Conditions: Arthritis, Rheumatoid
Keywords: Rheumatoid Arthritis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 645
Healthy volunteers: no

Brief summary:
The purpose of the study is to compare the long-term safety, effectiveness and immunogenicity of FKB327 in comparison to Humira® in rheumatoid arthritis patients who have completed study FKB327-002 and have inadequate disease control on methotrexate.

Detailed description:
The first period of this extension study was an open label, randomised, comparative, multi centre, 2 arm extension Phase 3 study in patients with RA who were taking a stable dose of MTX and who had continued from the preceding Study FKB327-002 (NCT02260791). The transition from Study FKB327-002 was ideally to occur without interruption: the Week 24 visit of Study FKB327-002 was to be on the same day as the Week 0 visit of Study FKB327-003. Patients who had received FKB327 in Study FKB327-002 received FKB327 or Humira in a 2:1 ratio and patients who had received Humira in Study FKB327-002 received Humira or FKB327 in a 2:1 ratio (Period I). The second period of the study was an open label, single arm extension in which all patients received FKB327 treatment from Week 30 to Week 76 (Period II), followed by a 4 week Follow up period.

Clinic visits were scheduled for Weeks 0, 2, 4, 8, 12, 24, 30, 32, 34, 42, 54, 66, 76, and 80. The patient or carer was allowed to administer interim doses of study drug at home every other week (eow) between clinic visits.

Arms:
arm 1: Patients will receive the drug 40 mg every other week by subcutaneous injection. The treatment period may continue for 76 weeks. arm 2: Patients will receive the drug 40 mg every other week by subcutaneous injection. The treatment period may continue for 76 weeks.

Interventions: intervention 1: FKB327 intervention 2: Humira®
Intervention descriptions: intervention 1: Solution of FKB327 for subcutaneous injection administered in a dose of 40 mg every 2 weeks for 28 weeks. Patients may continue to receive FKB327 40 mg every other week by subcutaneous injection for up to 76 weeks. intervention 2: Solution of Humira® for subcutaneous injection administered in a dose of 40 mg every 2 weeks for 28 weeks. Patients may then receive FKB327 40 mg every other week by subcutaneous injection from week 30 to week 76.

Protocol document:
Prot_000.pdf: 
Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local 
Amendment 1) 
EudraCT No.: 2014-000110-61 
Confidential 
Page 1 
FUJIFILM KYOWA KIRIN BIOLOGICS CO., LTD 
CLINICAL PROTOCOL 
INCORPORATES GLOBAL AMENDMENT 4 AND LOCAL AMENDMENT 1 
FOR CZECH REPUBLIC, GERMANY, POLAND, ROMANIA, AND SPAIN 
An Open-label Extension Study to Compare the Long-term Efficacy, Safety, 
Immunogenicity and Pharmacokinetics of FKB327 and Humira® in Patients with
Rheumatoid Arthritis on Concomitant Methotrexate (ARABESC-OLE) 
FKB327-003 
ARABESC-OLE 
FKB327 (adalimumab) 
2014-000110-61 
Phase 3 
Protocol Number: 
Protocol Acronym: 
Compound: 
EudraCT Number:  
Phase: 
Version and Date: 
Name and Address of the Sponsor: 
Name and Address of the Medical 
Monitors: 
Version 4.3 (Based on Global 
Amendment 4 and Local Amendment 1), 
15 April 2016. 
Fujifilm Kyowa Kirin Biologics Co., Ltd 
1-6-1 Ohtemachi 
Chiyoda-ku 
Tokyo 100-8185 
Japan 
Redacted


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local 
Amendment 1) 
EudraCT No.: 2014-000110-61
Confidential 
Page 3 
PROTOCOL SUMMARY 
Sponsor: Fujifilm Kyowa Kirin Biologics Co., Ltd. 
Study Title: An Open-label Extension Study to Compare the Long-term Efficacy, Safety, 
Immunogenicity and Pharmacokinetics of FKB327 and Humira® in Patients with Rheumatoid 
Arthritis on Concomitant Methotrexate (ARABESC-OLE) 
Study Number: FKB327-003. 
Protocol Acronym: ARABESC-OLE. 
EudraCT Number: 2014-000110-61. 
Name of Investigational Product: FKB327. 
Name of Active Ingredient: adalimumab. 
Study Phase: 3. 
Number of Patients Planned: up to 680 patients (estimated 544 patients; approximately 
272 patients in each of the FKB327 and Humira® arms, allowing 20% dropout from study 
FKB327-002). 
Number of Sites Planned: approximately 130 - the sites will be the same as for study 
FKB327-002. 
Study Population: Only patients who completed the double-blind study FKB327-002 will be 
permitted to continue into this extension study.  These will be patients with rheumatoid arthritis 
(RA) who are taking concomitant methotrexate (MTX) and folate. 
Primary Objective: The primary objective of this study is to compare the safety of long-term 
treatment with FKB327 and Humira in patients with RA. 
Secondary Objectives: The secondary objectives of this study are as follows: 

To compare the efficacy of long-term treatment with FKB327 and Humira in patients with
RA.

To compare the proportion of patients developing anti-drug antibodies (ADAs) on long-term
treatment with FKB327 and Humira in patients with RA.

To compare the pharmacokinetics (PK) of long-term treatment with FKB327 and Humira in
patients with RA.

To evaluate safety, changes in efficacy, and changes in PK and immunogenicity in patients
who are switched from Humira in the preceding FKB327-002 double-blind study to FKB327
in the FKB327-003 open-label extension (OLE) study, and of patients who are switched from
FKB327 to Humira, respectively.

To evaluate safety, changes in efficacy, and changes in PK and immunogenicity in patients
who are switched from FKB327 in the preceding FKB327-002 double-blind study to Humira
in the FKB327-003 OLE study, and then switch back to FKB327 in the second part of the
FKB327-003 OLE study (from Week 30; double switch).
Inclusion Criteria: Patients will be eligible for enrolment into the study if they meet all of the 
following inclusion criteria: 


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local 
Amendment 1) 
EudraCT No.: 2014-000110-61 
Confidential 
Page 4 
1.
Have completed all 24 weeks of study procedures (including dosing) according to
protocol FKB327-002, with a minimum of 9 doses of study drug received, and are continuing
with stable concomitant MTX and folate.
2.
In the investigator‟s opinion, the patient showed a clinical response to treatment during
Study FKB327-002.
3.
Are willing to participate in the study and have provided written informed consent.
4.
Females of childbearing potential must have a negative pregnancy test prior to study dosing.
Both sexes must be willing to take adequate contraceptive precautions throughout the study
period and continuing for at least 5 months post study.  Acceptable methods of contraception
in this study are: surgical sterilisation, intrauterine devices, oral contraceptives, contraceptive
patch, long-acting injectable contraceptives, partner‟s vasectomy, or a double-protection
method (condom or diaphragm with spermicide).
Exclusion Criteria: Patients will be excluded from the study if any of the following exclusion 
criteria are met: 
1.
Evidence of a serious adverse event (SAE) ongoing from Study FKB327-002 at entry to this
study, including a serious infection, malignancy, or any other condition that may put patients
at increased risk when receiving treatment with adalimumab.
2.
Presence of active and/or untreated latent tuberculosis (TB) as detected by QuantiFERON test
at Week 22 combined with chest X-ray at Week 24 in Study FKB327-002.  Latent TB,
treated with prophylactic anti-mycobacterial therapy for at least 3 weeks before study dosing
is resumed, is acceptable.  Patients may have up to a maximum of 4 weeks interruption of
dosing between the last dose in Study FKB327-002 and Week 0 dosing in study FKB327-003
for this purpose.
3.
Were non-compliant with FKB327-002 study procedures, or with any condition or
circumstances, which, in the opinion of the Investigator, makes them unlikely or unable to
comply with study procedures and requirements.
4.
American College of Rheumatology (ACR) Functional Class IV.
5.
Acute infection requiring antibiotic treatment within 2 weeks of Week 0 dosing.  Patients
may have up to a maximum of 4 weeks interruption of dosing between the last dose in
Study FKB327-002 and Week 0 dosing in Study FKB327-003 in order to recover from
infection requiring antibiotic treatment.
6.
Presence of serious, uncontrolled disease of another body system including cardiovascular,
neurological, pulmonary, renal and hepatic disease.
7.
Presence of New York Heart Association (NYHA) Class III/IV heart failure.
8.
Presence of any uncontrolled disease for which steroid treatment is regularly required for
flares, eg, asthma.
9.
Patients with demyelinating diseases (eg, multiple sclerosis).
10. Pregnant or breastfeeding women.
Study Drug: Patients will receive subcutaneous (sc) FKB327 40 mg every other week (eow) or 
sc Humira 40 mg eow from Week 0 to Week 28; after this, all patients will receive FKB327 
40 mg eow from Week 30 to Week 76.  Patients will continue to take the same stable dose of 
MTX (10-25 mg/week) throughout this study as taken in Study FKB327-002, with folic/folinic 
acid at a dose of at least 5 mg/week. 
Presentations:  FKB327 will be supplied in a plastic pre-filled syringe (PFS) with a safety 
device.  FKB327 in an Auto-Injector device presentation will be introduced during the open-label 


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local 
Amendment 1) 
EudraCT No.: 2014-000110-61 
Confidential 
Page 5 
follow-up treatment period depending on availability of the Auto-Injector relative to the patient‟s 
progress within the study.  In both presentations, the dose will be 40 mg in 0.8 mL. 
From Week 0 to Week 28 only, patients randomised to Humira will be supplied US-licensed 
Humira in a glass PFS.  The dose will be 40 mg in 0.8 mL.  Note: The needle cover of the Humira 
PFS contains dry rubber (latex) which should not be handled by persons sensitive to this 
substance without using latex-free gloves. 
Blinding and Randomisation: This extension study is open-label throughout.  Patients from 
Study FKB327-002 will be randomised to receive either FKB327 40 mg eow or Humira 40 mg 
eow from Week 0 to Week 28.  Patients who received FKB327 in Study FKB327-002 will be 
randomised to receive FKB327 or Humira in a 2:1 ratio.  Patients who received Humira in 
Study FKB327-002 will be randomised to receive Humira or FKB327 in a 2:1 ratio.  From 
Week 30 to Week 76, all patients will receive FKB327 40 mg eow. 
Duration of Participation: Patients may remain on study treatment for up to 76 weeks with a 
further post-treatment follow-up period of 4 weeks, making a total maximum duration of 
80 weeks. 
Study Design and Methodology: The first part of this study is an open-label, randomised, 
comparative, multi-centre, 2-arm extension Phase 3 study in patients with RA who are taking a 
stable dose of MTX who will continue from the preceding Study FKB327-002.  Patients who 
complete Study FKB327-002 and consent to this open-label extension study will be randomised 
to receive treatment with either FKB327 40 mg eow or Humira 40 mg eow from Week 0 to 
Week 28.  The second part of the study is an open-label, multi-centre, single arm extension in 
which all patients receive prolonged FKB327 treatment from Week 30 to Week 76, followed by a 
4-week follow-up period.  Scheduled clinic visits will be conducted at Weeks 0, 2, 4, 8, 12, 24, 
30, 32, 34, 42, 54, 66, 76, and 80.  The patient or carer will administer interim doses of study drug 
at home (eow) between clinic visits.  FKB327 in an Auto-Injector device presentation will be 
introduced during the open label follow up treatment period depending on availability of the 
Auto-injector relative to the patient‟s progress within the study. 
At the Week 22 visit in Study FKB327-002, the investigator will discuss participation in this 
open-label extension study with the patient, if appropriate.  If the patient is eligible for this study 
and gives informed consent to participate, the patient will be randomised into the study and 
Week 0 study drug dose for this study will be administered after the Week 24 study procedures 
for Study FKB327-002 have been performed.  The first 3 doses of study drug (Weeks 0, 2, and 4 
for all patients and Weeks 30, 32, and 34 for patients switching from Humira to FKB327 at that 
point) will be self-administered (or administered by a carer) at the study site after training has 
been given.  Subsequent doses may be administered by the patient or carer at home, except when 
clinic visits for blood tests and efficacy assessments are scheduled when the dose must be given 
only after the blood samples have been drawn. 
Primary Efficacy Endpoint: As the primary endpoint is safety, there is no primary efficacy 
endpoint in this study. 
Secondary Efficacy Endpoint: The secondary efficacy endpoints are as follows: 

ACR20, ACR50 and ACR70 response rates from baseline (Week 0 from
Study FKB327-002).

Changes in Disease Activity Score 28 based on C-reactive protein (CRP) (DAS28-CRP)
score compared to baseline (Week 0 from Study FKB327-002).
Other Endpoints: The other endpoints are as follows: 


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local 
Amendment 1) 
EudraCT No.: 2014-000110-61 
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
Immunogenicity.

PK 
Safety Endpoints: The primary endpoint of the study is safety.  Safety will be evaluated using 
the following assessments: 

Adverse events (AEs).

SAEs, including serious infections and malignancies.

Vital signs.

Clinical laboratory tests.
Statistical Methods: 
Safety endpoints: AEs will be summarised by System Organ Class (SOC) and Preferred Term 
(PT) using the Medical Dictionary for Regulatory Activities (MedDRA).  AEs will be tabulated 
by treatment sequence and relationship to treatment.  SAEs, in particular infections and 
malignancies, will be summarised by treatment sequence.  Safety data including vital signs, 
haematology, serum chemistry and urinalysis will be summarised by treatment sequence for each 
visit.  Withdrawals from the study will be summarised by treatment sequence. 
The incidence and size of injection site reactions and injection site pain VAS scores will be 
summarised by FKB327-003 treatment using descriptive statistics. 
Efficacy endpoints: ACR20, ACR50 and ACR70 response rates from Baseline (Week 0) in 
Study FKB327-002 will be summarised by treatment sequence and visit.  DAS28 score and the 
change from Baseline (Week 0 in the FKB327-002 study) in DAS28 score, and individual ACR 
core set variables (swollen joint count, tender joint count, CRP, patient‟s assessment of disease 
activity, physician‟s assessment of disease activity, patient‟s assessment of pain, Health 
Assessment Questionnaire Disability Index [HAQ-DI]) will be summarised by treatment 
sequence and visit. 
Other endpoints: The proportion of patients positive for ADAs in the confirmatory and 
neutralising assays at each sampling time point will be summarised by treatment sequence. 
A mixed model for repeated measures will be fitted to the log transformed PK trough 
concentrations at Weeks 12, 24 and 30 (ie, during the randomised treatment period) with patient 
included as a random effect and fixed effect terms for week, treatment sequence, and Week x 
treatment sequence interaction.  Provided the interaction term for Week x treatment sequence is 
not significant at the 10% level, only differences (ratios of geometric means) averaged over all 
time points will be estimated with 90% confidence intervals (CIs).  The following comparisons 
will be of interest: 

FKB327 to Humira (based on treatment in FKB327-003).

Sequence group FKB327-Humira relative to Humira-Humira.

Sequence group Humira-FKB327 relative to Humira-Humira.
Due to the potential formation of ADAs, a secondary PK analysis will also be performed with 
ADA titre results. 
PK samples collected during the follow-up treatment period (ie, Weeks 54 and 76) will be listed 
and summarised only. 
Interim analysis: An interim analysis of planned endpoints for all patients will be performed once 
100 patients randomised to FKB327 in study FKB327-002 and also to FKB327 in the randomised 


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local 
Amendment 1) 
EudraCT No.: 2014-000110-61 
Confidential 
Page 7 
phase of study FKB327-003 plus 100 patients randomised to Humira in study FKB327-002 and 
also to Humira in the randomised phase of study FKB327-003 have reached Week 30 in this 
study.  This will provide more than 100 patient-years of exposure to FKB327 and to Humira 
across studies FKB327-002 and FKB327-003 for comparison. 


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local Amendment 
1) EudraCT No.: 2014-000110-61 
Confidential 
Page 8 
SCHEDULE OF EVENTS 
Table 1: Study Schedule - Randomised Treatment Period 
Study Visit 
Treatment Period 
Visit 
1a
2 
3 
NA 
4 
NA 
5 
NA 
6 
NA 
Week 
0 
2 
4 
6 
8 
10 
12 
14-22 
24 
26 and 28b 
Visit Type 
Clinic 
Clinic 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Informed consent 
● 
Medical history 
including contact with 
active TB 
●* 
Check of concomitant 
medication 
(●)* 
● 
● 
● 
● 
Physical examination 
(●) 
Weight 
(●) 
● 
Vital signs 
(●) 
● 
● 
● 
● 
12-lead ECG 
(●) 
Chest X-ray
(●)c 
Randomisation 
● 
Provide patient with 
study medication and 
dosing diary, and 
instruct on their use 
● 
● 
● 
● 
Provide Patient 
Instruction Sheet 
● 
● 
● 
● 
Dosing Diary 
● 
● 
● 
● 
Study medication 
administration (mg) 
40d 
40d
40d
40 
40 
40 
40 
40 (eow) 
40 
40 (eow) 
Concomitant MTX 
and folate 
Haematology 
(●)* 
● 
● 
● 
● 
Serum chemistry 
(●)* 
● 
● 
● 
● 
Dipstick urinalysise 
(●)* 
● 
● 
● 
● 
Pregnancy testingf
(●)* 
● 
● 
● 
● 
QuantiFERON testg 
● 
CRPh,i 
(●)* 
● 
● 
● 
● 
ESRj 
(●)* 


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local Amendment 
1) EudraCT No.: 2014-000110-61
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Page 9 
Study Visit 
Treatment Period 
Visit 
1a
2 
3 
NA 
4 
NA 
5 
NA 
6 
NA 
Week 
0 
2 
4 
6 
8 
10 
12 
14-22 
24 
26 and 28b 
Visit Type 
Clinic 
Clinic 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
MMP-3 
(●) 
Serum drug 
concentration 
(●)* 
● 
● 
ADA test 
(●)* 
● 
● 
Injection site 
assessment (including 
injection site pain 
VAS) 
● 
Adverse eventsk 
Assessment of 
tender/swollen joints 
(68/66 joints)h,i 
(●)* 
● 
● 
● 
● 
Patient global 
assessment of disease 
activity VASh,i 
(●)* 
● 
● 
● 
● 
Patient assessment of 
pain VASi 
(●)* 
● 
● 
● 
● 
Patient questionnaire 
for physical function 
(HAQ-DI)i 
(●)* 
● 
● 
● 
● 
Physician global 
assessment of disease 
activity VASi 
(●)* 
● 
● 
● 
●


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local Amendment 
1) EudraCT No.: 2014-000110-61 
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Page 10 
Study Visit 
Treatment Period 
Visit 
1a
2 
3 
NA 
4 
NA 
5 
NA 
6 
NA 
Week 
0 
2 
4 
6 
8 
10 
12 
14-22 
24 
26 and 28b 
Visit Type 
Clinic 
Clinic 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
TB = tuberculosis; ECG = electrocardiogram; eow = every other week; MTX = methotrexate; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; ADA = 
anti-drug antibody; HAQ-DI = Health Assessment Questionnaire Disability Index; VAS = visual analogue scale. 
Note: for Visit 2 and Visit 3 there will be a window of ±3 days.  For example, the Week 2 visit (Visit 2) should take place on Day 15, but could be as early as Day 12 or as 
late as Day 18.  From Visit 4 (Week 8) onwards, a window of ±7 days is permissible. 
At each visit all procedures are to be performed prior to dosing except recording of injection site reaction and any post-injection AEs. 
a  Pre-dose Week 0 assessments (represented by „(●)‟ in the table) are performed as part of the Week 24 visit of Study FKB327-002, which is the same as the Week 0 visit 
in this study. 
b  The Week 28 dose is the last dose of randomised study drug (FKB327 or Humira).  All patients will then switch to dosing with FKB327 for the remainder of the study. 
c  X-ray to be performed unless patient has negative QuantiFERON test at Week 22 of study FKB327-002 with no signs/symptoms suggestive of lower respiratory 
infection. 
d  The first 3 doses of study drug (Weeks 0, 2, and 4) will be self-administered at the study site after training has been given.  Subsequent doses may be administered by the 
patient or carer at home, except when clinic visits for blood tests and efficacy assessments are scheduled when the dose must be given after blood samples are drawn. 
e  If the dipstick reveals any clinically significant abnormalities a second sample (provided on the same day if, possible), should be sent to the central laboratory.  
f  Females of childbearing potential only. 
g  May be omitted if patient is receiving anti-mycobacterial treatment for latent tuberculosis. 
h  Assessment contributes to DAS28 score. 
i  Assessment contributes to determination of achievement of ACR20, ACR50, and ACR70 response. 
j  Part of Study FKB327-002 only. 
k  Ongoing events from Study FKB327-002 will be recorded in that study.  Any new or worsening events will be recorded for Study FKB327-003. 
* Procedures marked with an asterisk need to be repeated if there is a delay of 2 weeks or more (up to the maximum allowed delay of 4 weeks) between Week 24 of study
FKB327-002 and Week 0 of study FKB327-003, for example, due to the need to interrupt study drug while serious infection or latent tuberculosis is treated.


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local Amendment 
1) EudraCT No.: 2014-000110-61 
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Table 2: Study Schedule - Follow-up Treatment Period 
Study Visit 
Treatment Period 
Visit 
7 
8 & 9 
NA 
10 
NA 
11 
NA 
12 
NA 
13 
14 
Week 
30 
32 & 34 
36-40 
42 
44-52 
54 
56-64 
66 
68-74 
76 
80 or 
EOS 
Visit Type 
Clinic 
Clinic or 
Homea 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Clinic 
Check of concomitant 
medication 
● 
● 
● 
● 
● 
● 
Physical examination 
● 
Vital signs 
● 
Chest X-rayb 
● 
●
Provide patient with 
study medication and 
dosing diary, and 
instruct on their use 
● 
● 
● 
● 
● 
Provide Patient 
Instruction Sheet 
● 
● 
● 
● 
● 
FKB327 
administration (mg) 
40c 
40c 
40 (eow) 
40 
40 (eow) 
40 
40 (eow) 
40 
40 (eow) 
40 
Dosing Diary 
● 
● 
● 
● 
● 
Concomitant MTX and 
folate 
Haematology 
● 
● 
● 
● 
● 
● 
Serum chemistry 
● 
● 
● 
● 
● 
● 
Dipstick urinalysisd 
● 
● 
● 
● 
● 
● 
Pregnancy testinge
● 
● 
● 
● 
● 
QuantiFERON testf 
● 
●g 
CRPh,i 
● 
● 
● 
● 
● 
● 
Serum drug 
concentration 
● 
● 
● 
● 
ADA test 
● 
● 
● 
● 
Injection site 
assessment (including 
injection site pain 
VAS)j 
●


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local Amendment 
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Study Visit 
Treatment Period 
Visit 
7 
8 & 9 
NA 
10 
NA 
11 
NA 
12 
NA 
13 
14 
Week 
30 
32 & 34 
36-40 
42 
44-52 
54 
56-64 
66 
68-74 
76 
80 or 
EOS 
Visit Type 
Clinic 
Clinic or 
Homea 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Clinic 
Adverse events 
Assessment of 
tender/swollen joints 
(68/66 joints)h,i 
● 
● 
● 
● 
● 
● 
Patient global 
assessment of disease 
activity VASh,i 
● 
● 
● 
● 
● 
● 
Patient assessment of 
pain VASi 
● 
● 
● 
● 
● 
● 
Patient questionnaire 
for physical function 
(HAQ-DI)i 
● 
● 
● 
● 
● 
● 
Physician global 
assessment of disease 
activity VASi 
● 
● 
● 
● 
● 
●


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local Amendment 
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Study Visit 
Treatment Period 
Visit 
7 
8 & 9 
NA 
10 
NA 
11 
NA 
12 
NA 
13 
14 
Week 
30 
32 & 34 
36-40 
42 
44-52 
54 
56-64 
66 
68-74 
76 
80 or 
EOS 
Visit Type 
Clinic 
Clinic or 
Homea 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Clinic 
EOS = end-of-study; eow = every other week; MTX = methotrexate; CRP = C-reactive protein; ADA = anti-drug antibody; HAQ-DI = Health Assessment Questionnaire 
Disability Index; VAS = visual analogue scale; MMP-3 = matrix metalloproteinase-3. 
Note: for all visits during the follow-up treatment period, a window of ±7 days is permissible. 
At each visit all procedures are to be performed prior to dosing except recording of injection site reaction and any post-injection AEs. 
a  The Week 32 and 34 visits are to be performed in the clinic for patients who have switched from Humira to FKB327 only.  Patients remaining on FKB327 can dose at 
home. 
b  X-ray to be performed at Week 30/80 or EOS unless patient has negative QuantiFERON test at Week 24/76 or EOS, respectively, with no signs/symptoms suggestive of 
lower respiratory infection. 
c  For patients switching from Humira to FKB327, the first 3 doses of FKB327 (Weeks 30, 32, and 34) will be self-administered at the study site after training has been 
given.  Subsequent doses of FKB327 may be administered by the patient or carer at home, except when clinic visits for blood tests and efficacy assessments are 
scheduled when the dose must be given after blood samples are drawn. 
d  If the dipstick reveals any clinically significant abnormalities a second sample (provided on the same day if, possible), sho uld be sent to the central laboratory.   
e  Females of childbearing potential only. 
f  May be omitted if patient is receiving anti-mycobacterial treatment for latent tuberculosis. 
g  EOS only. 
h  Assessment contributes to DAS28 score. 
i  Assessment contributes to determination of achievement of ACR20, ACR50, and ACR70 response. 
j  An additional injection site assessment will be performed at the time of switching to the Auto-Injector during the open-label follow up treatment period 


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local 
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TABLE OF CONTENTS 
1 
BACKGROUND INFORMATION ...................................................................... 20 
1.1 
Indication ..................................................................................................... 20 
1.2 
Investigational Product ................................................................................. 20 
1.3 
Background Therapy..................................................................................... 21 
1.4 
Nonclinical Studies ....................................................................................... 21 
1.5 
Clinical Studies............................................................................................. 21 
1.5.1 
Clinical Studies with FKB327............................................................... 21 
1.5.2 
Clinical Studies with Humira ................................................................ 23 
1.6 
Potential Risks and Benefits .......................................................................... 24 
1.7 
Rationale for Study ....................................................................................... 24 
1.8 
Study Conduct .............................................................................................. 25 
1.9 
Population to be Studied ............................................................................... 25 
2 
STUDY OBJECTIVES ........................................................................................ 25 
2.1 
Primary Objective ......................................................................................... 25 
2.2 
Secondary Objectives.................................................................................... 25 
3 
STUDY DESIGN ................................................................................................ 25 
3.1 
Primary Endpoint.......................................................................................... 25 
3.2 
Secondary Endpoints .................................................................................... 26 
3.3 
Other Endpoints............................................................................................ 26 
3.4 
Description of Study ..................................................................................... 26 
3.5 
Randomisation and Blinding ......................................................................... 28 
3.5.1 
Randomisation ..................................................................................... 28 
3.5.2 
Blinding............................................................................................... 29 
3.6 
Duration of Patient Participation.................................................................... 29 
3.7 
Identification of Source Data......................................................................... 29 
4 
PATIENT SELECTION....................................................................................... 29 
4.1 
Inclusion Criteria .......................................................................................... 29 
4.2 
Exclusion Criteria ......................................................................................... 30 
4.3 
Patient Withdrawal Criteria ........................................................................... 30 
5 
STUDY TREATMENT ....................................................................................... 31 
5.1 
Allocation to Treatment ................................................................................ 31 
5.2 
Blinding ....................................................................................................... 31 
5.3 
Drug Supplies ............................................................................................... 31 


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5.3.1 
Preparation and Dispensing .................................................................. 31 
5.3.2 
Administration ..................................................................................... 32 
5.3.3 
Treatment Compliance ......................................................................... 32 
5.4 
Drug Storage and Accountability................................................................... 33 
5.5 
Concomitant Medication ............................................................................... 33 
5.5.1 
Permitted Concomitant Medication ....................................................... 33 
5.5.2 
Prohibited Concomitant Medication ...................................................... 34 
5.6 
Study Restrictions ......................................................................................... 34 
5.7 
Safety Precautions ........................................................................................ 35 
6 
STUDY PROCEDURES ...................................................................................... 36 
6.1 
Procedures for Baseline Visit (Week 0 [Visit 1]) ............................................ 36 
6.2 
Procedures during Treatment Period .............................................................. 37 
6.2.1 
Week 2 (Visit 2) ................................................................................... 37 
6.2.2 
Weeks 4, 8, and 12 (Visits 3, 4, and 5) .................................................. 37 
6.2.3 
Weeks 6, 10, 14, 16, 18, 20, 22, 26, and 28............................................ 38 
6.2.4 
Week 24 (Visit 6) ................................................................................. 38 
6.2.5 
Weeks 30, 54, and 76 (Visits 7, 11, and 13) ........................................... 39 
6.2.6 
Weeks 32 and 34 (Visits 8 and 9) .......................................................... 40 
6.2.7 
Weeks 36-40, 44-52, 56-64, and 68-74 .................................................. 40 
6.2.8 
Weeks 42 and 66 (Visits 10 and 12) ...................................................... 40 
6.2.9 
Week 80 or End-of-study (Visit 14) ...................................................... 40 
7 
ASSESSMENTS.................................................................................................. 41 
7.1 
Assessment of Efficacy ................................................................................. 41 
7.1.1 
Primary Efficacy Variable .................................................................... 41 
7.1.2 
Secondary Efficacy Variables ............................................................... 41 
7.2 
Assessment of Safety .................................................................................... 44 
7.2.1 
Clinical Laboratory Tests...................................................................... 44 
7.2.2 
Physical Examination ........................................................................... 45 
7.2.3 
Vital Signs ........................................................................................... 45 
7.2.4 
Chest X-ray.......................................................................................... 45 
7.2.5 
Injection Site Assessment ..................................................................... 45 
7.3 
Immunogenicity Assessments ....................................................................... 46 
7.4 
Pharmacokinetic Assessments ....................................................................... 46 
8 
REPORTING OF ADVERSE EVENTS ............................................................... 47 
8.1 
Definition of an Adverse Event ..................................................................... 47 
8.2 
Recording and Reporting an Adverse Event ................................................... 47 


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8.3 
Follow-up of Adverse Events ........................................................................ 48 
8.4 
Severity of an Adverse Event ........................................................................ 48 
8.5 
Relationship of an Adverse Event to Study Medication .................................. 48 
8.6 
Serious Adverse Events................................................................................. 49 
8.6.1 
Definition of a Serious Adverse Event .................................................. 49 
8.6.2 
Reporting a Serious Adverse Event ....................................................... 49 
8.7 
Withdrawals due to Adverse Events .............................................................. 50 
8.8 
Pregnancy..................................................................................................... 50 
8.9 
Device Complaints........................................................................................ 50 
9 
STATISTICAL METHODS ................................................................................. 51 
9.1 
Sample Size.................................................................................................. 51 
9.2 
Efficacy Analysis.......................................................................................... 52 
9.3 
Safety Analysis............................................................................................. 52 
9.4 
Immunogenicity Analysis.............................................................................. 52 
9.5 
Pharmacokinetic Analysis ............................................................................. 53 
9.5.1 
Primary Pharmacokinetic Analysis........................................................ 53 
9.5.2 
Secondary Pharmacokinetic Analysis .................................................... 53 
9.6 
Interim Analysis ........................................................................................... 53 
9.7 
Data Monitoring Committee.......................................................................... 54 
10 DIRECT ACCESS TO SOURCE DATA DOCUMENTS...................................... 54 
11 QUALITY CONTROL AND QUALITY ASSURANCE ...................................... 54 
11.1 
Protocol Amendments................................................................................... 54 
11.2 
Study Monitoring.......................................................................................... 55 
11.3 
Audit and Inspection ..................................................................................... 55 
12 ETHICS .............................................................................................................. 55 
12.1 
Informed Consent ......................................................................................... 55 
12.2 
Independent Ethics Committees/Institutional Review Boards ......................... 55 
12.3 
Confidentiality.............................................................................................. 56 
12.4 
Declaration of the End of the Study ............................................................... 56 
12.5 
Investigator Signatory Obligations................................................................. 56 
13 DATA HANDLING AND RECORD KEEPING .................................................. 56 
13.1 
Data Collection............................................................................................. 56 
13.2 
Data Quality Control..................................................................................... 56 
13.3 
Archiving of Case Report Forms and Source Documents ............................... 57 


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14 FINANCING AND INSURANCE........................................................................ 57 
15 PUBLICATION POLICY .................................................................................... 57 
16 APPENDICES ..................................................................................................... 58 
16.1 
American College of Rheumatology Revised Criteria for Classification of 
Functional Status in Rheumatoid Arthritis ..................................................... 58 
16.2 
Interpretation of TB Screening Results .......................................................... 59 
16.3 
New York Heart Association Classification ................................................... 63 
17 REFERENCES .................................................................................................... 64 
LIST OF TABLES 
Table 1: Study Schedule - Randomised Treatment Period............................................... 8 
Table 2: Study Schedule - Follow-up Treatment Period ................................................ 11 
Table 3 Analysis of Treatment Groups......................................................................... 51 
Table 4: Interpretation of QuantiFERON and Chest X-ray Results (Across Studies 
FKB327-002 and FKB327-003) .................................................................................. 61 
LIST OF FIGURES 
Figure 1: Overall Study Schema .................................................................................. 28 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACR 
American College of Rheumatology 
ADAs 
Anti-drug antibodies 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate transaminase 
BCG 
Bacillus Calmette–Guérin 
CD 
Crohn‟s disease 
CDM 
Clinical Data Manager 
cGMP 
Current Good Manufacturing Practice 
CI 
Confidence interval 
CRA 
Clinical Research Associate 
CRP 
C-reactive protein 
CS 
Clinically significant 
CSR 
Clinical Study Report 
DAS28 
Disease Activity Score 28 
DCR 
Device Complaint Report 
DMARD 
Disease modifying anti-rheumatic drug 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eDCF 
Electronic Data Clarification Forms 
eow 
Every other week 
ePRO 
Electronic patient-reported outcomes 
ESR 
Erythrocyte sedimentation rate 
EU 
European Union 
EULAR 
European League Against Rheumatism 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyltransferase 
HAQ-DI 
Health Assessment Questionnaire Disability Index 
Hb 
Haemoglobin 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
KHK 
Kyowa Hakko Kirin Co Ltd 
LSM 
Least squares means 
MCH 
Mean corpuscular haemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP-3 
Matrix metalloproteinase-3 
mTNF-α 
Transmembrane TNF-α 
MTX 
Methotrexate  
NCS 
Not clinically significant 
NSAID 
Non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
OLE 
Open-label extension 
PDF 
Portable Document Format 
PFS 
Pre-filled syringe 


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PK 
Pharmacokinetics 
PKAS 
PK Analysis Set 
PPD 
Purified protein derivative 
PT 
Preferred Term 
RA 
Rheumatoid arthritis 
RBC 
Red blood cell 
rhTNF-α 
Human recombinant TNF-α 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
Subcutaneous 
SDV 
Source Data Verification 
SJC 
Swollen joint count 
SOC 
System Organ Class 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Elimination half-life 
TB 
Tuberculosis 
TJC 
Tender joint count 
tmax
Time of maximum concentration 
TNF-α 
Tumour necrosis factor-alpha 
TSE 
Transmissible spongiform encephalopathy 
US 
United States of America 
VAS 
Visual analogue scale 
WBC 
White blood cell 


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1 
BACKGROUND INFORMATION 
1.1 
Indication 
Tumour necrosis factor (TNF)-α is a pro-inflammatory cytokine that is involved in 
normal inflammatory and immune response.  Overexpressed TNF-α has been implicated 
in the pathogenesis of various immunological diseases.  One such immunological disease 
is rheumatoid arthritis (RA), a common, chronic, inflammatory disorder.  The disease is 
characterised by a progressive inflammatory synovitis manifested by polyarticular joint 
swelling and tenderness.  The synovitis results in erosion of articular cartilage and 
marginal bone with subsequent joint destruction.  This bony destruction is thought to be 
irreversible.  RA is a systemic disease with non-articular manifestations including 
serositis and nodule formation.  There is currently no known cure for RA. 
RA produces substantial morbidity and increased mortality.  Specifically, pain, swelling 
and stiffness in multiple joints are the hallmark of the disease.  Analgesics are usually 
required on a chronic basis.  Patients usually experience moderate disability within 
2 years of diagnosis, and 30% of patients are severely disabled after 10 years.  In addition 
to loss of employment, this disability often compromises the ability of patients to 
undertake their activities of daily living and can impact sexual and social functioning. 
Cytokines play critical roles in normal biologic processes, such as cell growth, 
inflammation and immunity.  TNF and the other inflammatory cytokines are critical in 
the progression of inflammatory synovitis and articular matrix degradation and, therefore, 
represent promising targets for therapeutic intervention in RA.  Clinical experience with 
agents that block TNF activity demonstrate the central role for this cytokine in the 
pathogenesis of RA and other autoimmune diseases.1
1.2 
Investigational Product 
Adalimumab is a recombinant human monoclonal antibody against human TNF-α.  It 
neutralises the biological activity of TNF-α by blocking its interaction with TNF-α cell 
surface receptors.  TNF-α is a naturally occurring cytokine produced by many different 
cell types, including macrophages, mast cells and T cells.  TNF production is induced by 
a wide variety of stimuli, including bacteria, viruses, trauma, immune complexes, and 
other cytokines.  At low concentrations, TNF-α has beneficial effects, such as 
augmentation of host defence against infection.  However, high concentrations of TNF-α 
lead to inflammation and injury, and TNF-α has been implicated as an important 
pro-inflammatory cytokine involved in the pathogenesis of numerous autoimmune 
diseases, such as RA, psoriasis, Crohn‟s disease (CD) and ulcerative colitis. 
Adalimumab was first approved for the treatment of RA in December 2002 in the United 
States of America (US) and in September 2003 in the European Union (EU), and was 
subsequently launched globally under the brand name Humira®.  Humira is currently
indicated in the US for the treatment of RA, psoriatic arthritis, ankylosing spondylitis, 
CD, ulcerative colitis and plaque psoriasis in adults, and for the treatment of CD and 
polyarticular juvenile idiopathic arthritis in children, and in the EU for axial 
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for active enthesitis-related arthritis from 6 years of age.  The approved adult dose of 
Humira for all indications is 40 mg administered by subcutaneous (sc) injection every 
other week (eow).  Higher loading and maintenance doses are approved for indications 
other than RA.  Humira is presented for adult use as a pre-filled syringe (PFS) or 
pre-filled pen containing 40 mg adalimumab in 0.8 mL solution for injection.2
FKB327 is being developed as a proposed biosimilar product that contains adalimumab, 
the same active ingredient as Humira.  FKB327 contains different excipients to those in 
Humira, but the FKB327 excipients are all commonly used.  FKB327 is manufactured 
under current Good Manufacturing Practice (cGMP) and is supplied as a highly purified 
biological product, with appropriate steps for virus inactivation and removal, and there 
are no transmissible spongiform encephalopathy (TSE) risks. 
1.3 
Background Therapy 
Methotrexate (MTX) is an antimetabolite that has traditionally been used to treat certain 
types of cancer.  MTX is also used in lower doses in the treatment of RA, where it is 
thought to act by decreasing the activity of the immune system, and represents the 
conventional disease modifying anti-rheumatic drug (DMARD) of choice for RA 
treatment.3  In this study, MTX will be administered with concomitant folate therapy to
counter the adverse effects on red blood cells. 
1.4 
Nonclinical Studies 
In vitro studies have shown that FKB327 and Humira are similar in terms of binding to 
the target antigens (human recombinant TNF-α [rhTNF-α] and transmembrane TNF-α 
[mTNF-α]), binding to Fcγ receptors and neonatal Fc receptors, inhibition of cell killing, 
induction of apoptosis, and cellular cytotoxicity (antibody-dependent and complement-
dependent).  An in vivo study using the mouse polyarthritis model showed that the 
symptoms of arthritis were ameliorated to a similar extent by FKB327 and Humira, 
indicating similarity.  In this in vivo study, the toxicokinetic profile and anti-drug 
antibody (ADA) formation were also similar. 
The non-clinical data for Humira did not show any special hazard for humans based on 
studies of single dose toxicity, repeated dose toxicity, and genotoxicity.2  A comparative
4-week repeat dose toxicity of FKB327 and Humira in cynomolgus monkeys using a 
dose of 30 mg/kg sc once weekly has been performed in order to prepare for a global 
submission.  The results did not show any difference between FKB327 and Humira in 
terms of toxicity. 
Further information on the nonclinical studies of FKB327 can be found in the 
Investigator‟s Brochure.2
1.5 
Clinical Studies 
1.5.1 Clinical Studies with FKB327 
A Phase 1 study comparing the pharmacokinetic (PK) characteristics, safety and 
immunogenicity of a single dose of FKB327 with those of EU- and US-Humira in 
healthy subjects has been completed (Study FKB327-001).  In this parallel group study, 


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180 healthy male and female subjects were randomly assigned to receive a single 40 mg 
sc injection of FKB327, EU-licensed Humira, or US-licensed Humira in a 1:1:1 ratio.  
All subjects completed the study with the exception of 1 subject in the FKB327 treatment 
group who withdrew himself from the study.  The primary endpoints were the PK 
parameters area under the concentration-time up to the last non-zero value (AUC0-t), area 
under concentration-time curve extrapolated to infinite time (AUC0-∞), and maximum 
concentration (Cmax). 
The serum concentration time profiles of adalimumab following single sc administration 
of FKB327, EU-Humira, and US-Humira were similar, and were measurable, on average, 
up to 1536 hours post-dose across all treatments (ie, the last sampling time point 
post-dose).  Cmax of adalimumab was attained (tmax) at approximately 144 hours post-dose 
(median estimates) following single sc administration of FKB327 and US-Humira, with 
tmax attained slightly later for EU-Humira at 192 hours post-dose.  Thereafter, serum 
concentrations declined with geometric mean elimination half-life (t½) of 324, 345 and 
366 hours for FKB327, EU-Humira, and US-Humira, respectively.   
Using an analysis of covariance (ANCOVA), as the 90% confidence intervals (CIs) 
around the ratio of geometric least squares means (LSMs) were within the pre-defined 
limits of 0.80 to 1.25 for all treatment comparisons and primary PK endpoints (AUC0-∞, 
AUC0–t, and Cmax), similarity was indicated between all 3 treatments.  Similarity was also 
indicated between all 3 treatments for the secondary PK endpoint AUC0-360h, and for 2 of 
the 3 treatment comparisons for the secondary PK endpoint t½ (similarity could not be 
concluded between FKB327/US-Humira based on t½); however, with ADA titre values 
included as an additional covariate in the equivalence analysis, similarity was indicated 
between all 3 treatments for all median treatment comparisons and PK endpoints 
(including t½).  
Preliminary results of an analysis of variance (ANOVA) of these data, assuming equal 
variance, were similar to those of the ANCOVA analyses, although the 90% CI were 
wider.  The ANOVA results for the FKB327/US-Humira and EU-Humira/US-Humira 
comparisons still met the pre-specified limits (0.80 to 1.25) for all 3 primary endpoints.  
However, for the FKB327/EU-Humira comparison; Cmax (a primary endpoint) and 
AUC0-360h (a secondary endpoint) both had upper 90% CI which fell slightly outside the 
equivalence criteria of 0.80 to 1.25 using the ANOVA approaches.  The increased 
variability for FKB327/EU-Humira may be explained by differences in selected 
covariates (age, body weight, and sex) between the treatment groups.  Indeed, by 
accounting for these pre-specified covariates in the primary ANCOVA analysis, the 90% 
CI for Cmax met the equivalence limits (0.80, 1.25).  Overall, the data indicated PK 
similarity between all 3 treatments. 
The study demonstrated that the safety profile was similar across the 3 treatment groups. 
The most common treatment related adverse events (AEs) were headache, upper 
respiratory tract infection, oropharyngeal pain and injection site haematoma and were 
reported for similar numbers of subjects in each treatment group, with the exception of 
injection site haematoma which was reported for more subjects in the FKB327 treatment 


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group (4 subjects) than in the EU- and US-Humira treatment groups (1 and 2 subjects, 
respectively).  Most AEs were mild or moderate in intensity. 
Two subjects experienced serious adverse events (SAEs): 1 subject receiving FKB327 
experienced loss of consciousness 11 days after dosing and 1 subject receiving 
US-Humira developed a psychotic disorder 8 days after dosing, the same day that he was 
discharged from the study unit.  These 2 subjects were in the same dosing cohort and 
were dosed consecutively.  Both SAEs resolved and were considered to be possibly 
related to study drug due to the temporal relationship with study dosing.  There were no 
deaths, other significant AEs or AEs leading to withdrawal.  Two months after study 
dosing, 1 subject reported he had unprotected sex and his partner became pregnant.  The 
outcome of this pregnancy was successful. 
In total, 9 subjects had clinically significant (CS) abnormal laboratory results during the 
study: 3 subjects in the FKB327 treatment group, 2 subjects in the EU-Humira treatment 
group and 4 subjects in the US-Humira treatment group.  The most common CS 
abnormal laboratory result was low neutrophil count, which was reported as an AE of 
neutropenia for 4 subjects overall (2 on FKB327 and 2 on US-Humira); 2 of the subjects 
(1 on FKB327 and 1 on US-Humira) had abnormally low neutrophil counts at Screening 
which was not considered to be of clinical significance.  None of the CS abnormal 
laboratory test results was associated with any clinical signs or symptoms.  There were no 
other notable results for any of the other safety parameters. 
The distribution of ADA titre results at the last sampling time point was consistent 
between treatments: approximately 31.7%, 26.7% and 30.0% of subjects on FKB327, 
EU- and US-Humira, respectively, had negative ADA titres, and there were similar 
proportions of subjects in each treatment group at each positive ADA titre level.  Of all 
positive titres (non negative screening results) measured at the last sampling time point, 
approximately 82.7% were positive in the neutralising antibody assay, with a further 
10.2% considered to be inconclusive due to interference from high levels of drug 
(>500 ng/mL). 
Study FKB327-002, a randomised, double-blind, active-controlled, 26-week Phase 3 
study comparing the efficacy and safety of FKB327 and Humira in patients with RA who 
have had an inadequate response to MTX is scheduled to start in Q2 2014.  Study 
FKB327-002 will enrol approximately 680 patients (340 patients per arm).  Only patients 
who have completed Study FKB327-002 will be eligible to enter this open-label 
extension (OLE) study (FKB327-003). 
1.5.2 Clinical Studies with Humira 
Humira has been studied in >8,000 patients in pivotal controlled and open-label studies 
for up to 60 months or more.  The most commonly reported AEs were infections 
(nasopharyngitis, upper respiratory tract infection, and sinusitis), injection site reactions 
(erythema, itching, haemorrhage, pain or swelling), headache and musculoskeletal pain.  
Clinical response rate of 63.3% was observed for RA in combination therapy with MTX 
(American College of Rheumatology [ACR]20 at 6 months).  Other response rates 
observed for autoimmune indications were 58.0% for CD and 70.9% for psoriasis.4  It is


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expected that the efficacy and safety profiles of FKB327 will be similar to those of 
Humira in clinical studies. 
1.6 
Potential Risks and Benefits 
The mode of action and risks for FKB327 are expected to be the same as those for 
Humira since the active ingredient of both products is adalimumab.  Adalimumab binds 
specifically to TNF and neutralizes the biological function of TNF by blocking its 
interaction with cell surface TNF receptors.  Adalimumab also modulates biological 
responses that are induced or regulated by TNF, including changes in the levels of 
adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and 
ICAM-1).5  In the context of this OLE study, the benefit is to provide patients that
benefited from adalimumab therapy with a long-term treatment option.  Patients should 
have completed Study FKB327-002, which means they did not show any adverse 
reaction that prevented them from receiving long term therapy.  The main risk is 
decreased immune surveillance, leading to increased incidence of infections (including 
reactivation of latent infections) and potentially tumour formation. 
Humira is immunogenic.  In pivotal studies in RA and psoriatic arthritis, anti-adalimumab 
neutralizing antibodies were identified in 5.5% and 10% of patients, respectively,6
although these rates were lower in patients who were also receiving MTX, 1% and 7%, 
respectively.  Formation of neutralising ADAs is associated with a higher clearance of 
Humira and reduced efficacy.  Formation of ADA can also be associated with 
hypersensitivity reactions including anaphylaxis.  There is a risk that patients taking part 
in this study may develop ADAs.  If such patients subsequently required treatment with 
Humira in the future, therapeutic benefit might be reduced and the risk of hypersensitivity 
reactions increased. 
The most common adverse effects of Humira are injection site reactions and infections.  
The majority of injection site reactions are mild to moderate and reversible.6  The most
common infections seen in patients given repeated doses of Humira are upper respiratory 
tract infections, which are easily monitored and treatable.  Patients with a history of 
chronic or acute infection, including a positive result for hepatitis or untreated latent 
tuberculosis (TB), were not permitted to enter Study FKB327-002 and so will not be 
included in this OLE study.  Patients will be monitored during the study for development 
of such infections and, when required, study treatment will be promptly discontinued. 
1.7 
Rationale for Study 
This Phase 3 open-label extension study will compare the long-term safety, efficacy, 
immunogenicity and multiple-dose PK of FKB327 with Humira in patients with RA.  
This study will commence once a patient completes Study FKB327-002 and opts to enter 
this extension study. 
In order to make a long-term treatment comparison, a proportion of patients in the first 
part of this open-label extension study will receive Humira, and the findings in that 
treatment arm will be compared to those for patients receiving FKB327.  Therefore, in 
addition to providing longer term data regarding the safety, immunogenicity and efficacy 
of FKB327, the study will provide the opportunity for a descriptive and objective 


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comparison of these parameters between FKB327 and Humira over longer term treatment 
(approximately 1 year in total from the start of Study FKB327-002 to the end of 
Study FKB327-003).  Furthermore, the study will also permit an evaluation of these 
parameters in patients switching between the products after randomisation and could 
therefore provide relevant data for subsequent clinical practice. 
1.8 
Study Conduct 
This study will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP), and applicable regulatory requirements. 
1.9 
Population to be Studied 
The study will enrol only patients who completed Week 24 visit procedures and 22 weeks 
of treatment of the double-blind study FKB327-002 (with a minimum of 9 doses of study 
drug received). 
Inclusion and exclusion criteria are presented in Sections 4.1 and 4.2, respectively. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 

To compare the safety of long-term treatment with FKB327 and Humira in patients
with RA.
2.2 
Secondary Objectives 

To compare the efficacy of long-term treatment with FKB327 and Humira in patients
with RA.

To compare the proportions of patients developing ADAs on long-term treatment
with FKB327 and Humira in patients with RA.

To compare the PK of long-term treatment with FKB327 and Humira in patients with
RA.

To evaluate safety, changes in efficacy, and changes in PK and immunogenicity in
patients who are switched from Humira in the preceding FKB327-002 double-blind
study to FKB327 in the FKB327-003 OLE study, and of patients who are switched
from FKB327 to Humira, respectively.

To evaluate safety, changes in efficacy, and changes in PK and immunogenicity in
patients who are switched from FKB327 in the preceding FKB327-002 double-blind
study to Humira in the FKB327-003 OLE study, and then switch back to FKB327 in
the second part of the FKB327-003 OLE study (from Week 30; double switch).
3 
STUDY DESIGN 
3.1 
Primary Endpoint 

Safety will be evaluated using the following assessments: AEs; SAEs including
serious infections and malignancies, vital signs, and clinical laboratory tests.


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3.2 
Secondary Endpoints 

ACR20, ACR50 and ACR70 response rates from baseline (Week 0 from
Study FKB327-002).

Changes in Disease Activity Score 28 based on C-reactive protein (CRP)
(DAS28-CRP) score compared to baseline (Week 0 from Study FKB327-002).
3.3 
Other Endpoints 

Immunogenicity.

PK.
3.4 
Description of Study 
The first part of this study is an open-label, randomised, comparative, multi-centre, 2-arm 
extension Phase 3 study in patients with RA who are taking a stable dose of MTX and 
folate who will continue from the preceding Study FKB327-002.  Eligible patients who 
complete Study FKB327-002 and consent to this open-label extension study will be 
randomised to receive treatment with either FKB327 40 mg eow or Humira 40 mg eow 
from Week 0 to Week 28.  Patients who received FKB327 in Study FKB327-002 will 
receive FKB327 or Humira in a 2:1 ratio and patients who received Humira in 
Study FKB327-002 will receive Humira or FKB327 in a 2:1 ratio.  The second part of the 
study is an open-label, single arm extension in which all patients receive prolonged 
FKB327 treatment from Week 30 to Week 76, followed by a 4-week follow-up period.  
Scheduled clinic visits will be conducted at Weeks 0, 2, 4, 8, 12, 24, 30, 32, 34, 42, 54, 
66, 76, and 80.  The patient or carer will be allowed to administer interim doses of study 
drug at home (eow) between clinic visits.  FKB327 in an Auto-Injector device 
presentation will be introduced during the open-label follow-up treatment period 
depending on availability of the Auto-injector relative to the patient‟s progress within the 
study. 
At the Week 22 visit of Study FKB327-002 the investigator will discuss participation in 
this open-label extension study with the patient, if appropriate.  If the patient is eligible 
for this study and gives informed consent to participate, the patient will be randomised 
into the study and Week 0 study drug dose for this study will be administered after the 
Week 24 study procedures for Study FKB327-002 have been performed.  The first 
3 doses of study drug (Weeks 0, 2, and 4 for all patients and Weeks 30, 32, and 34 for 
patients switching from Humira to FKB327 at that point) will be self-administered (or 
administered by a carer) at the study site after training has been given.  Subsequent doses 
may be administered by the patient or carer at home, except when clinic visits for blood 
tests and efficacy assessments are scheduled when the dose must be given after blood 
samples are drawn. 
If, for any reason, it is not possible to conduct Week 24 visit procedures for study 
FKB327-002 and Week 0 procedures for this study on the same day, the maximum 
permitted interval between study drug doses in the 2 studies (Week 22 dosing in 
Study FKB327-002 and Week 0 dosing in this study) will be 4 weeks.  If Week 24 visit 
procedures for Study FKB327-002 and Week 0 procedures have an interval of 2 weeks or 


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more between them then some procedures will need to be repeated prior to dosing at 
Week 0 for this study (see Table 1 – all procedures marked with an asterisk). 
The study schema is presented in Figure 1; this schema assumes that approximately 
544 patients out of 680 (80%) complete Study FKB327-002 and are eligible for 
Study FKB327-003.  A drop-out rate of approximately 20% is anticipated in the present 
study by the time all remaining patients are switched to FKB327 at Week 30, so an 
estimated 435 patients will enter the single-arm part of the study.  However, all patients 
who are eligible to enter this study from FKB327-002 may do so even if the estimated 
numbers are exceeded. 
An interim analysis of planned endpoints for all patients will be performed once 
100 patients randomised to FKB327 in study FKB327-002 and also to FKB327 in the 
randomised phase of study FKB327-003 plus 100 patients randomised to Humira in study 
FKB327-002 and also to Humira in the randomised phase of study FKB327-003 have 
reached Week 30 in this study.  This will provide more than 100 patient-years of 
exposure to FKB327 and to Humira across studies FKB327-002 and FKB327-003 for 
comparison. 


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Figure 1: Overall Study Schema 
3.5 
Randomisation and Blinding 
3.5.1 Randomisation 
The first part of this study is a comparative, randomised, open-label extension study.  
Patients who complete Week 24 of Study FKB327-002 and meet inclusion and exclusion 
criteria for this open-label extension study will be eligible to enrol in this study.  Patients 
will attend the Week 0 visit of this study (which is the same clinic visit as Week 24 from 
Study FKB327-002), and will be randomised to receive either FKB327 40 mg eow or 
Weeks 30 to 76 
Open-label follow-up 
treatment period 
FKB327 40 mg eow 
N=435 (approx) 
Completed 
Week 24 of 
FKB327-002 
N=544 (approx) 
End of Study 
Week 80 
Received 
Humira in 
FKB327-002 
N=272 (approx) 
Received 
FKB327 in 
FKB327-002 
N=272 (approx) 
Weeks 0 to 28 
Randomised 
open-label 
treatment 
period 
FKB327 
40 mg eow 
N=181 
(approx) 
Weeks 0 to 28 
Randomised 
open-label 
treatment 
period 
Humira 
40 mg eow 
N=91 
(approx) 
Weeks 0 to 28 
Randomised 
open-label 
treatment 
period 
FKB327 
40 mg eow 
N=91 
(approx) 
Weeks 0 to 28 
Randomised 
open-label 
treatment 
period 
Humira 
40 mg eow 
N=181 
(approx) 


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Humira 40 mg eow from Week 0 to Week 28, according to the scheme presented in 
Figure 1. 
Consequently, patients who received FKB327 in Study FKB327-002 may receive Humira 
in this study, and patients who received Humira in Study FKB327-002 may receive 
FKB327 in this study, whilst some patients will receive either FKB327 or Humira for the 
entire duration of the randomised period of the combined studies. 
Randomisation will be carried out using the Medidata Balance® randomization and trial
supply management system, which is directly linked to the electronic case report form 
(eCRF). 
After this period of randomised treatment, all patients will then receive FKB327 40 mg 
eow from Weeks 30 to 76. 
3.5.2 Blinding 
As this is an open-label study no blinding is required. 
3.6 
Duration of Patient Participation 
For each patient, the study is expected to last 80 weeks. 
3.7 
Identification of Source Data 
All data recorded for the study must be supported by appropriate source documents. 
Source documents are considered to be all information in original records (and certified 
copies of original records) of clinical findings, observations, data or other activities in a 
clinical study necessary for the reconstruction and evaluation of the study.  Source data 
should be recorded contemporaneously with the activities performed. 
All study data are to be captured on the eCRF with the exception of clinical laboratory, 
PK and immunogenicity data, which will be provided electronically by the laboratories, 
electronic patient-reported outcomes (ePRO, recorded using the SitePRO device), and 
joint and disease evaluations data.  Reports received by the site from the central 
laboratory should be printed, retained as source documentation and signed by a medically 
qualified Investigator, indicating which values are considered CS and to be reported as 
AEs.  All data recorded on the SitePRO device will be regarded as source data. 
4 
PATIENT SELECTION 
4.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for enrolment into 
the study: 
1.
Have completed all 24 weeks of study procedures (including dosing) according to
protocol FKB327-002, with a minimum of 9 doses of study drug received, and are
continuing with stable concomitant MTX and folate.
2.
In the investigator‟s opinion, the patient showed a clinical response to treatment
during Study FKB327-002.


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3.
Are willing to participate in the study and have provided written informed consent.
4.
Females of childbearing potential must have a negative pregnancy test prior to study
dosing.  Both sexes must be willing to take adequate contraceptive precautions
throughout the study period and continuing for at least 5 months post study.
Acceptable methods of contraception in this study are: surgical sterilisation,
intrauterine devices, oral contraceptives, contraceptive patch, long-acting injectable
contraceptives, partner‟s vasectomy, or a double-protection method (condom or
diaphragm with spermicide).
4.2 
Exclusion Criteria 
Patients presenting with any of the following will not be included in the study: 
1.
Evidence of an SAE ongoing from Study FKB327-002 at entry to this study,
including a serious infection, malignancy, or any other condition that may put patients
at increased risk when receiving treatment with adalimumab.
2.
Presence of active and/or untreated latent TB as detected by QuantiFERON test at
Week 22 combined with chest X-ray at Week 24 in Study FKB327-002.  Latent TB,
treated with prophylactic anti-mycobacterial therapy for at least 3 weeks before study
dosing is resumed, is acceptable (see Appendix 16.2).  Patients may have up to a
maximum of 4 weeks interruption of dosing between the last dose in
Study FKB327-002 and Week 0 dosing in study FKB327-003 for this purpose.
3.
Were non-compliant with FKB327-002 study procedures, or with any condition or
circumstances, which, in the opinion of the Investigator, makes them unlikely or
unable to comply with study procedures and requirements.
4.
ACR Functional Class IV (see Appendix 16.1).
5.
Acute infection requiring antibiotic treatment within 2 weeks of Week 0 dosing.
Patients may have up to a maximum of 4 weeks interruption of dosing between the
last dose in Study FKB327-002 and Week 0 dosing in Study FKB327-003 in order to
recover from infection requiring antibiotic treatment (see Section 5.7).
6.
Presence of serious, uncontrolled disease of another body system including
cardiovascular, neurological, pulmonary, renal and hepatic disease.
7.
Presence of New York Heart Association (NYHA) Class III/IV heart failure (see
Appendix 16.3).
8.
Presence of any uncontrolled disease for which steroid treatment is regularly required
for flares, eg, asthma.
9.
Patients with demyelinating diseases (eg, multiple sclerosis).
10. Pregnant or breastfeeding women.
4.3 
Patient Withdrawal Criteria 
Patients are free to withdraw consent to the study at any time without giving reasons.  
Furthermore, the Investigator must withdraw a female patient in the event of pregnancy. 
The Investigator may also withdraw a patient for medical reasons such as intercurrent 
illness, need for medication which is contraindicated and poor compliance or any other 


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safety issues.  The Investigator will assess reasons for withdrawal as far as possible and 
will fully record the circumstances and medical details.   
5 
STUDY TREATMENT 
5.1 
Allocation to Treatment 
At entry to this open label study, patients will be randomised to receive either FKB327 
40 mg eow or Humira 40 mg eow from Week 0 to Week 28 using the Medidata Balance®
randomization and trial supply management system.  Patients who received FKB327 in 
Study FKB327-002 will be randomised to FKB327 or Humira in a 2:1 ratio and patients 
who received Humira in Study FKB327-002 will be randomised to Humira or FKB327 in 
a 2:1 ratio. 
From Week 30 onwards, all patients will receive FKB327 40 mg eow. 
5.2 
Blinding 
This is an open-label study; therefore, no blinding is required. 
5.3 
Drug Supplies 
FKB327 will be manufactured by Kyowa Hakko Kirin Co., Ltd. (KHK), Japan. 
FKB327 will be supplied by the Sponsor in a plastic PFS with a safety device for single 
use only.  FKB327 in an Auto-Injector device presentation for single use only will be 
introduced during the open-label follow-up treatment period depending on availability of 
the Auto-Injector relative to the patient‟s progress within the study.  In both 
presentations, the dose will be 40 mg in 0.8 mL.  Training in the use of the Auto-Injector 
device for 1 or more doses will be provided at the point of switching to this device; 
patients may be required to attend additional clinic visits for this to occur (unscheduled 
visit forms should be used if the switch training does not fit with the specified visit 
schedule). 
From Week 0 to Week 28 only, patients randomised to Humira will be supplied 
US-licensed Humira in a glass PFS by the Sponsor.  The dose will be 40 mg in 0.8 mL.  
Note: The needle cover of the Humira PFS contains dry rubber (latex) which should not 
be handled by persons sensitive to this substance without using latex-free gloves. 
It is planned that all patients will be introduced to treatment by self-injection (or injection 
by a carer) in order to be able to dose at home between scheduled clinic visits. 
Further details on drug supplies can be found in the Pharmacy Manual. 
5.3.1 Preparation and Dispensing 
The Medidata Balance® system will be used to indicate to site staff which study drug
kit(s) to select to dispense to each patient. 
During the randomised part of this study FKB327 and Humira will be provided as PFSs 
ready for injection.  At a suitable point during the open-label study all patients will be 
provided with FKB327 in an Auto-Injector presentation. 


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As the patient or carer will be administering doses at home, they must have the facility to 
refrigerate study drug at home and will be provided with the means to keep study drug 
chilled while transporting between the site and home.  Along with these supplies, patients 
will be given a Patient Instruction Leaflet, describing how study drug should be kept 
refrigerated at home, and a Dosing Diary to record the dates on which study drug was 
administered and any problems with dosing. 
All used study drug must be disposed of into the disposal container provided and returned 
by the patient to the study site together with any unused study drug at each visit for drug 
accountability and dosing compliance purposes. 
Further details on the preparation and dispensing of study drug at site can be found in the 
Pharmacy Manual. 
5.3.2 Administration 
FKB327 and Humira will be administered via sc injection.  Drug will be administered by 
subcutaneous injection either into the anterior thigh or anterior abdominal wall (within a 
10-cm radius around the umbilicus, but not closer to the umbilicus than approximately 
5 cm).  Injection sites should be changed between dosing occasions to minimise local 
side effects. 
The first 3 doses (Weeks 0, 2, and 4 for all patients and Weeks 30, 32, and 34 for patients 
switching from Humira to FKB327 at that point) will be administered by the patient or 
carer, under supervision by study site staff, at the study site and after appropriate training 
by study site staff.  Subsequent doses may be administered by the patient or carer at 
home, except when clinic visits for blood tests and efficacy assessments are scheduled 
when the dose must be given after blood samples are drawn. 
The maximum interval permitted between doses of study drug is 4 weeks.  This also 
applies to the transition from FKB327-002 into this study.  Study drug may need to be 
interrupted for treatment of serious infection, latent TB or other AE (see Section 5.7).  In 
this case the maximum permitted gap between study drug doses is 4 weeks.  If it is 
necessary, in the investigator's judgement, to interrupt study drug treatment for longer 
than 4 weeks, the patient will be withdrawn from study treatment but will be followed for 
resolution of the AE.  The minimum permitted gap between study drug doses is 8 days. 
5.3.3 Treatment Compliance 
Written records of study medication administration will be kept at the study site.  Patients 
will be asked to keep a diary card recording dates and times of dosing.  This information 
will be transcribed into the eCRF by site staff.  PK and ADA samples are taken at 
intervals during the study.   
Unused study drug will be returned to the site by the patient and retained at the study site 
for compliance checks but need not be refrigerated. 
5.3.3.1 Product Complaints 
Product complaints might include malfunctions or breakages of the FKB327 injection 
device (PFS), safety issues with the device, problems with the labelling or instructions. 


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Issues with the quality of the investigational medicinal products (eg, cloudiness or 
precipitation of the drug product solution) might also be considered product complaints. 
Any such product complaints should be entered on the Device Complaint Form and 
submitted to the Sponsor via email as soon as possible.  The faulty product should 
be retained for return at the Sponsor's request. 
If the product complaint results in an AE, it must be documented on the AE page of the 
CRF, and if it meets any of the serious criteria it needs to be reported through to the 
Sponsor‟s pharmacovigilance department on an SAE form (see Section 8.6.2). 
5.4 
Drug Storage and Accountability 
The study drug and supplies will be refrigerated at the site in a locked facility with 
monitored temperature.  Only authorised personnel will be allowed access.  An inventory, 
including the description and quantity of study medication received will be maintained.  
A record of study medication dispensed, along with the patient number and date and time 
of administration will be kept in the separate pharmacy section of the Investigator Site 
File (ISF) and filed with the main body of the ISF after database lock.  When doses are 
self-administered by the patient (or carer) at home, the Dosing Diary will be completed to 
record the administration. 
At the end of the study, any unused study drug kits will be returned to the Sponsor or 
designee, or destroyed in accordance with the Sponsor‟s instructions. 
5.5 
Concomitant Medication 
5.5.1 Permitted Concomitant Medication 
Patients will be taking MTX (oral or parenteral) at a stable dose of 10-25 mg/week from 
Study FKB327-002, and will continue to take MTX during this OLE study.  The route of 
administration of MTX should not change throughout the study.  The patient‟s MTX dose 
can be reduced for toxicity only.  If toxicity occurs, this should be recorded as an AE.  
The patient‟s MTX dose may also be increased if an RA flare occurs, although attempts 
should be made to reduce it back to the Baseline dose if possible. 
Patients should also continue to take accompanying folic/folinic acid (at a dose of at least 
5 mg/week) during this OLE study. 
Oral corticosteroids (≤10 mg/day prednisone or equivalent) are permitted during the 
study.  A temporary increase in oral steroid dose (≤10 mg/day prednisone or equivalent) 
is permitted to treat concomitant conditions, eg, asthma.  The reason for any such 
increase in dose should be recorded as an AE (eg, asthma flare).  The dose must be 
tapered back down as soon as medically viable.  The oral steroid dose may also be 
increased if an RA flare occurs although attempts should be made to taper it back to the 
Baseline dose if possible.  A short course of oral steroids (≤10 mg/day prednisone or 
equivalent) may also be initiated in patients who had not previously been taking them, if 
an RA flare occurs.  
If a patient‟s RA is adequately controlled and stable on study treatment, the Investigator 
may start to taper the concomitant oral steroid dose at their discretion.  A comment in the 


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eCRF „Comments page‟ that oral steroid reduction is being initiated should be created.  
All changes (increases or decreases) to oral steroid use should be carefully documented in 
the concomitant medication section of the eCRF. 
Inhaled and topical steroids are permitted during the study.  Treatment with intra-articular 
steroids is allowed during the study; however, repeated requirement for joint injection 
could be considered evidence of lack of efficacy and the investigator should consider 
withdrawing the patient from study treatment.  A joint which has been injected with 
intra-articular steroids should be excluded from joint counts (marked as unassessable on 
the SitePRO) for 12 weeks after the injection. 
Non-steroidal anti-inflammatory drugs (NSAIDs) up to the maximum approved dose are 
permitted during the study.  NSAID dose may be increased (not above the maximum 
approved dose) although attempts should be made to taper it back to Baseline level if 
possible.  Additional NSAIDs may also be added in this circumstance, according to local 
approved prescribing instructions.  Topical NSAIDs are permitted during the study. 
Analgesics up to the maximum approved dose are permitted during the study but should 
not be taken in the 24 hours prior to efficacy evaluations. 
All concomitant medications (including over-the-counter medications, herbal 
medications, preventative vaccines, vitamins and food supplements) and procedures must 
be recorded in the eCRF.  Concomitant medications for chronic conditions should be kept 
stable throughout the study wherever possible. 
Prophylactic anti-mycobacterial treatment may be given to patients found to have latent 
TB on completion of Study FKB327-002.  This treatment should be given prior to 
Week 0 of the present study (see Appendix 16.2). 
5.5.2 Prohibited Concomitant Medication 
Immunisation with a live or attenuated vaccine is prohibited for the duration of this study, 
including the follow-up period, and for 3 months after administration of the last dose. 
Treatment with an investigational agent is prohibited for the duration of this study. 
Treatment with parenteral steroids for RA is prohibited for the duration of this study.  If 
the patient requires parenteral steroids to manage their RA they should be withdrawn 
from the study for lack of efficacy.  However, a short course (maximum of 3 days) of 
parenteral steroid treatment for another condition, eg, allergy (not related to study 
treatment) or asthma, is permitted. 
Treatment with other DMARDs (apart from MTX) is prohibited for the duration of the 
study.  In the event the Investigator wishes to treat a patient with a DMARD (other than 
MTX or adalimumab) during the study, the patient must be withdrawn from study 
treatment and the reason for withdrawal documented. 
5.6 
Study Restrictions 
All patients must use a reliable method of contraception during the study, and for 
5 months after the last dose of study medication unless they (or their partners) are women 


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who are not of childbearing potential.  Acceptable methods of contraception are: surgical 
sterilisation, intrauterine devices, oral contraceptives, contraceptive patch, long-acting 
injectable contraceptives, partner‟s vasectomy, or a double-barrier protection method 
(condom or diaphragm with spermicide).  Women who are not of childbearing potential 
are defined as: post-menopausal women (no menstrual periods for at least 12 consecutive 
months); or women who have undergone a hysterectomy, a bilateral oophorectomy or a 
bilateral salpingectomy. 
All patients will be strongly advised (in the ICF) that they (or the female partners of male 
patients) should not become pregnant while on study treatment or for 5 months after the 
last dose.  Female patients will be advised that if they believe they may be pregnant, they 
must report immediately to the study site for pregnancy testing and appropriate 
management. 
5.7 
Safety Precautions 
All patients will be given an alert card stating that they are taking part in a clinical study 
involving administration of adalimumab, in accordance with the prescribing information 
for Humira. 
Patients will be advised that if they experience symptoms of infection, such as cough, 
loss of weight or fever, they should report this to study site staff immediately by 
telephone (a contact number will be provided).  This may necessitate an unscheduled visit 
to the study site for investigations, at the discretion of the investigator, and initiation of 
treatment.  If severe infection develops, study treatment may need to be interrupted, again 
at the discretion of the Investigator and in discussion with the study Medical Monitors.  If 
it is necessary to interrupt study dosing for more than 4 weeks despite antibiotic 
treatment, the patient will be discontinued from the study. 
Patients will also be advised that if they experience any symptoms suggestive of 
anaphylaxis, they should seek immediate local medical assistance then contact the study 
site. 
The needle cover of the Humira PFS contains dry rubber (latex), which should not be 
handled by persons sensitive to this substance without using latex-free gloves. 
If a patient is diagnosed with any of the following conditions during the study, they may 
be discontinued from the study, again involving discussion with the Medical Monitors: 

Malignancy (with the exception of carcinoma in situ of the cervix or basal cell
carcinoma of the skin that has been fully excised)

Anaphylactic reaction

Significant haematological or biochemical abnormality

Newly diagnosed or worsening heart failure

Newly diagnosed lupus-like syndrome with positive test for antibodies to double-
stranded DNA

Newly diagnosed demyelinating conditions

Pregnancy (see Section 8.8).


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
Any severe or opportunistic infection
Patients needing to undergo surgery during the study will be monitored closely for 
infection.  If evidence of infection develops following surgery it may be necessary to 
interrupt study dosing as described above. 
6 
STUDY PROCEDURES 
Study procedures and assessments with their timings are summarised in Table 1 for the 
randomised treatment period and Table 2 for the follow-up treatment period. 
For visits when dosing is performed, all procedures will be performed prior to dosing 
except for injection site assessment and recording of any post-injection AEs. 
Patients will have been taking MTX for at least 3 months prior to screening for 
Study FKB327-002 and for the duration of that study; consequently, continuous MTX 
therapy (with concomitant folate) is assumed and is not detailed in each of the following 
sections. 
6.1 
Procedures for Baseline Visit (Week 0 [Visit 1]) 
Patients who have completed Week 24 of Study FKB327-002 will be eligible to enrol 
into this study at the discretion of the investigator.  The Baseline (Week 0) visit for this 
study is the same as the Week 24 visit in Study FKB327-002.  Procedures on that day up 
until confirmation of eligibility for this study will be considered part of 
Study FKB327-002.  Procedures from confirmation of eligibility onwards will be 
considered part of this study.  Patients will be identified by the same number as in 
Study FKB327-002 (4-digit site number, a hyphen then the 4-digit patient number, eg, 
0001-0001).  It will be necessary to confirm in the eCRF for study FKB327-002 that the 
patient will transition to this study (FKB327-003) in order for the patient identifier 
number to be available within this study (and site) database.  A signed and dated 
informed consent form will be obtained before procedures specific to this study 
commence.  After informed consent is obtained, and eligibility is confirmed, patients will 
be randomised by the Medidata Balance® system.
The following procedures will be performed.  Some of these procedures will have been 
performed as part of the Week 24 visit of Study FKB327-002 and so will not be repeated 
specifically for this study and are presented below in parentheses.  NOTE: Procedures 
marked with an asterisk need to be repeated if there is a delay of 2 weeks or more 
between Week 24 of study FKB327-002 and Week 0 of study FKB327-003, for example, 
due to the need to interrupt study drug while serious infection or latent TB is treated. 

[Record concomitant medication].*

Review and record medical history and current conditions, including AEs that were
ongoing from Study FKB327-002 and any possible contact with individuals with
active TB since Screening in Study FKB327-002.*

[Perform physical examination including weight].

[Perform vital signs measurements (blood pressure, pulse and temperature)].

[Perform 12-lead electrocardiogram (ECG)].


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
[Perform chest X-ray unless patient has negative QuantiFERON test at Week 22 of
study FKB327-002 with no signs/symptoms of clinically significant lower respiratory
infection].

[Perform clinical laboratory tests: haematology, serum chemistry, dipstick urinalysis
(at site), CRP and erythrocyte sedimentation rate (ESR)].*

[Perform urine pregnancy test at site (females of childbearing potential only)].*

[Take blood sample for assessment of serum blood concentrations of adalimumab].*

[Take blood for ADA sampling].*

[Perform test for matrix metalloproteinase (MMP)-3].

[Administer patient assessment of physical function questionnaire (Health
Assessment Questionnaire Disability Index [HAQ-DI])].*

[Assess tender/swollen joints (68/66 joints)].*

[Administer patient global assessment of disease activity visual analogue scale (VAS)
and patient assessment of pain VAS].*

[Perform physician global assessment of disease activity VAS].*

Obtain written informed consent before any other study-related procedures specific to
FKB327-003 are performed.

Randomise patient using the Medidata Balance® system.

Train patient and/or carer in self-administration of study drug

Supervise self-administration of study medication (or administration by carer) at
study site.

Perform injection site assessment including injection site pain VAS.
6.2 
Procedures during Treatment Period 
Note: for Visit 2 and Visit 3 there will be a window of ±3 days.  For example, the Week 2 
visit (Visit 2) should take place on Day 15, but could be as early as Day 12 or as late as 
Day 18.  From Visit 4 (Week 8) onwards, a window of ±7 days is permissible. 
6.2.1 Week 2 (Visit 2) 

Supervise self-administration of study medication (or administration by carer) at
study site.

Record AEs.
6.2.2 Weeks 4, 8, and 12 (Visits 3, 4, and 5) 

Record concomitant medications.

Perform vital signs measurements (blood pressure, pulse and temperature).

Perform clinical laboratory tests (haematology, serum chemistry, urinalysis and
CRP).

Perform urine pregnancy test at site (females of childbearing potential only).


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
Week 12 only: take blood sample for assessment of serum blood concentrations of
adalimumab.

Week 12 only: take blood for ADA sampling.

Record AEs.

Administer patient assessment of physical function questionnaire (HAQ-DI).

Assess tender/swollen joints (68/66 joints).

Administer patient global assessment of disease activity VAS and general assessment
of pain VAS.

Perform physician global assessment of disease activity VAS.

Week 4 only: supervise self-administration of study medication (or administration by
carer) at study site.

Dispense study medication for patient/carer to administer at home and Dosing Diary.

Instruct patient/carer (i) to dose at home (specify dates), (ii) to complete Dosing Diary
card, (iii) to keep study drug refrigerated and secure at home, and (iv) to seek
immediate local medical advice or contact study site staff in case of any AEs, 
depending on the severity of the event.

Provide Patient Instruction Sheet.
6.2.3 Weeks 6, 10, 14, 16, 18, 20, 22, 26, and 28 

Patient/carer to administer study drug at home and complete Dosing Diary.

Contact study site staff in case of any AEs.
Note: Week 28 will be the last administration of randomised treatment. 
6.2.4 Week 24 (Visit 6) 

Record concomitant medication.

Record weight.

Perform vital signs measurements (blood pressure, pulse and temperature).

Perform clinical laboratory tests (haematology, serum chemistry, urinalysis, CRP).

Perform urine pregnancy test at site (females of childbearing potential only).

Perform QuantiFERON test (may be omitted if patient is receiving anti-mycobacterial
treatment for latent TB).

Take blood sample for assessment of serum blood concentrations of adalimumab.

Take blood for ADA sampling.

Record AEs.

Administer patient assessment of physical function questionnaire (HAQ-DI).

Assess tender/swollen joints (68/66 joints).

Administer patient global assessment of disease activity VAS and general assessment
of pain VAS.


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
Perform physician global assessment of disease activity VAS.

Supervise self-administration of study medication (or administration by carer) at
study site.

Dispense study medication for patient/carer to administer at home and Dosing Diary.

Instruct patient/carer (i) to dose at home (specify dates), (ii) to complete Dosing Diary
card, (iii) to keep study drug refrigerated and secure at home, and (iv) to seek
immediate local medical advice or contact study site staff in case of any AEs,
depending on the severity of the event.

Provide Patient Instruction Sheet.
6.2.5 Weeks 30, 54, and 76 (Visits 7, 11, and 13) 
Note: from Week 30, all patients will receive FKB327. 

Record concomitant medication.

Perform clinical laboratory tests (haematology, serum chemistry, urinalysis and
CRP).

Perform urine pregnancy test at site (females of childbearing potential only).

Week 76 only: perform QuantiFERON test (may be omitted if patient is receiving
anti-mycobacterial treatment for latent TB).

Take blood sample for assessment of serum blood concentrations of adalimumab.

Take blood for ADA sampling.

Week 30 only: chest X-ray, performed only in the event of a new positive or
confirmed (ie, repeated) indeterminate QuantiFERON test result (eg, from Week 24)
and/or signs/symptoms of lower respiratory infection (see Appendix 16.2).

Record AEs.

Administer patient assessment of physical function questionnaire (HAQ-DI).

Assess tender/swollen joints (68/66 joints).

Administer patient global assessment of disease activity VAS and general assessment
of pain VAS.

Perform physician global assessment of disease activity VAS.

Supervise self-administration of study medication (or administration by carer) at
study site.

Week 30 only: perform injection site assessment including injection site pain VAS
(Note: an additional injection site assessment will be performed at the time of
switching to the Auto-Injector during the open-label follow-up treatment period).

Dispense study medication for patient/carer to administer at home and Dosing Diary.

Instruct patient/carer (i) to dose at home (specify dates), (ii) to complete Dosing Diary
card, (iii) to keep study drug refrigerated and secure at home, and (iv) to seek
immediate local medical advice or contact study site staff in case of any AEs,
depending on the severity of the event.


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
Provide Patient Instruction Sheet.
6.2.6 Weeks 32 and 34 (Visits 8 and 9) 
For patients switched from Humira to FKB327, the Weeks 32 and 34 visits must be 
performed at the clinic: 

Record AEs.

Supervise self-administration of study medication (or administration by carer) at
study site.
For patients continuing with FKB327, the patient or carer can administer at home: 

Patient/carer to administer study drug and complete Dosing Diary.

Contact study site staff in case of any AEs.
6.2.7 Weeks 36-40, 44-52, 56-64, and 68-74 

Patient/carer to administer study drug at home and complete Dosing Diary.

Contact study site staff in case of any AEs.
6.2.8 Weeks 42 and 66 (Visits 10 and 12) 

Record concomitant medication.

Perform clinical laboratory tests (haematology, serum chemistry, urinalysis and
CRP).

Perform urine pregnancy test at site (females of childbearing potential only).

Record AEs.

Administer patient assessment of physical function questionnaire (HAQ-DI).

Assess tender/swollen joints (68/66 joints).

Administer patient global assessment of disease activity VAS and general assessment
of pain VAS.

Perform physician global assessment of disease activity VAS.

Supervise self-administration of study medication (or administration by carer) at
study site.

Dispense study medication for patient/carer to administer at home and Dosing Diary.

Instruct patient/carer (i) to dose at home (specify dates), (ii) to complete Dosing Diary
card, (iii) to keep study drug refrigerated and secure at home, and (iv) to seek
immediate local medical advice or contact study site staff in case of any AEs,
depending on the severity of the event.

Provide Patient Instruction Sheet.
6.2.9 Week 80 or End-of-study (Visit 14) 
In the event of early treatment discontinuation, patients will be asked to attend an 
end-of-study visit.  Early treatment discontinuation is defined as withdrawal from the 


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study prior to Week 80.  The reason for early treatment discontinuation should be 
recorded in the eCRF. 
The following procedures will be performed at the Week 80 or end-of-study visit: 

Record concomitant medication.

Perform physical examination.

Perform vital signs measurements (blood pressure, pulse and temperature).

Perform clinical laboratory tests (haematology, serum chemistry, urinalysis and
CRP).

Take blood sample for assessment of serum blood concentrations of adalimumab.

Take blood for ADA sampling.

EOS only: perform QuantiFERON test (may be omitted if patient is receiving
anti-mycobacterial treatment for latent TB)

Perform chest X ray unless patient has negative QuantiFERON test at Week 76 or
EOS, as appropriate, with no signs/symptoms suggestive of lower respiratory
infection (see Appendix 16.2).

Record AEs.

Administer patient assessment of physical function questionnaire (HAQ-DI).

Assess tender/swollen joints (68/66 joints).

Administer patient global assessment of disease activity VAS and general assessment
of pain VAS.

Perform physician global assessment of disease activity VAS.
7 
ASSESSMENTS 
7.1 
Assessment of Efficacy 
7.1.1 Primary Efficacy Variable 
There are no primary efficacy variables. 
7.1.2 Secondary Efficacy Variables 
7.1.2.1 ACR20, ACR50, and ACR70 
ACR20, ACR50 and ACR70 response rates are secondary efficacy variables.  The ACR 
response criteria involve improvement in tender joint count, swollen joint count 
(68/66-joint count) and improvement in at least 3 of the following 5 other specified ACR 
Core Data Set elements: 

Acute phase reactant (CRP).

Patient global assessment of disease activity.

Physician global assessment of disease activity.

Patient pain scale.


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
Disability/functional questionnaire (patient completed HAQ-DI)
An ACR20 response means that the patient achieved a 20% improvement in tender and 
swollen joint counts and in at least 3 of the other 5 Core Data Set elements listed above. 
ACR50 response means that the patient achieved a 50% improvement in tender and 
swollen joint counts and in at least 3 of the other 5 criteria, and an ACR70 response 
means that the patient achieved a 70% improvement in tender and swollen joint counts 
and in at least 3 of the other 5 criteria.7
The percent of patients achieving ACR20, ACR50 and ACR70 response will be assessed 
at the time points detailed in Table 1 and Table 2 as the ACR response rate (%), 
calculated using the Core Set variables described below.  The baseline used for the ACR 
response will be the baseline of Study FKB327-002. 
7.1.2.1.1 Tender and Swollen Joint Counts (68/66 Joints) 
Counts of tender and swollen joints from amongst 68/66 selected joints will be performed 
by a trained and qualified joint assessor as scheduled in Table 1 and Table 2 using 
standardised techniques recommended by the European League Against Rheumatism 
(EULAR).  Results will be recorded immediately on the SitePRO tablet device provided 
(constituting source data).  To maintain consistency in evaluating each patient, efforts 
will be made to use the same joint evaluator as in study FKB327-002 and at all 
FKB327-003 visits.  Joint evaluators will have received standardisation training for 
FKB327-002 and any new or replaced joint evaluators should also be trained.  The 
training opportunities will include, the site initiation visit, WebEx presentations, a video 
and written manual detailing how to perform the joint assessment.  Training will be 
documented by certificates held on the site file.  Additionally, the number of joint 
evaluators used across the study will be kept as low as is logistically possible. 
If, at any visit, a joint is not evaluable for any reason, this will be recorded on the 
SitePRO device.  If this is due to amputation, the joint will automatically be recorded as 
unevaluable for the remainder of the study.  If a joint is not evaluable for any other reason 
(such as infection, injury or surgery), the joint should be reassessed for evaluability at 
each visit by the joint examiner.  If the joint is not evaluable due to an injection into the 
joint it should be marked as not evaluable for a period of 12 weeks post injection.  
Criteria for excluding such joints from the joint count used to calculate the 
ACR20/50/70/DAS28 will be detailed in the Statistical Analysis Plan (SAP). 
7.1.2.1.2 C-reactive Protein (CRP) 
Analysis of serum CRP concentrations for randomisation stratification and 
inclusion in the ACR20/50/70 and DAS28-CRP scores will be performed by XXX
laboratory. 
7.1.2.1.3 Visual Analogue Scales (VAS) 
Patient global assessment of disease activity VAS (ranging from very well to extremely 
bad), and physician global assessment of disease activity VAS (ranging from very low to 
very high) will be assessed on 100-point scales at the time points detailed in Table 1 and 
Table 2.  These VASs must be completed by the patient/physician themselves on a 
SitePRO tablet.  The patient global assessment of disease activity VAS will contribute to 


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the calculation of the DAS28 score.  The patient global assessment of disease activity 
VAS, and physician global assessment of disease activity VAS will contribute to the 
calculation of ACR20, ACR50 and ACR70 response.  Patient-recorded data will not be 
corrected or revised in any way.  VAS data recorded on the SitePRO device will be 
regarded as source data. 
7.1.2.1.4 HAQ-DI 
The HAQ-DI8 is a 20-question, self-administered instrument that measures the patient‟s
functional ability on a 4-level difficulty scale (0-3, with 0 representing normal or no 
difficulty, and 3 representing inability to perform).  Eight categories of functioning are 
included: dressing, rising, eating, walking, hygiene, reach, grip, and usual activities.9
This scale is sensitive to change and is a good predictor of future disability.10  The
HAQ-DI questionnaire will be completed on the SitePRO device by the patients 
themselves at the time points indicated in Table 1 and Table 2.  Patient-recorded data will 
not be corrected or revised in any way. 
7.1.2.1.5 Disease Activity Score 28 (DAS28) 
The DAS28 score is a combined index that has been developed to measure the disease 
activity in patients with RA and has been extensively validated for its use in clinical 
studies.11  The DAS28 assessment involves evaluating the tender joint count (TJC) and
swollen joint count (SJC) (out of 28 specified joints), serum CRP and patient global 
assessment of disease activity (VAS from 0 to 100, very well to extremely bad).  The 
results are then used to calculate the DAS28 using the following formula: 
DAS28-CRP = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC) + 0.36*ln(CRP+1) + 0.014*VAS + 
0.96 
The DAS28 is a number on a scale from 0 to 10 indicating the current activity of the 
patient‟s RA.  A DAS28 above 5.1 means high disease activity whereas a DAS28 ≤3.2 
indicates low disease activity.  Remission is achieved by a DAS28 lower than 2.6. 
The DAS28 will be calculated using information from the assessments performed at the 
time points detailed in Table 1 and Table 2. 
The baseline DAS28 score from Study FKB327-002 will be used to calculate the change 
from baseline. 
7.1.2.1.6 Components of the DAS28-CRP 
Joint count results (28 joints) will be extrapolated automatically in the SitePRO device 
from the results of the 68/66 joint counts performed for the purpose of ACR response 
calculation.  Results of the patient global assessment of disease activity VAS will be the 
same as used for the ACR response.  CRP values will be the results from samples 
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7.2 
Assessment of Safety 
In this study, safety will be assessed by evaluating the following: AEs, physical 
examination findings, vital signs measurements, and clinical laboratory test results.  The 
process for reporting AEs is detailed in Section 8. 
7.2.1 Clinical Laboratory Tests 
Laboratory testing will be performed by a central laboratory facility with the exception of 
ESR testing and dipstick urinalysis, which will be performed locally.  All clinical 
laboratory test results outside of the reference range will be flagged and interpreted by the 
Investigator according to the following categories: 

Abnormal, not clinically significant (NCS)

Abnormal, CS
CS laboratory abnormalities will be recorded as AEs.  Laboratory tests will be performed 
at the time points detailed in Table 1 and Table 2. 
7.2.1.1 Haematology 
The following haematology tests will be performed: haemoglobin (Hb), red blood cell 
count, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean 
corpuscular haemoglobin concentration (MCHC), haematocrit, white blood cell (WBC) 
count and differential, platelets and (at Week 0 only, as part of Study FKB327-002) ESR. 
7.2.1.2 Serum Chemistry 
The following serum chemistry tests will be performed: urea, creatinine, uric acid, total 
bilirubin, total protein, albumin, globulin, alkaline phosphatase, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase 
(GGT), glucose, phosphate, cholesterol, triglycerides, potassium, sodium, calcium, and 
chloride. 
7.2.1.3 Urinalysis 
Dipstick urinalysis (by local study site staff) will include testing for the following: 
protein, blood, glucose and leukocyte esterase.  If the dipstick reveals any clinically 
significant abnormalities a second sample (provided on the same day, if possible), should 
be sent to the central laboratory.  Microscopy will be performed by the central laboratory 
in the case of abnormal results. 
7.2.1.4 Pharmacodynamic Markers 
Serum MMP-3 will be analysed at the time points detailed in Table 1 and Table 2. 
7.2.1.5 Pregnancy Testing 
Females of childbearing potential will take a urine pregnancy test (performed at site) as 
scheduled in Table 1 and Table 2.  Female patients will be advised that, if they believe 
they may be pregnant, they must report immediately to the study site for pregnancy 
testing and appropriate management. 


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7.2.1.6 Other 
The QuantiFERON-TB Gold In-Tube test will be performed at Weeks 24 and 76 or EOS 
although this may be omitted in patients receiving anti-mycobacterial treatment for latent 
TB.  This may be repeated, at the discretion of the Investigator or to comply with local 
practices, at additional time points.  The test is approved by the Food and Drug 
Administration (FDA) and is used to detect active or latent Mycobacterium tuberculosis 
infection.  The test is based on the quantification of interferon-gamma (IFN-γ) released 
from sensitised lymphocytes in whole blood incubated overnight with purified protein 
derivative (PPD) from M. tuberculosis and control antigens.12  A positive result for active
TB (as determined in association with chest X-ray and clinical evaluation) or untreated 
latent TB (unless prophylactic treatment is started) will lead to the patient being 
excluded/withdrawn from the study (see TB testing flow chart in Appendix 16.2).  Latent 
TB treated with prophylactic anti-mycobacterial therapy for at least 3 weeks (or longer if 
required by local guidelines) before study treatment is commenced/resumed is 
acceptable.  If the result is indeterminate the test may first be repeated or combined with 
PPD testing.  If confirmed indeterminate, the patient should be managed as though they 
have a positive test result or excluded from the study (see Appendix 16.2). 
7.2.2 Physical Examination 
Physical examination will be performed by the Investigator at Week 0 (Week 24 of study 
FKB327-002) and Week 80 or end-of-study visit.  The following will be examined: 
general appearance; head; ears; eyes; nose and throat; thyroid; lymph nodes; heart; chest 
(including lungs); abdomen; urogenital system (optional); skin; breasts; extremities; 
musculoskeletal system and neurological system. 
7.2.3 Vital Signs 
Vital signs (blood pressure, pulse, and temperature) will be measured at the time points 
detailed in Table 1 and Table 2.  Blood pressure and pulse rate will be measured prior to 
dosing after the patient has rested in a supine or semi-recumbent position for at least 
5 minutes. 
7.2.4 Chest X-ray 
Chest X-rays (posterior and lateral views) will be performed at Week 30 and Week 80 or 
EOS unless patient has negative QuantiFERON test at Week 24 or 76 or EOS, 
respectively, with no signs/symptoms suggestive of lower respiratory infection.  The 
chest X-ray will be examined by a qualified radiologist to ensure that there is no evidence 
of active TB, other chest infection or interstitial pneumonitis in particular.  An additional 
X-ray will be performed at the Investigator‟s discretion at additional time points in the 
presence of signs/symptoms suggestive of lower respiratory infection. 
7.2.5 Injection Site Assessment 
An injection site assessment will be performed within 30 minutes of dosing at Week 0 
and Week 30, as well as at the time of switching to the Auto-Injector during the 
open-label follow-up treatment period.  Study staff will apply light pressure at the 
injection site and record any tenderness, erythema and induration.  Local reactions will be 


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assessed according to the FDA Guidance for Industry on Skin Irritation and Sensitization 
Testing of Generic Transdermal Drug Products,13 as follows:
0 = no evidence of irritation. 
1 = minimal erythema, barely perceptible. 
2 = definite erythema, readily visible; minimal oedema or minimal papular response. 
3 = erythema and papules. 
4 = definite oedema. 
5 = erythema, oedema, and papules. 
6 = vesicular eruption. 
7 = strong reaction spreading beyond test site. 
The size of any injection site reaction will be measured along its longest axis.  If a patient 
has a CS local reaction, it will be recorded as an AE.  Any evidence of an injection site 
reaction at visits other than Week 0, Week 30, or at the assessment conducted at the point 
of switching to the Auto-Injector will also be recorded as an AE. 
As part of this assessment, an injection site pain VAS will be completed by the patient 
using the SitePRO tablet.  To determine the extent of the pain, patients will be asked to 
place a small vertical mark on a horizontal scale from 0 to 100, the ends of which are 
labelled with the extreme responses to be measured (“No pain” and “Intolerable pain”). 
7.3 
Immunogenicity Assessments 
Blood samples for the assessment of ADAs will be collected prior to dosing at Baseline 
(Week 0) and at the time points detailed in Table 1 and Table 2. 
Blood (10 mL) will be placed into 2 × 5 mL polymer gel tubes, and allowed to clot.  
Serum will be separated by centrifugation, and divided into 8 aliquots of approximately 
equal volume (about 0.5 mL per aliquot) in capped cryovials (2 mL polythene tubes).  
Serum samples will be stored at –70°C (-20°C if a -70°C freezer is not available).  The 
ADA analysis will be done by inVentiv Health Clinical.  
Specific details of the sample collection procedure, the storage conditions, and the 
shipping instructions will be detailed in the laboratory manual. 
7.4 
Pharmacokinetic Assessments 
Blood samples for the quantification of adalimumab in serum will be collected prior to 
dosing at Baseline (Week 0) and at the time points detailed in Table 1 and Table 2.  
Concentrations of MTX will not be assessed. 
Blood (3.5 mL) will be placed in a polymer gel tube, and allowed to clot.  Serum will be 
separated by centrifugation, and divided into 2 aliquots of approximately equal volume 
(about 0.5 mL per aliquot) in capped cryovials (2 mL polythene tubes).  Serum samples 
will be stored at –70°C (-20°C if a -70°C freezer is not available).  The PK concentration 
measurement will be done by inVentiv Health Clinical. 


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8 
REPORTING OF ADVERSE EVENTS 
8.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical study subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with that treatment. 
An AE can, therefore, be any unfavourable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of the study, 
or significant worsening of the disease under study or of any concurrent disease, whether 
or not considered related to the study medication.  A new condition or the worsening of a 
pre-existing condition will be considered an AE. 
All overdoses should be recorded as an AE.  An overdose is any dose of study treatment, 
including protocol prescribed concomitant medication, given to a patient or taken by a 
patient that exceeds the protocol prescribed amount.  An overdose should be recorded as 
an AE even if it does not result in an adverse effect to the patient.  An overdose that 
results in an AE that meets any of the outcomes defined as serious must be reported on an 
SAE form and sent to the Sponsor‟s pharmacovigilance department within 24 hours of 
becoming aware of the event (as described in Section 8.6.2). 
8.2 
Recording and Reporting an Adverse Event 
Patients will be carefully monitored for AEs from signing of informed consent until the 
End of Study visit (Week 80) or Early Termination visit if the patient does not complete 
the study.  Ongoing AEs from Study FKB327-002 will be recorded in the FKB327-003 
eCRF as medical history/concurrent conditions.  Any AE occurring or worsening after 
randomisation to the FKB327-003 study will be recorded in the FKB327-003 eCRF as an 
AE. 
SAEs will be followed until resolution, the Investigator confirms the event is unlikely to 
resolve or the patient is recorded as lost to follow-up.  The Investigator or delegate will 
question the patient about AEs using a non-leading question, such as „How are you 
feeling?‟  The Investigator will also record AEs reported spontaneously by the patient. 
CS changes in the findings of physical examination, and CS abnormalities in the results 
of objective tests (eg, laboratory parameters, X-ray and ECG) may also be recorded as 
AEs.  The Investigator will use the following criteria when deciding whether or not to 
report an abnormal result as an AE: 
1.
The test result is associated with accompanying symptoms.
2.
Results of additional diagnostic tests cause concern or necessitate medical
intervention.
3.
As a consequence of the test result, the patient is withdrawn or the patient is given
concomitant treatment.
4.
The Investigator considers the result to constitute an AE.
If any of the above criteria are met, the Investigator will report the result as an AE.  A 
record of all AEs reported, regardless of causality, will be kept in the eCRF. 


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8.3 
Follow-up of Adverse Events 
All AEs, including CS laboratory values or physical examination changes relative to 
Baseline values, must be followed until the AE resolves, is no longer of clinical concern, 
has stabilised or is otherwise explained, or the patient is lost to follow-up. 
AEs ongoing at the final visit must be followed for as long as necessary to adequately 
evaluate the safety of the patient or until the event stabilises, resolves or is no longer an 
ongoing clinical concern.  If resolved, a resolution date for the AE should be documented 
on the eCRF.  The Principal Investigator must ensure that follow-up includes any 
supplemental investigations indicated to elucidate the nature and/or causality of the AE.  
This may include additional laboratory tests or investigations, or consultation with other 
healthcare professionals as considered clinically appropriate by the Principal Investigator. 
8.4 
Severity of an Adverse Event 
The severity of each AE must be recorded according to the following categories: 
Mild: the AE does not interfere with the patient‟s daily routine and does not require 
intervention; it causes slight discomfort. 
Moderate: the AE interferes with some aspects of the patient‟s routine or requires 
intervention but is not damaging to health; it causes moderate discomfort. 
Severe: the AE results in alteration, discomfort or disability which is clearly damaging to 
health. 
8.5 
Relationship of an Adverse Event to Study Medication 
The relationship of each AE to study medication must be recorded according to the 
following categories: 
Related: an event which occurs after exposure to the test product, has a reasonable 
temporal relationship to dosing and is likely to be caused by it.  The event may or may 
not be a known side effect of the test product.  The event is not easily attributable to 
another cause.  There may be evidence of a positive de-challenge and/or re-challenge. 
Possibly related: An event for which, after careful medical evaluation, a connection with 
study medication cannot be ruled out with certainty.  The event occurs after exposure to 
the test product.  The event may occur at a reasonable time in relation to the time of 
administration of study medication, but might also be attributable to a commonly 
occurring alternative cause.  Alternatively, the event may not occur at a reasonable time 
in relation to the time of administration of study medication, but not be attributable to an 
alternative cause. 
Unrelated: an event which occurs before exposure to the test product, which can clearly 
be attributed to another cause or is clearly unrelated to the study, eg, road traffic accident 
in which the patient is a victim. 


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8.6 
Serious Adverse Events 
8.6.1 Definition of a Serious Adverse Event 
An SAE is an AE occurring at any dose that results in any of the following outcomes or 
actions: 

Death.

A life-threatening AE (ie, the patient was at immediate risk of death from the event as
it occurred); it does not include an event that, had it occurred in a more severe form,
might have caused death.

Inpatient hospitalization (defined as an overnight stay) or prolongation of existing
hospitalization means that hospital inpatient admission and/or prolongation of
hospital stay were required for treatment of an AE, or that they occurred as a
consequence of the event.  Hospitalizations scheduled for an elective procedure or for
treatment of a pre-existing condition that has not worsened during participation in the
study, or for social reasons (eg, renewal of disease certification) will not be
considered SAEs.

Persistent or significant disability or incapacity (refers to a substantial disruption of
one‟s ability to conduct normal life functions)

A congenital anomaly/birth defect

An important medical event that may not result in death, be life-threatening, or
require hospitalization, but may jeopardize the patient and may require medical
intervention to prevent one of the outcomes listed in this definition.  Examples of
such events are intensive treatment in an emergency room or at home for allergic
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization;
or the development of drug dependency or drug abuse.  Development of active TB, an
opportunistic infection, or a malignancy should always be considered an important
medical event.  Note: Any suspected transmission of an infectious agent via a
medicinal product is considered an important medical event.
8.6.2 Reporting a Serious Adverse Event 
In the event of any SAE which, in the Investigator‟s opinion, justifies termination or 
modification of the study, dosing will be stopped and the Sponsor will be informed 
immediately. 
For all SAEs, the Investigator will complete an SAE form and provide it to the 
Sponsor‟s pharmacovigilance department within 24 hours of becoming aware of the 
event: 
email: safety@XXX.com (Sponsor‟s pharmacovigilance department)
Fax: +XX XXX XXX XX (Sponsor‟s pharmacovigilance department)
The Sponsor‟s pharmacovigilance department will confirm receipt of the report within 
1 business day.  The Principal Investigator should re-send any report where 
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The Principal Investigator will assess whether an event is causally related to study 
medication (see Section 8.5).  The Sponsor will consider the Principal Investigator‟s 
assessment and determine whether an event meets the criteria for being reportable as a 
7-day or 15-day safety report. 
The Sponsor (or delegate) will notify the relevant Competent Authority(ies) of all 
suspected unexpected serious adverse reaction (SUSARs), and will be responsible for 
ensuring that the Central Ethics Committees (CEC)/Institutional Review Boards (IRBs) 
are notified of relevant SUSARs, as applicable.  SUSARs that are fatal or life-threatening 
must be notified to the Competent Authority and CEC/IRB within 7 days after the 
Sponsor (or delegate) has first knowledge of them, with a follow-up report submitted 
within a further 8 calendar days.  Other SUSARs must be reported to the relevant 
Competent Authority(ies) and CEC/IRB within 15 days after the Sponsor (or delegate) 
has first knowledge of them. 
Documentation of all submissions must be retained within the Study Master File. 
Following the initial report, any additional information received by the Principal 
Investigator about an SAE must be reported promptly to the Sponsor‟s 
pharmacovigilance department as above. 
Details of the expectedness of an SAE can be found in the Investigator‟s Brochure.2
8.7 
Withdrawals due to Adverse Events 
The Investigator will assess the reason for withdrawal as far as possible and will fully 
record the circumstances and medical details.  Provided that patients give written 
informed consent, they will undergo the standard medical examination and laboratory 
tests at withdrawal from the study which they would have undergone had they completed 
it (see Table 1 and Table 2).  Any SAEs ongoing at the time of withdrawal will be 
followed until resolution or confirmation from the Investigator that the event is unlikely 
to resolve. 
8.8 
Pregnancy 
Any patient who becomes pregnant during the study will be withdrawn from the study.  
All pregnancies (in patients and patient‟s partners) occurring during the study, or within 
5 months of completion of the study, are to be reported immediately to the Sponsor‟s 
pharmacovigilance department on a Pregnancy Report Form and the Investigator will 
take reasonable steps to follow the patient (or patient‟s partner) until the outcome of the 
pregnancy is determined.  Any premature termination of pregnancy must also be reported 
to the Sponsor‟s pharmacovigilance department by the Investigator. 
The process for reporting a pregnancy is the same as that for reporting an SAE (see 
Section 8.6.2) except that the Pregnancy Report Form is used instead of the SAE form. 
8.9 
Device Complaints 
Where the study site personnel becomes aware of an issue with the study device (PFS or 
auto-injector), a Device Complaint Report (DCR) form is to be completed by the 
Investigator or designee and forwarded to the contact whose details are provided in 


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Section 8.6.2.  Such issues may include problems with the identity (labelling, packaging), 
quality, durability, reliability, safety, effectiveness or performance of the device.  The 
issues may be detected at the study site by site personnel or reported by the patient via 
phone call to the site personnel or recorded on their home dosing diary card.  
9 
STATISTICAL METHODS 
Detailed methodology for the statistical analyses, including details of the data summary 
tables and figures, will be documented in a SAP.  The statistical methodology presented 
in this section of the protocol represents a broad outline of the analyses planned at the 
time of writing.  More specific details of the statistical analyses will be presented in the 
SAP; and the contents of the SAP should be considered to be the definitive 
documentation of the planned analyses; superseding, where necessary, the information 
contained within the protocol.  Where a protocol is amended for operational reasons only, 
such amendments may not always be updated to reflect the analyses planned in the SAP, 
even when the date of the protocol amendment is later than the date of the SAP.  Methods 
for handling missing data will be detailed in the SAP. 
The data from this study will be analysed in 4 groups as detailed in Table 3. 
Table 3 Analysis of Treatment Groups 
Treatment in 
FKB327-002 
Treatment in 
FKB327-003 
Treatment Sequence 
for Analysis (from 
Week 0 in 002 study to 
Week 30 in 003 study) 
Treatment Sequence for 
Analysis (across studies 
002 and 003) 
FKB327 
FKB327-FKB327 
FKB327-FKB327 
FKB327-FKB327-FKB327 
FKB327 
Humira-FKB327 
FKB327-Humira 
FKB327-Humira-FKB327 
Humira 
FKB327-FKB327 
Humira-FKB327 
Humira-FKB327-FKB327 
Humira 
Humira-FKB327 
Humira-Humira 
Humira-Humira-FKB327 
The safety population will comprise all patients who received at least one dose of 
randomised treatment in the FKB327-003 study.  The safety analysis will be based on the 
safety population.  Patient safety data will be analysed according to treatment actually 
received (for both studies). 
The Full Analysis Set (FAS) population will comprise all patients who received at least 
1 dose of the randomised treatment and who had at least 1 evaluable efficacy 
measurement after their first dose of randomised treatment in the FKB327-003 study.  
The efficacy analysis will be based on the FAS population.  Patients will be analysed 
according to randomised treatment (for both studies). 
The PK Analysis Set (PKAS) will include all patients who received at least 1 dose of the 
randomised treatment and have at least 1 serum adalimumab concentration result after 
receiving randomised treatment in the FKB327-003 study. 
9.1 
Sample Size 
As this is an open-label extension of Study FKB327-002, no formal sample size has been 
calculated.  The number of patients (see Section 3.4) is based on the assumed number of 


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patients expected to complete Study FKB327-002 and the number of expected drop-outs 
in Study FKB327-003. 
9.2 
Efficacy Analysis 
The percentage of patients (%) achieving ACR20, ACR50 and ACR70 response from 
baseline in FKB327-002 will be summarised by treatment sequence and visit. 
The percentage of patients (%) achieving ACR20, ACR50 and ACR70 response from 
baseline in Study FKB327-002 over time will be plotted by treatment sequence. 
Mean DAS28 score and the change from Baseline (Week 0 from Study FKB327-002) in 
mean DAS28 score, and individual ACR core set variables (swollen joint count, tender 
joint count, CRP, patient‟s assessment of disease activity, physician‟s assessment of 
disease activity, patient‟s assessment of pain, HAQ-DI) will be summarised by treatment 
sequence and visit. 
The mean DAS28 and change from baseline (from Study FKB327-002) in DAS28 over 
time will be plotted by treatment sequence. 
9.3 
Safety Analysis 
Safety data including vital signs, haematology, serum chemistry and urinalysis will be 
summarised by treatment sequence for each visit. 
Withdrawals from the study will be summarised by treatment sequence. 
AEs will be summarised by System Organ Class (SOC) and Preferred Term (PT) using 
the Medical Dictionary for Regulatory Activities (MedDRA).  AEs will be tabulated by 
treatment sequence and relationship to treatment.  SAEs, in particular infections and 
malignancies, will be summarised by treatment sequence.   
The incidence and size of injection site reactions and injection site pain VAS scores will 
be summarised by FKB327-003 treatment using descriptive statistics.   
9.4 
Immunogenicity Analysis 
All ADA activity will be listed and summarised for each treatment period (by treatment 
sequence during the randomised treatment period), and the proportion of ADA positive 
cases (in the confirmatory assay) during the randomised treatment period will be 
compared between treatment sequences. 
The frequency (percentage) of titre results will be summarised for each treatment by day; 
summaries will include the median and upper and lower ADA quartiles for the overall 
safety population.  In addition, ADA titre results will be presented graphically for each 
treatment group during the randomised treatment period. 
The frequency (percentage) of ADA neutralising results (positive, negative, inconclusive) 
during the randomised treatment period will be summarised for each treatment. 


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9.5 
Pharmacokinetic Analysis 
Serum trough concentrations of adalimumab will be listed and summarised by treatment 
sequence, and individual and mean concentration-time profiles will be presented 
graphically on linear scales. 
In addition to individual and mean concentration-time plots presented for each treatment, 
individual concentration-time plots will also be presented to illustrate graphically the 
effect of ADA activity on the PK profiles. 
9.5.1 Primary Pharmacokinetic Analysis 
For the PKAS (Section 9), a mixed model for repeated measures will be fitted to the log 
transformed PK trough concentrations at Weeks 12, 24 and 30 (ie, during the randomised 
treatment period) with patient included as a random effect and fixed effect terms for 
week, treatment sequence, week x treatment sequence interaction where treatment 
sequence is the 4-level term as shown in Table 3.  The LSM for each treatment sequence 
will be estimated at each week and averaged over time with 95% CIs and plotted over 
time. 
Provided the interaction term for week x treatment sequence is not significant at the 10% 
level, only differences in LSMs averaged over all time points will be estimated with 90% 
CIs.  Otherwise, difference will be estimated at each time point.  Estimates will be 
back-transformed to give geometric LSMs and ratios of geometric LSMs.  The following 
comparisons will be of interest: 

FKB327 to Humira (based on treatment in Study FKB327-003).

Sequence group FKB327-Humira relative to Humira-Humira.

Sequence group Humira-FKB327 relative to Humira-Humira.
Different covariance structures may be considered to improve the fit of the model (eg, 
autoregressive). 
PK samples collected during the non-randomised period (ie, at Weeks 54 and 76) will be 
listed and summarised only, as described in Section 9.5. 
9.5.2 Secondary Pharmacokinetic Analysis 
Due to the potential formation of ADAs, a secondary PK analysis will be performed with 
ADA titre results. 
Full details of the primary and secondary analyses will be provided in the SAP. 
9.6 
Interim Analysis 
An interim analysis of all planned endpoints for all patients will be performed once 
100 patients randomised to FKB327 in study FKB327-002 and also to FKB327 in the 
randomised phase of study FKB327-003 plus 100 patients randomised to Humira in study 
FKB327-002 and also to Humira in the randomised phase of study FKB327 003 have 
reached Week 30 in this study (FKB327-003).  This will provide more than 
100 patient-years of exposure to FKB327 and to Humira across studies FKB327-002 and 
FKB327-003 for comparison.  The analyses to be performed will be detailed in the SAP. 


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9.7 
Data Monitoring Committee 
Following due consideration of the available guidance, including International 
Conference on Harmonisation Note for Guidance E6(R1) (Good Clinical Practice) and 
the European Medicines Agency published Guideline on Data Monitoring Committees 
(EMEA/CHMP/EWP/5872/03 Corr), this study will not require a Data Monitoring 
Committee (DMC). 
The rationale for this decision includes consideration that (i) the indication under 
investigation is not a disease considered to be within the class of life-threatening diseases, 
or within a patient population of a specific vulnerability usually requiring a DMC; (ii) the 
potential risks with FKB327 treatment are expected to follow those associated with 
Humira which are described in detail within the Summary of Product 
Characteristics/Prescribing Information for Humira; and (iii) the processes to be used for 
the recording and reporting of adverse events as described within Section 8 are 
considered adequate to allow the timely identification and management of any 
unexpected safety event without the additional requirement of DMC oversight. 
10 DIRECT ACCESS TO SOURCE DATA DOCUMENTS 
The sponsor, medical experts, study monitors, auditors, Independent Ethics Committee 
(IEC)/IRB, and health authority inspectors (or their agents) will be given direct access to 
source data and documentation (eg, medical charts/records, laboratory test results, 
printouts, videotapes) for source data verification, provided that patient confidentiality is 
maintained in accordance with local requirements. 
The Investigator must maintain the original records (ie, source documents) of each 
patient‟s data at all times.  Examples of source documents are hospital records, office 
visit records, examining physician‟s finding or notes, consultant‟s written opinion or 
notes, laboratory reports, drug inventory, study medication label records, diary data, 
protocol required worksheets, and eCRFs/SitePRO data that are used as the source (see 
Section 3.7). 
The Investigator will maintain a confidential patient identification list that allows the 
unambiguous identification of each patient.  All study-related documents must be kept 
until notification by the Sponsor. 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Protocol Amendments 
After the protocol has been approved by the IEC/IRB, no changes may be made without 
the agreement of the Sponsor.  Any changes to the protocol will be documented in a 
protocol amendment which will be signed and dated by the Investigator and Sponsor, and 
attached to the original protocol.  The IEC/IRB must approve substantial amendments 
before they are implemented. 
The Sponsor and Investigator may take appropriate urgent safety measures to protect the 
patients from any immediate hazard to their health and safety.  Any such measures should 
be taken immediately and may be done without prior Competent Authority(ies) or 


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IEC/IRB approval.  However, the Competent Authority(ies) and IEC/IRB must be 
informed in writing in the form of a substantial amendment within 3 days of the urgent 
safety measures being implemented. 
11.2 Study Monitoring 
The study will be monitored to ensure that the study is conducted and documented 
properly according to the protocol, GCP, and all applicable regulatory requirements. 
On-site visits will be made at appropriate times during the period of the study and will be 
conducted by authorised representatives of the Sponsor.  Monitors (eg, Clinical Research 
Associates [CRAs]) will be given direct access to source documentation in order to check 
the accuracy and consistency of the data recorded in the CRFs.  Remote monitoring may 
be conducted by direct review of electronic data or by contact with site staff. 
In addition, the investigator will work closely with the Monitors and, as needed, provide 
them appropriate evidence that the conduct of the study is being done in accordance with 
applicable regulations and GCP guidelines.  
The Investigator will ensure entry of CRF data, response to data queries, review/signature 
of source documentation and resolution of issues are completed in a timely manner. 
11.3 Audit and Inspection 
The Sponsor, or delegate, may perform a quality assurance audit, and regulatory 
authorities may inspect this study, at any time during or after the study.  The Sponsor and 
Investigator agree to allow auditors and inspectors direct access to all relevant 
documents, and to allocate time to discuss findings with the auditors or inspectors. 
12 ETHICS 
12.1 Informed Consent 
The Investigator, or a qualified person designated by the Investigator, should fully inform 
the patient of all pertinent aspects of the study, including the written information 
approved by the IRB/IEC.  Written informed consent will be obtained from each patient 
before any study-specific procedures or assessments are done and after the aims, 
methods, anticipated benefits, and potential hazards are explained, according to the 
IRB/IEC requirements.  The patient‟s willingness to participate in the study will be 
documented in writing in a consent form, which will be signed and personally dated by 
the patient.  The Investigator will keep the original consent forms, and the patient will be 
given a copy of all written information and the informed consent.  It will also be 
explained to the patients that they are free to refuse entry into the study and free to 
withdraw from the study at any time without prejudice to future treatment. 
12.2 Independent Ethics Committees/Institutional Review Boards 
Before this study starts, the protocol will be submitted to each applicable IEC/IRB for 
review.  As required, the study will not start at a given investigational site before the 
IEC/IRB have given written approval or a favourable opinion. 


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12.3 Confidentiality 
All personal details of the participating patients and the results of the study will be kept 
strictly confidential.  Each patient‟s General Practitioner (or equivalent physician) will be 
informed of the nature and timing of the study.  All unpublished documents including the 
protocol, the eCRF, and the Investigator‟s Brochure are confidential.  Those documents 
cannot be disclosed to a third party without the written consent of the Sponsor.  However, 
submission of those documents to the IEC/IRB is expressly permitted.  The Investigator 
agrees that the Sponsor maintains the right to use the results of this study, in their original 
form and/or in a global report, for submission to governmental and regulatory authorities 
of any country. 
12.4 Declaration of the End of the Study 
For clinical investigational centres located in the EU, a declaration of the end of the 
clinical study (defined as last patient, last visit) will be made according to the procedures 
outlined in Directive 2001/20/ED, Article 10(c); for other countries, local regulations will 
be followed. 
12.5 Investigator Signatory Obligations 
The Clinical Study Report (CSR) will be signed by the Coordinating Investigator for this 
multi-centre study on behalf of all investigators.  The Coordinating Investigator, 
identified by the Sponsor, will either be: 

A recognised expert in the therapeutic area.

An investigator or expert who provided significant contributions to either the
design or interpretation of the study.
13 DATA HANDLING AND RECORD KEEPING 
13.1 Data Collection 
Data management will be performed by XXX.  The data will be entered into the eCRF
within 2 working days of the visit by the designated staff at the site.  Relevant 
electronic Data Clarification Forms (eDCF) will occur on the data once that particular 
data point is saved.  Manual queries may be raised by the CRA as part of Source Data 
Verification (SDV), the Clinical Data Manager (CDM) as part of consistency review of 
the data, or as a result of the coding process.  Patient Recorded Outcomes, joint counts, 
and physician VAS assessments will be recorded electronically at the site using an 
Electronic Patient Recorded Outcome device.  This will be in the form of a SitePad 
provided by XXX.  Data captured on this device will be automatically uploaded to the
XXX database when the device is connected to the internet.  In the event of limited
internet access, the device will store the data offline and will then upload the data 
when a connection to the internet is restored. 
13.2 Data Quality Control 
As this study will be conducted using Electronic Data Capture (EDC), data cleaning will 
commence when First Patient First Visit data is entered into the EDC system. 


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Validation checks run on data which have been entered by site staff into the clinical 
database will be run as the page is saved.  Once the page has been saved, queries will be 
visible for the site.  The site is then able to answer the query at this stage or return to the 
page at a later date.  
The RAVE system will be used to produce and track discrepancies and DCFs and details 
of this information will be automatically auditable. 
13.3 Archiving of Case Report Forms and Source Documents 
Upon completion of the study and post Database Lock, the eCRF (including all audit 
trails and eDCFs) will be copied using an open standard for electronic document 
exchange.  In this case a Portable Document Format (PDF) will be used. 
The PDF copies of the eCRFs will be stored in a DVD and the Study Master File will be 
sent to relevant parties within 3 months of the completion of the final CSR. 
14 FINANCING AND INSURANCE 
Details of financing and insurance will be presented in a separate document that will be 
retained within the Study Master File. 
15 PUBLICATION POLICY 
The Investigator and the Sponsor will discuss the preparation of a manuscript for 
publication in a peer-reviewed professional journal or an abstract for presentation, oral or 
written, to a learned society or symposium.  Either party may undertake the task but both 
must agree to the strategy before the work is started.  Each party will allow the other 
30 days to comment before any results are submitted for publication or presentation.  
Authorship should reflect work done by the Investigators and personnel of the Sponsor, 
in accordance with generally recognised principles of scientific collaboration. 


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16 APPENDICES 
16.1  American College of Rheumatology Revised Criteria for Classification of 
Functional Status in Rheumatoid Arthritis 
Class I 
Completely able to perform usual activities of daily living (self-care, 
vocational, and avocational)a
Class II 
Able to perform usual self-care and vocational activities, but limited 
in avocational activities 
Class III 
Able to perform usual self-care activities, but limited in vocational 
and avocational activities 
Class IV 
Limited ability to perform usual self-care, vocational, and avocational 
activities 
a Usual self-care activities include dressing, feeding, bathing, grooming, and toileting.  Avocational 
(recreational and/or leisure) and vocational (work, school, homemaking) activities are patient-desired and 
age- and sex-specific 
Source: Hochberg MC1, Chang RW, Dwosh I, Lindsey S, Pincus T, Wolfe F.  The American College of 
Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis.  
Arthritis Rheum.  1992 May;35(5):498-502. 


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16.2 Interpretation of TB Screening Results 
Immunosuppressant biologic treatments have been shown to increase risk of TB infection 
or to cause conversion from latent to active TB in some circumstances.  Because of this, 
and in accordance with approved prescribing instructions of Humira, patients must be 
screened for active or latent TB prior to entry to this study. 
Definitions 
Active TB is a disease caused by M. tuberculosis in any part of the body and that is in an 
active state as determined by either a smear or culture taken from any source in the 
person‟s body which tests positive for TB or radiographic evidence.  Individuals with 
active TB are symptomatic, depending upon the location of the disease (most commonly 
in the lungs but also possibly in the brain, kidneys, spine or elsewhere), and can spread 
the infection to others. 
Latent TB is said to exist when an individual is infected with M. tuberculosis, as 
evidenced by a positive Tuberculin Skin Test or Interferon Gamma Release Assay (such 
as QuantiFERON-TB Gold) but is asymptomatic and has no evidence of active infection 
on screening pathology or radiographic tests.  Such individuals do not pass the disease to 
others and should commence a course of prophylactic anti-mycobacterial treatment to 
eliminate the infection at least 3 weeks prior to randomisation in Study FKB327-002 (or 
longer, if local guidelines specify) and commit to completing the course of treatment. 
TB screening 
As part of recording the patient‟s medical history, the patient should be asked if they have 
presented with active or latent TB in the past and whether they have received a Bacillus 
Calmette–Guérin (BCG) vaccination.  They should also be asked if they have been in 
contact with any individuals known to have active TB, or been placed in any 
circumstances that may have exposed them an increased risk of TB infection, such as 
travels to TB endemic regions, close contacts with persons with active TB, work at risk 
(prison, hospitals, etc). 
A QuantiFERON test will be performed at Screening for Study FKB327-002.  A chest 
X-ray should also be performed and reported by a qualified radiologist (if not done within 
12 weeks prior to Screening for Study FKB327-002). 
Patients will be screened for active or latent TB using QuantiFERON-TB Gold-In-Tube 
tests performed by the Central Laboratory and chest X-rays performed locally (see 
Table 1 and Table 2 and Sections 7.2.1.6 and 7.2.4).  A combination of the results of the 
QuantiFERON test, chest X-ray and any other investigations deemed appropriate by the 
Investigator based on clinical signs and symptoms will therefore be used to determine 
study eligibility at transition from FKB327-002 to FKB327-003, and during the studies as 
detailed in Table 4. 
Note: i) Positive results of the QuantiFERON test may be reduced by immune 
suppression.  Indeterminate results are more common in this population than in healthy 
individuals. 


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ii) If an initial QuantiFERON test result is indeterminate, the investigator is advised to
repeat the test to confirm the result. 
iii) The QuantiFERON test should not usually be positive/indeterminate due to prior
BCG vaccination.  In this situation positive/indeterminate results should be taken to 
indicate possible active or latent TB. 
iv) Whilst QuantiFERON test results should revert to negative after successful treatment
for active or latent TB, results may remain positive/indeterminate during and for some 
time after completion of anti-mycobacterial therapy. 


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Table 4: Interpretation of QuantiFERON and Chest X-ray Results (Across Studies 
FKB327-002 and FKB327-003) 
QuantiFERON 
Test Result 
Chest X-ray 
(evidence of current, 
active TB) 
Interpretation 
Positive 
Positive 
Active TB present.  Ineligible for entry to study FKB327-002 
or -003.  If already on study, withdraw patient from study 
treatment, report SAE and treat TB appropriately. 
Positive 
Negative 
Possible latent TB or extra-pulmonary TB present.  Exclude 
extra-pulmonary TB using further investigations appropriate to 
any sign/symptoms.  Once extra-pulmonary TB has been 
excluded and if at Screening for FKB327-002, patient is only 
eligible for study entry after at least 3 weeks of prophylactic 
anti-mycobacterial therapy (or longer, if local guidelines 
specify) and if committed to completing this course of 
treatment.  If these test results are found after Screening, 
discuss with the Medical Monitors and either interrupt study 
dosing until at least 3 weeks of anti-mycobacterial treatment 
have been completed (with a commitment to complete 
treatment) or withdraw patient from study treatment. 
If patient was found with latent TB in the past and can provide 
at Screening complete documentation of previous prophylactic 
treatment, they may be enrolled provided no signs of 
extrapulmonary TB are detected. 
Negative 
Positive 
Likely anomalous QuantiFERON result.  Repeat 
QuantiFERON test if in doubt.  Ineligible for entry to study 
FKB327-002 or -003.  If already on study, withdraw patient 
from study treatment, report SAE and treat TB appropriately. 
Negative 
Negative 
Eligible for study FKB327-002 or -003 
Indeterminate 
Positive 
Likely anomalous QuantiFERON result.  Repeat tests if in 
doubt.  Ineligible for entry to study FKB327-002 or -003.  If 
already on study, withdraw patient from study treatment, report 
SAE and treat TB appropriately. 
Indeterminate 
Negative 
Possible anomalous QuantiFERON result or latent TB.  
Either: 
a)
Repeat QuantiFERON test.  If negative, patient is
eligible for study FKB327-002 or -003.  If positive,
patient is ineligible for either study.  If result still
indeterminate, manage patient as though they have a
positive QuantiFERON result and negative chest
X-ray (see above).  If already on study, discuss with
Medical Monitors.  Consider prophylactic anti-
mycobacterial treatment or withdrawal from study
treatment.
Or: 
b) Repeat QuantiFERON test and perform a PPD test*.
If both are negative, patient is eligible for study
FKB327-002 or -003.  If either is positive, patient is
ineligible for either study.  If either is indeterminate 
exclude from the study.
* PPD injected intracutaneously into the volar surface of the forearm and the result measured as millimetres
of induration after 2 to 3 days.  A positive result requires ≥5 mm of induration. 


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local 
Amendment 1) 
EudraCT No.: 2014-000110-61 
Confidential 
Page 62 
Management of signs/symptoms of TB during the study 
If new signs/symptoms of TB infection develop during the study, perform diagnostic tests 
as above, and any other additional investigation as deemed appropriate by the 
investigator or a TB specialist.  If active TB infection (active or latent) is diagnosed, 
interrupt study treatment and consult the Medical Monitors.  Report active TB infection 
as a medically important SAE.  Treat appropriately. 
Treatment of latent or active TB 
Treatment should be according to local guidelines, which may vary depending upon the 
sensitivity of strains of M. tuberculosis present locally.  As a guide, the US Centers for 
Disease Control and Prevention recommendations are at 
http://www.cdc.gov/TB/publications/LTBI/default.htm.  Patients with latent TB at 
screening should have received appropriate treatment for at least 3 weeks (or longer, 
according to local guidelines) prior to commencement of study treatment and should be 
committed to completing the course of anti-mycobacterial therapy during the study.  If 
latent TB is diagnosed during the study, study treatment should be interrupted until at 
least 3 weeks of anti-mycobacterial treatment have been completed (with a commitment 
to complete the treatment course) or the patient should be withdrawn from study 
treatment. 
In case of any doubt as to the diagnosis of latent TB and the appropriate course of 
anti-mycobacterial therapy, it is advised that a local physician with expertise in the 
treatment of TB is consulted.  
Although QuantiFERON test results may remain positive/indeterminate for some time 
after treatment of active or latent TB, patients with a positive test result at Screening 
should continue to undergo protocol scheduled QuantiFERON tests and chest X-rays in 
order to document TB status and monitor for reinfection/reactivation. 


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local 
Amendment 1) 
EudraCT No.: 2014-000110-61 
Confidential 
Page 63 
16.3 New York Heart Association Classification 
Class I 
Cardiac disease, but no symptoms and no limitation in ordinary 
physical activity, e.g. shortness of breath when walking, climbing 
stairs etc. 
Class II 
Mild symptoms (mild shortness of breath and/or angina) and slight 
limitation during ordinary activity. 
Class III 
Marked limitation in activity due to symptoms, even during less-than-
ordinary activity, e.g. walking short distances (20–100 m).  
Comfortable only at rest. 
Class IV 
Severe limitations.  Experiences symptoms even while at rest. 
Mostly bedbound patients 
Source: The Criteria Committee of the New York Heart Association.  Nomenclature and criteria for 
diagnosis of diseases of the heart and blood vessels.  Boston: Little Brown; 1964. 


Protocol No.: FKB327-003, Version 4.3 (Based on Global Amendment 4 and Local 
Amendment 1) 
EudraCT No.: 2014-000110-61
Confidential 
Page 64 
17 REFERENCES 
1. Chatzantoni K, Mouzaki A.  Anti-TNF-alpha antibody therapies in autoimmune
diseases.  Curr Top Med Chem. 2006;6(16):1707-14.
2. Investigator‟s Brochure for FKB327.  Fujifilm Kyowa Kirin Biologics Co., Ltd.
Version 4, 18 June 2015.
3. Methotrexate.  MedlinePlus.  Available from:
http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682019.html [accessed
21 March 2014]. 
4. Summary of Product Characteristics (SmPC) for EU licensed Humira®.
Available from: http://www.emea.europa.eu [accessed 21 March 2014].
5. den Broeder AA, Joosten LA, Saxne T, Heinegård D, Fenner H, Miltenburg AM,
Frasa WL, van Tits LJ, Buurman WA, van Riel PL, van de Putte LB, Barrera P.
Long term anti-tumour necrosis factor alpha monotherapy in rheumatoid arthritis:
effect on radiological course and prognostic value of markers of cartilage turnover
and endothelial activation.  Ann Rheum Dis. 2002 Apr;61(4):311-8.
6. Poddubnyy D, Rudwaleit M.  Efficacy and safety of adalimumab treatment in
patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis.
Expert Opin Drug Saf.  2011;10:655-73.
7. What Is ACR (American College of Rheumatology) Criteria?  18 November
2012.  Available from: http://arthritis.about.com/od/trials/f/ACR_criteria.htm
[accessed 21 March 2014].
8. Fries JF, Spitz P, Kraines RG, Holman HR.  Measurement of patient outcome in
arthritis.  Arthritis Rheum.  1980;23:137 45.
9. Bruce B, Fries J.  The Stanford Health Assessment Questionnaire: Dimensions
and Practical Applications.  Health and Quality of Life Outcomes.  2003;1:20.
10. Aletaha D, Smolen J, Ward MM.  Measuring function in rheumatoid arthritis:
identifying reversible and irreversible components.  Arthritis and Rheumatism.
2006;54:2784 92.
11. The DAS28 score website.  Radboud University Nijmegen.  2013.  Available
from: www.das-score.nl [accessed 21 March 2014].
12. Mazurek GH, Villarino ME.  Guidelines for Using the QuantiFERON®-TB Test
for Diagnosing Latent Mycobacterium tuberculosis Infection.  Centers for Disease
Control and Prevention.  31 January 2003.  Available from:
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5202a2.htm [accessed 21 March
2014]. 
13. FDA Guidance for Industry on Skin Irritation and Sensitization Testing of
Generic Transdermal Drug Products.  US Department of Health and Human
Services Food and Drug Administration Center for Drug Evaluation and Research
(CDER).  December 1999

SAP_001.pdf: 
Statistical Analysis Plan 
Protocol Number: FKB327-003 
An Open-label Extension Study to Compare the Long-term 
Efficacy, Safety, Immunogenicity and Pharmacokinetics of 
FKB327 and Humira® in Patients with Rheumatoid Arthritis on 
Concomitant Methotrexate (ARABESC-OLE) 
Customer: Fujifilm Kyowa Kirin Biologics Co., Ltd (FKB), Tokyo 100-8185, 
Japan 
Compound: FKB327 (adalimumab) 
Study Phase: Phase 3 
Version: 4.0.0 
Date:   10 JUL 2018 
Author:  


Statistical Analysis Plan 
Fujifilm Kyowa Kirin Biologics Co Ltd 
Protocol Number: FKB327-003  
Document: S:\Q_054\Q_01341\EU 05 DBL Run\Prog_Stat\Documentation\SAP\FKB327-003 
Final Run SAP V4.0.0.doc 
Author:  
Version and Date: Version 4.0.0, 10 JUL 2018 
Page 2 of 68 
Confidential 
VERSION CONTROL 
Version 
Date 
Author(s) 
Changes/Comments 
Version 1.0.0 
25AUG2016 
Version 1 issued 
Version 2.0.0 
05JUN2017 
Updated section 1 on general 
features of the SAP + new IA 
rationale brief introduction. 
Specified Auto-Injector as part 
of the secondary objectives. 
Added rationale for second 
Interim Analysis to Section 5.4. 
Added details to Section 6 
relevant subsections related to 
all additional analyses included 
after finalisation of SAP v1.0.0. 
Created a Section 7 related to 
outputs to be produced only for 
the final analysis. 
Details on changes from V1.0.0 
of the SAP to 2.0.0 added in 
Section 8.2. 
Version 3.0.0 
19OCT2017 
Updated section 1 with new IA 
rationale brief introduction. 
Details on changes from V2.0.0 
of the SAP to 3.0.0 added in 
Section 8.3 
Version 4.0.0 
10JUL2018 
Added 
in 
Additional 
D120 
tables 
requested 
for 
CSR, 
which consider summaries of 
Adverse Events, Neutralizing 
Antibody, Anti-Drug Antibody 
Titres 
and 
Injection 
site 
reactions 
stratified 
by 
administration 
method 
(pre-
filled syringe or auto-injector) 
whilst exposed to FKB327. 
Introduction section 
is also 
updated to reflect most recent 
SAP versioning, purpose and 
DBL date. 
Sections 6.8.2, 6.9.4 and 6.9.5 
are also updated to reflect the 
above summaries.  


Statistical Analysis Plan 
Fujifilm Kyowa Kirin Biologics Co Ltd 
Protocol Number: FKB327-003  
Document: S:\Q_054\Q_01341\EU 05 DBL Run\Prog_Stat\Documentation\SAP\FKB327-003 
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Version and Date: Version 4.0.0, 10 JUL 2018 
Page 3 of 68 
Confidential 
Add 
additional 
column 
for 
outputs which are included in 
final 
analysis 
and 
update 
abbreviation 
list 
with 
Auto-
Injector 
Details on changes from V3.0.0 
of the SAP to 4.0.0 added in 
Section 8.3 
Update 
the 
title 
of 
table 
14.3.1.2.10, 
as 
per 
FKB 
request, and change mentions 
of drug-related to treatment 
related where appropriate. 


Statistical Analysis Plan 
Fujifilm Kyowa Kirin Biologics Co Ltd 
Protocol Number: FKB327-003  
Document: S:\Q_054\Q_01341\EU 05 DBL Run\Prog_Stat\Documentation\SAP\FKB327-003 
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TABLE OF CONTENTS 
1 
INTRODUCTION ....................................................................................................................... 9 
1.1 
Rationale .................................................................................................................................... 9 
2 
SUMMARY OF THE PROTOCOL .......................................................................................... 10 
2.1 
Study Objectives ...................................................................................................................... 10 
2.1.1 
Primary Objective .................................................................................................................... 10 
2.1.2 
Secondary Objectives .............................................................................................................. 10 
2.2 
Study Design ........................................................................................................................... 10 
2.3 
Sample Size Determination ..................................................................................................... 14 
2.4 
Schedule of Events .................................................................................................................. 15 
3 
PATIENT ANALYSIS SETS .................................................................................................... 21 
3.1 
Safety Analysis Set .................................................................................................................. 21 
3.2 
Full Analysis Set (FAS) ............................................................................................................ 21 
3.3 
Pharmacokinetic Analysis Set (PKAS) .................................................................................... 21 
4 
STUDY MEASURES ............................................................................................................... 21 
4.1 
Assessment of Efficacy ........................................................................................................... 21 
4.1.1 
Secondary Efficacy Variables .................................................................................................. 21 
4.2 
Safety Measures ...................................................................................................................... 24 
4.2.1 
Exposure to Study Medication ................................................................................................. 24 
4.2.2 
Adverse Events ....................................................................................................................... 24 
4.2.3 
Clinical Laboratory Tests ......................................................................................................... 26 
4.2.4 
Vital Signs Evaluations ............................................................................................................ 28 
4.2.5 
Physical Examination .............................................................................................................. 28 
4.2.6 
Chest X-ray .............................................................................................................................. 28 
4.2.7 
Injection Site Assessment ....................................................................................................... 28 
4.3 
Other Measures ....................................................................................................................... 29 
4.3.1 
Patient Disposition ................................................................................................................... 29 
4.3.2 
Baseline Patient Characteristics .............................................................................................. 29 
4.3.3 
Medical History ........................................................................................................................ 29 
4.3.4 
Prior and Concomitant Medications ........................................................................................ 30 
4.3.5 
Treatment Compliance ............................................................................................................ 31 
4.3.6 
Immunogenicity Assessments ................................................................................................. 31 


Statistical Analysis Plan 
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4.3.7 
Pharmacokinetic Assessments................................................................................................ 31 
5 
STATISTICAL METHODOLOGY............................................................................................ 31 
5.1 
General Statistical Methods ..................................................................................................... 31 
5.1.1 
General Information ................................................................................................................. 31 
5.1.2 
Default Descriptive Statistics and Data Rules ......................................................................... 31 
5.2 
Hypotheses and Decision Rules.............................................................................................. 32 
5.2.1 
Primary Hypothesis ................................................................................................................. 32 
5.2.2 
Secondary Hypotheses ........................................................................................................... 32 
5.3 
Handling of Missing Data ......................................................................................................... 32 
5.3.1 
Safety endpoints ...................................................................................................................... 32 
5.3.2 
Other Endpoints ....................................................................................................................... 33 
5.4 
Interim Analyses ...................................................................................................................... 33 
6 
STATISTICAL ANALYSES ..................................................................................................... 34 
6.1 
Patient Disposition ................................................................................................................... 34 
6.2 
Protocol Deviations .................................................................................................................. 35 
6.3 
Demographics.......................................................................................................................... 35 
6.4 
Baseline Patient Characteristics .............................................................................................. 35 
6.5 
Medical History and Concurrent Medical Conditions .............................................................. 36 
6.6 
Prior and Concomitant Medication .......................................................................................... 36 
6.7 
Efficacy Analyses .................................................................................................................... 37 
6.7.1 
Secondary Efficacy Analyses .................................................................................................. 37 
6.8 
Safety Analyses ....................................................................................................................... 38 
6.8.1 
Treatment Compliance and Exposure to Study Medication .................................................... 38 
6.8.2 
Adverse Events ....................................................................................................................... 38 
6.8.3 
Clinical Laboratory Parameters ............................................................................................... 40 
6.8.4 
Vital Signs ................................................................................................................................ 41 
6.9 
Other Analyses ........................................................................................................................ 41 
6.9.1 
Physical Examination .............................................................................................................. 41 
6.9.2 
Chest X-ray .............................................................................................................................. 41 
6.9.3 
QuantiFERON Test ................................................................................................................. 41 
6.9.4 
Injection Site Assessment ....................................................................................................... 41 
6.9.5 
Immunogenicity Analysis ......................................................................................................... 42 
6.9.6 
Pharmacokinetic Analysis ........................................................................................................ 42 


Statistical Analysis Plan 
Fujifilm Kyowa Kirin Biologics Co Ltd 
Protocol Number: FKB327-003  
Document: S:\Q_054\Q_01341\EU 05 DBL Run\Prog_Stat\Documentation\SAP\FKB327-003 
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7 
FINAL ANALYSIS ................................................................................................................... 44 
7.1 
Overall Disposition ................................................................................................................... 44 
7.2 
ACR20/50/70 Response at Week 76 ...................................................................................... 44 
8 
CHANGES TO THE PLANNED ANALYSES ......................................................................... 44 
8.1 
Changes to the Analyses Described in the Study Protocol and Protocol 
Amendments............................................................................................................................ 44 
8.2 
Changes from the Statistical Analysis Plan Version 1.0 to Version 2.0 .................................. 45 
8.3 
Changes from the Statistical Analysis Plan Version 2.0 to Version 3.0 .................................. 46 
8.4 
Changes from the Statistical Analysis Plan Version 3.0 to Version 4.0 .................................. 46 
9 
ATTACHMENTS AND APPENDICES .................................................................................... 47 
9.1 
Attachment 1 List of Tables, Listings and Figures................................................................... 47 
9.2 
Appendix 1 Joints Considered for the 68/66 and 28 Joint Counts .......................................... 66 
10 
REFERENCES ........................................................................................................................ 68 


Statistical Analysis Plan 
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Protocol Number: FKB327-003  
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List of Abbreviations 
Abbreviation 
Definition 
ACR 
ADAs 
AE 
AESI 
AI 
ALT 
AST 
ATC 
BLA 
CDISC 
CI 
CRP 
CS 
CV 
DAS28 
DMARD 
ECG 
eCRF 
eow 
 
ESR 
EU 
EULAR 
FAS 
GCP 
GGT 
GH 
HAQ-DI 
Hb 
LSM 
MCH 
MCHC 
MCV 
MedDRA 
MMP-3 
MTX 
NEC 
NCS 
NSAID 
OLE 
PDF 
PFS 
PK 
PKAS 
PRO 
PT 
RA 
American College of Rheumatology 
Anti-drug antibodies 
Adverse event 
Adverse Events of Special Interest 
Auto-Injector 
Alanine transaminase 
Aspartate transaminase 
Anatomical Therapeutic Chemical 
Biologics Licence Application 
Clinical Data Interchange Standards Consortium 
Confidence interval 
C-reactive protein 
Clinically significant 
Coefficient of variation 
Disease Activity Score 28 
Disease modifying anti-rheumatic drug 
Electrocardiogram 
Electronic Case Report Form 
Every other week 
 
Erythrocyte sedimentation rate 
European Union 
European League Against Rheumatism 
Full Analysis Set 
Good Clinical Practice 
Gamma glutamyl transferase 
Global Health 
Health Assessment Questionnaire Disability Index 
Haemoglobin 
Least squares means 
Mean corpuscular haemoglobin 
Mean corpuscular haemoglobin concentration 
Mean corpuscular volume 
Medical Dictionary for Regulatory Activities 
Matrix metalloproteinase-3 
Methotrexate  
Not elsewhere classified 
Not clinically significant 
Non-steroidal anti-inflammatory drug 
Open-label extension 
Portable Document Format 
Pre-filled syringe 
Pharmacokinetics 
PK Analysis Set 
Patient reported outcomes 
Preferred Term 
Rheumatoid arthritis 


Statistical Analysis Plan 
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Protocol Number: FKB327-003  
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RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
sc 
Subcutaneous 
SD 
Standard deviation 
SI 
Système Internationale 
SJC 
Swollen joint count 
SLE 
Systemic lupus erythematosus 
SMQ 
Standardised MedDRA Queries 
SOC 
System Organ Class 
t1/2 
Elimination half-life 
TB 
Tuberculosis 
TJC 
Tender joint count 
tmax 
Time of maximum concentration 
TNF-α 
Tumour necrosis factor-alpha 
US(A) 
United States of America 
VAS 
Visual analogue scale 
WBC 
White blood cell 


Statistical Analysis Plan 
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Protocol Number: FKB327-003  
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1 
Introduction 
This statistical analysis plan (SAP) is being updated from the FKB327-003 study SAP version 3.0.0 
dated 19 OCT 2017and based on protocol FKB327-003 Version 4.4/4.5 (based on Global amendment 
5) dated 19 MAY 2017. This SAP contains a complete and detailed specification of the statistical and
pharmacokinetic (PK) analyses for interim and final analyses and should be used and authorised in 
conjunction with the document ‘FKB327-003 Final Run shells V4.0.0', dated  XX JUL 2018. 
A Marketing Authorisation Application (MAA) for FKB327 was submitted to the European Medicines 
Agency (EMA) in April 2017 using data from a planned interim analysis of study FKB327-003 whose 
rationale, timing and content were detailed in FKB327-003 Statistical Analysis Plan Version 3.0.0. FKB 
decided that a further interim analysis of study FKB327-003 should be performed in order to be able to 
provide updated safety, efficacy, PK and immunogenicity data on the ongoing FKB327-003 study, 
should this be requested. The need for this additional interim analysis and its regulatory implications 
were documented in the internal “Document Revision Assessment Form” (FKB Form 302) signed off on 
28th April 2017. A Non-substantial Global Amendment to the study protocol was then prepared and 
signed off on 19th May 2017. A data-base lock and subsequent interim analysis was planned for July 
2017 based on data collected for all patient visits that occurred from the beginning of the study up until 
the 30th April 2017. Following this additional interim analysis, the final DBL took place on 13APR2018, 
and during the reporting process that followed it was agreed to create additional tables to complement 
assessments of safety, efficacy and immunogenicity, following specific requirements from the 
regulators during the review process. The present SAP version includes details for the creation of such 
tables.  
This version of the statistical analysis plan has only been used for the final analysis of FKB327-003 
study, although guidance is provided in the Attachments section with respect to which outputs have 
been created for which analysis (i.e. either interim and/or final).  
1.1 Rationale 
This Phase 3 open-label extension study will compare the long-term safety, efficacy, 
immunogenicity and multiple-dose PK of FKB327 with Humira in patients with rheumatoid arthritis 
(RA). This study will commence once a patient completes Study FKB327-002 and opts to enter 
this extension study.  
In order to make a long-term treatment comparison, a proportion of patients in the first part of this 
open-label extension study will receive Humira, and the findings in that treatment arm will be 
compared to those for patients receiving FKB327. Therefore, in addition to providing longer-term 
data regarding the safety, immunogenicity and efficacy of FKB327, the study will provide the 
opportunity for a descriptive and objective comparison of these parameters between FKB327 and 
Humira over longer term treatment (approximately 1 year in total from the start of Study 
FKB327-002 to Visit 7 (Week 30) of Study FKB327-003). Post Week 30, all patients will transition 
on to FKB327 in order to gain further long-term exposure on FKB327.  Furthermore, the study will 
also permit an evaluation of the above mentioned parameters in patients switching between the 
products after randomisation and could therefore provide relevant data for subsequent clinical 
practice. 
The study will only enroll patients who completed Week 24 visit procedures and 22 weeks of 
treatment in the double-blind study FKB327-002 (with a minimum of 9 doses of study drug 
received). 


Statistical Analysis Plan 
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2 
Summary of the Protocol 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective of the study is to compare the safety of long-term treatment with FKB327 
and Humira in patients with RA. 
2.1.2 Secondary Objectives 
The secondary efficacy objectives of the study comprise the following: 

To compare the efficacy of long-term treatment with FKB327 and Humira in patients with RA.

To compare the proportion of patients developing anti-drug antibodies (ADAs) on long-term
treatment with FKB327 and Humira in patients with RA.

To compare the PK of long-term treatment with FKB327 and Humira in patients with RA.

To evaluate safety, changes in efficacy, and changes in PK and immunogenicity in patients
who are switched from Humira in the preceding FKB327-002 double-blind study to FKB327 in
the FKB327-003 open-label extension (OLE) study, and of patients who are switched from
FKB327 to Humira, respectively.

To evaluate safety, changes in efficacy, PK and immunogenicity in patients who are switched
from FKB327 in the preceding FKB327-002 double-blind study to Humira in the FKB327-003
OLE study, and then switch back to FKB327 in the second part of the FKB327-003 OLE study
(from Week 30; double switch).

To evaluate safety and PK profile of patients switching to administration of FKB327 using an
Auto-Injector (AI) device during Period II (i.e. on or after Week 30) as opposed to the Pre-filled
Syringe (PFS) device used during Period I.
2.2 Study Design 
The first part of this study is an open-label, randomised, comparative, multi-centre, 2-arm 
extension Phase 3 study in patients with RA who are taking a stable dose of Methotrexate (MTX) 
and folate who will continue from the preceding Study FKB327-002. Eligible patients who 
complete Study FKB327-002 and consent to participate in this open-label extension study will be 
randomised to receive treatment with either FKB327 40 mg every other week (eow) or Humira 40 
mg eow from Week 0 to Week 28. Patients who received FKB327 in Study FKB327-002 will 
receive FKB327 or Humira in a 2:1 ratio and patients who received Humira in Study FKB327-002 
will receive Humira or FKB327 in a 2:1 ratio. The second part of the study is an open-label, single 
arm extension in which all patients receive prolonged FKB327 treatment from Week 30 to 
Week 76, followed by a 4-week follow-up period. Scheduled clinic visits will be conducted at 
Weeks 0, 2, 4, 8, 12, 24, 30, 32, 34, 42, 54, 66, 76, and 80, where Week 0 is intended as the 
Baseline visit occurring within this extension study (see Table 3). The patient or carer will be 
allowed to administer interim doses of study drug at home (eow) between clinic visits (see Table 
3). FKB327 in an AI device presentation will be introduced during the open-label follow-up 
treatment period depending on availability of the Auto-injector relative to the patient’s progress 
within the study.  
The study design is presented in Figure 1. 


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Figure 1 
Study Schema 
End of Period I is defined as just before treatment at Week 30. 
Randomised patients will be administered the Week 0 study drug dose after the Week 24 study 
procedures for Study FKB327-002 have been performed.  
FKB327-002 
study 
FKB327-003 
Period I - 
Randomised 
OLE Treatment 
Period 
FKB327-003 
Period II - 
FKB327 Single 
Treatment 
Period 


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If, for any reason, it is not possible to conduct Week 24 visit procedures for study FKB327-002 
and Week 0 procedures for this study on the same day, the maximum permitted interval between 
study drug doses in the 2 studies (Week 22 dosing in Study FKB327-002 and Week 0 dosing in 
this study) will be 4 weeks. If Week 24 visit procedures for Study FKB327-002 and Week 0 
procedures have an interval of 2 weeks or more between them, then some procedures will need 
to be repeated prior to dosing at Week 0 for this study (see Table 4 – all procedures marked with 
an asterisk).  
The study schema presented in Figure 1 assumes that approximately 544 patients out of 680 
(80%) complete Study FKB327-002 and are eligible for Study FKB327-003. A drop-out rate of 
approximately 20% is anticipated in the present study by the time all remaining patients are 
switched to FKB327 at Week 30, so an estimated 435 patients will enter the single-arm part of the 
study. However, all patients who are eligible to enter this study from FKB327-002 may do so even 
if the estimated numbers are exceeded.  
Tables 1 and 2 present the treatment group and sequence labels that will be used in all outputs. 
The choice of presenting the 2-term or 3-term treatment sequence will depend on the output, as 
detailed in the shells. 
Table 1 
Study Treatments 
Actual Treatment 
Treatment Label 
US-licensed Humira 40 mg 
Humira 
FKB327 40 mg 
FKB327  
Table 2 
Treatment Sequence 
Treatment Groups 
Treatment Sequence 
FKB327-002 
FKB327-003 
(Period I) 
FKB327-003 
(Period II) 
2-Term 
3-Term 
FKB327 
FKB327 
FKB327 
F-F 
F-F-F 
FKB327 
Humira 
FKB327 
F-H 
F-H-F 
Humira 
FKB327 
FKB327 
H-F 
H-F-F 
Humira 
Humira 
FKB327 
H-H 
H-H-F 
Table 3 presents the visit labels that will be used in all outputs. 
Table 3 
Study Visits 
Visit Week 
Visit Type 
Visit label 
Week 0 (from Study FKB327-002) 
Clinic 
Baseline_002 
Week 0 
Clinic 
Baseline_003 
Week 2 
Clinic 
Week 2 
Week 4 
Clinic 
Week 4 
Week 6 
Home 
Week 6 
Week 8 
Clinic 
Week 8 


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Visit Week 
Visit Type 
Visit label 
Week 10 
Home 
Week 10 
Week 12 
Clinic 
Week 12 
Week 14 
Home 
Week 14 
Week 16 
Home 
Week 16 
Week 18 
Home 
Week 18 
Week 20 
Home 
Week 20 
Week 22 
Home 
Week 22 
Week 24 
Clinic 
Week 24 
Week 26 
Home 
Week 26 
Week 28 
Home 
Week 28 
Week 30 
Clinic 
Week 30 
Week 32 
Clinic or Home** 
Week 32
Week 34 
Clinic or Home** 
Week 34
Week 36 
Home 
Week 36 
Week 38 
Home 
Week 38 
Week 40 
Home 
Week 40 
Week 42 
Clinic 
Week 42 
Week 44 
Home 
Week 44 
Week 46 
Home 
Week 46 
Week 48 
Home 
Week 48 
Week 50 
Home 
Week 50 
Week 52 
Home 
Week 52 
Week 54 
Clinic 
Week 54 
Week 56 
Home 
Week 56 
Week 57 
Home 
Week 57 
Week 58 
Home 
Week 58 
Week 60 
Home 
Week 60 
Week 62 
Home 
Week 62 
Week 64 
Home 
Week 64 
Week 66 
Clinic 
Week 66 
Week 68 
Home 
Week 68 


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Visit Week 
Visit Type 
Visit label 
Week 70 
Home 
Week 70 
Week 72 
Home 
Week 72 
Week 74 
Home 
Week 74 
Week 76 
Clinic 
Week 76 
Week 80 
Clinic 
Week 80 
End of Study 
Clinic 
End of Study (EOS) 
Auto-Injector Start 
AIS 
** The Week 32 and 34 visits are to be performed in the clinic for patients who have switched from Humira to FKB327 (treatment sequences F-H-F and 
H-H-F) only. Patients remaining on FKB327 can dose at home. 
2.3 Sample Size Determination 
As this is an open-label extension of Study FKB327-002, no formal sample size has been 
calculated. The number of patients is based on the assumed number of patients expected to 
complete Study FKB327-002 and the number of expected drop-outs in Study FKB327-003. 


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2.4 Schedule of Events 
Table 4 presents the schedule of study events for the randomised OLE part of the study (Period I) and Table 5 presents the study schedule for the 
treatment follow up period (Period II). 
Table 4 
Schedule of Study Events – Randomised Treatment Period 
Study Visit 
Treatment Period 
Visit 
1a 
2 
3 
NA 
4 
NA 
5 
NA 
6 
NA 
Week 
0 
2 
4 
6 
8 
10 
12 
14-22 
24 
26 and 28b
Visit Type 
Clinic 
Clinic 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Informed consent 
● 
Medical history 
including contact with 
active TB 
●* 
Check of concomitant 
medication 
(●)* 
● 
● 
● 
● 
Physical examination 
(●) 
Weight 
(●) 
● 
Vital signs 
(●) 
● 
● 
● 
● 
12-lead ECG 
(●) 
Chest X-ray
(●)c
Randomisation 
● 
Provide patient with 
study medication and 
dosing diary, and 
instruct on their use 
● 
● 
● 
● 
Provide Patient 
Instruction Sheet 
● 
● 
● 
● 
Dosing Diary 
● 
● 
● 
● 
Study medication 
administration (mg) 
40d
40d
40d
40 
40 
40 
40 
40 (eow) 
40 
40 (eow) 


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Study Visit 
Treatment Period 
Visit 
1a 
2 
3 
NA 
4 
NA 
5 
NA 
6 
NA 
Week 
0 
2 
4 
6 
8 
10 
12 
14-22 
24 
26 and 28b
Visit Type 
Clinic 
Clinic 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Concomitant MTX and 
folate 
Haematology 
(●)* 
● 
● 
● 
● 
Serum chemistry 
(●)* 
● 
● 
● 
● 
Dipstick urinalysise
(●)* 
● 
● 
● 
● 
Pregnancy testingf
(●)* 
● 
● 
● 
● 
QuantiFERON testg
● 
CRPh,i
(●)* 
● 
● 
● 
● 
ESRj
(●)* 
MMP-3 
(●) 
Serum drug 
concentration 
(●)* 
● 
● 
ADA test 
(●)* 
● 
● 
Injection site 
assessment (including 
injection site pain VAS) 
● 
Adverse eventsk
Assessment of 
tender/swollen joints 
(68/66 joints)h,i
(●)* 
● 
● 
● 
● 
Patient global 
assessment of disease 
activity VASh,i
(●)* 
● 
● 
● 
● 
Patient assessment of 
pain VASi
(●)* 
● 
● 
● 
● 
Patient questionnaire 
for physical function 
(HAQ-DI)i
(●)* 
● 
● 
● 
●


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Study Visit 
Treatment Period 
Visit 
1a 
2 
3 
NA 
4 
NA 
5 
NA 
6 
NA 
Week 
0 
2 
4 
6 
8 
10 
12 
14-22 
24 
26 and 28b
Visit Type 
Clinic 
Clinic 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Physician global 
assessment of disease 
activity VASi
(●)* 
● 
● 
● 
● 
TB = tuberculosis; ECG = electrocardiogram; eow = every other week; MTX = methotrexate; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; 
ADA = anti-drug antibody; HAQ-DI = Health Assessment Questionnaire Disability Index; VAS = visual analogue scale; DAS = disease activity score; MMP-3 = 
matrix metalloproteinase 3. 
Note: for Visit 2 and Visit 3 there will be a window of ±3 days.  For example, the Week 2 visit (Visit 2) should take place on Day 15, but could be as early as 
Day 12 or as late as Day 18. From Visit 4 (Week 8) onwards, a window of ±7 days is permissible. 
At each visit all procedures are to be performed prior to dosing except recording of injection site reaction and any post-injection AEs. 
a  Pre-dose Week 0 assessments (represented by ‘(●)’ in the table) are performed as part of the Week 24 visit of Study FKB327-002, which is the same as the 
Week 0 visit in this study. 
b  The Week 28 dose is the last dose of randomised study drug (FKB327 or Humira).  All patients will then switch to dosing with FKB327 for the remainder of the 
study. 
c  X-ray to be performed unless patient has negative QuantiFERON test at Week 22 of study FKB327-002 with no signs/symptoms suggestive of lower 
respiratory infection. 
d  The first 3 doses of study drug (Weeks 0, 2, and 4) will be self-administered at the study site after training has been given.  Subsequent doses may be 
administered by the patient or carer at home, except when clinic visits for blood tests and efficacy assessments are scheduled when the dose must be given 
after blood samples are drawn. 
e  If the dipstick reveals any clinically significant abnormalities a second sample (provided on the same day if, possible), should be sent to the central laboratory.  
f  Females of childbearing potential only. 
g  May be omitted if patient is receiving anti-mycobacterial treatment for latent tuberculosis. 
h  Assessment contributes to DAS28. 
i  Assessment contributes to determination of achievement of ACR20, ACR50, and ACR70 response. 
j  Part of Study FKB327-002 only. 
k  Ongoing events from Study FKB327-002 will be recorded in that study.  Any new or worsening events will be recorded for Study FKB327-003. 
* Procedures marked with an asterisk need to be repeated if there is a delay of 2 weeks or more (up to the maximum allowed delay of 4 weeks) between Week
24 of study FKB327-002 and Week 0 of study FKB327-003, for example, due to the need to interrupt study drug while serious infection or latent tuberculosis is 
treated. 


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Table 5  
 Study Schedule - Follow-up Treatment Period 
Study Visit 
Treatment Period 
Visit 
7 
8 & 9 
NA 
10 
NA 
11 
NA 
12 
NA 
13 
14 
Week 
30 
32 & 34 
36-40 
42 
44-52 
54 
56-64 
66 
68-74 
76 
80 or 
EOS 
Visit Type 
Clinic 
Clinic or 
Homea
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Clinic 
Check of 
concomitant 
medication 
● 
● 
● 
● 
● 
● 
Physical 
examination 
● 
Vital signs 
● 
Chest X-rayb
● 
●
Provide patient with 
study medication 
and dosing diary, 
and instruct on their 
use 
● 
● 
● 
● 
● 
Provide Patient 
Instruction Sheet 
● 
● 
● 
● 
● 
FKB327 
administration (mg) 
40c
40c
40 (eow) 
40 
40 (eow) 
40 
40 (eow) 
40 
40 (eow) 
40 
Dosing Diary 
● 
● 
● 
● 
● 
Concomitant MTX 
and folate 
Haematology 
● 
● 
● 
● 
● 
● 
Serum chemistry 
● 
● 
● 
● 
● 
● 
Dipstick urinalysisd
● 
● 
● 
● 
● 
● 
Pregnancy testinge
● 
● 
● 
● 
● 
QuantiFERON testf
● 
●g 


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Study Visit 
Treatment Period 
Visit 
7 
8 & 9 
NA 
10 
NA 
11 
NA 
12 
NA 
13 
14 
Week 
30 
32 & 34 
36-40 
42 
44-52 
54 
56-64 
66 
68-74 
76 
80 or 
EOS 
Visit Type 
Clinic 
Clinic or 
Homea
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Clinic 
CRPh,i
● 
● 
● 
● 
● 
● 
Serum drug 
concentration 
● 
● 
● 
● 
ADA test 
● 
● 
● 
● 
Injection site 
assessment 
(including injection 
site pain VAS)j
● 
Adverse events 
Assessment of 
tender/swollen joints 
(68/66 joints)h,i
● 
● 
● 
● 
● 
● 
Patient global 
assessment of 
disease activity 
VASh,i
● 
● 
● 
● 
● 
● 
Patient assessment 
of pain VASi
● 
● 
● 
● 
● 
● 
Patient 
questionnaire for 
physical function 
(HAQ-DI)i
● 
● 
● 
● 
● 
● 
Physician global 
assessment of 
disease activity VASi
● 
● 
● 
● 
● 
●


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Study Visit 
Treatment Period 
Visit 
7 
8 & 9 
NA 
10 
NA 
11 
NA 
12 
NA 
13 
14 
Week 
30 
32 & 34 
36-40 
42 
44-52 
54 
56-64 
66 
68-74 
76 
80 or 
EOS 
Visit Type 
Clinic 
Clinic or 
Homea
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Home 
Clinic 
Clinic 
EOS = end-of-study; eow = every other week; MTX = methotrexate; CRP = C-reactive protein; ADA = anti-drug antibody; HAQ-DI = Health Assessment 
Questionnaire Disability Index; VAS = visual analogue scale; MMP-3 = matrix metalloproteinase-3; DAS = disease activity score. 
Note: for all visits during the follow-up treatment period, a window of ±7 days is permissible. 
At each visit all procedures are to be performed prior to dosing except recording of injection site reaction and any post-injection AEs. 
a  The Week 32 and 34 visits are to be performed in the clinic for patients who have switched from Humira to FKB327 only.  Patients remaining on FKB327 
can dose at home. 
b X-ray to be performed at Week 30/80 or EOS unless patient has negative QuantiFERON test at Week 24/76 or EOS, respectively, with no 
signs/symptoms suggestive of lower respiratory infection. 
c  For patients switching from Humira to FKB327, the first 3 doses of FKB327 (Weeks 30, 32, and 34) will be self-administered at the study site after training 
has been given.  Subsequent doses of FKB327 may be administered by the patient or carer at home, except when clinic visits for blood tests and efficacy 
assessments are scheduled when the dose must be given after blood samples are drawn. 
d  If the dipstick reveals any clinically significant abnormalities a second sample (provided on the same day if, possible), should be sent to the central 
laboratory.  
e  Females of childbearing potential only. 
f  May be omitted if patient is receiving anti-mycobacterial treatment for latent tuberculosis. 
g  EOS only. 
h  Assessment contributes to DAS28. 
i  Assessment contributes to determination of achievement of ACR20, ACR50, and ACR70 response. 
j  An additional injection site assessment will be performed at the time of switching to the AI during the open-label follow up treatment period 


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3 
Patient Analysis Sets 
3.1 Safety Analysis Set 
The safety set will comprise all patients who gave consent for this study and received at least 1 
dose of treatment in the FKB327-003 study. The safety analysis will be based on the Safety 
Analysis Set.  Patient safety data will be analysed according to treatment actually received (for 
both studies). 
3.2 Full Analysis Set (FAS) 
The FAS will comprise all patients who received at least 1 dose of the randomised treatment and 
who had at least 1 evaluable efficacy measurement after their first dose of randomised treatment 
in the FKB327-003 study. The efficacy analysis will be based on the FAS. Patients will be 
analysed according to their randomised treatment sequence (for both studies) or randomised 
treatment group (see Table 2). 
3.3 Pharmacokinetic Analysis Set (PKAS) 
The PKAS will include all patients who received at least 1 dose of the randomised treatment and 
have at least 1 serum adalimumab concentration result after receiving randomised treatment in 
the FKB327-003 study. Patients will be analysed according to the treatment they actually received 
in the FKB327-003 study. 
4 
 Study Measures 
This section describes the measures that were collected and/or derived during the study at the 
time points specified in the Schedule of Events (Table 4 and Table 5).  This includes efficacy, 
safety, immunogenicity and patient characteristics data. 
4.1 Assessment of Efficacy 
4.1.1 Secondary Efficacy Variables 
4.1.1.1 Measured Variables 
4.1.1.1.1 
Tender and Swollen Joint Counts (68/66 Joints) 
Counts of tender and swollen joints from amongst 68/66 selected joints will be performed by a 
trained and qualified joint assessor as scheduled in Table 4 and Table 5 using standardised 
techniques recommended by the European League Against Rheumatism (EULAR). XXX will send 
SAS (Statistical Analysis System) datasets of the joint counts.  
If, at any visit, a joint is not evaluable for any reason, this will be recorded on the patient-reported 
outcomes devices, SitePRO. If this is due to amputation, the joint will automatically be recorded 
as unevaluable for the remainder of the study. If a joint is not evaluable for any other reason (such 
as infection, injury or surgery), the joint should be reassessed for evaluability at each visit by the 
joint examiner. If the joint is not evaluable due to an injection into the joint it should be marked as 
not evaluable for a period of 12 weeks post injection. Missing or unevaluable joints will be treated 
as follows: 

If the joint assessment is missing, then the joint will be regarded as non-tender and non-
swollen at Baseline and tender and swollen at post-Baseline.


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
If the joint is assessed as unevaluable due to prior surgery at any visit, then the joint will
be counted as non-tender and non-swollen at Baseline and all post-Baseline
assessments.

If the joint is unevaluable due to surgery conducted during the study, then the joint will be
counted as tender and swollen from that point onwards.

If the joint is unevaluable due to steroid injection, then the joint will be counted as tender
and swollen for 12 weeks after the date of injection.

If the joint is unevaluable due to other conditions or procedures at any visit post-Baseline,
then the joint will be counted as swollen and tender at that visit.
4.1.1.1.2 
C-reactive Protein (CRP) 
Analysis of serum CRP concentrations for inclusion in the American College of Rheumatology 
20%/50%/70% improvement criteria (ACR20/50/70) and disease activity score 28 (DAS28-CRP) 
will be performed by XXX laboratory and transferred to the clinical database. 
4.1.1.1.3 
Visual Analogue Scales (VAS) 
Patient global assessment of disease activity VAS (global health [GH]; ranging from very well to 
extremely bad), patient assessment of pain (ranging from no pain to intolerable pain) and 
physician global assessment of disease activity VAS (ranging from very low to very high) will be 
assessed on 100-point scales at the time points detailed in Table 4 and Table 5. These VASs 
must be completed by the patient/physician themselves on a SitePRO tablet. All these VASs will 
contribute to the calculation of ACR20, ACR50 and ACR70 response (see Section 4.1.1.2.1), 
whereas the patient global assessment of disease activity VAS only will contribute to the 
calculation of the DAS28 (see Section 4.1.1.2.2). Patient-recorded data will not be corrected or 
revised in any way. Patient assessment of pain is collected from the health assessment 
questionnaire – disease index (HAQ-DI) . XXX will send SAS datasets of the VAS scores.  
4.1.1.1.4 
Health Assessment Questionnaire – Disease Index (HAQ-DI) 
The HAQ-DI is a 20-question, self-administered instrument that measures the patient’s functional 
ability on a 4-level difficulty scale (0-3, with 0 representing normal or no difficulty, and 
3 representing inability to perform).  Eight categories of functioning are included: dressing, rising, 
eating, walking, hygiene, reach, grip, and usual activities.  This scale is sensitive to change and is 
a good predictor of future disability. The HAQ-DI questionnaire will be completed on the SitePRO 
device by the patients themselves at the time points indicated in Table 4 and Table 5, following 
which XXX would send SAS datasets with the results. Patient-recorded data will not be corrected 
or revised in any way. 
The score for each category is the single response within the category with the highest score 
(greatest difficulty). If a component question is left blank or the response is too ambiguous to 
assign a score, then the score for that category is determined by the remaining completed 
question(s). However, if any "aids or devices" and/or "help from another person" items at the 
bottom of each page are checked, all the categories for 
 
Group 1: Dressing and grooming, getting up, eating and walking, or 
 
Group 2: Personal care, reaching, gripping and usual activities 


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are adjusted upward to "2", depending on which group this has been selected for. If the basic 
score is already "2" or "3", the score remains unchanged. "Aids or devices" and "help from another 
person" can only change a category's score to "2"; they do not change the score to a "1" or a "3". 
For the ‘Aids or devices’ option, these are the possible responses (i.e. the specific aid or device 
used) for each group: 

Group 1: Cane, Walker, Crutches, Wheelchair, Devices used for dressing (button hook,
zipper pull, long-handled shoe horn, etc.), Built up or special utensils, Special or built up
chair, Other.

Group 2: Raised toilet seat, Bathtub seat, Jar opener (for jars previously opened), Bathtub
bar, Long-handled appliances for reach, Long-handled appliances for in bathroom, Other.
The score for the disability index is the mean of the eight category scores, presented to 1 decimal 
place. If more than two of the categories, (i.e., >25%), are missing, the score is not calculated. If 2 
or fewer of the categories are missing, the sum of the categories is divided by the number of 
answered categories.  The higher score indicates greater disability. 
4.1.1.2 Derived variables 
4.1.1.2.1 
ACR20, ACR50 and ACR70 
The ACR response criteria will be derived and used as secondary efficacy variables. These 
criteria look at improvement in tender joint count (TJC), swollen joint count (SJC) (68/66-joint 
count) and improvement in at least 3 of the following 5 other specified ACR Core Data Set 
elements:  

Acute phase reactant (CRP, see Section 4.1.1.1.2).

Patient global assessment of disease activity (see Section 4.1.1.1.3).

Physician global assessment of disease activity (see Section 4.1.1.1.3).

Patient pain scale (see Section 4.1.1.1.3).

Disability/functional questionnaire (patient completed HAQ-DI, see Section 4.1.1.1.4)
An ACR20 positive response means that the patient achieved a 20% improvement in tender and 
swollen joint counts and a 20% improvement in at least 3 of the other 5 Core Data Set elements 
listed above. ACR50 response means that the patient achieved a 50% improvement in tender and 
swollen joint counts and a 50% improvement in at least 3 of the other 5 criteria, and an ACR70 
response means that the patient achieved a 70% improvement in tender and swollen joint counts 
and a 70% improvement in at least 3 of the other 5 criteria.  
If either the tender or the swollen joint counts at Baseline or at a given post-Baseline visit are 
missing, the ACR20 will be set to missing. If both joint counts are not missing at Baseline and 
post-Baseline and the available data allow a proper ACR20 estimation (e.g. only 3 components 
are available but either a ≥20% or <20% improvement is observed for all of them such that the 
missing components do not have an impact on the ACR20 value), then the ACR20 will be 
assessed following the rule described above. Otherwise, if the available components data is not 
sufficient for an ACR20 assessment (e.g. 4 components are available but for 2 of them there’s a 
<20% improvement and for the other 2 a ≥20% improvement, so that the last missing component 
would be crucial in determining the ACR20 status), the ACR20 will be set to missing. Similar logic 
will be applied for the estimation of the ACR50 and ACR70 scores. 
The percentage of patients achieving ACR20, ACR50 and ACR70 response from Baseline will be 
assessed at the time points detailed in Table 4 and Table 5.  The Baseline Visit used for the ACR 
response derivation will be the Week 0 visit of Study FKB327-002 (Baseline_002). 


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4.1.1.2.2 
Disease Activity Score 28 (DAS28) 
The DAS28 is a combined index that has been developed to measure the disease activity in 
patients with RA and has been extensively validated for its use in clinical studies. DAS28 will refer 
to the DAS28-CRP, unless otherwise specified. The DAS28 assessment involves evaluating the 
TJC and SJC (out of 28 specified joints), serum CRP and patient global assessment of disease 
activity (see Section 4.1.1.1.3). The results are then used to calculate the DAS28 using the 
following formula: 
DAS28-CRP = 0.56*sqrt(TJC) + 0.28*sqrt(SJC) + 0.36*ln(CRP+1) + 0.014*VAS + 0.96 
The DAS28 is a number on a scale from 0 to 10 indicating the current activity of the patient’s RA.  
A DAS28 above 5.1 means high disease activity; DAS28 in the range of >3.2 to 5.1 indicates 
moderate disease activity; whereas a DAS28 ≤3.2 indicates low disease activity.  Remission is 
achieved by a DAS28 lower than 2.6. 
The DAS28 will be calculated using information from the assessments performed at the time 
points detailed in Table 4 and Table 5. The Baseline DAS28, obtained at Week 0 from 
Study FKB327-002 (Baseline_002), will be used to calculate the change from Baseline. 
If any one of the 4 components (28 tender joint counts, 28 swollen joint counts, CRP and VAS 
GH) is missing, the DAS28 cannot be derived. 
Joint count results (28 joints) will be derived by Programming from the results of the 68/66 joint 
counts performed for the purpose of ACR response calculation.  Results of the patient global 
assessment of disease activity VAS will be the same as used for the ACR response. CRP values 
will be the results from samples analysed by XXX central laboratory. 
The 28-joint counts will be derived from the 68/66 joints using the specified joints (shoulders, 
elbows, wrists, metacarpophalangeal joints, proximal interphalangeal joints and the knees) with a 
score of 1 (=Pain/Tender only) and 3 (=Pain/Tender and Swollen) being included in the tender 
joint count and scores of 2 (=Swollen only) and 3 (=Pain/Tender and Swollen) being included in 
the swollen joint count. The joints that assessed as part of the 68/66 and 28 joint counts are 
highlighted in Appendix 8.2. 
A joint will be counted as tender and/or swollen if the tender and/or swelling code(s) is ‘Present’  
or as described in Section 4.1.1.1.1 if the joint count is missing or the joint is unevaluable. 
4.2 Safety Measures 
In this study, safety will be assessed by evaluating the following: AEs, physical examination 
findings, vital signs measurements, and clinical laboratory test results. 
4.2.1 Exposure to Study Medication 
Exposure to study medication in this study will happen in 2 periods. In the first period (Period I), 
eligible patients will be randomised to either FKB327 (40 mg) or Humira (40 mg) eow from Week 0 
(Baseline_003) to Week 28. In the second period of the study (Period II), all patients receive 
FKB327 (40 mg) eow from Week 30 through to Week 76. Exposure to study medication will be 
recorded in the eCRF. Patient’s concomitant doses of MTX and folic/folinic acid will also be 
recorded. 
4.2.2 Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical study patient administered a 
medicinal product and which does not necessarily have a causal relationship with that treatment. 


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An AE can, therefore, be any unfavourable and unintended physical sign, symptom, or laboratory 
parameter that develops or worsens in severity during the course of the study, or significant 
worsening of the disease under study or of any concurrent disease, whether or not considered 
related to the study medication.  A new condition or the worsening of a pre-existing condition will 
be considered an AE. 
All overdoses should be recorded as an AE.  An overdose is any dose of study treatment, 
including protocol prescribed concomitant medication, given to a patient or taken by a patient that 
exceeds the protocol prescribed amount.  An overdose should be recorded as an AE even if it 
does not result in an adverse effect to the patient. An overdose that results in an AE that meets 
any of the outcomes defined as serious must be reported on an SAE form and sent to the 
Sponsor’s pharmacovigilance department within 24 hours of becoming aware of the event. 
Patients will be carefully monitored for AEs from signing of the informed consent until the End of 
Study visit (Week 80) or Early Termination visit if the patient does not complete the study. 
Ongoing AEs from the Study FKB327-002 will be recorded in the FKB327-003 eCRF as medical 
history/concurrent conditions. Any AE occurring or worsening after randomisation to the FKB327-
003 study will be recorded in the FKB327-003 eCRF as an AE. Clinically significant (CS) changes 
in the findings of physical examination, and CS abnormalities in the results of objective tests (eg, 
laboratory parameters, X-ray and electrocardiogram [ECG]) may also be recorded as AEs. 
4.2.2.1 Adverse Event Definitions 
A serious adverse event (SAE) is an AE which is fatal, life threatening, requires or prolongs 
inpatient treatment, results in persistent or significant disability or incapacity, is a congenital 
anomaly or birth defect, or is a medically important event that may jeopardise the patient. 
A treatment-emergent adverse event (TEAE) is defined as an AE that occurred or increased in 
severity after the first dose of study medication was taken.  
A treatment-related TEAE is defined as a TEAE where the relationship to study drug was 
recorded as “Possibly related” or “Related”. 
A treatment-emergent serious adverse event (TESAE) is defined as a SAE occurring or increasing 
in severity after the first dose of study medication was taken. 
An AE leading to treatment interruption will be defined as an AE where the response to the 
question “What action was taken with regard to study medication?” was recorded as “Temporarily 
Interrupted” on the Adverse Event Log case report form (CRF) page. 
An AE leading to treatment discontinuation will be defined as an AE where the response to the 
question “What action was taken with regard to study medication?” was recorded as “Permanently 
Discontinued” on the Adverse Event Log CRF page. 
4.2.2.2 Coding of Adverse Event Terms 
The AE term (Investigator term) will be assigned to the lowest level term (LLT), and a preferred 
term (PT) will be classified by a high level term (HLT), a high level group term (HLGT) and a 
system organ class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA) 
thesaurus, Version 17.1. 
Although there can be multiple SOCs for a PT, each PT will be linked with 1 SOC, namely the 
primary SOC which is automatically assigned by MedDRA via 1 HLT, HLGT route. 
The following coding data will be presented: 

LLT (Investigator term).


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
PT.
Coding data per primary SOC: 

HLT.

HLGT.
In the event that no coding information is available for a specific AE, the AE will be presented as 
an ‘Uncodable Event’ in all summary tables. 
Adverse events will be reported on a per-patient basis and per-event. On a per-patient basis this 
means that even if a patient reported the same event repeatedly (ie, events mapped to the same 
PT) during the study period, the event will be counted only once. In the latter case the event will 
be assigned the worst severity and the strongest relationship to the study medication. The earliest 
date will be regarded as start date of the event and the latest date/time will be regarded as stop 
date of the event within the assigned study period. 
4.2.2.3 Severity of an Adverse Event 
The severity of each AE must be recorded according to the following categories: 
Mild: the AE does not interfere with the patient’s daily routine and does not require intervention; it 
causes slight discomfort. 
Moderate: the AE interferes with some aspects of the patient’s routine or requires intervention but 
is not damaging to health; it causes moderate discomfort. 
Severe: the AE results in alteration, discomfort or disability which is clearly damaging to health. 
4.2.2.4 Relationship of an Adverse Event to Study Medication 
The relationship of each AE to study medication must be recorded according to the following 
categories: 
Related: an event which occurs after exposure to the test product, has a reasonable temporal 
relationship to dosing and is likely to be caused by it.  The event may or may not be a known side 
effect of the test product.  The event is not easily attributable to another cause.  There may be 
evidence of a positive de-challenge and/or re-challenge. 
Possibly related: An event for which, after careful medical evaluation, a connection with study 
medication cannot be ruled out with certainty. The event occurs after exposure to the test product.  
The event may occur at a reasonable time in relation to the time of administration of study 
medication, but might also be attributable to a commonly occurring alternative cause. 
Alternatively, the event may not occur at a reasonable time in relation to the time of administration 
of study medication, but not be attributable to an alternative cause. 
Unrelated: an event which occurs before exposure to the test product, which can clearly be 
attributed to another cause or is clearly unrelated to the study, eg, road traffic accident in which 
the patient is a victim. 
4.2.3 Clinical Laboratory Tests 
Laboratory testing will be performed by a central laboratory facility with the exception of 
erythrocyte sedimentation rate (ESR) testing and dipstick urinalysis, which will be performed 
locally.  All clinical laboratory test results outside of the reference range will be flagged and 
interpreted by the Investigator according to the following categories: 

Abnormal, not clinically significant (NCS)


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
Abnormal, CS
CS laboratory abnormalities will be recorded as AEs.  Laboratory tests will be performed at the 
time points detailed in Table 4 and Table 5. 
For the laboratory parameters, if a re-test was performed prior to a study medication 
administration at any visit, all values will be included in the listings, and will be clearly identified as 
unscheduled with the time of the repeat measurement. If a test is repeated, the initial value will be 
used in the summaries, unless the result is missing or non-evaluable (for example, due to 
haemolysis of a blood sample) in which case the repeat result will be used.  
For each laboratory test (quantitative and qualitative), the Baseline value is defined as the result 
at Week 0 for study FKB327-002 (Baseline_002), in general. However, if the result at this visit is 
missing, the last non-missing measurement collected/derived prior to the first study medication 
administration from study FKB327-002 will be imputed as the Baseline value, i.e. the last 
measurement taken at the Screening visit from FKB327-002. For quantitative laboratory tests, the 
change from Baseline value at each post-Baseline visit will be calculated as the difference 
between the value obtained at the specific post-Baseline visit, and the Baseline value. 
4.2.3.1 Haematology 
The following haematology tests will be performed: haemoglobin (Hb), red blood cell (RBC) count, 
mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular 
haemoglobin concentration (MCHC), haematocrit, white blood cell (WBC) count and differential, 
platelets and (at Week 0 only, as part of the FKB327-002 study) ESR. 
4.2.3.2 Serum Chemistry 
The following serum chemistry tests will be performed: urea, creatinine, uric acid, total bilirubin, 
total protein, albumin, globulin, alkaline phosphatase, aspartate transferase (AST), alanine 
transferase (ALT), gamma glutamyl transferase (GGT), glucose, phosphate, cholesterol, 
triglycerides, potassium, sodium, calcium, and chloride. 
4.2.3.3 Urinalysis 
Dipstick urinalysis (performed by local study site staff) will include testing for the following: protein, 
blood, glucose and leukocyte esterase. If the dipstick reveals any CS abnormalities, a second 
sample (provided on the same day, if possible) should be sent to the central laboratory. 
Microscopy will be performed by the central laboratory in the case of abnormal results. 
4.2.3.4 Pharmacodynamic Markers 
Serum MMP-3 will be analysed at the time points detailed in Table 4 and Table 5. 
4.2.3.5 Pregnancy Testing 
Females of childbearing potential will take a urine pregnancy test (performed at site) at the time 
points detailed in Table 4 and Table 5. 
4.2.3.6 Other 
The QuantiFERON-TB Gold In-Tube test will be performed at Weeks 24 and 76 or EOS although 
this may be omitted in patients receiving anti-mycobacterial treatment for latent tuberculosis (TB). 
This may be repeated, at the discretion of the Investigator or to comply with local practices, at 
additional time points. 


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4.2.4 Vital Signs Evaluations 
Vital signs will be collected in accordance with the Schedule of events (see Table 4 and Table 5). 
The following variables will be collected: 

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

Pulse rate (bpm)

Temperature (oC or F). All presentations will show the temperature in oC.
Blood pressure and pulse rate will be measured prior to dosing after the patient has rested in a 
supine or semi-recumbent position for at least 5 minutes. For each vital signs variable, the 
Baseline value is defined as the last non-missing measurement collected prior to the first study 
medication administration in the FKB327-002 study (Baseline_002). 
For each variable, the change from Baseline value at each post-Baseline time point will be 
calculated as the difference between the measurements obtained at the specific post-Baseline 
time point, and the Baseline value. 
4.2.5 Physical Examination 
Physical examination will be performed by the Investigator at Week 0 (Week 24 of study FKB327-
002) and Week 80 or EOS. The following will be examined: general appearance; head; ears; 
eyes; nose and throat; thyroid; lymph nodes; heart; chest; abdomen; urogenital system (optional); 
skin; breasts; extremities; musculoskeletal system and neurological system. CS findings will be 
reported as AEs. 
4.2.6 Chest X-ray 
Chest X-rays (posterior and lateral views) will be performed at Week 30 and Week 80 or EOS 
unless patient has a negative QuantiFERON test at Week 24 or 76 or EOS, respectively, with no 
signs/symptoms suggestive of lower respiratory infection. The chest X-ray will be examined by a 
qualified radiologist to ensure that there is no evidence of active TB, other chest infection or 
interstitial pneumonitis in particular. An additional X-ray will be performed at the Investigator’s 
discretion at additional time points in the presence of signs/symptoms suggestive of lower 
respiratory infection.  
4.2.7 Injection Site Assessment 
An injection site assessment will be performed within 30 minutes of dosing at Week 0 
(Baseline_003) and Week 30, as well as at the time of switching to the AI during the open-label 
follow-up treatment period. Study staff will apply light pressure at the injection site and record any 
tenderness, erythema and induration. Local reactions will be assessed as follows:  
0 = no evidence of irritation.  
1 = minimal erythema, barely perceptible.  
2 = definite erythema, readily visible; minimal oedema or minimal papular response. 
3 = erythema and papules.  
4 = definite oedema.  
5 = erythema, oedema, and papules.  
6 = vesicular eruption.  
7 = strong reaction spreading beyond test site.  


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The size of any injection site reaction will be measured along its longest axis. If a patient has a CS 
local reaction, it will be recorded as an AE. Any evidence of an injection site reaction at visits other 
than Week 0 (Baseline_003), Week 30, or at the assessment conducted at the point of switching 
to the AI will also be recorded as an AE.  
As part of this assessment, an injection site pain VAS will be completed by the patient using the 
SitePRO tablet. To determine the extent of the pain, patients will be asked to place a small vertical 
mark on a horizontal scale from 0 to 100, the ends of which are labelled with the extreme 
responses to be measured (“No pain” and “Intolerable pain”). 
4.3 Other Measures 
4.3.1 Patient Disposition 
Patient disposition data was collected on the ‘Study Discontinuation’ CRF page when a patient 
completed or discontinued from the study. 
The following data will also be presented: 

Date of informed consent

Date of early termination of study medication

Date of final study contact

Whether patient completed study according to protocol

Reason for early withdrawal
The analysis sets defined in Section 3 will be analysed and presented as part of the patient 
disposition data. 
4.3.2 Baseline Patient Characteristics 
Baseline patient characteristics include characteristics that patients presented with prior to the first 
administration of study medication in the FKB327-002 study. The last available vital signs 
variables, laboratory results and ECG results collected prior to the first administration of study 
medication in the FKB327-002 study will be presented in order to assess homogeneity of the 
treatments. ECG results will consist of the incidence (Yes or No) of clinically significant findings for 
ECG. The characteristics prior to study drug administration at Week 0 (Baseline_003) are also of 
interest. 
4.3.3 Medical History 
Medical history contains information about conditions that a patient might have suffered from prior 
to the first administration of study medication at Week 0 (Baseline_003), or conditions that were 
ongoing at the time of the first administration of study medication. Ongoing AEs from the FKB327-
002 study will also be recorded as medical history. Any changes to medical history conditions 
during the course of the study that meet the criteria for an AE will be recorded as such. 
Medical history data was collected at Week 0 (Baseline_003) on the ‘Medical History and Medical 
Conditions’ CRF page. 
4.3.3.1 Coding of Medical History Terms 
The medical history term (Investigator term) is assigned to the LLT, and a PT will be classified by 
a HLT, a HLGT and a SOC according to the MedDRA thesaurus, Version 17.1. 


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Although there can be multiple SOCs for a PT, each PT will be linked with 1 SOC, namely the 
primary SOC which is automatically assigned by MedDRA via 1 HLT, HLGT route. 
The following coding data will be presented: 

LLT.

PT.

Coding data per primary SOC:
- 
HLT.
- 
HLGT.
Medical history will be reported on a per-patient basis.  This means that even if a patient suffered 
the same clinical event repeatedly (i.e., events mapped to the same PT) the event will be counted 
only once and the earliest date will be regarded as start date of the event and the latest date will 
be regarded as stop date of the event. 
The same rule for counting applies for PTs mapped to the same HLT and for HLTs mapped to the 
same HLGT and for HLGTs mapped to the same SOC. 
4.3.4 Prior and Concomitant Medications 
Concomitant medications include all medications that a patient used at any stage during the 
study.  Any medication started prior to Week 0 and used during the study, or medication started at 
any time after the first study medication administration, will be included. 
Medications that started and ended before the first dose of study medication in the FKB327-002 
study will be defined as prior medications. 
Concomitant medications data are collected throughout the study on the ‘Concomitant 
Medications’ CRF page. Any new concomitant medication or change to an existing one will be 
recorded in the Concomitant Medication Log Form.  
Missing concomitant medications data will be handled according to the rules specified in 
Section 5.3.2.5. 
4.3.4.1 Coding of Prior and Concomitant Medication Terms 
Prior and Concomitant medications are classified according to active drug substance using the 
current version World Health Organization-Drug Dictionary (WHO-DD). 
The WHO-DD drug identity (ID) has 11 characters.  The preferred name, for example, the 
salt/ester of the substance is defined by the first 8 characters, and the WHO-DD name is defined 
by the 11 characters. 
In addition, the Anatomical Therapeutic Chemical (ATC) classes are assigned to the drug ID. An 
ATC code has 7 characters. The first character gives the anatomical main group (1st level), the
first 3 characters give the therapeutic main group (2nd level), the first 4 characters give the
therapeutic subgroup (3rd level), the first 5 characters give a further level therapeutic subgroup (4th
level), whereas the 7 characters give the subgroup for the chemical substance.  In this study, 
ATC codes are defined to the 4th level.
Although there can be multiple ATC classes for some drugs, each drug will be linked with 1 ATC 
class which will be assigned manually during the coding process when more than 1 class is 
available, based on information about the indication and route in relation to the study therapeutic 
area.  This 1 ATC class will be indicated as the ‘primary’ ATC class, and only the primary class will 
be presented. 


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4.3.5 Treatment Compliance 
Written records of study medication administration will be kept at the study site.  Patients will be 
asked to keep a diary card recording dates and times of dosing. This information will be 
transcribed into the eCRF by site staff. 
Unused study drug will be returned to the site by the patient and retained at the study site for 
compliance checks but need not be refrigerated. 
The following data from clinic visits will be listed as a record of treatment administration: 

Date of administered study medication

Whether full dose of study drug was administered or not
4.3.6 Immunogenicity Assessments 
Blood samples for the assessment of ADAs will be collected prior to dosing at Week 0 
(Baseline_003) and at the time points detailed in Table 4 and Table 5. 
4.3.7 Pharmacokinetic Assessments 
Blood samples for the quantification of adalimumab in serum will be collected prior to dosing at 
Week 0 (Baseline_003) and at the time points detailed in Table 4 and Table 5. Concentrations of 
MTX will not be assessed. 
5 
Statistical Methodology 
5.1 General Statistical Methods 
5.1.1 General Information 
All analysis data sets and output, will be produced by the Biostatistics Department of XXX using 
the SAS® system Version 9.3 or higher.
5.1.2 Default Descriptive Statistics and Data Rules 
Unless otherwise stated, summary statistics including the number of patients, mean, standard 
deviation (SD), median, minimum and maximum, will be presented for all continuous variables.  
Minimum and maximum values will be presented to the same decimal precision as the raw values, 
the mean and median values to 1 more, and the standard deviation, to 2 more decimal places 
than the raw values. 
For categorical variables, per category, the absolute counts (n) and percentages (%) of patients 
with data, and if appropriate, the number of patients with missing data, will be presented.  All 
percentages will be presented to 1 decimal place. 
For AEs reported on a per-patient basis, medical history and concomitant medications, the 
denominator for the percentage calculation will be the number of patients in each treatment arm in 
the Safety Analysis Set. A patient will be considered at risk if the patient is in the Safety Analysis 
Set.   
For AEs reported on a per-event basis, the incident rate will be displayed, adjusting the number of 
AEs by the total exposure to each treatment in person-years. 


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5.2 Hypotheses and Decision Rules 
5.2.1 Primary Hypothesis 
No formal primary hypothesis will be tested. 
5.2.2 Secondary Hypotheses 
No formal secondary hypothesis will be tested. 
5.3 Handling of Missing Data 
In general missing data will not be imputed except the situations described below. 
5.3.1 Safety endpoints 
5.3.1.1 Adverse Events 
Missing or incomplete dates and times for AEs are imputed in a manner resulting in the earliest 
onset or the longest duration during the treatment period, taking additionally into account that the 
start date and time should not be after the stop date and time.  Stop dates and times will not be 
imputed if the AE is ongoing.  
This will be done as follows: 
For a missing/incomplete start date the minimum of the following will be imputed: 

The maximum of the earliest possible start date/time and the date of study medication
administration.

The latest possible start date.

The latest possible stop date.
For a missing/incomplete stop date the maximum of the following will be imputed: 

The minimum of the latest possible stop date/time and the date/time of study medication
administration.

The earliest possible stop date.

The earliest possible start date.
The earliest (latest) possible date is defined as: 

The date itself if it is complete.

The date of the first (last) day of the month, if month and year are available but day is
missing.

The date of the first (last) day of the year, if year is available but day and month are
missing.

A very early (late) date, e.g., 01JAN1000 (01JAN3000), if the date is completely missing.
The imputation method will only be used to determine treatment emergence and to determine the 
time of the event relative to the first administration of study medication. 
A worst-case approach will be followed in the event of missing severity or causality data.  If the 
severity is missing, ‘Severe’ will be imputed.  If causality data is missing, ‘Related’ will be imputed. 


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In the event that no coding information is available for a specific AE, the AE will be presented as 
an ‘Uncodable Event’ in summary tables. 
5.3.2 Other Endpoints 
5.3.2.1 Exposure 
If the start of treatment date is missing, the latest possible time of all the pre-dose assessments, 
up to and including randomisation will be imputed as the start of treatment date. 
If the end of treatment date is missing, the latest possible time of all the post-dose assessments 
will be imputed as the end of treatment date. 
5.3.2.2 Pharmacokinetics 
Missing data will be excluded from the PK analysis (i.e. values will not be interpolated or carried 
forward).  Removal of anomalous data (outliers) will also be considered on an individual basis, 
and will be documented in the report, along with justification for the removal of data and an 
assessment of the impact on the study. 
5.3.2.3 Immunogenicity 
Where ADA screen results are negative, confirmatory assays will not be performed therefore titre 
and Neutralising results will not be available. Confirmatory ADA assay results for all negative 
screens will therefore be considered to be negative and presented as Negative for all ADA 
analyses. In addition, the associated titre result will be imputed as 0.0625 in order to estimate the 
median and lower/upper quartiles and be included as a covariate in the secondary PK analyses. 
Values below the lower limit of quantification (<LLOQ or reported as 0) will be imputed as 0.25; 1, 
will be not imputed, ≥2, ≤4, will be imputed as 4; >4, ≤16 will be imputed as 16; >16, ≤64 will be 
imputed as 64; >64, ≤256 will be imputed as 256; >256, ≤1024 will be imputed as 1024; >1024, 
≤4096 will be imputed as 4096; >4096, ≤16384 will be imputed as 16384 and values above 16384 
will be imputed as 65536. 
Missing ADA titre results at Week 30 (for Period I) and Week 80 (for Period II and Overall) will be 
imputed with values carried forward from the previous sampling time(s), as appropriate. 
5.3.2.4 Demographics 
Date of birth is required to determine age. If date of birth is incomplete the following rules will be 
applied,  

If only day is missing, day will be imputed as the 15th,

If day and month are missing this will be imputed as the 2nd of July which is day 183 in the
year.
5.3.2.5 Concomitant Medications 
Missing concomitant medication dates will be handled in a similar fashion as described for 
Adverse Events in Section 5.3.1.1. 
5.4 Interim Analyses 
An interim analysis of all planned endpoints for all patients will be performed once 100 patients 
randomised to FKB327 in study FKB327-002 and also to FKB327 in the randomised phase of 
study FKB327-003 plus 100 patients randomised to Humira in study FKB327-002 and also to 
Humira in the randomised phase of study FKB327-003 have reached Week 30 in this study 


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(FKB327-003).  This will provide more than 100 patient-years of exposure to FKB327 and to 
Humira across studies FKB327-002 and FKB327-003 for comparison.   
It is anticipated that the interim analysis would be performed after the FKB327-002 study has 
been locked and unblinded so that no extra precautions would be required to maintain the 
randomisation blinding for the FKB327-002 treatment assignments. The analysis will therefore be 
performed on the unblinded treatment allocations. 
Following the first interim analysis, it’s been decided to perform an additional interim analysis in 
order to provide a more robust and mature body of evidence related to safety, efficacy, PK and 
Immunogenicity profile of FKB327 during Period II of the study, with particular interest for the PK 
and safety profile following the switch to AI use for all applicable patients. Given the absence of 
formal hypothesis testing and the unblinded nature of the trial, this additional interim analysis 
should not introduce any unwanted issue in terms of study results interpretation. 
All displays described in this SAP and accompanying shells will be produced for all patients in the 
interim analyses, following the scheme provided in Attachment 1 (Section 9.1). All outputs 
produced for either interim analysis will be produced also for the Final Analysis. A few additional 
outputs that weren’t originally part of the study reporting will be created for the purpose of the 
Final Analysis only, to specifically address some remarks raised by the regulators during the 
application review process.  
6 
Statistical Analyses 
6.1 Patient Disposition 
Patient disposition will be summarised by absolute counts (n) and percentages (%).  Percentages 
will be based on the number of randomised patients. The following will be presented by treatment 
sequence and by treatment in Period I: 

Number of patients enrolled

Number of patients randomised to treatment

Number of patients with study drug administered

Number of patients who completed Period I

Number of patients still ongoing in Period I (only for interim analyses)

Number of patients who prematurely discontinued the study during Period I (and primary
reason for discontinuation)
The following will be presented by treatment sequence for Period II: 

Number of patients who started Period II

Number of patients who started the AI

Number of patients still ongoing in Period II (only for the interim analyses)

Number of patients who completed Period II (only for the second interim analysis)

Number of patients who prematurely discontinued the study during Period II and primary
reason for discontinuation.
In addition, the number of patients in each analysis set and the reasons for exclusion will be 
summarised by treatment sequence and treatment in Period I. 


Statistical Analysis Plan 
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The number and percentage of patients randomised will be displayed by geographical region 
(Europe, North America, Rest of World) and strata (screening DAS28-CRP ≤5.1/>5.1 and biologic 
naïve or not) as per study FKB327-002, and will be summarised by treatment sequence and 
treatment in Period I. 
6.2 Protocol Deviations 
Protocol deviations will be fully described in a separate document which will be finalised prior to 
database lock. Protocol deviations will be summarised by treatment sequence and treatment in 
Period I for all randomised patients, split by major and minor protocol deviations, as defined 
below:   

Major protocol deviations are protocol deviations that would significantly impact on patient
safety, GCP compliance or analysis of efficacy or safety endpoints.

Minor protocol deviations are protocol deviations which have less potential to affect the
patient safety or integrity of the data.
Protocol deviations will also be listed. 
6.3 Demographics 
The age and height of patients from the Screening visit of the FKB327-002 study, and weight from 
Week 0 (Week 24 of the FKB327-002 study) of the FKB327-003 study will be summarised as a 
continuous variable. Sex, race and ethnicity will be summarised by absolute counts (n) and 
percentages (%). Percentages will be based on the number of patients in each analysis set. 
Summaries will be by treatment sequence and treatment in Period I.  
Demographic data will also be listed. 
6.4 Baseline Patient Characteristics 
Baseline patient characteristics will be summarised by treatment sequence and treatment in 
Period I using standard summary statistics for each analysis set (see Section 5.1.2). 
Baseline RA disease will be summarised using the following parameters collected at Week 0 of 
the FKB327-002 study (Baseline_002) and Week 0 of the FKB327-003 study (Baseline_003): 

Rheumatoid factor status (only for Baseline_002)

Serum MMP-3 concentration

Anti-CCP antibody status (only for Baseline_002)

Swollen joint count (66 and 28 Joint Count)

Tender joint count (68 and 28 Joint Count)

Patients assessment of disease activity

Physicians assessment of disease activity

Patients assessment of pain

HAQ-DI

CRP

ESR

DAS28-CRP


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
DAS28-ESR
ESR is only collected at Week 0, as part of the Week 24 assessments of the FKB327-002 study. 
The following formula will be used to derive the DAS28-ESR, similar to DAS28-CRP, as follows: 
DAS28-ESR = 0.56*sqrt(TJC) + 0.28*sqrt(SJC) + 0.70*ln(ESR) + 0.014*GH 
6.5 Medical History and Concurrent Medical Conditions 
Medical history and Concurrent Medical Conditions will be separately summarised by SOC and 
PT by absolute counts (n) and percentages (%). Percentages will be calculated based on the 
number of patients in the Safety Analysis Set by treatment sequence and treatment in Period I. 
Medical history and concurrent medical conditions data will also be listed. 
6.6 Prior and Concomitant Medication 
Concomitant Medications and Prior Medications, including prior biologics, will be listed and 
summarised separately by PT for any medications taken for RA and by ATC and PT for 
medications taken for any other reason. These summaries will be by absolute counts (n) and 
percentages (%).  Percentages will be calculated based on the number of patients in the Safety 
Analysis Set for the specific treatment sequence or treatment in Period I. 
Specifically, the following will be summarised by treatment sequence and treatment in Period I for 
the Safety Analysis Set: 
 - Patients who have received DMARDs for RA prior to Screening in the FKB327-002 study.  A 
summary will also be included for the number of prior DMARDs for RA (1, 2, 3, 4, etc). 
 - Patients who have received biologic treatment for RA prior to Screening in the FKB327-002 
study 
 - Patients who have received anti-TNF treatment for RA prior to Screening in the FKB327-002 
study 
 - Patients who used oral steroids for RA prior to Screening in the FKB327-002 study 
 - Patients who used NSAIDs for RA prior to Screening in the FKB327-002 study 
 - Concomitant use of oral steroids for RA 
 - Concomitant use of NSAIDs for RA 
 - Concomitant use of both oral steroids and NSAIDs for RA 
 - Concomitant use of commonest drugs for diseases other than RA. These drugs would be 
identified as those having a frequency of ≥5%. 
 - Duration of continuous MTX treatment prior to Screening from the FKB327-002 study 
 - Average dose of concomitant MTX during the study 
 - Route of concomitant MTX during the study 
 - Concomitant use of oral steroids for RA, by drug name (both overall and by geographical 
region) 
 - Concomitant use of NSAIDs for RA, by drug name (both overall and by geographical region) 


Statistical Analysis Plan 
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6.7 Efficacy Analyses 
6.7.1 Secondary Efficacy Analyses 
The secondary efficacy analyses will be based on the FAS. 
6.7.1.1 Tender and Swollen Joint Counts 
Tender joint count, and swollen joint count, based on the 68/66 joint counts and their change from 
Baseline_002, will be summarised as continuous variables by treatment sequence and visit over 
the whole study period. The DAS28-CRP specific tender and swollen joint counts (28 joint count) 
and their change from Baseline_002 will be summarised similarly. 
Individual tender and swollen joint data will be listed, along with the 68/66 joint counts. 
The mean tender and swollen joint counts will also be plotted over time by treatment sequence 
alongside their 95% CI. 
6.7.1.2 CRP 
Values and change from Baseline_002 for CRP will be summarised as continuous variables by 
treatment sequence and visit over the whole study period. CRP values will be listed and plotted 
over time alongside their 95% CI. 
6.7.1.3 VAS 
Each of the scores for patient’s assessment of disease activity, physician’s assessment of disease 
activity, and patient’s assessment of pain, together with their change from Baseline_002 will be 
summarised as continuous variables (the VASs on a scale from 0 to 100), by treatment sequence 
and visit over the whole study period. Values at each visit will also be listed and plotted over time 
alongside their 95% CI. 
6.7.1.4 HAQ-DI 
Disability Index score and change from Baseline_002 will be summarised as continuous variables 
by treatment sequence and visit over the whole study period. The HAQ-DI individual categories 
scores will also be listed and the Disability Index Score will also be plotted over time alongside the 
95% CI. 
6.7.1.5 ACR20, ACR50 and ACR70 Response Rates 
The percentage of patients (%) achieving ACR20, ACR50 and ACR70 response will be 
summarised by overall treatment sequence and visit as well as by treatment separately for each 
period (Period I, Period II). 95% exact binomial CIs, via the Clopper-Pearson method will also be 
given for these rates. 
The percentage of patients (%) achieving ACR20, ACR50 and ACR70 response over the whole 
study period will be plotted by treatment sequence. Another set of 2-panel plots will be produced 
for the treatment sequence and treatment in Period I only. 
A bar plot of the percentage of patients achieving ACR20, ACR50 and ACR70 response will also 
be presented by treatment sequence at Week 30.. 
ACR response values will also be listed. 
6.7.1.6 DAS28-CRP 
DAS28-CRP and the change from Baseline_002 will be summarised by overall treatment 
sequence and visit as well as by treatment for each period (Period I, Period II). 


Statistical Analysis Plan 
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The mean DAS28-CRP and mean change from Baseline_002 alongside their 95%CI over the 
whole study period will be plotted by treatment sequence. Another set of 2-panel plots will be 
produced for the treatment sequence and treatment in Period I only. 
DAS28-CRP data will also be listed. 
6.8 Safety Analyses 
All safety analyses will be based on the Safety Analysis Set. 
6.8.1 Treatment Compliance and Exposure to Study Medication 
A full listing of study dosing dates (including missed or incomplete doses) and duration of 
exposure by patient will be produced. 
The number and percentage of patients fully dosed with study drug at each visit will be 
summarised separately by treatment sequence and treatment group for both Periods I and II. 
The duration of exposure to FKB327 and Humira will be summarised by treatment group both as 
continuous (in days) and categorical (in weeks) variables  
The duration of exposure to FKB327 in days is defined as: 
(Date of last FKB327 administration – Date of first FKB327 administration) + 14. If a patient 
misses a dose of FKB327, dosing will be assumed to be continuous. 
The duration of exposure to Humira in days is defined as: 
(Date of last Humira administration – Date of first Humira administration) + 14. If a patient misses 
a dose of Humira, dosing will be assumed to be continuous. 
The duration of exposure to the AI is defined as: 
(Date of last FKB327 AI administration – Date of first FKB327 AI administration) + 14. If a patient 
misses a dose of AI, dosing will be assumed to be continuous.  
Overall exposure to each study drug (FKB327, Humira) will be calculated by treatment group in 
patient-years by summing the individual patient values. 
The number and percentage of patients receiving full dosing (16 doses for Period I and 23 for 
Period II) will also be summarised separately by treatment sequence and treatment group for both 
Periods I and II along with the number of patients who received delayed or interrupted dosing. A 
summary of the number of doses received will also be included. 
Overall exposure to AI will also be calculated by treatment sequences in patient-years by 
summing individual patient values, 
6.8.2 Adverse Events 
Treatment-emergent adverse events (TEAEs) will be summarised by SOC and (PT using 
MedDRA by absolute counts (n) and percentages (%) for each period (Period I, Period II) and 
overall. Treatment-related TEAEs will also be summarised. Percentages will be calculated based 
on the number of patients in the Safety Analysis Set for the specific treatment sequence or 
treatment group. Non-treatment-emergent AEs will be listed only (separately). Any tables 
displaying coding information for Period II will display by treatment sequence summaries only at 
the Final Analysis due to the low number of patients available at Interim; for the Interim Analysis, 
the by treatment group summaries will be presented only with the percentages calculated out of 
the number of patients who have entered Period II by that point.   


Statistical Analysis Plan 
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Results will be sorted alphabetically by SOC, and by decreasing frequency of the PTs within a 
SOC. In the event of PTs having equal frequencies, the PTs will be sorted alphabetically within 
the SOC.  
Summary statistics will be presented by treatment and relationship to treatment to provide an 
overview of the AEs for each period (Period I, Period II) and overall. This will include the number 
of deaths, the number of treatment-emergent deaths, the number of patients with at least 1 SAE, 
the number of patients with at least 1 TESAE, the number of TESAEs, the number of patients who 
prematurely discontinued the IMP treatment due to a TEAE, the number of patients who 
prematurely discontinued the IMP treatment due to a TESAE, the number of patients who had a 
treatment interruption due to a TEAE, the number of patients who had a treatment interruption due 
to a TESAE, the number of patients with at least 1 TEAE, the number of patients with at least 1 
severe TEAE and the number of patients with at least 1 treatment-related TEAE. These 
summaries will also be presented by treatment sequence for each period (Period I, Period II) and 
overall. 
Summary statistics will be presented based on the strongest relationship to study medication of 
the TEAEs for each period (Period I, Period II) and overall by treatment sequence and treatment 
group. Relationship to study medication is recorded as ‘Related’, ’Possibly related, or ‘Unrelated’. 
Missing will be counted as ‘Related’. This summary for Period II will be repeated using only 
patients that switch to the AI, including only AEs that start on or after the first date of AI treatment. 
Summary statistics for TEAEs will be presented based on the maximum severity (‘Mild’, 
‘Moderate’ or ‘Severe’) for each period (Period I, Period II) and overall by treatment sequence and 
treatment group. This summary for Period II will be repeated using only patients that switch to the 
AI, including only AEs that start on or after the first date of AI treatment. 
Summary statistics will be presented for the incidence of TEAEs leading to treatment interruption 
and TEAEs leading to treatment discontinuation for each period (Period I, Period II) by treatment 
sequence and treatment group. 
Individual TEAEs (including TESAEs) will be summarised by primary SOC then by PT for each 
period (Period I, Period II) by treatment sequence and treatment group. This summary for Period 
II will be repeated using only patients that switch to the AI, including only AEs that start on or after 
the first date of AI treatment. Individual TEAEs with an incidence of ≥5% will be tabulated for each 
period (Period I, Period II) by treatment sequence and treatment group. Individual treatment-
related TEAEs with an incidence of ≥3% will also be summarised. 
In addition TESAEs will be summarised by SOC and PT by treatment sequence and treatment 
group for each period (Period I, Period II).  
The following treatment-emergent AEs of special interest (AESIs) will be summarised by SOC and 
PT using MedDRA by absolute counts (n) and percentages (%) by treatment sequence and 
treatment group for each period (Period I, Period II): 

Infections including SAEs identified by any PT within MedDRA SOC Infections and
Infestations

Serious infections (including TB) identified by any PT within MedDRA SOC Infection and
Infestations classified as serious

Malignancies and lymphoproliferative disorders identified using MedDRA SMQs
Malignancies and Malignant Lymphomas

Injection site reactions to study drug identified using all PTs within MedDRA HLT infusion
and injection site reactions classified as possibly related or related to study drug


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
Hypersensitivity reactions and anaphylaxis to study drug identified by Standardised
MedDRA Queries (SMQs) Hypersensitivity (narrow) and Anaphylactic Reaction (narrow)
classified as possibly related or related to study drug

Haematological events identified using the MedDRA PTs pancytopenia and aplastic
anaemia,

Neutropenia identified using MedDRA HLT neutropenias and PTs neutrophil count
decreased, neutrophil count abnormal and band neutrophil count decreased

Thrombocytopenia identified using MedDRA HLT thrombocytopenias and PTs platelet
count decreased and platelet count abnormal

New or worsening congestive heart failure identified using MedDRA HLTs heart failures
not elsewhere classifiable (NEC), left ventricular failures and right ventricular failures

Demyelination identified using MedDRA SMQ Demyelination (narrow)

Lupus-like reactions identified using MedDRA SMQ Systemic lupus erythematosus
(narrow)
The number of patients with at least 1 of the AESIs mentioned above will also be summarised for 
each bullet of the list by both treatment sequence and treatment group for both periods (Period I 
and Period II) and overall. 
The number of events and incidence rates (events per patient year) of TEAEs, TESAEs, TEAEs 
leading to treatment discontinuation and treatment-emergent AESIs will be displayed by treatment 
group, SOC and PT for the overall treatment period. 
An overall summary of AEs by administration method for those that occurred whilst FKB327 was 
taken (PFS or AI) will be created, similar to the first summary detailed in this section, including 
counts and percentage at a subject level and counts and incidence rates at an event level. 
Adverse events will also be summarized by administration method , with exposure-adjusted IRs 
by SOC and PT. Similar summaries with incidence rates by administration method will be created 
for TEAES occurring whilst exposed to FKB327 , with separate summaries for TEAES which are 
treatment-related, serious, of special interest or are treatment-related treatment-emergent 
Hypersensitivity/Anaphylaxis AEs. 
In addition to the above summaries, the following listings will also be presented: 
- Listing of all AEs (both treatment-emergent and non-treatment emergent) 
- Listing of SAEs 
- Listing of AEs leading to permanent treatment discontinuation 
- Listing of AEs leading to temporary treatment interruption 
- Listing of AEs leading to death 
- Listing of TEAEs 
- Listing of non-TEAEs 
6.8.3 Clinical Laboratory Parameters 
Clinical Laboratory Parameters include collected and derived quantitative and qualitative 
parameters.  Laboratory data will be converted to SI (Système Internationale) units during the 
creation of Clinical Data Interchange Standards Consortium(CDISC) datasets, where required and 
all will be listed showing flags for abnormal high and low values and assessments of clinical 
significance by the investigator. Parameters will be grouped by category (see Section 4.2.3.1 to 


Statistical Analysis Plan 
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Section 4.2.3.64.2.3.6) Quantitative parameters will be summarised by the number of patients, 
mean, SD, median, minimum and maximum values. Qualitative parameters will be summarised by 
absolute counts (n) and percentages (%).   
Mean (± SD) values over time will be plotted by treatment sequence over the whole study period 
as well as treatment sequence and treatment group for each period (Period I, Period II), for all 
continuous laboratory parameters. 
Summary statistics (including absolute and change from Baseline_002 values), for all quantitative 
lab parameters will be presented by visit and treatment sequence over the whole study period as 
well as by treatment for each period (Period I, Period II). 
Summary statistics will be presented by visit and treatment sequence over the whole study period 
as well as by treatment for each period (Period I, Period II) for all qualitative lab parameters based 
on the incidence of clinically significant abnormal values. 
6.8.4 Vital Signs 
Vital signs parameters with change from Baseline_002 will be summarised by treatment sequence 
over the whole study period as well as by treatment for each period (Period I, Period II) for each 
visit.  
Continuous variables will be summarised by the number of patients, mean, SD, median, minimum 
and maximum values.  Percentages will be based on the Safety Analysis Set. 
Mean (± SD) values over time will be plotted for all vital sign parameters for each treatment 
sequence and treatment group for each period (Period I, Period II) and for each treatment 
sequence for the overall treatment period. 
6.9 Other Analyses 
6.9.1 Physical Examination 
Physical examination information from all applicable visits will be listed. 
6.9.2 Chest X-ray 
The number of patients with an abnormality will be presented for patients with any abnormality. 
Chest x-ray results (abnormal clinically significant or not abnormal clinically significant) will be 
summarised by overall treatment sequence and treatment group in terms of absolute counts (n) 
and percentages (%). Percentages will be based on Safety Analysis Set. 
Chest x-ray information will also be listed. 
6.9.3 QuantiFERON Test 
QuantiFERON test results (Negative, Positive, Indeterminate) will be summarised by overall 
treatment sequence and treatment group for all the relevant visits in terms of absolute counts (n) 
and percentages (%). Percentages will be based on Safety Analysis Set. 
Full QuantiFERON test data will be listed. 
6.9.4 Injection Site Assessment 
The proportion of patients experiencing an injection site reaction at Week 0 will be summarised 
both by treatment sequence and actual Period I treatment group, whereas the summary at Week 
30 will be by treatment sequence only, using counts (n) and percentages (%), following the 
categories presented in Section 4.2.7.  Similar summaries, by treatment sequence only, will be 


Statistical Analysis Plan 
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displayed separately for patients switching and not-switching to the auto-injector, including Week 
0 and, respectively, the switching time-point or Week 30. A summary of injection site reactions at 
Week 30 will also be provided by administration method, AI or PFS, based upon the actual 
administration method used at this visit. 
The size of injection site reactions will be summarised for each of these categories by visit, 
following the same scheme as presented in the above paragraph (i.e. at Week 0 by actual Period I 
treatment group and sequence, at Week 30 by Sequence, at Week 0 and Auto-Injector start for 
patients switching to Auto-Injector and at Week 0 and 30 for patients not switching to the Auto-
Injector), in terms of absolute counts (n) and percentages (%) for each of the following 
magnitudes: 0, 1-5, 6-10, 11-15, 16-20, and >20mm.  These data will additionally be summarised 
as continuous variables. 
Percentages will be based on the number of patients in the Safety Analysis Set, unless otherwise 
mentioned in the tables footnotes.  
The injection site pain VAS (ranging from 0 “No pain” to 100 “Intolerable pain”) scores will be 
summarised as a continuous variable using the same scheme already described in the previous 
paragraphs.. Full listing of injection site assessment will be produced. 
6.9.5 Immunogenicity Analysis 
All ADA activity will be listed and summarised for each treatment sequence by time point during 
the overall treatment period as well as treatment group for each period (Period I, Period II). 
Descriptive statistics will include absolute counts (n) and percentages (%).  
The titre results will be summarised as continuous variables, for each time point and the last 
sampling day by treatment sequence for the overall treatment period as well as treatment group 
for each period (Period I, Period II); summaries will include the upper and lower ADA quartiles for 
the overall safety population. The frequency (percentage) of titre results in each treatment 
sequence for the overall treatment period as well as treatment group for each period (Period I, 
Period II) will be summarised for each time point and the last sampling day using the following 
imputed categories: 0.0625, 0.25, 1, 4, 16, 64, 256, 1024, 4096, 16384, 65536 (the actual 
categories displayed may depend on the data). The maximum value across all time points will 
also be presented by treatment sequence for the overall treatment period as well as treatment 
group for each period (Period I, Period II). 
In addition, ADA titre results at all time-points will be presented graphically (bar charts) for each 
treatment sequence for the overall treatment period and by treatment group for Period I. 
The frequency (percentage) of ADA neutralising results (positive, negative, inconclusive)  will be 
summarised for each treatment sequence for the overall treatment period, as well as treatment 
group for each period (Period I, Period II), by time point. 
A summary of ADA activity as well as a summary of frequency of Nab results during Period II will 
be displayed by administration method (AI vs PFS).  
The percentages will be based on the Safety Analysis Set. 
6.9.6 Pharmacokinetic Analysis 
Serum trough concentrations of adalimumab will be listed and summarised using descriptive 
statistics by treatment sequence for the overall treatment period as well as by treatment group for 
each period (Period I, Period II). Concentrations below the lower limit of quantification (<LLOQ) 
will be taken as zero for the calculation of descriptive statistics on adalimumab concentrations. 
Serum concentrations will be summarised by treatment sequence at each blood sampling time by 
the number of patients, arithmetic mean, arithmetic SD, arithmetic coefficient of variation (CV), 


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median, minimum and maximum values. The arithmetic CV will be displayed to 1 decimal place 
and all other values will be reported to 3 significant digits. A summary by visit of serum 
concentration data will also be provided for patients switching to the auto-injector. In addition, an 
overall summary by administration method (PFS vs auto-injector) will be provided pooling together 
records at different time-points after Week 0. 
Individual and mean (±SD) concentration-time plots will be presented for each treatment 
sequence (on linear-linear scales) for the overall treatment period and Period I, individual trough 
concentration-time plots will be presented on linear scales to illustrate graphically the effect of 
ADA activity on the PK plots (according to ADA titre results); in particular, plots will be displayed in 
3 panels according to whether the patient’s last sampling day titre (Week 30 for Period I, Week 80 
for Period II and overall or EOS visit for patients who prematurely discontinue the study) result is: 
• 
Low: less than or equal to the lower quartile; 
• 
Moderate: between the lower and upper quartile (both not included). 
• 
High: greater than or equal to the upper quartile. 
PK analysis will be based on PKAS. 
6.9.6.1 Primary PK Analysis 
A mixed model for repeated measures (MMRM) will be fitted to the log transformed PK trough 
concentrations at Weeks 12, 24 and 30 (i.e., during the randomised treatment period) with patient 
included as a random effect and fixed effect terms for week, treatment group  (or sequence) and 
week x treatment group (or sequence) interaction. The least squares mean (LSM) for each 
treatment group (or sequence) will be estimated at each week and averaged over time with 95% 
CIs and plotted over time. If the interaction term for week x treatment group (or sequence) is not 
significant at the 10% level, only differences in LSMs averaged over all time points will be 
estimated with 90% CIs. Otherwise, difference will be estimated at each time point. Estimates will 
be back-transformed to give geometric LSMs and ratios of geometric LSMs. The following 
comparisons will be of interest: 

FKB327 to Humira (based on treatment in Study FKB327-003).

Treatment sequence group Humira-FKB327 relative to FKB327-Humira.

Treatment sequence group FKB327-Humira relative to Humira-Humira.

Treatment sequence group FKB327-FKB327 relative to Humira-FKB327.

Treatment sequence group FKB327-FKB327 relative to FKB327-Humira.

Treatment sequence group Humira-FKB327 relative to Humira-Humira.

Treatment sequence group Humira-Humira relative to FKB327- FKB327.
Two models will be fitted. The first model will be using treatment group for the comparison 
FKB327 to Humira. The second model will be fitted using treatment sequences. 
Different covariance structures may be considered to improve the fit of the model (eg, 
autoregressive).    
PK samples collected during the non-randomised period (i.e., at Weeks 54 and 76) will be listed 
and summarised only (see Section 6.9.6 for details). 


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6.9.6.2 Secondary PK Analysis 
Due to the potential formation of ADAs, a secondary PK analysis will be performed: the analysis in 
Section 6.9.6.1 will be repeated for the overall treatment period with ADA titre results at the last 
sampling time point (Week 80 or EOS visit for patients who prematurely discontinue the study) 
included as an additional covariate, along with an ADA titre × treatment sequence interaction term 
to test for differences in the effect of ADA activity on the PK data. Note that the overall period 
analysis will only present the treatment sequence comparisons for FKB327-Humira-FKB327 vs 
Humira-Humira-FKB327 and Humira-FKB327-FKB327 vs Humira-Humira-FKB327. 
7 
Final Analysis 
The details of the analysis including analysis sets definitions, endpoints, statistical methodology 
and the displays of study results will be the same across the interim and the final analysis of 
FKB327-003 study, which will be performed when all the patients have either completed or 
discontinued the study and the database will have been locked, apart from a few additional 
outputs which will only be produced for the Final Analysis. These exceptions are detailed below.  
7.1 Overall Disposition 
An overall disposition table will be presented by treatment sequence including the following 
summaries: 

Number of patients enrolled

Number of patients randomised to treatment

Number of patients with study drug administered

Number of patients who completed the study

Number of patients who prematurely discontinued the study during any period (and
primary reason for discontinuation)
7.2 ACR20/50/70 Response at Week 76 
Similar to what described in Section 6.7.1.5, a bar plot of the percentage of patients achieving 
ACR20, ACR50 and ACR70 response will also be presented by treatment sequence at Week 76. 
All outputs proposed for the final analysis are identified in Attachment 1. 
8 
Changes to the Planned Analyses 
8.1 Changes to the Analyses Described in the Study Protocol and Protocol 
Amendments 
According to Version 4.2 of the protocol (based on Global Amendment 4) dated 06 APR 2016 the 
“proportion of ADA positive cases (in the confirmatory assay) during the randomised treatment 
period will be compared between treatment sequences.” This analysis will no longer be 
performed. 
In addition, many additional summaries were introduced that were explicitly mentioned and 
described neither in the study protocol nor in Version 1.0.0 of the SAP. All these additional 
exploratory summaries have been detailed in Section 8.2, and no formal hypothesis has been 
specified nor has any statistical testing been performed.  


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8.2 Changes from the Statistical Analysis Plan Version 1.0 to Version 2.0 
The following table details the changes that occurred from Version 1.0.0 of the SAP to the current 
Version 2.0.0. 
Section 
Details of Changes 
1 (Introduction) 
Protocol numbering has been updated and the reasoning behind the second 
Interim Analysis has been described. 
2.1.2 (Secondary 
Objectives) 
The Auto-Injector safety and PK profile has been added to the list of 
secondary objectives 
5.4 
(Interim 
Analyses) 
A rationale for the second interim analysis has been discussed and a 
reference to the new list of outputs (as presented in the Attachment 1) has 
been introduced. 
6.1 
(Patient 
Disposition) 
The summaries have been aligned to what was produced for the primary 
analysis, eventually detailing what needs to be summarised for the interim 
analyses only. 
6.5 
(Medical 
History 
and 
Concurrent 
Medical 
Conditions) 
The title has been changed to account for split summaries of medical history 
(prior to the study) and concurrent medical conditions (which start or end after 
the study Baseline). 
6.7.1.5 (ACR20, 
ACR50 
and 
ACR70 
Response Rates) 
The bar plot at Week 76 has been removed from here and placed into a 
section specific for ‘Final Analysis’-only outputs. 
6.6 
(Prior 
and 
Concomitant 
Medication) 
Additional summaries for concomitant medications have been included to 
account for reporting decisions made during the first interim analysis. In 
particular, summaries of concomitant use of NSAIDs and oral steroids for RA 
have been added, overall and by geographical region (including a drug 
preferred term breakdown). 
6.8.1 (Exposure 
and Compliance) 
The formula for estimating exposure to the auto-injector has been added and 
an additional table for auto-injector exposure summary has been included. 
6.8.2 
(Adverse 
Events) 
Three additional tables have been added, summarising all TEAEs, TEAEs by 
maximum severity and by strongest relationship during Period II only for 
patients switching to the auto-injector. In addition, the full set of AE listings 
has been detailed as well, accounting for 3 additional listings: a listing of all 
AEs, a listing only for TEAEs and one only for non-TEAEs. 
6.9.4 
(Injection 
Site Reactions) 
The summaries related to injection site reactions have been amended to 
reflect what was done during the first interim. In particular, for all endpoints 
(number of patients with injection site reactions, size of injection site reactions 
and related VAS score) 4 different tables have been detailed: one by 
treatment sequence and group reflecting summaries at Week 0, one by 
sequence only reflecting summaries at Week 30, one only for patients 
switching to the auto-injector reflecting summaries at Week 0 and at the 
switching time-point and one for patients not switching to the auto-injector 
reflecting summaries at Week 0 and 30. 


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6.9.6 
(Pharmacokinetic 
Analysis) 
Two additional tables have been added, displaying a by-visit summary of 
serum concentration data only for patients switching to the auto-injector and 
an overall summary of serum concentration data for FKB327-related 
administration by injection method (auto-injector vs PFS). 
6.9.6.1 (Primary 
PK Analysis) 
Four pair-wise sequence comparisons have been added to the 2 originally 
planned. The new ones added are the following: Humira-FKB327 vs FKB327-
Humira, FKB327-FKB327 vs Humira-FKB327, FKB327-FKB327 vs FKB327-
Humira and Humira-Humira vs FKB327- FKB327. 
7 (Final Analysis) 
Newly created section to detail which outputs will only be created for the final 
analysis. Includes an overall disposition table and Week 76 ACR20/50/70 
response bar plot. 
8.3 Changes from the Statistical Analysis Plan Version 2.0 to Version 3.0 
In Section 1 (Introduction) the new scope of the additional Interim Analysis has been introduced, 
detailing the key role of this interim in the US BLA submission process. 
8.4 Changes from the Statistical Analysis Plan Version 3.0 to Version 4.0 
Section 
Details of Changes 
Abbreviations 
AI (Auto-Injector) has been added 
1 (Introduction) 
Updated the SAP version numbers where 
appropriate, updated DBL date and removed 
interim analysis specific text that was no longer 
needed 
6.8.2 (Adverse Events) 
Add in specific details of what type of Adverse 
events are to be summarized by administration 
method 
6.9.4 (Injection Site Assessment) 
Add in specific details of timepoint for injection 
site summaries (Week 30) to be summarized by 
administration method 
6.9.5 (Immunogenicity Analysis) 
Add in specific details for Anti-Drug Antibody 
activity and Neutralising Anti Body Results 
summary by administration method 
9.1 Attachment 1 List of Tables, Listings and 
Figures 
Added the following tables 
Table 
14.2.2.1.4 
Summary 
of 
Anti-Drug 
Antibody 
Activity 
during 
Period 
II, 
by 
Administration Method: Safety Analysis Set 
Table 14.2.2.4.4 Summary of Frequency of 
Neutralising Antibody Results during Period II, 
by Administration Method: Safety Analysis Set 
Table 14.3.1.5.1.5 Summary of Injection Site 
Reactions at Week 30, by Administration 


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Method: Safety Analysis Set 
Table 14.3.1.1.3 Summary of Adverse Events, 
by Administration Method: Safety Analysis Set 
Table 14.3.1.2.9 Incidence of Treatment-
Emergent Adverse Events, by Administration 
Method: Safety Analysis Set 
Table 14.3.1.2.10 Incidence of Drug-Related 
Treatment-Emergent 
Adverse 
Events, 
by 
Administration Method: Safety Analysis Set 
Table 14.3.2.1.4 Incidence of Treatment-
Emergent 
Serious 
Adverse 
Events, 
by 
Administration Method: Safety Analysis Set 
Table 14.3.2.4.2.4 Incidence of Treatment-
Emergent Adverse Events of Special Interest, 
by Administration Method: Safety Analysis Set 
Table 14.3.2.4.2.5 Incidence of Treatment-
Related Treatment-Emergent Hypersensitivity 
and 
Anaphylaxis 
Adverse 
Events, 
by 
Administration Method: Safety Analysis Set 
A column has been added which denotes if the 
table, figure or listing is used in the final 
analysis 
Drug-Related is changed to Treatment-Related 
for Table 14.3.1.2.10, and drug-related is 
changed 
to 
treatment-related 
where 
appropriate.  
9 
Attachments and Appendices 
9.1 Attachment 1 List of Tables, Listings and Figures 
Attachment 1 is redacted from the document.


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Statistical Analysis Plan 
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Protocol Number: FKB327-003  
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Statistical Analysis Plan 
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Protocol Number: FKB327-003  
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Statistical Analysis Plan 
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Protocol Number: FKB327-003  
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Statistical Analysis Plan 
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Protocol Number: FKB327-003  
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Statistical Analysis Plan 
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Protocol Number: FKB327-003  
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
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9.2 Appendix 1 Joints Considered for the 68/66 and 28 Joint Counts 
Joint 
Assessed for 
the 68 joint 
count (Tender) 
Assessed for 
the 66 joint 
count (Swollen) 
Assessed for 
the 28 joint 
count 
Right Temporomandibular 
x 
x 
Right Sternoclavicular 
x 
x 
Right Acromio-clavicular 
x 
x 
Right Shoulder 
x 
x 
x 
Right Elbow 
x 
x 
x 
Right Hip 
x 
Right Wrist 
x 
x 
x 
Right Metacarpophalangeal I 
x 
x 
x 
Right Metacarpophalangeal II 
x 
x 
x 
Right Metacarpophalangeal III 
x 
x 
x 
Right Metacarpophalangeal IV 
x 
x 
x 
Right Metacarpophalangeal V 
x 
x 
x 
Right Proximal Interphalangeal I 
x 
x 
x 
Right Proximal Interphalangeal II 
x 
x 
x 
Right Proximal Interphalangeal III 
x 
x 
x 
Right Proximal Interphalangeal IV 
x 
x 
x 
Right Proximal Interphalangeal V 
x 
x 
x 
Right Distal Interphalangeal II 
x 
x 
Right Distal Interphalangeal III 
x 
x 
Right Distal Interphalangeal IV 
x 
x 
Right Distal Interphalangeal V 
x 
x 
Right Knee 
x 
x 
x 
Right Ankle 
x 
x 
Right Tarsus 
x 
x 
Right Metatarsophalangeal I 
x 
x 
Right Metatarsophalangeal II 
x 
x 
Right Metatarsophalangeal III 
x 
x 
Right Metatarsophalangeal IV 
x 
x 
Right Metatarsophalangeal V 
x 
x 
Right Interphalangeal I 
x 
x 
Right Interphalangeal II 
x 
x 
Right Interphalangeal III 
x 
x 
Right Interphalangeal IV 
x 
x 
Right Interphalangeal V 
x 
x 
Left Temporomandibular 
x 
x 
Left Sternoclavicular 
x 
x 
Left Acromio-clavicular 
x 
x 
Left Shoulder 
x 
x 
x 
Left Elbow 
x 
x 
x 


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Left Hip 
x 
Left Wrist 
x 
x 
x 
Left Metacarpophalangeal I 
x 
x 
x 
Left Metacarpophalangeal II 
x 
x 
x 
Left Metacarpophalangeal III 
x 
x 
x 
Left Metacarpophalangeal IV 
x 
x 
x 
Left Metacarpophalangeal V 
x 
x 
x 
Left Proximal Interphalangeal I 
x 
x 
x 
Left Proximal Interphalangeal II 
x 
x 
x 
Left Proximal Interphalangeal III 
x 
x 
x 
Left Proximal Interphalangeal IV 
x 
x 
x 
Left Proximal Interphalangeal V 
x 
x 
x 
Left Distal Interphalangeal II 
x 
x 
Left Distal Interphalangeal III 
x 
x 
Left Distal Interphalangeal IV 
x 
x 
Left Distal Interphalangeal V 
x 
x 
Left Knee 
x 
x 
x 
Left Ankle 
x 
x 
Left Tarsus 
x 
x 
Left Metatarsophalangeal I 
x 
x 
Left Metatarsophalangeal II 
x 
x 
Left Metatarsophalangeal III 
x 
x 
Left Metatarsophalangeal IV 
x 
x 
Left Metatarsophalangeal V 
x 
x 
Left Interphalangeal I 
x 
x 
Left Interphalangeal II 
x 
x 
Left Interphalangeal III 
x 
x 
Left Interphalangeal IV 
x 
x 
Left Interphalangeal V 
x 
x 


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10 
References 
1.
DAS28 – Twenty-eight joints: http://www.das-score.nl/das28/en/difference-between-the-
das-and-das28/how-to-measure-the-das28/twenty-eight-joints.html [accessed
31 January 2016]