ticip
icip
be
mplet
mplet
used 
Up E
Up E
i
to
tion
tion
support
ing in
ng in
will ha
will h
n d
n d
any 
t
marketing
from 
om
isit.
sit.
authorization 
od (Pe
d (Pe
m th
m th
application
ment f
ment 
and 
se e 
of the
f the
f
any
flam
flam
to, h
to, h
extensions 
oup, 
up,
n adu
n adu
mm
mm
or variations 
h
iitis 
tis 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 212 of 255
transitioned to open-label CZP treatment do not need to visit the site at Week 54 and Week 56, 
and should continue their open-label CZP treatment regimen.
For the remainder of the SFE Period, CZP can be administered at the site by dedicated study 
personnel, or by self-injection of the subject under the supervision of the dedicated study 
personnel, or subjects may self-administer their study treatment Q2W at home. 
Starting at Week 64, all subjects are to visit the site approximately every 12 weeks for
assessments. 
The last dosing visit will be at Week 154. The final study assessments are performed at 
Week 156/SFE-WD.
Change #8
Section 5.1.2 Study duration per subject
For each subject, the study will last a maximum of 66 weeks, as follows:
x Up to 6 weeks in the Screening Period
x 52 weeks in the Double-Blind Period
x A FU visit 8 weeks after the Week 52/WD visit
The estimated recruitment period is up to 15 months. The first subject first visit is planned in 
Quarter 3 of 2015. A completed subject is one who completes the Week 52/WD visit. Subjects 
will either transition to open-label CZP treatment offered by UCB or to other treatment 
(including biologics) at the discretion of the Investigator until the assessment of the primary 
endpoint at Week 52/WD. At the completion of the Week 52/WD visit, and in accordance with 
the local regulatory requirements, CZP will be provided for a maximum duration of 2 years or 
until marketing authorization is granted for CZP (if applicable), whichever comes first.
Has been changed to:
For each subject, the first 3 periods of the study will last a maximum of 66 weeks, as follows:
x Up to 6 weeks in the Screening Period
x 52 weeks in the Double-Blind Period
x A FU visit 8 weeks after the Week 52/WD visit (for subjects not participating in the SFE 
Period).
For subjects participating in the SFE Period, the study will extend up to a maximum of 
104 additional weeks.
The estimated recruitment period is up to 15 months. The first subject first visit is planned in 
Quarter 3 of 2015. The end of the study will be defined as the date of the last subject’s last visit, 
defined as the FU visit 8 weeks after the Week 52/WD visit for subjects not participating in the 
SFE Period, or the last visit of the SFE Period  
REDACTED
wh
ment 
ment
the Inv
the Inv
pletion
pletion
ZP w
ZP w
COPY 
hs. Th
hs. T
ho c
ho c
This document
Quar
Quar
de
de
cannot
dition
ition
e estim
esti
be
ts pa
ts pa
used
wee
wee
to 
eeks
ek
support
Screen
Scree
ouble
ouble
any
riods
riods
marketing 
will b
ill b
ed for C
d for 
authorization 
he 
compl
ompl
offere
offere
vestig
vestig
n of th
n of t
be
b
application 
e first
first
and any extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 213 of 255
Change #9
Section 5.2 
Schedule of study assessments
The Schedule of assessments is shown in Table 5-1 for subjects who complete the study on either 
CZP 200mg Q2W or placebo.
In order to optimize the treatment the Investigator may adjust the background medication in 
accordance with the specifications described in Table 7‒1.
At any time during the study course, but preferably not before Week 12, the Investigator may 
discontinue the double-blind study treatment and start open-label treatment with either CZP 
(which will be provided free of charge by UCB) or an alternative drug (eg, other treatment 
[including biologics]). Table 5‒2 shows the schedule of assessments for subjects receiving 
open-label treatment with CZP and Table 5‒3 shows the schedule of assessments for subjects 
receiving an alternative treatment (not CZP). 
Has been changed to:
The Schedule of assessments is shown in Table 5-1 for subjects who complete 52 weeks of 
treatment on either CZP 200mg Q2W or placebo.
In order to optimize the treatment the Investigator may adjust the background medication in 
accordance with the specifications described in Table 7-1.
At any time during the study course, but preferably not before Week 12, the Investigator may 
discontinue the double-blind study treatment and start open-label treatment with either CZP 
(which will be provided free of charge by UCB) or an alternative drug (eg, other treatment 
[including biologics]). Table 5-2 shows the schedule of assessments for subjects receiving 
open-label treatment with CZP and Table 5-3 shows the schedule of assessments for subjects 
receiving an alternative treatment (not CZP).
Table 5-6 shows the schedule of assessments for subjects participating in the SFE Period.
Change #10
The title of Table 5-1:
Table 5‒1:
Schedule of study assessment -– Study Periods 1 to 3 (Screening until FU)
Has been changed to:
Table 5‒1:
Schedule of study assessments -– Screening through Week 52 and FU 
And the visit number, 29, has been removed from the column of assessments to be 
performed at the Follow-Up Visit.
And the following note has been added under the table:
Note: At the completion of the Week 52 visit, subjects may receive open-label CZP treatment for 
an additional 2 years in the SFE Period.
And footnote b under Table 5-1:
b
FU: 8 weeks after Week 52/WD visit. 
REDACTED
ab
t and s
t and 
y UCB
y UCB
ws the s
s the 
Table
Table
t
COPY
y a
y 
le 7
le 7-1
bly n
ly n
This document 
And
nd
No
No
cannot 
vis
vi
rmed
med
d th
d th
be 
isit
isit
used 
ed t
d 
Sch
Sch
to 
to:
to:
support 
ule of 
ule of 
any marketing 
 5-3
t CZP)
CZP)
assessm
ssess
authorization 
not be
ot be
start o
start o
B) or a
B) or a
sched
ched
3
application 
ho 
ust the b
st the
.
nd 
o com
com
any extensions
atmen
atme
receiv
receiv
ents fo
nts fo
or
CZP
CZP
variations 
may 
may 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 214 of 255
Has been changed to:
b
FU: 8 weeks after Week 52/WD visit for subjects not participating in the SFE. 
And footnote k under Table 5-1:
k. TB test: IGRA test (QuantiFERON test [or Elispot test when the QuantiFERON indicated is 
not available]). The TB test will be repeated at Week 52 (or at WD visit if medically indicated) 
for subjects with previously negative TB test result. Subjects who tested positive for TB should 
be encouraged to complete a FU visit (8 weeks after the Week 52/WD visit) and follow-up
information of suspected and confirmed TB cases should be provided to UCB at least after 3, 9, 
and 12 months of the start date of anti-TB treatment.
Has been changed to:
k TB test: IGRA test (QuantiFERON test [or Elispot test when the QuantiFERON indicated is not 
available]). The TB test will be repeated at Week 52 (or at WD visit if medically indicated) for 
subjects with previously negative TB test result. Subjects who tested positive for TB should be 
encouraged to complete a FU visit (8 weeks after the Week 52/WD visit for subjects not 
participating in the SFE) and follow-up information of suspected and confirmed TB cases should 
be provided to UCB at least after 3, 9, and 12 months of the start date of anti-TB treatment.
Change #11
Table 5‒2:
Schedule of alternative study assessment with CZP - after subject 
discontinuation of the double blind study treatment
The following note has been added under the table:
Note: At the completion of the Week 52 visit, subjects who transitioned to open-label CZP 
treatment after withdrawal from the Double-Blind Period are eligible to participate in the SFE 
Period.
And footnote a of Table 5-2:
a
FU: 8 weeks after Week 52/WD visit.
Has been changed to:
a
FU: 8 weeks after Week 52/WD visit for subjects not participating in the SFE Period.
Change #12
Table 5‒3:
Schedule of alternative study assessment with other treatment (including 
biologics) - after subject discontinuation of the double-blind study treatment
Pregnancy testing has been added to the table with the following footnote g:
g Pregnancy testing must be carried out for women of childbearing potential and will be a serum 
test at the FU visit and a urine test (dipstick) at wdt Week 0 and Week 52/WD visit.
Change #13
A Schedule of assessments for the SFE Period (Table 5-6) has been added:
REDACTED
reatm
reat
der the
der th
52
52 vivi
e Do
e Do
COPY 
sessm
sessm
m
This document
Pre
Pre
test
test
cannot 
s) ) 
gnanc
nanc
egn
be 
af
af
used 
Sc
Sc
to 
er 
support 
Wee
Wee
any 
2/WD
2/WD
marketing 
isi
ouble
ouble
authorization
ment
ment
ment
ent
e tabl
e tabl
it, su
t, su
application
and 
and
art da
rt dat
w
and 
osi
os
visit f
visit f
c
any
dica
dica
itive 
tive 
extensions 
RON i
RON i
all
all
or
er 3
er 
variations 
ld 
r 3,3
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 215 of 255
Table 5‒6: 
Schedule of study assessments - Safety Follow-Up Extension Period 
Visit #
29 
30 
31 
32
33
34
35
36
37
38
39
40
Overall Study Week/SFE Week
Protocol Activity
52/0a
54/2 
56/4 
64/12 
76/24 
88/36 
100/48 
112/60 
124/72 
136/84 
148/96 
156/104/WD 
Informed consentb
X
 
 
AEs
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
IXRSc
X 
X 
X 
X 
X 
X 
X
X 
X
X 
X
X
Study drug loading dose 
administration scd
X
X
X
 
 
 
 
 
 
 
 
Study drug dispensatione
X
X
X
X
X
X
X
X
X
AEs=adverse events; CZP=certolizumab pegol; FU=Follow-Up; IXRS=Interactive Response System; SFE=Safety Follow-Up Extension; WD=Withdrawal; 
a Assessments performed at the Week 52 Visit for subjects who completed the previous Double-Blind Period are in Table 5‒1; Assessments performed at the 
Week 52 Visit for subjects who transitioned to open-label CZP treatment after withdrawal from the Double-Blind Period are in Table 5‒2.
b A separate informed consent form will be obtained from subjects consenting to participate in the SFE Period.
c Contact IXRS to register the visit and obtain next kit number, where applicable, or to indicate that the subject has completed the SFE Period or withdrawn from 
the study.
d At Weeks 52, 54, and 56, study treatment administration should be performed at the site by unblinded study personnel in order to keep the blind (see 
Section 7.2.1).
e Starting at Week 52 for subjects completing open-label CZP treatment and the Week 52 visit, dispense the assigned study medication to the subject for use at 
home, as appropriate.
REDACTED 
er w
er w
ting to 
ing to 
pplicab
pplica
be per
be per
COPY 
Y
Respon
Respo
revious
evious
with
with
Y
This document cannot be used to support any marketing 
rform
orm
atment a
ment
authorization
s Dou
Dou
hdrawa
drawa
partici
partici
ble, or 
ble, or
me
me
app
se Syst
e Sys
blb
plication 
ati
X
at
at
at
pp
and 
X
nd any 
ny
an extensions 
13
13
sio
ns
ex
or 
8
o variations 
va
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 216 of 255
Change #14
A new schematic diagram for the SFE Period (Figure 5-3) has been added:
Figure 5-3: Schematic diagram for subjects completing the double-blind study treatment and rolling over to the 
SFE Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 W0/BL 
 
 
 W52/SFE-W0 
 
 
 W156/SFE-W104 
 
 randomized treatment (CZP or PBO) 
 
 
 
 
 
 
 
 
SCR 
Double-Blind Period 
 
 
Open-Label SFE Period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BL=Baseline; CZP=certolizumab pegol; FU=Follow-Up; SFE=Safety Extension; PBO=placebo; SCR=Screening; SFE=safety Follow-Up Extension; W=week
Note: Subjects who complete either double-blind treatment or open-label CZP-treatment and all assessments at Week 52 are eligible to roll-over to the SFE 
Period. Subjects who complete alternative treatment must finish the study at Week 52 and be scheduled for the final FU visit (8 weeks after the Week 52 visit).
REDACTED 
afety
afety
COPY 
OP
This document cannot be used to support any
nish t
nish
marketing 
Extens
Exten
open
pen-lal
the
th
authorization application 
Period
Period
n
ap
and 
a
any extensions
ent a
nt a
or 
an
an
variations thereof. 
1

UCB
17 Dec 2108
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 217 of 255
Change #15
Section 5.4
Rationale for study design and selection of dose
Paragraph 2:
In accordance with prescribing information for CZP, 3 loading doses of 400mg Q2W should be 
administered upon initiation of therapy. Thus all subjects who transition to open-label CZP 
within the AS0006 study from the Double-Blind Period will receive this loading dose prior to the 
maintenance dose of 200mg Q2W. It is recognized that some subjects would have been on active 
CZP prior to transition to open-label CZP. However, this dosing approach is justified in all 
transitioning subjects as there will be no change in benefit-risk due to administration of loading 
dose and the blinding will be maintained in the study, preserving the data integrity.
Has been changed to:
In accordance with prescribing information for CZP, 3 loading doses of 400mg Q2W should be 
administered upon initiation of therapy. Thus all subjects who withdraw from double-blind 
treatment prior to Week 52 and transition to open-label CZP within the AS0006 study will 
receive this loading dose prior to the maintenance dose of 200mg Q2W. It is recognized that 
some subjects would have been on active CZP prior to transition to open-label CZP. However, 
this dosing approach is justified in all transitioning subjects as there will be no change in benefit-
risk due to administration of loading dose and the blinding will be maintained in the study, 
preserving the data integrity.
Change #16
Section 6.3 Withdrawal criteria 
Criterion 4:
4. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test.
Has been changed to:
4. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test (see Section 12.1.6 for more information regarding pregnancies).
Change #17
A new subsection has been added:
Section 6.4 Eligibility for the SFE Period
To be eligible to participate in the SFE Period, subjects on double-blind study treatment and 
subjects who withdrew from double-blind study treatment and transitioned to open-label CZP 
treatment must complete all of the Week 52 visit assessments. Subjects on alternative treatments 
are not eligible to participate in the SFE Period. 
Eligible subjects are allowed to roll-over to the SFE-Period up to 3 months after completion of 
the Week 52 assessments.
Prior to initiating the SFE assessments, all subjects will be asked to read and sign a separate 
informed consent form.
REDACTED COPY 
bjej
blindin
blindi
This document
treatm
reatm
are
are
cannot 
eligib
igi
jects 
ects 
be
4 Eli
4 El
used 
tion h
ion h
to support
of a pr
f a pr
6 for m
for m
any marketing 
ncy dur
cy du
authorization application
g Q2W
g Q2W
on to o
on to 
s as the
as th
ng will
g wil
and 
w f
w 
the A
he A
W
any
0mg
0m
from
from
extensions
of lo
of l
y.
mg
mg
or 
all
all
loa
oa
variations 
the 
the 
active
active
l
thereof. 

UCB
17 Dec 2108
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 218 of 255
Questions concerning the eligibility of a subject to continue participation in the study should be 
made in consultation with the Medical Monitor.
Change #18
Section 7.2.1 Treatment administration
Paragraph 1, first sentence:
A pharmacy manual will be provided to each site containing instructions regarding drug 
preparation and dosing. The injection schedule is described in Section 7.2.2.
Has been changed to:
A pharmacy manual will be provided to each site containing instructions regarding drug 
preparation and dosing. The injection schedule through Week 52 is presented in Figure 7‒1. The 
injection schedule for the SFE Period is presented in Figure 7‒2.
And new paragraphs 4, 5, and 6 were added
During the SFE Period, CZP will be administered sc by dedicated unblinded study personnel at 
the study site on Weeks 52, 54, and 56 for subjects completing double-blind treatment in order to 
maintain the blind. Subjects who complete the Week 52 visit on placebo treatment will receive 
loading doses of CZP 400mg at these visits. Subjects who complete the Week 52 visit on CZP 
treatment will receive 1 injection of CZP 200mg and 1 injection of placebo at these visits to 
continue their previous CZP treatment regimen.
Subjects who withdrew from double-blind study treatment and transitioned to open-label CZP 
treatment do not need to visit the site at Week 54 and Week 56, and should continue their 
open-label CZP treatment regimen.
For the remainder of the SFE Period, CZP can be administered at the site by dedicated study 
personnel, or by self-injection of the subject under the supervision of the dedicated study 
personnel, or subjects may self-administer their study treatment Q2W at home. 
Change #19
The title of the figure:
Figure 7-1:
Injection schedule
Has been changed to:
Figure 7-1:
Injection schedule through Week 52
Change #20An injection schedule for the OLE Period (Figure 7-2) has been added:
REDACTED 
study 
study 
Week
Week
C
COPY
wh
wh
and 1
nd 1 i
This document cannot
#20
#20
be 
A
used
ged t
ed t
In
In
to 
ctio
t
support 
ion s
on s
any marketing 
CZP ca
ZP ca
e subje
 subj
dminis
min
authorization 
inj
y treatm
treatm
k 54 an
54 a
application
double
double
on pla
on pla
compl
comp
jectio
ectio
and 
nblin
blin
any extensions 
ng dru
g dru
in Figu
n Fig
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 219 of 255
Figure 7‒2: Injection schedule for the SFE Period
CZP=Certolizumab pegol; FU=follow-up; H=home; SFE=Safety Follow-Up Extension; W=week
* Subjects who complete either double-blind treatment or open-label CZP-treatment and all assessments at Week 52 are eligible to roll-over to the SFE Period. 
Subjects who complete alternative treatment must finish the study at Week 52 and be scheduled for the final FU visit (8 weeks after the Week 52 visit).
** Subjects rolling over from open-label CZP-treatment to the SFE Period can self-administer their study medication at home from Weeks 2 to 10.
*** Subjects will complete the study assessments at Week 52 according to the protocol and be invited for the final FU visit 8 weeks after Week 52.
W50 
H
H
H
H
H
H
H
H
H
week
and before
SFE-W 0
2
4
6 - 10
12
14-22
24
26-34
36
38-46
48
50-58
60
62-70
72
74-82
84
86-94
96
98-102
104
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
○
○
○
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
●
according to the 
assigned treatment regimen
CZP        
200 mg
Placebo
●
○
Safety Follow-up Extension
Double-blinded
●
●
W52*
open other 
treatment
***
●
open CZP 
200 mg
● **
REDA
Follow
Follow
bel
bel C
DACTED 
Y
COPY 
This document cannot be used to support any 
a
marketing 
Up
Up
CZP
CZP-tre
tre
y at We
y at W
FE Per
E Pe
accord
ccor
aut
p E
p E
uthorization pplication 
cation
c tio
tion
ca
pli
app
an
and 
d
an
a
any 
an
●
ny
ny
an
an extensions
ions
exte
●
ns
ns
io
ns
ns
te
ten
e
or
or
or
or 
o variations 
v
82
ar
aria
ar
ar
v
thereof. 
1

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 220 of 255
Change # 21
Section 7.4 
Labeling
Clinical drug supplies will be labeled in accordance with the current International Conference on 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and GMP and will include any 
locally required statements. If necessary, labels will be translated into the local language. Details 
on Labeling will be provided in the Pharmacy manual.
Has been changed to:
Clinical drug supplies will be labeled in accordance with the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and GMP and will include any 
locally required statements. If necessary, labels will be translated into the local language. Details 
on Labeling will be provided in the Pharmacy manual.
Change #22
7.8.1
Permitted concomitant treatments for axSpA (medications and therapies)
Paragraph 12
If the Investigator discontinues the double-blind study treatment and initiates therapy with CZP, 
UCB will supply the subject with the CZP. UCB is offering CZP in accordance with the local 
regulatory requirements for a maximum duration of 2 years or until marketing authorization is 
granted for CZP (if applicable), whichever comes first. If the decision is made to start a different 
treatment (including biologics), UCB will not be supplying the medication. 
Has been changed to:
If the Investigator discontinues the double-blind study treatment and initiates therapy with CZP, 
UCB will supply the subject with the CZP. If the decision is made to start a different treatment 
(including biologics), UCB will not be supplying the medication. 
Change #23
A new subsection has been added: 
Section 7.8.3 Concomitant medication(s)/treatments during the SFE Period
At the completion of the Week 52 visit assessments, subjects on double-blind study treatment 
may receive open-label CZP treatment for an additional 2 years (SFE Period). During this time, 
CZP will be provided by the Sponsor. Concomitant medication usage during the SFE Period is at 
the discretion of the Investigator.
Change #24
Section 7.9 
Blinding
Paragraph 1, first sentence:
Due to differences in presentation and viscosity between CZP and placebo, special precautions 
will be taken in order to ensure blinding of the study. 
REDACTED
mes
ot be s
ot be 
double
double
C
COPY
fferi
ffer
of 2
f 2 ye
s firs
s firs
This document 
ectc
Par
Par
cannot 
ge #2
ge #2
tion
tion
be
p
ion o
ion o
used
en-lala
rovid
rovid
to
of th
of th
b
support 
add
ad
mitant 
itan
he
he
any 
ded
ded
marketing 
e-bli
bl
CZP. If
ZP. If
t be sup
be su
authorization 
ea
rst. If t
st. If t
supply
upply
lin
lin
application 
ent and
ent an
g CZP
g CZP
ars or
rs or
and
s and
and
any 
d t
d
extensions
ll incl
l inc
anguag
ngua
or
cil f
cil f
variations 
f
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 221 of 255
Has been changed to:
Due to differences in presentation and viscosity between CZP and placebo, special precautions 
will be taken in order to ensure blinding during the Double-Blind Period of the study. 
Change #25
Section 7.9.1 Maintenance of study treatment blind
A 4th paragraph has been added:
For the SFE Period, in order to maintain the blind for subjects completing the Double-Blind 
Period, study treatment will be administered sc by unblinded study staff at the study site on 
Weeks 52, 54, and 56. Subjects who completed the Week 52 visit on placebo treatment will 
receive loading doses of CZP 400mg at these visits. Subjects who completed the Week 52 visit 
on CZP treatment will receive 1 injection of CZP 200mg and 1 injection of placebo at these 
visits to continue their previous CZP treatment regimen. 
Change #26
Section 7.10.2  
Randomization
The following sentence
The IXRS will be designed to ensure that at least 20% and no more than 40% of the randomized 
subjects belong to 1 of the 3 clinical subgroups above.
Has been changed to:
The IXRS will be designed to ensure that at least 20% of the randomized subjects belong to each 
of the 3 clinical subgroups above.
Change #27
Section 8 Study procedures by visit
Paragraphs 2 and 3:
During the study the Investigator will assess the subjects over the entire study period of 
approximately 66 weeks including a FU Period of 8 weeks after the final Week 52/WD visit. 
Visit windows of ±3 days on either side of the scheduled visit are permitted; however, the 
Investigator should try to keep the subjects on the original dosing schedule. The window of 
±3 days is relative to Baseline and is applicable for all subsequent visits. Changes to the dosing 
schedule outside of the 3-day window must be discussed with the Medical Monitor and may 
result in subject withdrawal. 
Has been changed to:
During the first 3 periods of the study the Investigator will assess the subjects over the entire 
study period of approximately 66 weeks including a FU Period of 8 weeks after the 
Week 52/WD visit. Visit windows of ±3 days on either side of the scheduled visit are permitted; 
however, the Investigator should try to keep the subjects on the original dosing schedule. The 
window of ±3 days is relative to Baseline and is applicable for all subsequent visits. Changes to 
the dosing schedule outside of the 3-day window must be discussed with the Medical Monitor 
and may result in subject withdrawal. 
REDACTED 
t at le
at le
COPY
0% an
% an
bove.
bove.
This document
Duri
Duri
stu
stu
cannot
su
sub
s been
been
be
utsid
tsid
bje
bje
used
uld t
uld t
ative t
ative 
d
to
3 da
3 d
try
try
support
stigat
tigat
ks inclu
s incl
days
day
any 
tor
t
marketing 
visit
isit
authorization 
east 20
ast 20
application 
d no m
d no m
and any extensions
ite o
te 
ment w
ment w
e Wee
Wee
placeb
aceb
or 
n
on
on
variations 
nd d
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 222 of 255
Change #28
Section 8.5
Week 52/WD (±3 days)
The last bullet:
x Contact IXRS to indicate that subject has completed or withdrawn from the study
Has been changed to:
x Contact IXRS to indicate that subject has rolled over to the SFE Period or withdrawn from 
the study
Change #29
A new subsection 8.6 has been added and subsequent subsections were renumbered 
accordingly:
Section 8.6
SFE Period (Week 52 to Week 156) 
All eligible subjects must complete the Week 52 visit assessments.
Eligible subjects are allowed to roll-over to the SFE-Period up to 3 months after completion of 
the Week 52 assessments.
Prior to rolling over to the SFE Period, subjects will be asked to read and sign a separate 
informed consent form.
Telephone contacts are upon the discretion of the Investigator. Starting at Week 56, and at the 
discretion of the Investigator, it is recommended to contact the subject by phone at least once in 
between the on-site visits.
Starting at Week 64, all subjects are to visit the site approximately every 12 weeks for
assessments performed according to local standard medical practice, as needed, including:
x Document AEs (Note: any [possible] drug-related AE must be followed-up, at least by 
phone.) 
x Contact IXRS 
 to register the visit and obtain next kit number at Weeks 54 and 56 for subjects receiving 
loading doses of study drug administration at the study site
 to register the visit and obtain next kit number for subjects receiving study drug 
administration at the study site approximately Q12W during the remainder of the study
 to indicate that subject has completed the SFE Period or withdrawn from the study 
(Week156/WD)
Change #30
Section 8.6 FU visit (8 weeks after the Week 52/WD visit [±3 days])
Has been renumbered section 8.7 and a new paragraph has been added:
Subjects not participating in the SFE Period will attend a FU visit 8 weeks after the 
Week 52/WD visit (±3 days). 
REDACTED
f the 
f the 
mended
ended
to v
to v
COPY
l be a
be a
This document
Chan
Cha
S
cannot
to in
to in
(W
be
minis
ni
used 
ster th
ter th
istr
str
to
es o
es o
support 
visit a
visit a
of s
f
any marketing
visit th
isit th
local st
ocal s
ossible
ssibl
authorization 
Invest
Invest
d to c
d to c
h
application
o 3
o 3 mo
m
sked to
ked t
and any extensions 
umbe
mbe
or variations 
rom
om
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 223 of 255
Change #31
Section 12.1.6
Pregnancy
Paragraph 1: 
If an Investigator is notified that a subject has become pregnant after the first intake of any IMP, the 
Investigator must immediately notify UCB’s Drug Safety (DS) department by providing the completed 
Pregnancy Report and Outcome form (for contact details see Serious Adverse Event reporting 
information at the beginning of this protocol). The subject should be withdrawn from the study as soon as 
the pregnancy is known (by positive pregnancy test), and the following should be completed:
x 
The subject should return for an Early Withdrawal Visit.
x 
The subject should immediately stop the intake of the IMP or be down-titrated as instructed at the 
Early Withdrawal Visit. 
x 
A FU visit should be scheduled 8 weeks after the Week 52/WD visit.
Has been changed to:
If an Investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the Investigator must immediately notify UCB’s Drug Safety (DS) department by providing the 
completed Pregnancy Report and Outcome form (for contact details see Serious Adverse Event 
reporting information at the beginning of this protocol). The subject should be withdrawn from 
the study as soon as the pregnancy is known (by positive pregnancy test), and the following 
should be completed:
x The subject should return for an Early Withdrawal Visit.
x The subject should immediately stop the intake of the IMP. 
x A FU visit should be scheduled 8 weeks after the Week 52/WD visit.
And the following paragraph has been added:
Should a subject become pregnant while participating in the study, the subject may be offered the 
option to enroll in a separate observational pregnancy follow-up study sponsored by UCB and 
conducted independently from study AS0006. If the study is available locally, the AS0006 
Principle Investigator will be provided with the locally approved information about the 
observational pregnancy follow-up study to inform the subject at the time the pregnancy is 
reported. Participation in this separate study will be voluntary and will not impact therapeutic 
management of the subject nor interfere with termination and follow-up procedures as described 
in study protocol AS0006.
Change #32
Section 12.3
Adverse events of interest
A new paragraph 2 has been added:
Note : Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total 
bilirubin in the absence of ≥2xULN ALP, with no alternative explanation for the biochemical 
abnormality, must ALWAYS be reported to UCB as an AE of interest (ie, without waiting for 
any additional etiologic investigations to have been concluded). Follow-up information should 
REDACTED 
y p
y p
rly Wi
rly Wi
stop 
stop 
COPY
r con
r con
tocol).
ocol
posi
pos
This document
Secti
Secti
A
cannot
y pro
pro
ange #
ange 
be
nt of
nt o
toto
used
egna
gna
icipat
cipat
f
to
tor w
or w
an
an
support
eg
rate ob
ate ob
ntly fro
ly fro
will
wil
any 
nant 
nant 
marketing
the i
the i
 week
week
as be
s be
authorization 
. Th
T
itive p
tive 
ithdra
thdra
i
application
after t
after 
y (DS) 
y (DS)
act det
ct de
The s
he
and any extensions 
nstruc
struc
or variations 
oon as
oon as
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 224 of 255
then be reported if an alternative etiology is identified during investigation and monitoring of the 
subject.
Change #33
Section 12.5
Laboratory measurements
The title of Table 12‒1: Laboratory measurements
Have been changed to:
Table 12‒1
Laboratory measurements up to Week 52 (including the FU visit (8 weeks 
after the Week 52/WD visit)
And new paragraph 3 has been added beneath the table:
For subjects participating in the SFE Period after Week 52, it is recommended that laboratory 
assessments be performed at the local laboratory at the discretion of the Investigator according to 
local standard medical practice to evaluate potential AEs.
Change #34
Section 12.6.1
Pregnancy testing
A new paragraph 2 has been added:
For subjects participating in the SFE Period after Week 52, it is recommended that pregnancy 
testing be performed according to local standard medical practice.
Change #35
Section 12.6.2
Physical assessments
Paragraph 1:
Physical examination will be performed at Screening, Baseline, Weeks 2, 4, 8, 12, 16, 24, 36, 
52/WD, and at the FU visit (8 weeks after the Week 52/WD visit). Physical examination findings 
will be recorded in the CRF only at Screening. Clinically important abnormal changes in 
subsequent physical examinations will be recorded as AEs. Physical examinations must be 
documented in source documentation.
Have been changed to:
Physical examination will be performed at Screening, Baseline, Weeks 2, 4, 8, 12, 16, 24, 36, 
52/WD, and at the FU visit (8 weeks after the Week 52/WD visit for subjects not participating in 
the SFE Period). It is recommended that physical examinations be performed according to local 
standard medical practice for subjects participating in the SFE Period after Week 52,
And paragraph 4:
In addition the TB signs and symptoms will be assessed at Screening, Baseline, Weeks 2, 4, 8, 
12, 16, 24, 36, completion at Week 52/WD visit and FU (8 weeks after the Week 52/WD visit).
Has been changed to:
In addition, the TB signs and symptoms will be assessed at Screening, Baseline, Weeks 2, 4, 8, 
12, 16, 24, 36, completion at Week 52/WD visit and FU (8 weeks after the Week 52/WD visit for 
subjects not participating in the SFE Period).
REDACTED
rd m
rd m
nts
nts
COPY 
Week
Wee
me
me
This document 
nd
nd
In a
In a
1
annot 
Pe
Pe
ard me
rd me
d pa
d pa
be 
d at
eriod
eriod
used
inatio
natio
t the
t the
to
d to
d to
support
inatio
nati
ocume
ocum
to:
o:
any 
ee
nlnly at
y a
on
marketing 
rmed a
med 
eks af
eks a
authorization
k 52
52
edical 
dical 
application 
2, it
2 it
and any
vest
ves
extensions 
d that
that
stig
stig
or 
ee
ee
variations 
eks 
eks
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 225 of 255
Change #36
Section 12.6.3
Assessment and management of TB and TB risk factors
Paragraphs 10-13:
Active TB/NTMB
Subjects who develop active TB or NTMB infection during the study (conversion demonstrated 
by IGRA) must be immediately discontinued from study medication, and a withdrawal visit must 
be scheduled as soon as possible, but not later than the next regular visit. The subject should be 
encouraged to keep the FU visit (8 weeks after the Week 52/WD visit). The TB must be 
documented as an SAE. Treatment for TB should be started based on local guidelines.
Note that subjects with history of or active NTMB infection are excluded from the study 
regardless of prior or current therapy.
Confirmed active TB is an SAE and an adverse event of special interest (AESI) and must be 
captured on an SAE report form and provided to the Sponsor in accordance with SAE reporting 
requirements. As with all SAEs, periodic follow-up reports should be completed as per protocol 
requirement until such time as the TB infection resolves. 
Subjects who prematurely discontinue treatment for LTB, or, in the opinion of the Investigator or 
Sponsor, are noncompliant with anti-TB therapy must discontinue further use of study 
medication and be immediately withdrawn. Once withdrawn from study treatment, subjects 
should return for the Week 52/WD visit, complete all Week 52/WD assessments, and complete a 
FU visit (8 weeks after the Week 52/WD visit).
Have been changed to:
Active TB/NTMB
Subjects who develop active TB or NTMB infection during the study (conversion demonstrated 
by IGRA) must be immediately discontinued from study medication, and a withdrawal visit must 
be scheduled as soon as possible, but not later than the next regular visit. The subject should be 
encouraged to keep the FU visit (8 weeks after the Week 52/WD visit for subjects not 
participating in the OLE Period). The TB must be documented as an SAE. Treatment for TB 
should be started based on local guidelines.
Note that subjects with history of or active NTMB infection are excluded from the study 
regardless of prior or current therapy.
Confirmed active TB is an SAE and an adverse event of special interest (AESI) and must be 
captured on an SAE report form and provided to the Sponsor in accordance with SAE reporting 
requirements. As with all SAEs, periodic follow-up reports should be completed as per protocol 
requirement until such time as the TB infection resolves. 
Subjects who prematurely discontinue treatment for LTB, or, in the opinion of the Investigator or 
Sponsor, are noncompliant with anti-TB therapy must discontinue further use of study 
medication and be immediately withdrawn. Once withdrawn from study treatment, subjects not
participating in the OLE Period should return for the Week 52/WD visit, complete all 
Week 52/WD assessments, and complete a FU visit (8 weeks after the Week 52/WD visit).
REDACTED
plete
plete
visit).
visit).
COPY
TB
T
ust di
ust di
e with
with
e a
This document
equi
equi
Su
Su
cannot
ed on 
d on 
uireme
irem
uire
uir
be
acti
acti
used
ts w
prior o
rior 
to 
with
with
support 
visi
vis
E Perio
Peri
ed on l
d on
any
ble, bu
ble, b
sit (
it
marketing 
NTMB
NTM
iscont
scon
authorization
hdraw
hdraw
all W
all W
application 
be
r, in th
, in th
scontin
conti
wn
nd
danc
danc
e co
e co
any
AESI
AES
ce
ce
extensions 
es.s.
the stu
he stu
or variations 
must
must
ld be
ld be
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 226 of 255
Change #37
Section 12.6.3.1
Tuberculosis assessments
Paragraph 1, first sentence:
During conduct of the study the TB assessment by IGRA will be performed at Screening and 
should be repeated at Week 52/WD for all subjects. 
Has been changed to:
During conduct of the study the TB assessment by IGRA will be performed at Screening and 
should be repeated at Week 52/WD for all subjects not participating in the SFE Period. It is 
recommended that TB testing be performed according to local standard medical practice during 
the SFE Period. 
Change #38
Section 12.6.3.2
Chest x-ray
Paragraph 1:
A plain posteroanterior chest x-ray must be done at Screening unless a chest x-ray (or a 
computed tomography of the chest) has been done within 3 months prior to the Screening visit. 
The chest x-ray must be clear of signs of TB infection (previous or current) before first study 
drug administration. The chest x-ray will be repeated at Week 52/WD visit (if chest x-ray was 
performed more than 12 weeks prior to Week 52/WD visit), only if the TB test was confirmed 
positive or any further evidence is suggestive of potential TB infection (eg, exposure). 
Radiographic findings suggestive of inactive TB or active TB may include but are not limited to: 
apical fibrosis, pleural thickening, pulmonary nodules, fibrotic scars, calcified granulomas, upper 
lobe infiltrates, cavitations and pleural effusions, calcified lung nodules, calcified hilar lymph 
nodes, and pericardial calcification.
Has been changed to:
A plain posteroanterior chest x-ray must be done at Screening unless a chest x-ray (or a 
computed tomography of the chest) has been done within 3 months prior to the Screening visit. 
The chest x-ray must be clear of signs of TB infection (previous or current) before first study 
drug administration. For subjects not participating in the SFE Period the chest x-ray will be 
repeated at Week 52/WD visit (if chest x-ray was performed more than 12 weeks prior to 
Week 52/WD visit), only if the TB test was confirmed positive or any further evidence is 
suggestive of potential TB infection (eg, exposure). It is recommended that the chest x-ray be 
repeated for subjects participating in the SFE Period, if the TB test was confirmed positive or 
any further evidence is suggestive of potential TB infection (eg, exposure). Radiographic 
findings suggestive of inactive TB or active TB may include but are not limited to: apical 
fibrosis, pleural thickening, pulmonary nodules, fibrotic scars, calcified granulomas, upper lobe 
infiltrates, cavitations and pleural effusions, calcified lung nodules, calcified hilar lymph nodes, 
and pericardial calcification.
REDACTED
52/W
52/
ve of p
ve of p
ctive T
ctive 
lmona
lmona
ral e
ral e
COPY
on (p
on (p
ated a
ated a
W
This document
nd
nd
fibro
fibro
inin
canno
d for
for
further
urther
dings
ings
be
of p
of p
r s
r s
used
k 52
52
vivisit)
sit
po
po
to 
. Fo
F
2/W
2/W
support
t
the ch
the c
be clear
e cle
For s
or
any 
x-ray
ray
h
marketing
ar
effusio
ffusio
authorization
at W
t W
WD vis
D vis
poten
poten
TB or
TB or
ry no
y no
application 
unless 
nless
month
month
revious
eviou
Wee
We
and any extensions
d. It
. It
actice
actice
or 
an
a
It is
t is
variations 
and 
nd
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 227 of 255
Change #39
Section 12.6.3.3
QuantiFERON or Elispot testing
At Screening all subjects will have an IGRA test (QuantiFERON tube test or Elispot, if 
QuantiFERON test indicated is not available). The TB test will be repeated at completion at 
Week 52/WD. Results of the tests will be reported as positive, negative, or indeterminate.
Has been changed to:
At Screening all subjects will have an IGRA test (QuantiFERON tube test or Elispot, if 
QuantiFERON test indicated is not available). The TB test will be repeated at completion at 
Week 52/WD for subjects not participating in the SFE Period. It is recommended that TB testing 
be performed according to local standard medical practice during the SFE Period. Results of the 
tests will be reported as positive, negative, or indeterminate.
Change #40
Section 12.6.4 Vital signs
Paragraph 2:
Vital signs, including temperature will be measured at all on-site visits including the FU visit 
(8 weeks after the Week 52/WD visit) with the exception of the Week 1 visit (respiration rate 
will be measured at Screening and Baseline only unless the subject has an AE).
Has been changed to:
Vital signs, including temperature will be measured at all on-site visits including the FU visit 
(8 weeks after the Week 52/WD visit) with the exception of the Week 1 visit (respiration rate 
will be measured at Screening and Baseline only unless the subject has an AE). It is 
recommended that vital signs be measured according to local standard medical practice during 
the SFE Period. 
Change #41
Section 14.1 Definition of analysis sets
A new paragraph 6 was added:
The SFE Safety Set (SFE-SS) will be defined as all subjects who continued into the SFE Period 
and who received at least 1 dose of CZP in the SFE Period.
Change #42
Section 14.5
Other efficacy analyses
Paragraph 1, first sentence:
Treatment group comparisons for CZP 200mg Q2W versus placebo will be performed based on 
the change from Baseline in other selected efficacy variables. 
Has been changed to:
Double-Blind Period treatment group comparisons for CZP 200mg Q2W versus placebo will be 
performed based on the change from Baseline in other selected efficacy variables.
REDACTED 
measu
measu
with t
with t
Baselin
Baselin
su
s
COPY
ption
tio
unless 
nles
This document
Trea
Trea
thth
cannot
14.5
14.5
ragra
agra
be 
2
5
used
d at 
d at
to
t (SF
t (S
l
support
ana
ana
was add
as ad
FE
FE
any 
aly
aly
marketing
ne o
ne o
ured ac
red ac
authorization 
 th
sured a
ured a
the ex
he ex
on
application 
site vis
site v
of the W
f the 
he su
he su
and any extensions
hat TB
at TB
d. Resu
Resu
or
n at
n a
variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 228 of 255
Change #43
Section 14.6
Planned safety and other analyses
The following text was added:
The Safety Set (SS) will be used for analysis of safety data from the Double-Blind Period as well 
as the combined Double-Blind and SFE Period (as applicable), and the SFE-SS will be used for 
analysis of safety data from the SFE Period.
Change #44
Section 14.9
Planned interim analysis and data monitoring
A new paragraph 1 was added:
An interim analysis is planned after the completion of the Double-Blind Period of the last subject 
at Week 52. At this time, the database from the Double-Blind Period will be locked, the 
treatment codes will be made available to relevant UCB personnel, and an interim study report 
will be written. The Investigators and subjects will remain blind to the assigned CZP dose 
regimen of the Double-Blind Period. After the completion of the SFE Period of the last subject, 
the database will be locked, and a final study report will be written. From the Week 52 Visit 
onward, subjects will be treated with open-label CZP until the last dosing visit of the study 
(SFE Week 104).
REDACTED COPY 
un
un
This document cannot be used to support any marketing authorization application
SFE 
SFE
itten. F
tten. 
the last
he las
and
a
he ass
e ass
E P
E P
any
e lo
e l
n inte
n int
extensions 
od of t
d of t
loc
oc
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 229 of 255
18.16 
Protocol Amendment 4 
Rationale for the amendment
The purpose of this substantial amendment is to add an alternative primary efficacy variable for 
Canada and any other country where applicable or where requested by Regulatory Authorities. In 
response to feedback from the Canadian Health Authorities, the primary efficacy variable for 
Canada (and any other country where applicable or where requested by Regulatory Authorities) 
will be the ASAS40 response at Week 12. For these geographies, the ASDAS-MI at Week 52 
was moved to the list of secondary efficacy variables. In addition, the following 3 efficacy 
variables have been added to the bottom of the testing hierarchy lists for all countries:
x Change from Baseline in ASQoL at Week 52 (elevated from “other” to “secondary” efficacy 
variable) 
x Change from Baseline in nocturnal spinal pain [NRS] at Week 52 (elevated from “other” to 
“secondary” efficacy variable)
x Number of subjects with AU or new AU flares through Week 52 (new variable)   
Specific changes to the lists of efficacy variables, the hierarchical testing procedure, and 
statistical analyses are described in detail below.
Other changes in this amendment include replacement of the current assay for measuring 
anti-CZP (anti-drug antibodies) in plasma samples (a validated screening enzyme-linked 
immunosorbent assay (ELISA) method based on a double-antigen sandwich [bridge] format) 
with new methods in order to align with current regulatory guidelines. This change is being made 
across the CZP development program. In the current version of the AS0006 protocol, an ADAb 
level >2.4 units/mL is defined as positive according to the bioanalytical method and testing 
strategy. The updated strategy for immunogenicity testing will take a tiered approach consisting 
of initial screening for ADAb positive samples in subjects randomized to CZP or placebo, using 
a population-specific cutpoint resulting in a 5% false positive rate. Samples scored positively in 
the screening assay will be confirmed using a confirmatory assay with a population-specific 
confirmatory cutpoint resulting in a 1% false positive rate. Characterization of confirmed 
positive samples will consist of determination of the titer, and for a subset of samples, 
assessment of the neutralizing potential using a cell-based neutralizing antibody assay. 
An additional change to the amendment is to correctly describe the version of the MOS Sleep 
Scale used in the study. References to the older 6-point scale, which was not used, were updated 
to reflect the newer 5-point scale, and a copy of the 6-point scale questionnaire in Appendix 18.8
was replaced with the correct 5-point scale questionnaire.
Additional minor changes to the protocol include correction of the order of presentation of the 
subsections for secondary and other efficacy variables, and corrections of minor typographical 
errors. Specific changes are listed below.
REDACTED
d on a
d on 
urrent
urrent
In the
In the
sitive 
sitive 
m
COPY 
ment of
ment o
es (a 
es (a 
This document
ubse
ubs
erro
erro
cannot
lace
ace
ditiona
tiona
sec
sec
be
e ne
n
ed w
ed
used
ang
ng
the stu
he stu
ew
ew
to 
ge t
ge t
support
lting
ing
nsist o
nsist o
tralizi
tralizi
any
nfirm
nfirm
g in
g i
marketing
acc
acc
munoge
unoge
ive sam
ve sam
ulting
ulting
authorization
valid
valid
a doub
a doub
t regu
t regu
e curre
curre
cor
cor
application 
cal test
al tes
f the cu
the c
and 
2 (new
(new
any 
ate
ate
extensions 
ndary”
dary
ted f
ed
or 
y
variations 
) ) 
2 2 
y
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 230 of 255
Modifications and changes
Specific changes
Change #1
Section 1 Summary
Paragraph 13:
The primary efficacy variable is Ankylosing Spondylitis Disease Activity Score major 
improvement (ASDAS-MI) response at Week 52. The secondary efficacy variables are 
ASAS 40% (ASAS40) response at Weeks 12 and 52, change from Baseline in Bath Ankylosing 
Spondylitis Functional Index (BASFI) at Weeks 12 and 52, change from Baseline in BASDAI at 
Weeks 12 and 52, change from Baseline in SI joint Spondyloarthritis Research Consortium of 
Canada (SPARCC) score at Week 12, and the number of subjects without relevant changes to 
background medication.
Has been changed to:
The primary efficacy variable is Ankylosing Spondylitis Disease Activity Score major 
improvement (ASDAS-MI) response at Week 52. The secondary efficacy variables are 
ASAS 40% (ASAS40) response at Weeks 12 and 52, change from Baseline in Bath Ankylosing 
Spondylitis Functional Index (BASFI) at Weeks 12 and 52, change from Baseline in BASDAI at 
Weeks 12 and 52, change from Baseline in SI joint Spondyloarthritis Research Consortium of 
Canada (SPARCC) score at Week 12, the number of subjects without relevant changes to 
background medication, change from Baseline in Ankylosing Spondylitis Quality of Life 
(ASQoL ) at Week 52, change from Baseline in nocturnal spinal pain (NRS) at Week 52, and the 
number of subjects with anterior uveitis (AU) or new AU flares through Week 52.
And a new paragraph 14 has been added:
For Canada (and any other country where applicable or where requested by Regulatory 
Authorities), the primary efficacy variable is the ASAS40 response at Week 12. The secondary 
efficacy variables are ASAS40 response at Week 52, ASDAS-MI at Week 52, change from 
Baseline in BASFI at Weeks 12 and 52, change from Baseline in BASDAI at Weeks 12 and 52, 
change from Baseline in SI joint SPARCC score at Week 12, the number of subjects without 
relevant changes to background medication, change from Baseline in ASQoL at Week 52, 
change from Baseline in nocturnal spinal pain (NRS) at Week 52, and the number of subjects 
with AU or new AU flares through Week 52.
Change #2
Section 3.3 Other objectives
The other objectives of the study are to assess the effect of CZP on the following: 
x Spinal mobility
x Total and nocturnal spinal pain (NRS)
mber
mber
eline in
line in
seline 
seline
itis (A
itis (A
COPY
ch
ch
and 5
and 
int Sp
nt Sp
o
This document
The 
he 
x
cannot 
#2
#2
ion 3.3
on 3.3
otot
be 
2
used
selin
elin
ew AU
w A
to
bac
ba
ne
ne
support 
S40
4
eeks 12
eks 1
in SI j
n SI 
ackg
ck
any
cy v
cy v
0 res
0 res
marketing 
AU
AU
added:
dded
y wher
y wh
var
va
authorization
pondy
pond
of sub
f sub
n Ank
n Ank
 in no
in no
U) or
U) o
application
Acti
Acti
ary effi
ry eff
ge from
e from
52, cha
2, ch
ylol
and 
tiviv
any extensions
Anky
nky
in BA
n BA
Conso
Conso
levant
evant
or 
kylo
ylo
variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 231 of 255
Has been changed to:
The other objectives of the study are to assess the effect of CZP on the following: 
x Spinal mobility
x Total spinal pain (NRS)
Change #3
Section 4.1.1 Primary efficacy variable
x ASDAS-MI at Week 52
Has been changed to:
x ASDAS-MI at Week 52
The primary efficacy variable for Canada (and any other country where applicable or where 
requested by Regulatory Authorities) is the ASAS40 response at Week 12.
Change #4
The subsection for “other efficacy variables” was moved down and the header was 
corrected from Section 4.1.2 to Section 4.1.3.
Section 4.1.3 Other efficacy variables
And the following variables were removed from the list of other efficacy variables:
x Nocturnal spinal pain (NRS) 
x Change from Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) 
Change #5
The subsection for “secondary efficacy variables” was moved up and the header was 
corrected from Section 4.1.3 to Section 4.1.2.
Section 4.1.2 Secondary efficacy variables
And the following variables were added to the list of secondary efficacy variables:
x Change from Baseline in ASQoL at Week 52
x Change from Baseline in ASQoL at timepoints other than Week 52
x Change from Baseline in nocturnal spinal pain (NRS) at Week 52
x Number of subjects with AU or new AU flares through Week 52 
And a new paragraph has been added:
For Canada (and any other country where applicable or where requested by Regulatory 
Authorities), the secondary efficacy variables are:
x ASAS40 response at Week 52
x ASDAS-MI at Week 52 
x Change from Baseline in BASFI at Weeks 12 and 52
REDACTED
from
from
ing Sp
ing S
COPY 
m t
m
This document 
nd
nd
For
For
A
cannot 
umber
mber
d a n
d a n
be
e fro
e fro
used
om Ba
m Ba
to
asel
ase
support 
ffic
fic
iables 
ables
eliline
n
any 
S
cacy
cac
marketing 
p
fficacy
ficac
Secti
Sec
authorization 
the li
he li
pondy
ondy
application 
own an
wn a
and 
1
any
plic
pli
2.2.
extensions 
cab
cab
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 232 of 255
x Change from Baseline in BASDAI at Weeks 12 and 52
x Change from Baseline in SI joint SPARCC score at Week 12
x Number of subjects without relevant changes to background medication
x Change from Baseline in ASQoL at Week 52
x Change from Baseline in ASQoL at timepoints other than Week 52
x Change from Baseline in nocturnal spinal pain (NRS) at Week 52
x Number of subjects with AU or new AU flares through Week 52 
Change #6
Section 4.3 Immunological variables
Anti-CZP antibody (anti-CZP Ab) concentrations will be assessed at Baseline and Weeks 1, 2, 4, 
12, 24, 36, 52/WD, and the FU visit (8 weeks after the Week 52/WD visit). In addition, the 
anti-CZP Ab concentrations will be assessed in subjects who withdraw from study drug and 
transition to open-label CZP. 
The number and percent of subjects with anti-CZP Ab concentrations above 2.4 units/mL will be 
reported as follows: 
x Number and percentage of subjects with anti-CZP Ab >2.4 units/mL at the time of each visit
x Number and percentage of subjects with anti-CZP Ab >2.4 units/mL at any visit during 
treatment (not including posttreatment withdrawal or FU visits)
x Number and percentage of subjects with anti-CZP Ab >2.4 units/mL at any visit including 
posttreatment withdrawal or FU visits
Has been changed to:
Anti-CZP antibody/anti-drug antibody (anti-CZP Ab/ADAb) concentrations will be assessed at 
Baseline and Weeks 1, 2, 4, 12, 24, 36, 52/WD, and the FU visit (8 weeks after the Week 52/WD 
visit). In addition, the anti-CZP Ab concentrations will be assessed in subjects who withdraw 
from study drug and transition to open-label CZP. 
Determination of ADAb will be done using a validated screening, confirmation and titration 
ADAb bridging assay, with potential further characterization by a neutralizing antibody assay. 
The immunogenicity data will be processed according to dedicated Bioanalytical Analysis plans.
Change #7
Section 9.1.11 MOS Sleep Scale
Paragraph 2, second sentence:
The frequency with which each problem has been experienced during the previous 4 weeks is 
rated on a 6-point scale ranging from “none of the time” to “all of the time,” except sleep 
quantity, which is reported in hours. 
REDACTED 
anti
anti C
nt with
nt with
cts wit
cts wi
vis
vis
COPY 
CZP
CZP
This document
Parag
Para
T
cannot 
e #7
#7
tion 9
ion 9
be 
oge
g
used
A
g assa
assa
genic
enic
to
ADA
ADA
support 
12
1
ti-CZP
CZP
ransitio
ansiti
b
any
ntibo
ntib
2, 24
2, 2
marketing 
ith h 
sitsts
od
od
authorization
Ab 
Ab 
CZP A
CZP 
hdraw
hdraw
ant
ant
application 
ntratio
ntratio
>2
and 
isisi
aw fro
aw fro
any
line 
line
t). In
t). 
extensions 
e a
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 233 of 255
Has been changed to:
The frequency with which each problem has been experienced during the previous 4 weeks is 
rated on a 5-point scale ranging from “none of the time” to “all of the time,” except sleep 
quantity, which is reported in hours. 
Change #8
Section 10  Assessment of pharmacokinetics, exploratory biomarkers, and 
pharmacogenomics variables
Paragraph 2
These plasma samples may be used for possible analyses of exploratory biomarkers, selected 
from the following list: MMP-3, BMP-2, -4 and -7, WNT1, WISP, Gremlin, DKK1, Sclerostin, 
Hedgehog proteins (Shh, Ihh, Dhh), Collagen turnover/cleavage products, collagen type X, 
VEGF, citrullinated vimentin fragments, cytokines: IL13, IL17 A and F, IL23, IL34, (TGF-β, 
M-CSF, GM-CSF, CSF-1, sCSF1r levels. The results of the analyses of CZP and its constituent 
moieties from alternative methods may be reported separately.
Has been changed to:
These plasma samples may be used for possible analyses of exploratory biomarkers which might 
include, but are not limited to: MMP-3, BMP-2, -4 and -7, WNT1, WISP, Gremlin, DKK1, 
Sclerostin, Hedgehog proteins (Shh, Ihh, Dhh), Collagen turnover/cleavage products, collagen 
type X, VEGF, citrullinated vimentin fragments, cytokines: IL13, IL17 A and F, IL23, IL34, 
(TGF-β, M-CSF, GM-CSF, CSF-1, sCSF1r levels. The results of the analyses of CZP and its 
constituent moieties from alternative methods may be reported separately.
Change #9
Section 11ASSESSMENT OF IMMUNOGENICITY VARIABLES
Plasma samples for the measurement of anti-CZP antibodies will be taken at Baseline and 
Weeks 1, 2, 4, 12, 24, 36, 52/WD, and the FU visit (8 weeks after the Week 52/WD visit). 
The number and percent of subjects with anti-CZP concentrations above 2.4 units/mL will be 
reported as follows: 
x At the time of each visit 
x At any visit during treatment (not including posttreatment withdrawal or FU visits)
x At any visit including posttreatment withdrawal or FU visits
The sampling, handling, and shipment of samples will be performed as detailed in the Laboratory 
Manual.
Has been changed to:
Plasma samples for the measurement of anti-CZP antibodies and potentially neutralizing 
antibodies will be taken at Baseline and Weeks 1, 2, 4, 12, 24, 36, 52/WD, and the FU visit 
(8 weeks after the Week 52/WD visit). 
The sampling, handling, and shipment of samples will be performed as detailed in the Laboratory 
Manual.
REDACTED
nts, c
nts, 
r leve
r leve
ethods
ethod
COPY
se
and 
and -7
Collag
Collag
c
This document 
Has
Has
cannot 
y
ampli
ampli
nual.
nual.
be
visit
visi
used 
it dur
t dur
to
each
ach
support
of sub
f sub
v
any
WD, a
WD, 
j
marketing 
MUNO
MUNO
ment o
ent o
authorization
gen tu
gen t
ytokin
tokin
els. Th
s. Th
s may
may
application 
f explor
explo
7, WN
, WN
ur
and 
f C
f C
any
L23,
L23
CZP 
CZP 
extensions 
rs, sele
s, sele
KK1, S
K1, S
ollagen
lagen
3 I
3
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 234 of 255
Change #10
Section 14.1 Definition of analysis sets
Paragraph 4:
The Full Analysis Set (FAS) will consist of all subjects in the RS who have received at least 
1 dose of study medication and who have a valid Baseline efficacy measurement for ASDAS. 
Has been changed to:
The Full Analysis Set (FAS) will consist of all subjects in the RS who have received at least 
1 dose of study medication. 
Change #11
Section 14.2 General statistical considerations
All efficacy analyses will be performed using the FAS. The PPS will be used for a sensitivity 
analysis on the primary endpoint only. 
The statistical analysis of the primary efficacy variable and selected secondary efficacy variables 
will account for multiplicity by using a fixed sequence testing procedure. The predefined order 
of hypothesis testing, each at a 2-sided 0.05 significance level for the comparison between 
CZP 200mg Q2W and placebo, will be performed in the sequence shown below. After the first 
test, each subsequent test is performed only if the previous test is significant in favor of CZP at 
the 2-sided 0.05 level. Note that the first test relates to the primary efficacy variable while the 
others provide the sequence testing for selected secondary efficacy variables.
1. ASDAS-MI response at Week 52 
2. ASAS40 response at Week 12 
3. Change from Baseline in BASDAI at Week 12
4. Change from Baseline in BASFI at Week 12 
5. ASAS40 response at Week 52
6. Change from Baseline in BASDAI at Week 52
7. Change from Baseline in BASFI at Week 52
8. Change from Baseline in SI joint SPARCC score at Week 12
Variables evaluated over time will be summarized using imputed and observed case values. 
Further details on data summarization will be provided in the SAP.
Has been changed to:
All efficacy analyses will be performed using the FAS. The PPS will be used for a sensitivity 
analysis on the primary endpoint only. 
The statistical analysis of the primary efficacy variable and selected secondary efficacy variables 
will account for multiplicity by using a fixed sequence testing procedure. The predefined order 
of hypothesis testing, each at a 2-sided 0.05 significance level for the comparison between 
CZP 200mg Q2W and placebo, will be performed in the sequence shown below. After the first 
test, each subsequent test is performed only if the previous test is significant in favor of CZP at
REDACTED
elate
elat
ected s
ected s
COPY
n the 
n the
e prev
 prev
es
es
This document
All e
All e
an
an
canno
deta
deta
s been
been
be
valu
alu
ail
ail
used
m Ba
m Ba
ua
to
asel
ase
support 
eek
ek
ine in B
ne in 
eline
lin
any 
ASF
AS
k 52
k 5
marketing 
AI at W
AI at 
SFI a
FI
authorization
vious
ous
s to th
to th
second
econd
application
ed s
d s
procedu
roced
el for t
el for 
sequen
equen
s te
s t
and 
sec
sec
any
sed f
sed 
extensions 
f
or 
eas
a
variations 
ast 
st
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 235 of 255
the 2-sided 0.05 level. Note that the first test relates to the primary efficacy variable while the 
others provide the sequence testing for selected secondary efficacy variables.
1. ASDAS-MI response at Week 52 
2. ASAS40 response at Week 12 
3. Change from Baseline in BASDAI at Week 12
4. Change from Baseline in BASFI at Week 12 
5. ASAS40 response at Week 52
6. Change from Baseline in BASDAI at Week 52
7. Change from Baseline in BASFI at Week 52
8. Change from Baseline in SI joint SPARCC score at Week 12
9. Change from Baseline in ASQoL at Week 52
10. Change from Baseline in nocturnal spinal pain (NRS) at Week 52
11. Number of subjects with AU or new AU flares through Week 52
Hierarchical testing of efficacy variables for Canada and any other country where applicable:  
1. ASAS40 response at Week 12 
2. ASDAS-MI response at Week 52  
3. Change from Baseline in BASDAI at Week 12
4. Change from Baseline in BASFI at Week 12 
5. ASAS40 response at Week 52
6. Change from Baseline in BASDAI at Week 52
7. Change from Baseline in BASFI at Week 52
8. Change from Baseline in SI joint SPARCC score at Week 12
9. Change from Baseline in ASQoL at Week 52
10. Change from Baseline in nocturnal spinal pain (NRS) at Week 52
11. Number of subjects with AU or new AU flares through Week 52
Variables evaluated over time will be summarized using imputed and observed case values. 
Further details on data summarization will be provided in the SAP.
Change #12
Section 14.3 Planned efficacy analyses
A new paragraph 4 has been added
For Canada (and any other country where applicable or where requested by Regulatory 
Authorities), the primary efficacy variable measurement is the ASAS40 response at Week 12.
REDACTED 
AI at W
AI at W
ata
COPY 
ada an
ada a
CO
This document 
urtrt
Cha
Ch
cannot 
be
be
ables e
bles e
ther 
her 
be 
er of 
er of
used 
Ba
Ba
om B
om B
o
asel
ase
support
e in BA
in B
eline 
line inin
i
any
ASD
ASD
A
marketing 
We
t Week
Week
DA
authorization 
nd a
d a
n
eek 
eek 
application 
ek 52
k 52
any 
any
and 
2
any extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 236 of 255
Analysis of the ASAS40 response at Week 12 will be performed as described above for 
ASDAS-MI response at Week 52. Similar to the ASADAS-MI efficacy endpoint, the ASAS40 
will be treated as a composite endpoint when it is analyzed. Specifically, subjects will need 
to: 1) achieve the relevant response (ASAS40); and 2) remain in the study and on their 
randomized double-blind study treatment through Week 12.
Paragraph 5 has been revised:
Subgroup analyses by age, gender, race, symptom duration, smoking history, HLA-B27 
genotype, anti-CZP Ab status, region, prior anti-TNF exposure, and MRI/CRP classification 
(MRI+/CRP+; MRI+/CRP-; MRI-/CRP+) will be performed for the primary efficacy variable. 
Subgroup analyses will be summarized using descriptive statistics only.
Has been changed to:
Subgroup analyses by age, gender, race, symptom duration, smoking history, HLA-B27 
genotype, anti-CZP Ab (ADAb) status, region, prior anti-TNF exposure, Baseline SPARCC 
score ≥5, and MRI/CRP classification (MRI+/CRP+; MRI+/CRP-; MRI-/CRP+) will be 
performed for the primary efficacy variable. Subgroup analyses will be summarized using 
descriptive statistics only.
Change #13
Section 14.4 Secondary efficacy analyses
The changes from Baseline in BASDAI and BASFI at Week 12 and Week 52 are specified as 
secondary efficacy variables. As these are continuous variables, missing data must be handled 
using a different approach from what is specified for the primary efficacy endpoint (a responder 
variable). In the current study, Investigators will be given discretion to discontinue the 
double-blind study treatment for subjects not responding in order to provide them with 
alternative therapy to treat the condition. Therefore, in many cases, missing efficacy data due to 
the double-blind study treatment discontinuation should be dependent on the observed efficacy 
scores, but independent of unobserved data. This would be consistent with a missing at random
(MAR) assumption. However, the possibility of discontinuation due to tolerability or other 
unobserved data cannot be completely discounted. Therefore, a missing not at random 
mechanism will be used for the analysis of continuous secondary efficacy variables.
A reference-based multiple imputation (MI) procedure will be used for this analysis, which will 
impute missing data as well as data at the time points following the discontinuation of the 
double-blind study treatment for both the CZP and placebo groups. This procedure will use an 
imputation model developed based on available data from the placebo group, thereby assuming a 
placebo trajectory for missing data following study treatment discontinuation for subjects in both 
treatment groups (Mallinckrodt, 2013). The estimand being evaluated in this case is the 
difference in the outcome of improvement in all randomized subjects at the planned endpoint, 
attributable to the initially randomized medication. This is an effectiveness estimand of the de 
facto hypothesis which has been referred to as “estimand 6” (Mallinckrodt, 2012).
Additionally, change from Baseline in SI joint SPARCC score at Week 12 is a continuous 
secondary efficacy variable. The same MI procedure specified as the main analysis approach for 
BASDAI and BASFI will be used to account for missing SPARCC data. However, it should be 
noted that, unlike BASDAI and BASFI, SPARCC score will not be measured at any time points 
REDACTED
BASF
BAS
contin
contin
speci
speci
tigator
tigato
bject
bjec
COPY 
FI
FI
This document
diffe
diffe
attr
att
cannot 
on m
n 
bo traj
o tra
atmen
tmen
be 
d stst
mo
mo
used 
d m
g data
data
stud
tud
o
mul
mul
support 
ver,
er
be com
e co
ed for 
ed for
i
any
bserv
bser
, the
th
marketing 
rs w
s 
cts not 
s not 
tion. T
ion. T
discont
discon
ve
authorization 
I at W
at W
nuous
uous
ified f
ied f
f
wil
wil
application 
ill b
ll b
and
MRI
RI-/
be 
be
any 
y, 
y,
Basel
Base
CR
C
extensions 
var
, HL
HL
or
riab
riab
variations 
on 
on 
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 237 of 255
between Baseline and Week 12, meaning that those are the only 2 time points that can be 
considered in the evaluation of SPARCC score at Week 12. Comparisons between treatment 
groups will be made using an analysis of covariance (ANCOVA) model on the imputed data set. 
The model will include Baseline score, treatment group, region, and MRI/CRP classification. 
The ASAS40 response at Week 12 and Week 52 are responder secondary efficacy endpoints.  As 
a responder variable, ASAS40 will be analyzed using logistic regression based on a model 
similar to the one described for the primary analysis. As with the primary efficacy endpoint, the 
ASAS40 will be treated as a composite endpoint when it is analyzed. Specifically, subjects will 
need to 1) achieve the relevant response (ASAS40) and 2) remain in the study and on their 
randomized double-blind study treatment through the time point being analyzed (Week 12 or 
Week 52).
The comparison of CZP 200mg Q2W to placebo as described above for the ASAS40 response, 
BASDAI, and BASFI at Week 12 and Week 52 and for SI joint SPARCC score at Week 12 will 
be part of the fixed sequence testing procedure outlined in Section 14.2.
Additionally, sensitivity analyses will be conducted on these secondary efficacy endpoints. In 
particular, the assumptions related to missing data will be investigated further. These analyses 
are described in Section 14.8.
An additional secondary efficacy variable is the number of subjects with relevant changes to 
background medication. This variable will be based on whether or not subjects take certain 
pre-specified background medications during the course of the study and will be defined in the 
SAP. The analysis for this variable will use the same logistic regression model described for the 
primary variable. 
Has been changed to:
The changes from Baseline in BASDAI and BASFI at Week 12 and Week 52, change from 
Baseline in ASQoL at Week 52, and change from Baseline in nocturnal spinal pain at 
Week 52are specified as secondary efficacy variables. As these are continuous variables, missing 
data must be handled using a different approach from what is specified for the primary efficacy 
endpoint (a responder variable). In the current study, Investigators will be given discretion to 
discontinue the double-blind study treatment for subjects not responding in order to provide them 
with alternative therapy to treat the condition. Therefore, in many cases, missing efficacy data 
due to the double-blind study treatment discontinuation should be dependent on the observed 
efficacy scores, but independent of unobserved data. This would be consistent with a missing at 
random (MAR) assumption. However, the possibility of discontinuation due to tolerability or 
other unobserved data cannot be completely discounted. Therefore, a missing not at random 
mechanism will be used for the analysis of continuous secondary efficacy variables.
A reference-based multiple imputation (MI) procedure will be used for this analysis, which will 
impute missing data as well as data at the time points following the discontinuation of the 
double-blind study treatment for both the CZP and placebo groups. This procedure will use an 
imputation model developed based on available data from the placebo group, thereby assuming a 
placebo trajectory for missing data following study treatment discontinuation for subjects in both 
treatment groups (Mallinckrodt, 2013). The estimand being evaluated in this case is the 
difference in the outcome of improvement in all randomized subjects at the planned endpoint, 
REDACTED
the c
he 
the sa
the sa
COPY
mber 
mber
ed on 
ed on
co
co
This document 
 rere
imp
imp
d
cannot
obs
obs
anism
anism
efer
fer
be
AR
AR
serv
ser
used 
blbl
s, but 
, but 
R) a
R) a
to 
rap
lind
lind
support
iable
able)
blind 
blind
py to 
py to 
any 
ary
ary
differ
differ
)
marketing 
AI and
AI and
nd chan
d cha
ry eff
y ef
authorization
n wh
wh
ourse o
urse o
ame lo
me l
application
igated
gated
of subje
f subj
heth
heth
and 
ary e
ary e
d
any 
co
co
extensions
eek 1
ek 1
ASAS4
SAS4
ore 
ore
or 
eir 
eir 
2
variations 
he
he
s will
will
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 238 of 255
attributable to the initially randomized medication. This is an effectiveness estimand of the de 
facto hypothesis which has been referred to as “estimand 6” (Mallinckrodt, 2012).
Additionally, change from Baseline in SI joint SPARCC score at Week 12 is a continuous 
secondary efficacy variable. The same MI procedure specified as the main analysis approach for 
BASDAI and BASFI will be used to account for missing SPARCC data. However, it should be 
noted that, unlike BASDAI and BASFI, SPARCC score will not be measured at any time points 
between Baseline and Week 12, meaning that those are the only 2 time points that can be 
considered in the evaluation of SPARCC score at Week 12. Comparisons between treatment 
groups will be made using an analysis of covariance (ANCOVA) model on the imputed data set. 
The model will include Baseline score, treatment group, region, and MRI/CRP classification. 
The ASAS40 response at Week 12 and Week 52 are responder secondary efficacy endpoints. 
(For Canada and any other country where applicable or where requested by Regulatory 
Authorities, the ASAS40 response at Week 12 is the primary efficacy variable; the ASAS40 
response at Week 52 and the ASDAS-MI response at Week 52 are secondary efficacy variables). 
As a responder variable, ASAS40 will be analyzed using logistic regression based on a model 
similar to the one described for the primary analysis. 
The number of subjects with new onset post-Baseline AU or new AU flares through Week 52 is 
a categorical secondary efficacy endpoint for all regions. Subjects with a new event at one or 
more visits post-Baseline will be classified as having had a flare, subjects without new events at 
all visits post-Baseline will be classified as not having had a flare. As a dichotomous outcome 
variable, treatment groups will be compared for differences using logistic regression based on a 
model similar to the one described for the primary analysis.
The comparison of CZP 200mg Q2W to placebo as described above for the ASAS40 response, 
BASDAI, and BASFI at Week 12 and Week 52, for SI joint SPARCC score at Week 12, for 
ASQoL at Week 52, nocturnal pain score at Week 52, and number of subjects with AU or new 
AU flares through Week 52 will be part of the fixed sequence testing procedure outlined in 
Section 14.2.
Additionally, sensitivity analyses will be conducted on these secondary efficacy endpoints. In 
particular, the assumptions related to missing data will be investigated further. These analyses 
are described in Section 14.8.
An additional secondary efficacy variable is the number of subjects with relevant changes to 
background medication. This variable will be based on whether or not subjects take certain 
pre-specified background medications during the course of the study and will be defined in the 
SAP. The analysis for this variable will use the same logistic regression model described for the 
primary variable. 
Change #14
Section 14.5 Other efficacy analyses
Paragraph 2: 
The following variables were removed from the list of other efficacy variables
x Nocturnal spinal pain (NRS) 
x Change from Baseline in Ankylosing Spondylitis Quality of Life (ASQoL) 
REDACTED
for di
for d
prima
prima
W to pla
to pl
nd W
nd W
COPY 
ons.
ons
ng had
ng ha
aving
aving
This document
Chan
ha
Se
Se
cannot
he an
e an
ary var
ry va
ang
ang
be
ed b
d b
ana
ana
used 
con
on
medicat
edicat
bac
bac
to 
ndar
nda
support
alys
alys
ons rela
ns rel
on 14.
n 14.
any 
yses 
ses
marketing
Week 5
Week 
core at
core a
e part o
part
authorization
ad 
g had
g had
ifferen
fferen
ary an
ary an
cebo
cebo
application 
new AU
ew A
ubjects
ubjec
a fla
a fla
and
ressio
essio
any 
ble
bl
dary e
dary 
extensions
ificat
fica
cy end
y end
Regulat
egula
le; t
e; t
o
dat
dat
titi
variations 
nt 
nt 
tata
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 239 of 255
Change #15
Section 14.6.2  Pharmacokinetic and immunogenicity variable analysis
Certolizumab pegol plasma concentrations will be tabulated and summarized by treatment group 
(overall and by anti-CZP Ab level - above or below 2.4 units/mL within each treatment group) 
for each visit at which samples were taken using the geometric mean, geometric coefficient of 
variation, 95% CIs, arithmetic mean, arithmetic SD, minimum and maximum, geomean plasma 
concentration time curves with their 95% CI will be plotted overall and by anti-CZP Ab status. 
Individual plasma concentrations for CZP and anti-CZP levels versus time will be produced on 
the same graph.
The number and percent of subjects with titer above 2.4 units/mL will be presented for each visit, 
at any visit during treatment (not including posttreatment withdrawal or FU visits) and at any 
visit including posttreatment withdrawal or FU visits. For the subjects with at least 
1 anti-CZP Ab titer above 2.4 units/mL, the first timepoint of occurrence of the titer above 
2.4 units/mL will also be displayed.
In addition, safety and efficacy profiles by anti-CZP Ab level will be investigated.
Has been changed to:
Certolizumab pegol plasma concentrations will be tabulated and summarized by treatment group 
for each visit at which samples were taken using the geometric mean, geometric coefficient of 
variation, 95% CIs, arithmetic mean, arithmetic SD, minimum and maximum. Individual plasma 
concentrations for CZP and anti-CZP levels versus time will be produced on the same graph.
Immunogenicity will be assessed through listing of individual results by subject and summary 
tables. Immunogenicity data will be correlated with PK and efficacy readout. In addition, 
immunogenicity will be correlated with possible safety findings.
Change #16
Section 14.8
Handling of dropouts or missing data
For analysis purposes, the primary efficacy variable is defined as a composite endpoint in which 
it is necessary to achieve ASDAS-MI at Week 52 and to remain on randomized double-blind 
study treatment through Week 52 in order to be considered a responder (see Section 14.3). 
Because this composite endpoint definition does not allow for a missing response status, no 
formal method for handling missing data is needed in the primary efficacy analysis. However, in 
order to assess the impact of various missing data assumptions on the analysis, additional 
sensitivity analyses of the primary efficacy variable will be performed as follows:
x Including observed data at Week 52: The observed data at Week 52 will be used and 
analyzed according to randomized treatment, regardless of whether or not the subject is still 
on his/her randomized double-blind study treatment at that time. Despite efforts to continue 
to collect data on all subjects (even if they discontinue the double-blind study treatment), 
there may still be subjects with missing data at Week 52. Such subjects will be considered as 
non-responders in accordance with the composite endpoint definition outlined above. The 
same logistic regression model specified for the primary analysis will be used.
x MI: The Markov Chain Monte Carlo (MCMC) method will be used to impute intermittent 
missing data. The resulting multiply imputed data sets will be monotone missing and will be 
c S
c S
versu
versu
gh list
gh list
correl
correl
with
with
COPY
bula
bula
the geo
the g
SD, 
SD
This document 
o
cannot 
y a
y 
ncludi
ncludi
anal
anal
be 
ess
anal
anal
used
po
p
for h
for h
s the
s the
to
osite
osit
suppor
prim
prim
e ASD
e ASD
gh We
gh W
any
opo
opo
mar
ma
marketing 
late
ate
h possib
possi
out
ou
authorization 
om
om
minim
mini
us tim
s tim
ting of
ng of
ted w
ed w
application 
be 
be
ed and 
d and
metri
metr
and 
e inv
in
any
of th
of th
extensions 
d for e
d for e
its) an
its) an
at leas
leas
h
or variations 
us. 
s. 
ed on
d on
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 240 of 255
imputed using monotone regression (assuming a MAR pattern). Note that the MI procedure 
will be done on the continuous ASDAS variable, which will be dichotomized for the logistic 
regression analysis. Ankylosing Spondylitis Disease Activity Score data collected following 
the discontinuation of double-blind study treatment will be treated as missing in the original 
data set for this sensitivity analysis.
x Tipping point analysis: In this analysis, various assumptions will be made about average 
outcomes among the subsets of subjects who prematurely discontinued double-blind study 
treatment. Various “delta adjustments” will be made to the assumed responses among 
missing data in each treatment arm with varying degrees of plausibility (O’Kelly, 2014). The 
goal of the tipping point analysis is to identify assumptions about the missing data under 
which the conclusions change, ie, under which there is no longer evidence of a treatment 
effect. Then, the plausibility of such assumptions would be discussed. Further details of this 
procedure will be described in the SAP.
x Observed case analysis: This analysis will only include the observed data for subjects still on 
the original double-blind study treatment. Data collected after the discontinuation of 
double-blind study treatment and all other missing data will be excluded from the analysis. 
The same logistic regression model specified for the primary efficacy analysis will be 
performed.
The sensitivity analyses of the secondary binary efficacy variables (ASAS40 at Weeks 12 and 
52) will be as follows:
x Including observed data at Week 52: As described for the primary efficacy variable.
x MI: As described for the primary efficacy variable. Note that as ASAS40 is a composite of 
4 different variables, the MI procedure will be performed on each of these components, and 
the ASAS40 response will be derived based on the multiply imputed datasets.
x Reference-based MI: This procedure will impute missing data as well as data at the time 
points following the discontinuation of the double-blind study treatment for both the CZP 
and placebo groups. This procedure will use an imputation model developed based on data 
from the placebo group (Mallinckrodt, 2013). The estimand being evaluated in this case is 
the difference in the outcome of improvement in all randomized subjects at the planned 
endpoint, attributable to the initially randomized medication, which has been referred to as 
“estimand 6” (Mallinckrodt, 2012). 
x Observed case analysis: As described for the primary efficacy variable.
The sensitivity analyses of secondary continuous efficacy variables (the change from Baseline in 
BASDAI and BASFI at Weeks 12 and 52 and the change from Baseline in the SI joint SPARCC 
score at Week 12) will be as follows:
x Including observed data at Week 52: As described for the primary efficacy variable.
x MI: As described for the primary efficacy variable.
x Observed case analysis: As described for the primary efficacy variable.
x LOCF
REDACTED 
s desc
s desc
fficac
fficac
cedur
cedur
i
COPY 
fficacy
ficacy
This document 
or
or
x
canno
sitiv
itiv
DAI a
DAI a
re at
e at
be 
d c
vit
vit
used
” (M
(M
case
case
to
utab
utab
Mal
Mal
support
s p
s p
up (Ma
p (M
he outc
e out
able 
ble
any
inua
inu
proce
proce
marketing
re wi
e wi
ved bas
ed bas
cedure
cedur
uati
uat
authorization 
y v
y
cribed
ribed
cy vari
y vari
will
will
application
e exc
ex
ry effic
y eff
varia
varia
and
e disc
disc
xcl
xcl
any 
data f
data 
extensions
ta un
a un
a treat
treat
her de
her de
o
14)
14)
d
variations 
y y
) T
)
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 241 of 255
Missing data for the other efficacy variables described in Section 14.5 will be handled as 
follows:
x With imputation: Non-responder imputation for binary variables and LOCF for continuous 
variables (as described in Section 14.5) 
x Observed case analysis: As described for the primary efficacy variable.
Additionally, algorithms for imputing missing or partial dates for safety evaluations will be 
detailed in the SAP.
Has been changed to: 
For analysis purposes, the primary efficacy variable is defined as a composite endpoint in which 
it is necessary to achieve ASDAS-MI at Week 52 and to remain on randomized double-blind 
study treatment through Week 52 in order to be considered a responder (see Section 14.3). 
Because this composite endpoint definition does not allow for a missing response status, no 
formal method for handling missing data is needed in the primary efficacy analysis. However, in 
order to assess the impact of various missing data assumptions on the analysis, additional 
sensitivity analyses of the primary efficacy variable will be performed as follows:
x Including observed data at Week 52: The observed data at Week 52 will be used and 
analyzed according to randomized treatment, regardless of whether or not the subject is still 
on his/her randomized double-blind study treatment at that time. Despite efforts to continue 
to collect data on all subjects (even if they discontinue the double-blind study treatment), 
there may still be subjects with missing data at Week 52. Such subjects will be considered as 
non-responders in accordance with the composite endpoint definition outlined above. The 
same logistic regression model specified for the primary analysis will be used.
x MI: The Markov Chain Monte Carlo (MCMC) method will be used to impute intermittent 
missing data. The resulting multiply imputed data sets will be monotone missing and will be 
imputed using monotone regression (assuming a MAR pattern). Note that the MI procedure 
will be done on the continuous ASDAS variable, which will be dichotomized for the logistic 
regression analysis. Ankylosing Spondylitis Disease Activity Score data collected following 
the discontinuation of double-blind study treatment will be treated as missing in the original 
data set for this sensitivity analysis.
x Tipping point analysis: In this analysis, various assumptions will be made about average 
outcomes among the subsets of subjects who prematurely discontinued double-blind study 
treatment. Various “delta adjustments” will be made to the assumed responses among 
missing data in each treatment arm with varying degrees of plausibility (O’Kelly, 2014). The 
goal of the tipping point analysis is to identify assumptions about the missing data under 
which the conclusions change, ie, under which there is no longer evidence of a treatment 
effect. Then, the plausibility of such assumptions would be discussed. Further details of this 
procedure will be described in the SAP.
x Observed case analysis: This analysis will only include the observed data for subjects still on 
the original double-blind study treatment. Data collected after the discontinuation of 
double-blind study treatment and all other missing data will be excluded from the analysis. 
The same logistic regression model specified for the primary efficacy analysis will be 
performed.
disc
dis
data a
data a
he com
e com
ecified
ecifie
arl
ar
COPY
gardle
gardl
atmen
atmen
scon
sco
This document
e
cannot
sing 
ng 
oal of
al of
whic
whic
be
ent. V
ent. V
g da
g d
used
t an
an
amon
mon
Va
Va
to 
naly
nal
support
kylo
kylo
f doub
f dou
nsitivi
nsitivi
any
uous 
uous
losin
os
marketing 
o (MC
(MC
tiply im
iply i
ession
ssion
A
authorization
nt at 
at
ontinue
ntinue
at We
t We
mposi
mposi
d for 
for 
application
ormed
ormed
at Wee
at We
ss of w
ss of 
t tha
t tha
and 
cacy
ac
e ana
e ana
d
any
espo
espo
cy an
y a
extensions 
point i
oint 
do
doub
ub
Sectio
Sectio
on
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 242 of 255
Sensitivity analyses of the primary efficacy variable for Canada (and any other country where 
applicable or where requested by Regulatory Authorities), ASAS40 response at Week 12, will 
mirror the approach described above for ASDAS-MI at Week 52. 
The sensitivity analyses of the secondary binary efficacy variables (ASAS40 at Week 52) will be 
as follows:
x Including observed data at Week 52: As described for the primary efficacy variable.
x MI: As described for the primary efficacy variable. Note that as ASAS40 is a composite of 
4 different variables, the MI procedure will be performed on each of these components, and 
the ASAS40 response will be derived based on the multiply imputed datasets.
x Reference-based MI: This procedure will impute missing data as well as data at the time 
points following the discontinuation of the double-blind study treatment for both the CZP 
and placebo groups. This procedure will use an imputation model developed based on data 
from the placebo group (Mallinckrodt, 2013). The estimand being evaluated in this case is 
the difference in the outcome of improvement in all randomized subjects at the planned 
endpoint, attributable to the initially randomized medication, which has been referred to as 
“estimand 6” (Mallinckrodt, 2012). 
x Observed case analysis: As described for the primary efficacy variable.
For the secondary efficacy variable “number of subjects with AU or new AU flares through 
Week 52,” missing values should only occur in the unlikely case that a subject does not have any 
post-Baseline AU assessments performed. Therefore, sensitivity analyses for this variable will 
focus on analyses adjusting for exposure time at risk such as event rate, incidence rate, and 
confidence interval.
The sensitivity analyses of secondary continuous efficacy variables (the change from Baseline in 
BASDAI and BASFI at Weeks 12 and 52, and the change from Baseline in the SI joint SPARCC 
score at Week 12, change from Baseline in ASQoL at Week 52, and change from Baseline in 
nocturnal spine pain at Week 52) will be as follows:
x Including observed data at Week 52: As described for the primary efficacy variable.
x MI: As described for the primary efficacy variable.
x Observed case analysis: As described for the primary efficacy variable.
x LOCF
Missing data for the other efficacy variables described in Section 14.5 will be handled as 
follows:
x With imputation: Non-responder imputation for binary variables and LOCF for continuous 
variables (as described in Section 14.5) 
x Observed case analysis: As described for the primary efficacy variable.
Additionally, algorithms for imputing missing or partial dates for safety evaluations will be 
detailed in the SAP.
REDACTED
n th
n th
Theref
Theref
e time 
time
y c
y c
COPY
mary
mar
ubject
ubjec
he u
he u
This document
W
cannot
dat
dat
ws:s:
Wi
Wi
be 
ata f
ata f
used 
se an
e a
to 
anal
ana
support
ata at W
a at 
for the
for the
any
52) w
52) w
W
marketing 
continu
ontinu
and 52,
nd 52
aselin
aselin
i
authorization
ts w
s w
unlike
unlike
fore, s
fore, s
at ris
at ris
application
whic
hic
fficacy
fficac
with
with
and
subje
ubje
ich
ch
any 
op
op
aluate
aluat
t
extensions 
a at the
at the
or bot
or bot
ped
ped
or
nts, 
nts,
variations 
te of 
e of 
an
a
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 243 of 255
Change #17
Section 14.10 Determination of sample size
A new Paragraph 2 has been added
With Protocol Amendment 4, ASAS40 response at Week 12 was elevated to be the primary 
efficacy variable for Canada (and any other country where applicable or where requested by 
Regulatory Authorities); however, the study was fully enrolled at the time of this amendment. 
The expected responder rates for ASAS40 response at Week 12 are also 40% for CZP and 20% 
for placebo, which are identical to the assumed response rates cited for ASDAS-MI at Week 52. 
Therefore, the planned total sample size of 300 would provide 95% power for this variable, as 
well.
Change #18
Section 18.8 MOS Sleep Scale Questionnaire
The copy of the 6-point scale questionnaire in Appendix 18.8, which was not used in this study, 
was replaced with the correct 5-point scale questionnaire.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and
was 
was 
any 
no
n
extensions
riab
riab
or 
ee
ee
ble
ble
variations 
20%
20%
ek 5
ek 5
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 244 of 255
18.17 
Protocol Amendment 5 
Rationale for the amendment
The purpose of this substantial amendment is to gain additional information about the longer-
term disease progress and the effects of CZP treatment in patients with nr-axSpA. To support 
this, several PROs, a lab assessment, and an additional SI joint MRI will be taken at Week 
156/SFE-WD as updated in Table 5‒6. The visit windows for the SFE Period were also clarified.
Additional changes include: 
x An update to other efficacy variables to include the Week 156/SFE-WD timepoint. SFE-
WD added to Week 156 instances when needed to distinguish from Week 52/WD.
x An update to Table 5‒5 to remove collection of samples for CZP plasma concentration, 
anti-CZP antibodies, and Biomarkers as this is not done for subjects on alternative 
treatments.
x An update to the subheadings in Section 4.2.2, Section 4.2.3, and Section 4.3 to clarify 
categorization of variables.
x An update to Section 4.4 subheadings to clarify safety variables.
x An update of ASDAS-MD to ASDAS-LD (Machado et al, 2018).
x Minor editorial and administrative changes have been made throughout the protocol.
Modifications and changes
Specific changes
Change #1
Study Contact Information 
Clinical Trial Biostatistician 
Name:
, MS
Address:
8010 Arco Corporate Drive
Raleigh, NC 27617
United States of America
Phone:
Fax:
Has been changed to:
Clinical Trial Biostatistician 
Name:
, PhD
Address:
Alfred-Nobel-Str 10
40789 Monheim 
REDACTED 
g
COPY
Mach
Mach
es ha
es ha
This document 
Has 
as
Cl
C
cannot
Fax:
Fax:
t
nn
s be
be
be 
one:
ne:
b
used 
us
to suppor
801
80
po
su
t
ort any 
any
a
marketing authorization
ave be
ave be
application 
variab
variab
ado et a
do et
and
and S
and 
any 
Se
S
extensions
oin
2/WD
2/WD
a co
a conc
n
on alt
n alt
or
nt.
nt. S
variations 
d.d.
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 245 of 255
Germany 
Phone:
Fax:
Change #2
List of abbreviations
The following terms were added or modified:
ASDAS-LD
Ankylosing Spondylitis Disease Activity Score low disease
TEAE
treatment-emergent adverse event
SFE-FAS
Safety Follow-Up Full Analysis Set
Change #3
Section 2.5 Rationale
The addition of the SFE Period will allow collection of long-term safety data from eligible 
subjects on open-label CZP for up to 2 years. During the SFE Period, CZP will be provided by 
the Sponsor. The treating investigator is requested to apply routine, standard of care according to 
local standard medical practice and investigator clinical judgment. 
Has been changed to:
The addition of the SFE Period will allow collection of long-term safety data from eligible 
subjects on open-label CZP for up to 2 years. In addition, MRI assessment of SI joint structural 
damage and laboratory assessment for CRP will be performed, and data from other selected 
efficacy variables will be collected at the end of the SFE Period. During the SFE Period, CZP 
will be provided by the Sponsor. The treating Investigator is requested to apply routine, standard 
of care according to local standard medical practice and Investigator clinical judgment. 
Change #4
Section 4.1.3 Other efficacy variables
The following variables will be analyzed at scheduled time points through Week 52:
Has been changed to:
The following variables will be analyzed at scheduled time points through Week 52 and at Week 
156 for selected variables:
Change #5
Section 4.1.3 Other efficacy variables, bullets 5, 6, 10, and 11
x Change from BASMI linear
REDACTED 
r c
ow co
ow co
o 2 ye
o 2 ye
or
or
COPY
the 
the
to ap
to a
clini
clini
This document 
56
cannot 
n c
follow
follow
 for
for
be 
g
cha
cha
used 
her
er
g vari
vari
to 
r ef
r ef
support any
dard m
dard
marketing
ears.
ars.
CRP w
CRP w
at the e
at the 
The tr
The t
authorization 
pplp
ical ju
cal ju
ollecti
llecti
In
In
application 
term sa
term s
SFE Per
FE Pe
ly rou
y rou
and any extensions 
ns
s
xt
or r variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 246 of 255
x ASDAS disease activity (Ankylosing Spondylitis Disease Activity Score inactive disease 
[ASDAS-ID], Ankylosing Spondylitis Disease Activity Score moderate disease 
[ASDAS-MD], Ankylosing Spondylitis Disease Activity Score high disease activity 
[ASDAS-HD], Ankylosing Spondylitis Disease Activity Score very high disease activity 
[ASDAS-vHD]) and clinical improvement (Ankylosing Spondylitis Disease Activity Score 
clinically important improvement [ASDAS-CII], ASDAS-MI)
x Change from Baseline in SI joint SPARCC score at Week 52 and ankylosing spine MRI 
acuity (ASspiMRI-a) in the Berlin modification at Week 12 and Week 52
x Proportion of subjects with SI joint SPARCC score <2 at Week 12 and Week 52
Has been changed to:
x Change from Baseline in BASMI linear
x ASDAS disease activity (Ankylosing Spondylitis Disease Activity Score inactive disease 
[ASDAS-ID], Ankylosing Spondylitis Disease Activity Score low disease [ASDAS-LD; 
Machado et al, 2018], Ankylosing Spondylitis Disease Activity Score high disease activity 
[ASDAS-HD], Ankylosing Spondylitis Disease Activity Score very high disease activity 
[ASDAS-vHD]) and clinical improvement (Ankylosing Spondylitis Disease Activity Score 
clinically important improvement [ASDAS-CII], ASDAS-MI)
x Change from Baseline in SI joint SPARCC score at Week 52 and Week 156 and ankylosing 
spine MRI acuity (ASspiMRI-a) in the Berlin modification at Week 12 and Week 52
x Proportion of subjects with SI joint SPARCC score <2 at Week 12, Week 52, and Week 156
Change #6
The following text was moved from Section 4.4 Safety variables to Section 12 Assessment of 
Safety:
Safety variables to be assessed are physical examinations, AEs, vital signs, and measurements of 
laboratory parameters. 
Adverse events will be solicited at every visit, and recorded and coded according to the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA®) criteria.
Physical examination findings will be recorded in the CRF only at Screening. Clinically 
important abnormal changes in subsequent physical examinations will be recorded as AEs at all 
visits from Baseline to the FU visit.
Clinical laboratory values (hematology, biochemistry, urinalysis) will be collected and assessed 
at Screening, Baseline, Weeks 2, 4, 8, 12, 24, 36, at the end of study completion at Week 52/WD 
visit and at the FU visit (8 weeks after the Week 52/WD visit). In addition, clinical laboratory 
values will be collected and assessed at study visits during the administration of open-label CZP 
in subjects who withdraw from the double-blind study treatment.
Furthermore, CRP will be collected and assessed either in a blinded or open manner at 
Screening, 3 to 5 days before Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 
REDACTED
rlin 
rlin
PARC
ARC
COPY
ASD
AS
core a
core a
m
This document
at Sc
t Sc
vis
vis
cannot
om B
m B
nical l
ical 
be
abno
abno
B
used 
edic
di
minati
minati
to
b
ical 
ical
support 
sed
ed
e soli
e sol
any 
d are
d ar
marketing 
om Se
om S
authorization
at W
t W
modific
odifi
CC sco
CC sco
application
ore ver
re ve
pondyl
pondy
AS
AS-MI
M
Week
ee
and
dise
dis
Score
core
any
ore in
ore i
seas
sea
extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 247 of 255
at the end of study completion at Week 52/WD visit and at the FU visit (8 weeks after the 
Week 52/WD visit).
At Screening, all subjects will have an IGRA test (QuantiFERON® TB test or Elispot®test, when 
the QuantiFERON test indicated is not available), and a chest x-ray reading (or, if done, 
computed tomography of the chest) which must be reported consistent with standard clinical 
reporting practice by an experienced qualified TB specialist, radiologist, or a pulmonologist, who 
is specifically required to look for signs of active TB or signs of past/inactive TB infection. A 
chest x-ray will not be done at Screening if a chest x-ray (or computed tomography of the chest) 
was done within 3 months prior to the Screening visit. The official report of the imaging must 
specifically indicate the absence of findings suggestive of current active TB or prior inactive TB. 
In addition to a physical examination done intermittently throughout the study, subjects will be 
evaluated at Screening, Baseline, and every 12 weeks thereafter up to Week 36 and including the 
Week 52/WD visit, for signs and symptoms of LTB or active TB infection and risk factors for 
exposure to TB using the TB questionnaire.
Change #7
The following section was added:
Section 4.4.1 Secondary safety variables
Assessment time points for safety variables are specified in Table 5‒1 and Table 5‒6. The 
secondary safety variables are as follows:
x Incidence of treatment-emergent adverse events (TEAEs)
x Incidence of serious adverse events (SAEs)
x Adverse events leading to withdrawal from investigational medicinal product (IMP)
Change #8
The following section was added:
Section 4.4.2 Other safety variables
Other safety variables are assessed as specified in Table 5‒1 and Table 5‒6, and are as follows:
x Change from Baseline in vital signs (blood pressure, temperature, and pulse rate)
x Change from Baseline in clinical laboratory values (hematology, biochemistry, and 
urinalysis)
Physical examination findings considered clinically significant changes since the physical 
examination completed at the Screening Visit will be recorded as AEs.
Change #9
Section 5.1.1 Study periods 
e sp
e sp
verse 
verse 
nts (S
nts (
COPY 
peci
pec
This document
Phys
Phys
ex
ex
cannot
ange 
ange 
urinal
urinal
be
e fro
fro
used
riable
able
om
om
to 
r sa
sa
support 
was ad
was a
safet
afe
any marketing
SAE
SAE
rawal f
awal 
authorization 
ified i
fied 
event
event
E
application and any extensions
inact
nac
bjects
bjects
6 and i
and i
nd ris
d ris
o
mu
mu
titi
variations 
o 
chest)
hest)
us
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 248 of 255
Starting at Week 64, all subjects are to visit the site approximately every 12 weeks for
assessments. 
The last dosing visit will be at Week 154. The final study assessments are performed at 
Week 156.
Has been changed to:
Starting at Week 64, all subjects are to visit the site approximately every 12 weeks (±2 weeks) 
for assessments. 
The last dosing visit will be at Week 154. The final study assessments are performed at 
Week 156/SFE-WD.
Change #10
Table 5‒5 Schedule of study assessments – additional assessments for wdt 0 visit required 
for subjects transitioning to alternative treatment 
The CZP-plasma concentration/anti-CZP Abs/Biomarker row was removed. The table list of 
abbreviations was updated.
Change #11
Table 5‒6 Schedule of study assessments – Safety Follow-Up Extension Period
At Week 156 (Visit 40), the following assessments were added: blood sample for CRP, 
BASDAI, BASFI, ASQoL, total and nocturnal spinal pain, PGADA, and MRI SI joints. The 
table list of abbreviations was updated.
The column header for Visit 40 was updated to 156/104/SFE-WD. The table list of abbreviations 
was updated.
Change #12
Figure 5‒3: Schematic diagram for subjects completing the double-blind study treatment
and rolling over to the SFE Period
The label for Week156 was updated to W156/SFE-W104/SFE-WD. The schematic list of
abbreviations was also updated.
Change #13
Section 8.6 SFE Period (Week 52 to Week 156):
Starting at Week 64, all subjects are to visit the site approximately every 12 weeks for
assessments performed according to local standard medical practice, as needed, including:
x Document AEs (Note: any [possible] drug-related AE must be followed-up, at least by 
phone.) 
REDACTED 
– Safe
Safe
assess
assess
d noctu
d noctu
ed
ed
COPY 
This document
Chan
ha
Se
Se
cannot 
ioio
ang
ang
be 
r W
ons w
ons w
used
r to 
 to 
Wee
Wee
to
matic
ati
th
th
support 
ic di
c d
any marketing
urna
rn
as upda
s upd
authorization 
fety Fo
ty F
sments
ment
nal
nal
application
as rem
s rem
and 
or
any 
r wdt
wdt
extensions or variations 
)
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 249 of 255
x Contact IXRS 
 to register the visit and obtain next kit number at Weeks 54 and 56 for subjects receiving 
loading doses of study drug administration at the study site 
 to register the visit and obtain next kit number for subjects receiving study drug 
administration at the study site approximately Q12W during the remainder of the study
 to indicate that subject has completed the SFE Period or withdrawn from the study 
(Week156/WD)
Has been changed to:
Starting at Week 64, all subjects are to visit the site approximately every 12 weeks (±2 weeks) 
for assessments performed according to local standard medical practice, as needed, including:
x Document AEs (Note: any [possible] drug-related AE must be followed-up, at least by 
phone.) 
x Contact IXRS 
 to register the visit and obtain next kit number at Weeks 54 and 56 for subjects receiving 
loading doses of study drug administration at the study site 
 to register the visit and obtain next kit number for subjects receiving study drug 
administration at the study site approximately Q12W during the remainder of the study
 to indicate that the subject has withdrawn from the study, if applicable
At Week 156/SFE-WD (±1 week), all subjects are to visit the site for the following assessments:
x Blood sample for CRP
x BASDAI
x BASFI
x ASQoL
x Total and nocturnal spinal pain
x PGADA
x MRI SI joints
x AEs
x Contact IXRS to indicate that the subject has completed the SFE Period (Week 156/SFE-
WD)
Change #14
Section 9.1.1 ASDAS
The variables related to ASDAS disease activity are defined as follows:
x ASDAS-Inactive Disease (ASDAS-ID): ASDAS <1.3
REDACTED 
drawn 
drawn 
subjec
subjec
COPY 
ber fo
ber fo
ately 
ately
This document cannot 
ontact
ntac
WD)
WD)
be used 
nts
nts
to support 
l spinal
spina
any marketing authorization
y Q12
Q12
n from
from
cts are
s are
application 
s 54 an
54 a
dy site
dy site
r subje
subj
W
and any 
u
extensions 
s (±2 w
(±2 w
ded, in
ded, in
up, 
up,
or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 250 of 255
x ASDAS-Moderate Disease (ASDAS-MD): ASDAS ≥1.3, <2.1
x ASDAS-High Disease Activity (ASDAS-HD): ASDAS ≥2.1, ≤3.5
x ASDAS-very High Disease Activity (ASDAS-vHD): ASDAS >3.5
Has been changed to:
The variables related to ASDAS disease activity are defined as follows:
x ASDAS-Inactive Disease (ASDAS-ID): ASDAS <1.3
x ASDAS-Low Disease (ASDAS-LD): ASDAS ≥1.3, <2.1
x ASDAS-High Disease Activity (ASDAS-HD): ASDAS ≥2.1, ≤3.5
x ASDAS-very High Disease Activity (ASDAS-vHD): ASDAS >3.5
Change #15
Section 9.1.1 ASDAS
The ASDAS will be calculated at Screening, Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32 36, 
40, 44, 48, and 52/WD.
Has been changed to:
The ASDAS will be calculated at Screening, Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32 36, 
40, 44, 48, 52/WD, and Week 156/SFE-WD.
Change #16
Section 9.1.2 ASAS20, 40, ASAS 5/6 response, and ASAS partial remission:
The ASAS variables will be calculated at Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 
and 52/WD.
Has been changed to:
The ASDAS will be calculated at Screening, Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32 36, 
40, 44, 48, 52/WD, and Week 156/SFE-WD.
Change #17
Section 9.1.4 ASQoL
The ASQoL assessments per visit are described in Table 5‒1 and Table 5‒2.
Has been changed to:
The ASQoL assessments per visit are described in Table 5‒1, Table 5‒2, and Table 5‒6.
REDACTED
Base
Base
WD.
D.
COPY 
This document
The A
The 
H
cannot
e #17
#17
tion 9
ion 9
be 
7
used
WD, a
D, a
to 
e ca
ca
an
support 
alcu
alc
any
lcula
lcul
marketing 
5/6 re
5/6 r
ate
authorization 
eline, W
line, W
application 
s 2, 4, 
s 2, 4,
and any extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 251 of 255
Change #18
Section 9.1.5 BASDAI
The BASDAI assessments per visit are described in the schedule of study assessments Table 5‒
1, Table 5‒2, and Table 5‒3.
Has been changed to:
The BASDAI assessments per visit are described in the schedule of study assessments Table 5‒
1, Table 5‒2, Table 5‒3, and Table 5‒6.
Change #19
Section 9.1.6 BASFI
The BASFI assessments per visit are described in Table 5‒1, Table 5‒2, and Table 5‒3.
Has been changed to:
The BASFI assessments per visit are described in Table 5‒1, Table 5‒2, Table 5‒3, and Table 5‒
6.
Change #20
Section 9.1.12 MRI assessments
Magnetic resonance imaging of the spine and SI joints will be performed at Screening and at the 
Week 12 and at the Week 52/WD visits if MRI was performed more than 12 weeks prior to 
Week 52/WD. Magnetic resonance images will be assessed centrally and scoring will be done by 
2 independent readers, who are blinded to both the order of the scans and to the treatment group, 
using a previously reported scoring system.
Has been changed to:
Magnetic resonance imaging of the spine and SI joints will be performed at Screening and at the 
Week 12 and at the Week 52/WD visits if MRI was performed more than 12 weeks prior to 
Week 52/WD. A further MRI of the SI joints will be performed at Week 156/SFE-WD. 
Magnetic resonance images will be assessed centrally and scoring will be done by 2 independent 
readers, who are blinded to both the order of the scans and to the treatment group, using a 
previously reported scoring system.
Change #21
Section 9.1.13 PGADA (NRS)
The PGADA assessments per visit are described in Table 5‒1, Table 5‒2, and Table 5‒3.
Has been changed to:
The PGADA assessments per visit are described in Table 5‒1, Table 5‒2, Table 5‒3, and 
Table 5‒6.
REDACTED 
ne and
ne and
sits if 
sits if 
ima
ima
COPY 
This document 
ha
ha
Sec
Sec
annot 
ange
ange
be
repo
repo
used
ance 
nce
are bl
are bl
to
urthe
urth
e im
im
support 
ging of
ing o
eek 52
ek 5
her M
er
any marketing 
M
ages wi
ges w
ded to b
ed to
ng syst
g sys
authorization 
d SI jo
SI jo
MRI 
RI 
application 
ble 5‒
and any
nd 
nd T
extensions or variations 
5‒
thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 252 of 255
Change #22
Section 9.1.20 Total and nocturnal spinal pain NRS
The pain NRS assessments per visit are described in Table 5‒1, Table 5‒2, and Table 5‒3.
Has been changed to:
The pain NRS assessments per visit are described in Table 5‒1, Table 5‒2, Table 5‒3, and 
Table 5‒6.
Change #23
Section 12.5 Laboratory measurements
For subjects participating in the SFE Period after Week 52, it is recommended that laboratory 
assessments be performed at the local laboratory at the discretion of the Investigator according to 
local standard medical practice to evaluate potential AEs.
Has been changed to:
For subjects participating in the SFE Period after Week 52, it is recommended that laboratory 
assessments be performed at the local laboratory at the discretion of the Investigator according to 
local standard medical practice to evaluate potential AEs. At Week 156/SFE-WD, a blood 
sample will be taken for CRP measurement and analyzed at the central laboratory.
Change #24
Section 14.1 Definition of analysis sets
The following analysis set was added:
The SFE Full Analysis Set (SFE-FAS) will be defined as all subjects in the FAS, who continued 
into the SFE Period and who received at least 1 dose of CZP in the SFE Period.
Change #25
Section 14.2 General statistical considerations
All efficacy analyses will be performed using the FAS. The PPS will be used for a sensitivity 
analysis on the primary endpoint only.
Has been changed to:
All efficacy analyses will be performed using the FAS. The PPS will be used for a sensitivity 
analysis on the primary endpoint only. Analysis of efficacy variables in the SFE Period will be 
performed on the SFE-FAS.
REDACTED
enti
ent
and a
and a
COPY
eek 5
eek 
at the 
at the
tial
tial
This document
Has 
as 
All
Al
cannot
acy
acy
sis on
is on
s be
be
be 
y an
y a
used 
Gen
Gen
to support 
(SF
S
who re
ho re
any 
dd
d
FE
FE-F
marketing 
sets
sets
ded:
ded:
authorization
 dis
dis
l AEs.
AEs.
analyz
nalyz
application 
2, it is 
2, it is
scre
scre
and
the In
he In
any 
ended
ended
extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 253 of 255
Change #26
Section 17 References
The following reference was added:
Machado PM, Landewé R, van der Heijde D, Assessment of SpondyloArthritis international Society 
(ASAS). Letter. Ankylosing Spondylitis Disease Activity Score (ASDAS): 2018 update of the 
nomenclature for disease activity states. Ann Rheum Dis. 2018;77:1539-40.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 254 of 255
19 
DECLARATION AND SIGNATURE OF INVESTIGATOR 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and local 
laws and requirements.
I will ensure that all subinvestigators and other staff members read and understand all aspects of 
this protocol.
I have received and read all study-related information provided to me.
The objectives and content of this protocol as well as the results deriving from it will be treated 
confidentially, and will not be made available to third parties without prior authorization by 
UCB.
All rights of publication of the results reside with UCB, unless other agreements were made in a 
separate contract.
Investigator:
Printed name
Date/Signature
REDACTED COPY 
Date/S
Date/S
PY
This document cannot be used to support any marketing authorization
Signa
ign
application 
atut
pp
and any extensions
be 
zation 
zation
ents w
nts w
or
trea
tre
variations thereof. 

UCB
17 Dec 2018
Clinical Study Protocol
Certolizumab Pegol
AS0006
Confidential
Page 255 of 255
20 
SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice.
COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 

Approval Signatures
Name:
as0006-protocol-amend-5
Version:
1. 0
Document Number:
CLIN-000128521
Title:
AS0006 Protocol Amendment 5
Approved Date:
18 Dec 2018
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 18-Dec-2018 14:18:05 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 18-Dec-2018 14:30:20 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 18-Dec-2018 16:02:22 GMT+0000
DACTED 
REDA
DA
OPY
App
App
CO
CO
This document cannot be used to supp
pport 
pp
any marketing 
ma
ma
n
p
uthorization 
n
ori
Nam
Ca
aut
ut
application 
p
roval
ova
a
and any extensions or variations thereof.