Conditions: Arthritis, Rheumatoid
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 430
Healthy volunteers: no

Brief summary:
The main objective of this trial is to provide long-term safety, pharmacokinetics (PK), and immunogenicity data on BI 695501 administered via prefilled syringe in patients with Rheumatoid Arthritis who have completed Trial 1297.2. The primary endpoint thereby is the number (proportion) of patients with drug-related adverse events (AEs) during the treatment phase. The secondary objective in this trial is the assessment of Long-term efficacy of BI 695501 by evaluation of:

* the change from Baseline in DAS28 (ESR) at Week 48
* the proportion of patients meeting American College of Rheumatology 20% (ACR20) response criteria at Week 48
* the proportion of patients who meet the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) definition of remission at Week 48
* the proportion of patients with EULAR response (good response, moderate response, or no response) at Week 48.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: BI 695501
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol
TITLE PAGE
Document Number:
c03635799-02
EudraCT No.:
2015-002634-41 
BI Trial No.:
1297.3
BI Investigational 
Product:
BI 695501
Title:
Long-term assessment of safety, efficacy, pharmacokinetics and 
immunogenicity of BI 695501 in patients with rheumatoid arthritis 
(RA): an open-label extension trial for patients who have completed 
trial 1297.2 and are eligible for long-term treatment with adalimumab
Brief Title:
Open-label, long-term extension trial of BI 695501 in patients with 
rheumatoid arthritis
Clinical Phase:
IIIb
Trial Clinical Monitor:
Phone: 
Fax: 
Coordinating 
Investigator:
Tel.: 
 
Fax: 
Status:
Final Protocol (revised protocol based on global amendment 01)
Version and Date:
Version:
Date:
2.0
19 FEB 2016
Page 1 of 79
Proprietary confidential information.
2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
19 Feb 2016
Trial number:
1297.3
Revision date:
NA
Title of trial:
Long-term assessment of safety, efficacy, pharmacokinetics and immunogenicity of 
BI 695501 in patients with rheumatoid arthritis (RA): an open-label extension trial 
for patients who have completed trial 1297.2 and are eligible for long-term treatment 
with adalimumab
Coordinating
Investigator:
Trial site(s):
Multinational, multicenter trial in approximately 80 clinical sites across 
approximately 15 countries. Since this is an extension to Trial 1297.2, the actual 
number of sites and countries will be determined by the sites participating in Trial 
1297.2 that have patients eligible for Trial 1297.3.
Clinical phase:
IIIb
Objective(s):
The objective of this trial is to provide long-term safety, efficacy, 
pharmacokinetics (PK), and immunogenicity data on BI 695501 administered via 
prefilled syringe in patients with RA who have completed Trial 1297.2.
Methodology:
BI 695501 is a proposed biosimilar to adalimumab (Humira®). Humira has 
received regulatory approval for RA in the United States (US), the European 
Union (EU) and many other countries.
This is an open-label trial of BI 695501 with a 48-week treatment period in 
patients with RA continuing to receive methotrexate (MTX) within the dose range 
of the 1297.2 trial for at least 12 weeks. After Week 12, the MTX dose will be at 
the Investigator’s discretion.
Each patient who meets all the inclusion criteria and none of the exclusion criteria 
will self-administer 40 mg of BI 695501 every 2 weeks.
The trial is designed to generate data on long-term safety, efficacy, PK, and 
immunogenicity with BI 695501 in patients who have completed Trial 1297.2.  
This will include:

patients who were previously treated with BI 695501 in Trial 1297.2 for 
48 weeks, 

patients who were previously treated with US-licensed Humira® for 24 weeks 
followed by BI 695501 for 24 weeks in Trial 1297.2,

patients who were previously treated with US-licensed Humira® in 
Trial 1297.2 for 48 weeks
No. of patients: 
total entered:
It is anticipated that approximately 300 to 400 patients will be eligible and willing 


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Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
19 Feb 2016
Trial number:
1297.3
Revision date:
NA
to participate in this extension trial.
each treatment:
All patients will receive BI 695501.
Diagnosis :
Moderately to severely active RA.
Main criteria
for inclusion:
Adult patients with moderately to severely active RA who completed Trial 1297.2,
wish to participate in this extension trial and in the Investigator’s assessment can 
benefit from receiving BI 695501. Patients must not have experienced 
Investigator-reported drug-related serious adverse events (SAEs) during the 
1297.2 trial.
Patients willing and able to self-administer BI 695501 using a pre-filled syringe.
Test product:
BI 695501, solution for injection
dose:
40 mg/0.8 mL every 2 weeks via single pre-filled glass syringe
mode of 
administration:
Subcutaneous (SC) injection
Comparator product:
Not applicable
Duration of treatment:
Each patient will be treated with BI 695501 every 2 weeks.
The trial will consist of a 48-week treatment period. 
Every effort should be made for all patients who complete the 48-week treatment 
period or who discontinue the trial early (and do not withdraw their consent), to 
return for a safety follow-up visit 10 weeks after the last administration of trial 
medication.
Safety endpoints:
The primary endpoint of this trial is defined as the number (proportion) of patients 
with drug-related adverse events (AEs) during the treatment phase.


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Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
19 Feb 2016
Trial number:
1297.3
Revision date:
NA
Criteria for efficacy, 
immunogenicity 
and pharmacokinetics:
There is no primary efficacy endpoint in this trial. 
Unless otherwise specified, all endpoints will be assessed using the 1297.2 
baseline values.
Secondary efficacy endpoints

The change from Baseline in Disease Activity Score in 28 joints (DAS28)
(erythrocyte sedimentation rate [ESR]) at Week 48

The proportion of patients meeting American College of Rheumatology 
20% (ACR20) response criteria at Week 48

The proportion of patients who meet the ACR/European League Against 
Rheumatism (EULAR) definition of remission at Week 48 

The proportion of patients with EULAR response (good response, moderate 
response or no response) at Week 48 
 
 
 
 
 
 
 
 
 
 
 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
19 Feb 2016
Trial number:
1297.3
Revision date:
NA
Criteria for efficacy, 
immunogenicity 
and pharmacokinetics, 
continued:
 
 
 
 
 
Other endpoints

The proportion of patients with antidrug antibodies (ADAs) at Week 12, 
Week 24, and Week 48

The proportion of patients with neutralizing antidrug antibodies (nADAs) at 
Week 12, Week 24, and Week 48

The proportion of patients who discontinue due to lack of efficacy

The proportion of patients who discontinue due to a drug-related AE
PK Analysis
A population PK analysis with sparse blood sampling throughout the treatment 
period and at follow-up will be carried out to assess the PK of BI 695501. The PK 
analysis might involve combining data with data from other BI 695501 studies. If 
relevant, a relationship will be investigated between selected safety and efficacy 
parameters including the development of ADA/nADA.
Statistical methods:
Descriptive statistics for safety, efficacy, and other endpoints will be provided. 
Analyses will be based on data obtained in the current 1297.3 trial, and 
comparisons will be made depending on the treatment assignment in Trial 1297.2. 
The results will also be analyzed overall, according to the single open-label 
treatment in 1297.3.


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FLOW CHART
Visit
1
2
3
4
5
6
7
8
9
10
Week
Screening1
Baseline 
62
12
182
24
322
402
48 
EoT3
58
SFU
Day
-14
1
43
85
127
169
225
281
337
407
Permitted visit window (days)
±3
±1
-
±2
-
±2
-
-
±2
±2
Informed consent
X
Assessment of eligibility 
X
Self-administration evaluation4
X
Demographics
X
LABS/SAFETY ASSESSMENTS
Infection screen: Hepatitis B 
(HbsAg); HCV and optional HIV test
X
RF and anti-CCP antibodies
X
X
TB test5
X
X
ESR (local)
X
X
X
X
X
X
CRP
X
X
X
X
X
X
Pregnancy test6
X
X
X
X
X
X
Physical examination 
X
X
X
X
X
X
Vital signs7
X
X
X
X
X
X
Laboratory tests (serum chemistry, 
hematology, urinalysis)8
X
X
X
X
X
X
12-lead ECG9
X
X
X
Previous and concomitant therapy
X
X
X
X
X
X
Adverse events10
X
X
X
X
X
X


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FLOW CHART (CONT’D)
Visit
1
2
3
4
5
6
7
8
9
10
Week
Screening1
Baseline 
62
12
182
24
322
402
48 
EoT3
58
SFU
Day
-14
1
43
85
127
169
225
281
337
407
Permitted visit window (days)
(±3)
±1
-
±2
-
±2
-
-
±2
±2
EFFICACY ASSESSMENTS
Swollen and tender joint counts
X
X
X
X
X
Patient’s global assessment VAS11
X
X
X
X
X
Physician’s global assessment VAS
X
X
X
X
X
HAQ-DI11
X
X
X
X
X
SF-36 v211
X
X
X
X
X
OTHER ASSESSMENTS
Pharmacokinetics12
X
X
X
X
X
Antidrug antibody sampling12
X
X
X
X
X
Neutralizing antidrug antibody 
sampling12
X
X
X
X
X
TRIAL MEDICATION
Contact IRT
X
X
X
X
X
X
X
X
X
Review patient diary
X
X
X
X
X
X
X
X
Administration of trial medication
(X)13
X14
X15-----------------------------------------------------------------------X
Dispense trial medication16
X
X
X
X
X
X
X
Termination of trial medication
X
End of participation
X
anti-CCP: anti-cyclic citrullinated peptide; CRP: C-reactive protein; EoT: End of Treatment; ECG: electrocardiogram; ESR: erythrocyte sedimentation rate; HAQ-DI: Health 
Assessment Questionnaire – Disability Index; HbsAg: Hepatitis B surface antigen; HCV: hepatitis C; HIV: human immunodeficiency virus; IRT: Interactive Response 
Technology; RF: rheumatoid factor; SF-36 v2: 36-item Short Form Health Survey version 2; SFU: Safety Follow-up; TB: tuberculosis; VAS: visual analogue scale. 
1.
The Screening visit will be the Week 48 visit in Trial 1297.2 and the same visit window applies (±3 days). Informed consent for this extension trial must be obtained prior to 
conducting the Week 48 assessments in Trial 1297.2, in order for those assessments to serve as the screening assessments in this extension trial. VAS assessments and 
completion of the HAQ-DI and SF-36 v2 questionnaires must be done prior to any visit procedures at this day. Patient questionnaires completed for the 1297.2 trial will be 
used as baseline questionnaires for the 1297.3 trial. Trial medication should be administered after completion of all assessments at the Screening visit; this will be the last 
administration of trial medication in Trial 1297.2.


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2.
The Week 6, Week 18, Week 32, and Week 40 visits will be trial medication administration only visits, however the patient may choose to administer the trial medication at 
home and collect dispensed medication at a later date. At each visit, the Investigator/designee will dispense sufficient trial medication so that patients can continue to 
self-administer trial medication at home until the next site visit.
3.
Patients who discontinue the trial early will, at discontinuation, have an End of Treatment (EoT) Visit equivalent to the Week 48 assessments; patients who discontinue early 
will also return for a safety follow-up visit 10 weeks after the last dose of BI 695501. Every effort should be made for all patients who complete the total 48-week treatment 
period to return for a safety follow-up visit at Week 58. 
4.
Patients will be assessed at screening if they are willing and able, per investigator judgment, to self-administer the trial medication.
5.
Patients must have a negative tuberculosis (TB) test, including a QuantiFERON TB Gold test. A TB test can be performed at any time during the trial if the Investigator
considers it clinically necessary.
6.
Females only; a urine pregnancy test will be performed at Screening, on Day 1 (Baseline), and all subsequent visits (does not include trial medication only visits).
7.
Includes measurement of blood pressure, respiratory rate and pulse rate (all sitting after 5 minutes rest). The patient’s body temperature will also be recorded. 
8.
Findings of alanine aminotransferase or aspartate aminotransferase >3 times the upper limit of normal or hemoglobin <8.0 g/dL at baseline are criteria for exclusion.
9.
Two consecutive recordings need to be taken.
10.
Adverse events will be collected from the time of informed consent. Adverse events continuing at the EoT Visit must be followed to resolution or follow up as agreed by the 
Investigator and medical monitor. For patients who complete the trial or who discontinue the trial early, AEs will be captured for 10 weeks after the EoT visit. 
11.
Questionnaires will be completed at the site by the patient before any investigations or discussions about their disease with the clinic staff.
12.
Pharmacokinetic (PK) and anti-drug antibody (ADA) samples (including neutralizing ADA samples) should be taken at each visit designated with an “X”, and can be taken 
at any time during the visit (PK and ADA/neutralizing ADA samples will be taken at the same time point). For all PK samples, the day and time of sampling must be 
accurately recorded. All dosing dates and times must be accurately entered in the patient diary. See also Table 5.4: 1 for PK sampling time points.
13.
At the Screening visit, the administration of BI 695501 will be performed by a suitably qualified, designated trial personnel at the site and patients will be trained on 
self-administration. This will be the last administration of trial medication in Trial 1297.2.
14.
The first dose of trial medication in the extension trial will be administered at the Baseline visit, which is approximately 2 weeks after the Screening visit (the Week 48 visit 
of Trial 1297.2). The patients will self-inject BI 695501 with the support of the suitably qualified, designated trial personnel.
15.
For all subsequent injections. Patients will self-inject the trial medication every 2 weeks until trial completion or early withdrawal.
16.
1 to 5 syringes will be dispensed to the patient at each visit.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................15
1.1
MEDICAL BACKGROUND.............................................................................15
1.2
DRUG PROFILE................................................................................................15
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....18
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................18
2.2
TRIAL OBJECTIVES........................................................................................18
2.3
BENEFIT - RISK ASSESSMENT.....................................................................18
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................20
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................20
3.1.1
Administrative structure of the trial .................................................................21
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................21
3.3
SELECTION OF TRIAL POPULATION .......................................................21
3.3.1
Main diagnosis for trial entry ............................................................................22
3.3.2
Inclusion criteria .................................................................................................22
3.3.3
Exclusion criteria ................................................................................................22
3.3.4
Removal of patients from therapy or assessments...........................................24
3.3.4.1
Removal of individual patients .............................................................................24
3.3.4.2
Discontinuation of the trial by the sponsor...........................................................25
4.
TREATMENTS...................................................................................................26
4.1
TREATMENTS TO BE ADMINISTERED.....................................................26
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........26
4.1.2
Method of assigning patients to treatment groups...........................................26
4.1.3
Selection of doses in the trial..............................................................................26
4.1.4
Drug assignment and administration of doses for each patient......................26
4.1.5
Blinding and procedures for unblinding...........................................................27
4.1.5.1
Blinding.................................................................................................................27
4.1.5.2
Unblinding and breaking the code ........................................................................27
4.1.6
Packaging, labelling, and re-supply...................................................................27
4.1.7
Storage conditions...............................................................................................27
4.1.8
Drug accountability.............................................................................................28
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
TREATMENT.....................................................................................................29


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4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....29
4.2.2
Restrictions ..........................................................................................................29
4.2.2.1
Restrictions regarding concomitant treatment ......................................................29
4.2.2.2
Restrictions on diet and life style..........................................................................31
4.3
TREATMENT COMPLIANCE........................................................................31
5.
VARIABLES AND THEIR ASSESSMENT ....................................................32
5.1
TRIAL ENDPOINTS..........................................................................................32
5.1.1
Primary Endpoint ...............................................................................................32
5.1.2
Secondary Endpoints..........................................................................................32
5.2
ASSESSMENT 
OF EFFICACY ......................................................................................................................34
5.2.1
Joint assessments.................................................................................................34
5.2.2
Patient’s global assessment of disease activity VAS ........................................34
5.2.3
Patient’s assessment of pain...............................................................................35
5.2.4
Physician’s global assessment of disease activity VAS ....................................35
5.2.5
Patient’s assessment of disability.......................................................................35
5.2.6
SF-36 v2................................................................................................................35
5.2.7
Systemic inflammation: CRP level and ESR....................................................35
5.2.8
Calculation of DAS28 and ACR scores.............................................................35
5.2.9
Definition of ACR/EULAR remission...............................................................37
5.3
ASSESSMENT OF SAFETY.............................................................................37
5.3.1
Physical examination ..........................................................................................37
5.3.2
Vital Signs............................................................................................................37
5.3.3
Safety laboratory parameters ............................................................................37
5.3.4
Electrocardiogram ..............................................................................................38
5.3.5
Other safety parameters.....................................................................................39
5.3.6
Assessment of adverse events.............................................................................39
5.3.7
Adverse event collection and reporting.............................................................41
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................43
5.4.1
Assessment of Pharmacokinetics.......................................................................43
5.4.2
Methods of sample collection .............................................................................43
5.4.3
Analytical determinations ..................................................................................44
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................44
5.5
ASSESSMENT OF EXPLORATORY BIOMARKER(S)..............................44
5.6
OTHER ASSESSMENTS...................................................................................45
5.6.1
Immunogenicity – Antidrug antibodies ............................................................45
5.6.2
Lack of efficacy....................................................................................................46
5.6.3
Adverse Event leading to discontinuation ........................................................46
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................46


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6.
INVESTIGATIONAL PLAN.............................................................................47
6.1
VISIT SCHEDULE.............................................................................................47
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................48
6.2.1
Screening period..................................................................................................48
6.2.2
Treatment period(s)............................................................................................49
6.2.3
Follow-Up Period and Trial Completion ..........................................................51
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................52
7.1
STATISTICAL DESIGN - MODEL.................................................................52
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................52
7.3
PLANNED ANALYSES.....................................................................................52
7.3.1
Primary endpoint analyses.................................................................................53
7.3.2
Secondary endpoint analyses .............................................................................53
7.3.4
Safety analyses.....................................................................................................54
7.3.5
Pharmacokinetic analyses ..................................................................................54
7.3.6
Immunogenicity analyses ...................................................................................55
7.4
INTERIM ANALYSES ......................................................................................55
7.5
HANDLING OF MISSING DATA ...................................................................55
7.5.1
Safety and other endpoints.................................................................................55
7.5.2
Efficacy endpoints...............................................................................................55
7.6
RANDOMISATION ...........................................................................................55
7.7
DETERMINATION OF SAMPLE SIZE .........................................................56
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........57
8.1
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...........................................................................................................57
8.2
DATA QUALITY ASSURANCE ......................................................................58
8.3
RECORDS...........................................................................................................58
8.3.1
Source documents ...............................................................................................58
8.3.2
Direct access to source data and documents.....................................................58
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS58
8.4.1
Listedness.............................................................................................................58
8.4.2
Expedited reporting to health authorities and IEC/IRB.................................59
8.5
STATEMENT OF CONFIDENTIALITY........................................................59
8.6
END OF TRIAL..................................................................................................59
9.
REFERENCES....................................................................................................60
9.1
PUBLISHED REFERENCES............................................................................60
9.2
UNPUBLISHED REFERENCES......................................................................61
10.
APPENDICES.....................................................................................................62
10.1
FUNCTIONAL CLASS......................................................................................62
10.2
PATIENT AND PHYSICIAN GLOBAL ASSESSMENT VAS .....................63
10.3
HAQ DISABILITY INDEX...............................................................................65


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10.4
SF-36 V2...............................................................................................................67
10.5
CLINICAL EVALUATION OF LIVER INJURY ..........................................72
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................74


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ABBREVIATIONS
ACR
American College of Rheumatology
ACR20
American College of Rheumatology 20% response criteria
ACR50
American College of Rheumatology 50% response criteria
ACR70
American College of Rheumatology 70% response criteria
ADA(s)
Antidrug antibody(ies)
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase
Anti-CCP
Anti-cyclic citrullinated peptide
AST
Aspartate aminotransferase
BI
Boehringer Ingelheim
CRP
C-reactive protein
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DAS
Disease Activity Score
DAS28
Disease Activity Score in 28 joints
DILI
Drug-induced liver injury
DMARD
Disease-modifying antirheumatic drug
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EMA
European Medicines Agency
EoT
End of Treatment
ESR
Erythrocyte sedimentation rate
EU
European Union
EULAR
European League Against Rheumatism
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GH
General Health
HAQ-DI
Health Assessment Questionnaire – Disability Index
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEV
Hepatitis E virus
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
Intravenous
LOCF
Last observation carried forward


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MedDRA
Medical Dictionary for Regulatory Activities 
MMP
Matrix metalloproteinase
MTX
Methotrexate
nADA
Neutralizing ADAs
NSAIDs
Nonsteroidal anti-inflammatory drugs
PK
Pharmacokinetics
PPK
Population pharmacokinetic
RA
Rheumatoid arthritis
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RF
Rheumatoid Factor
SAE
Serious Adverse Event
SC
Subcutaneous
SF-36 v2
36-item Short Form Health Survey version 2
SFU
Safety Follow-up
SJC
Swollen joint count
SUSAR
Suspected unexpected serious adverse reaction
TB
Tuberculosis
TJC
Tender joint count
TNF
Tumor necrosis factor
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal
US
United States of America
VAS
Visual analogue scale
VCA
Virus capsid antigen


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder characterized by 
synovial inflammation in the joints and consequently, progressive joint destruction. 
Depending on the severity of the disease, systemic manifestations may occur including lung, 
cardiovascular, hematologic and ocular effects. If left untreated, RA may lead to severe 
functional disabilities, and therefore a considerable reduction in quality of life for the patient 
(R11-4384, R11-4383). The prevalence of RA varies with factors such as gender, race and 
smoking status and is approximately 0.5% to 1% (R07-0637). 
The cytokine tumor necrosis factor (TNF)-alpha is involved in inflammatory and immune 
responses. Elevated levels of TNF-alpha are found in the synovial fluid of RA patients, 
including juvenile idiopathic arthritis and psoriatic arthritis patients and it has been 
demonstrated that TNF-alpha (hereafter also referred to as TNF) plays a crucial role in both 
the pathologic inflammation and the joint destruction characteristic of these diseases. Thus, 
TNF targeted therapy plays an important role in RA through a reduction in the TNF-mediated 
downstream effects on other cell types involved in the inflammatory response.
There are five anti-TNF drugs that have been approved by the United States (US) Food and 
Drug Administration (FDA) and the European Medicines Agency (EMA) to treat moderate to 
severe RA that has not responded to one or more of the traditional disease-modifying 
antirheumatic drugs (DMARDs). These currently approved therapies include: adalimumab, 
etanercept, infliximab, certolizumab pegol, and golimumab. Efficacy has been demonstrated 
in all five therapies, in combination with methotrexate (MTX), by greater American College 
of Rheumatology 20%/50%/70% (ACR20/50/70) responses, an improvement in Disease 
Activity Score in 28 joints (DAS28), less radiographic progression, and an improvement in 
quality of life (Health Assessment Questionnaire – Disability Index [HAQ-DI], 36-item Short 
Form Health Survey version 2 [SF-36 v2]) (R12-2515).
1.2
DRUG PROFILE
BI 695501 is a monoclonal antibody being developed as a proposed biosimilar to the 
TNF-alpha blocker, adalimumab (US-licensed Humira® and EU-approved Humira®). 
Adalimumab is a recombinant human monoclonal immunoglobulin (Ig) G1 antibody specific 
to human TNF-alpha. It has human-derived heavy and light chain variable regions and human 
IgG1:k constant regions and is produced in a mammalian expression system (R15-0739 and 
R15-3225).  
Humira® binds specifically to TNF-alpha (and not TNF-beta) and blocks its interaction with 
the p55 and p75 cell surface TNF receptors. Humira® has also been shown to lyse cells 
expressing surface TNF in vitro in the presence of complement and modulate biological 
responses that are induced or regulated by TNF, including changes in adhesion molecules 
responsible for leukocyte migration (endothelial leukocyte adhesion molecule-1, vascular cell 
adhesion molecule-1, and intercellular adhesion molecule-1) (R15-0739).


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After subcutaneous (SC) administration of a single 40 mg dose in healthy adult subjects, peak 
serum concentrations of Humira® are reached approximately 5 days after administration. The 
average absolute bioavailability of Humira® estimated from three studies following a single 
40 mg SC dose was 64%. Following SC administration of 40 mg of Humira® every second 
week in adult RA patients, the mean steady-state trough concentrations were approximately 
5 μg/mL (without concomitant MTX) and 8 to 9 μg/mL (with concomitant MTX), 
respectively. The serum Humira® trough levels at steady-state increased roughly 
proportionally with dose following 20, 40 and 80 mg SC dosing every other week and every 
week (R15-0739 and R15-3225).
Population pharmacokinetic (PPK) analyses showed a trend toward higher apparent clearance 
of Humira® with increasing body weight. After adjustment for weight differences, gender and 
age appeared to have a minimal effect on Humira® clearance (R15-0739 and R15-3225). 
Humira® was evaluated in over 3000 patients in all RA trials that were performed prior to 
approval, with some patients treated for up to 60 months duration. In the EMA label, five 
randomized, double-blind and well-controlled studies were reported for Humira®, which 
assessed the efficacy and safety of Humira® for the treatment of RA (R15-3225). 
In two of the five studies, long-term administration of Humira® was evaluated; patients 
received Humira® for ≥52 weeks. 
In one study, 114 patients were enrolled to the open-label study and continued to receive 
Humira® 40 mg every other week for 60 months. Of these patients 86, 72 and 41 patients had 
ACR20, ACR50 and ACR70 responses, respectively, at Month 60 (R15-3225).
In a trial of 799 MTX-naïve, adult patients with moderate to severe active early RA, 42.9% of 
patients who received Humira®/MTX combination therapy achieved clinical remission 
(DAS28 <2.6) at Week 52 compared to 20.6% and 23.4% of patients receiving MTX 
monotherapy and Humira® monotherapy, respectively. Humira®/MTX combination therapy 
was clinically and statistically superior to MTX (p<0.001) and Humira® monotherapy 
(p<0.001) in achieving a low disease state (R15-0739 and R15-3225). 
In addition, it has been shown that individual components of the American College of 
Rheumatology (ACR) response criteria (number of tender and swollen joints, physician and 
patient assessment of disease activity and pain, and disability index scores) improved at 24 or 
26 weeks compared to placebo (R15-0739 and R15-3225). 
Humira® treatment in RA patients has been associated with a decrease in levels of acute 
phase reactants of inflammation, C-reactive protein (CRP) and erythrocyte sedimentation rate 
(ESR), and serum cytokines (interleukin-6), compared to Baseline. Serum levels of the matrix 
metalloproteinases (MMP)-1 and MMP-3 that induce the tissue remodelling responsible for 
cartilage destruction were also decreased and patients experienced improvement in 
hematological signs of chronic inflammation after Humira® administration (R15-3225).


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In addition to the analytical and pharmacological assays, the similarity between BI 695501 
and US-licensed Humira® was assessed in a single-dose pharmacokinetic (PK) study in the 
cynomolgus monkey and a local tolerance study in rabbits. Additionally, the three-way PK 
similarity between BI 695501, US-licensed Humira® and EU-approved Humira® was 
demonstrated in a Phase I clinical study in healthy volunteers. The results of these studies are 
provided in the Investigator’s Brochure (IB).
For a more detailed description of the drug profile, refer to the current IB which is included in 
the Investigator Site File (ISF).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Adalimumab (Humira®) has received regulatory approval for treatment of patients with RA in 
the US, the EU, and many other countries (R15-0739 and R15-3225). BI 695501 is being 
developed as a proposed biosimilar to US-licensed Humira® and EU-approved Humira®. 
This trial will be conducted in compliance with the Clinical Trial Protocol (CTP), the 
International Conference on Harmonisation (ICH) guidelines, Good Clinical Practice (GCP) 
and with all applicable and current regulatory requirements.
The rationale for conducting this trial is to generate long-term safety, efficacy, and 
immunogenicity data for the administration of the proposed biosimilar BI 695501 in patients 
with RA. This is a 1-year extension trial to Trial 1297.2, in which patient will have received 
48 weeks of treatment with US-licensed Humira® or BI 695501, or with US-licensed 
Humira® for 24 weeks then BI 695501 for 24 weeks.
2.2
TRIAL OBJECTIVES
The objective of this trial is to provide long-term safety, efficacy, PK, and immunogenicity 
data on BI 695501 administered via prefilled syringe in patients with RA who have 
completed Trial 1297.2.
2.3
BENEFIT - RISK ASSESSMENT
Patient risk will be minimized in this trial by implementing conservative eligibility criteria. 
Due consideration has been given to previous experience with US-licensed Humira® and 
EU-approved Humira® in RA patients and side effect management advice (e.g., for 
hypersensitivity reactions) is provided for in this CTP. All trial personnel are directed to the 
BI 695501 IB for a description of the non-clinical and clinical experience with BI 695501. To 
date, a total of 175 healthy male volunteers (includes data from Trial 1297.8 and 
Trial 1297.1) have received BI 695501. As of 01 July 2015, 465 patients were included in 
Trial 1297.2.
Representatives from Boehringer Ingelheim (BI) and 
 Safety, Clinical and Quality 
functions will review accumulating safety data at the monthly Medical and Quality Review 
Meeting. 
Given the progressive nature of the disease, each patient will receive active RA treatment 
throughout the trial. 
Patients will be carefully monitored during ambulatory (outpatient) visits for any safety signs 
and symptoms that may occur or arise following trial treatment. Adverse events (AEs), body 
temperature, vital signs, electrocardiograms (ECGs) and safety laboratory assessments as 


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well as immunogenicity data will be collected throughout the trial; therefore monitoring 
patients for safety outcomes over a prolonged period of time will be possible. 
A potential for drug-induced liver injury (DILI, a rare event) is under constant surveillance 
by sponsors and regulators. Therefore, timely detection, evaluation, and follow-up of 
alterations of selected liver laboratory parameters to ensure patients’ safety will be performed 
in this trial (see Section 5.3.6). 
In addition, hypersensitivity reactions, anaphylaxis, and serious infections are considered 
adverse events of special interest (AESI), see Section 5.3.6.
In patients treated with Humira®, common adverse reactions reported in greater than 10% of 
patients include infections (e.g., upper respiratory tract infections, sinus infections), injection 
site reactions, headache and rash. Allergic reactions (e.g., allergic rash, anaphylactic reaction, 
fixed drug reaction, non-specified drug reaction, urticaria) have been observed in 
approximately 1% of patients (R15-0739 and R15-3225).
Cases of hepatitis B virus (HBV) reactivation have been reported in patients receiving 
anti-TNF therapy. Some cases have been fatal, the majority of which were in patients 
concomitantly receiving other immunosuppressive medications. Carriers of HBV and patients 
with a history of HBV infection will be excluded from the trial.
Tuberculosis (TB) reactivation or new TB infections have been observed in patients receiving 
Humira® and other TNF-inhibitors, including patients who had previously received treatment 
for latent or active TB. Patients will be evaluated for TB risk factors and tested for latent 
infection prior to and during the trial due to the increased risk of opportunistic infections with 
Humira®.
In the controlled portions of clinical trials of some TNF-inhibitors, including Humira®, more 
cases of malignancies have been observed among TNF-inhibitor-treated adult patients 
compared to control-treated adult patients. Therefore, the possible risk for the development of 
malignancies cannot be excluded. 
Further information regarding relevant contraindications, special precautions, adverse 
reactions and other recommendations for the use of US-licensed Humira® and EU-approved 
Humira® in RA patients are described in the prescribing information (R15-0739 and 
R15-3225). 
BI 695501, as a proposed biosimilar product, is expected to provide comparable efficacy, 
safety, tolerability and immunogenicity in patients with RA and therefore is expected to 
provide a similar benefit-risk profile as US-licensed Humira® and EU-approved Humira®.  
An Independent Data Monitoring Committee (IDMC) is monitoring the 1297.2 trial and an 
IDMC safety review will be completed prior to the first patient’s enrolment in the extension 
trial.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is an open-label trial of BI 695501 with a 48-week treatment period in patients with RA 
continuing to receive MTX within the dose range of the 1297.2 trial for at least 12 weeks. 
After Week 12, the MTX dose will be at the Investigator’s discretion.
The trial will consist of a Screening visit 14 days prior to Day 1, a 48-week treatment period
and a 10-week safety follow-up visit. The Screening visit will be the Week 48 visit in 
Trial 1297.2. Informed consent for this extension trial must be obtained prior to conducting 
the Week 48 assessments in Trial 1297.2, in order for those assessments to serve as the 
screening assessments in this extension trial. Trial medication should be administered after 
completion of all assessments at the Screening visit; this will be the last administration of 
trial medication in Trial 1297.2.
Patients who discontinue the trial medication early (and do not withdraw consent) should 
return to the site for an End of Treatment (EoT) visit equivalent to the Week 48 assessments 
as soon as possible after last trial medication administration. For patients who discontinue 
treatment early, a safety follow-up visit should be performed 10 weeks after the last 
administration of BI 695501. All patients who complete the trial should return for a safety 
follow-up visit at Week 58.
It is anticipated that approximately 300 to 400 patients with moderately to severely active RA 
who have completed Trial 1297.2 will be eligible and willing to participate in this extension 
trial. Each patient who provides informed consent and meets all the inclusion criteria and
none of the exclusion criteria will self-administer 40 mg of BI 695501 every 2 weeks by SC 
injection.
Patients will undergo up to 10 visits over the duration of the trial (58 weeks). The trial
procedures to be undertaken at each visit are shown in the Flow Chart.
The primary endpoint of this trial is defined as the number (proportion) of patients with 
drug-related AEs during the treatment phase. Efficacy and other safety parameters will be 
assessed as secondary and other endpoints. For more details, see Section 5.1. 
Up to Week 12, patients will continue to take their regular MTX therapy and the associated 
stable weekly dose of adequate folic acid (at least 5 mg per week or as per local practice) or 
folinic acid (at least 1 mg per week or as per local practice) from their usual source. After 
Week 12, MTX therapy may be adjusted based on Investigator assessment. Patients may also 
continue to receive treatment with oral corticosteroids at a dose of ≤10 mg/day prednisolone 
or equivalent.
Patients may return for unscheduled visits should their medical condition warrant urgent 
attention at the discretion of the Investigator.


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The trial is designed to generate data on long-term safety, efficacy, PK, and immunogenicity 
with BI 695501 in patients who have completed Trial 1297.2. This will include:

patients who were previously treated with BI 695501 in Trial 1297.2 for 48 weeks,

patients who were previously treated with US-licensed Humira® for 24 weeks followed 
by BI 695501 for 24 weeks in Trial 1297.2, and 

patients who were previously treated with US-licensed Humira® in Trial 1297.2 for 
48 weeks.  
3.1.1
Administrative structure of the trial
 will perform Project Management, Clinical Field Monitoring, Medical Monitoring, 
Data Management and Statistical Evaluation according to 
 Standard Operating 
Procedures. A list of responsible persons and relevant local information can be found in the 
ISF.
A Coordinating Investigator will be nominated and will be responsible to coordinate 
Investigators at different centers participating in this multicenter trial. Tasks and 
responsibilities will be defined in a contract. Relevant documentation on the participating 
(Principal) Investigators and other important participants, including their curricula vitae, will 
be filed in the electronic trial master file.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This is a long-term, open-label extension trial to assess the safety, efficacy, PK, and 
immunogenicity of BI 695501 in patients with RA who have completed Trial 1297.2 and are 
eligible for long-term treatment with adalimumab. The trial has a 48-week treatment period in 
patients with RA continuing to receive MTX within the dose range of the 1297.2 trial for at 
least 12 weeks. After Week 12, the MTX dose will be at the Investigator’s discretion. All 
patients will be treated with BI 695501. No comparator was chosen as the purpose of the trial
is to collect data on the long-term safety (and efficacy) and to better characterize PK and 
immunogenicity of BI 695501. 
Each patient who meets all the inclusion criteria and none of the exclusion criteria will
self-administer 40 mg of BI 695501 every 2 weeks. This is the same dosing regimen the 
patients received in Trial 1297.2. 
3.3
SELECTION OF TRIAL POPULATION
A log of all patients enrolled into the trial (i.e., who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.


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3.3.1
Main diagnosis for trial entry
The main requirements for trial entry include patients who completed Trial 1297.2, wish to 
participate in this extension trial, and in the Investigator’s assessment can benefit from 
receiving BI 695501.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
1. All patients must sign and date an Informed Consent Form consistent with ICH GCP 
guidelines and local legislation prior to participation in the trial (i.e., prior to any trial 
procedures, which include medication washout and restrictions) and be willing to follow 
the protocol.
2. Adult patients with moderately to severely active RA who have completed Trial 1297.2, 
and who wish to participate in this extension trial and in the Investigator’s assessment can 
benefit from receiving BI 695501.
3. Patients willing and able to self-administer BI 695501 pre-filled syringe.
4. For participants of reproductive potential (males and females), a reliable means of 
contraception has to be used throughout trial participation. Acceptable methods of birth 
control include, for example, birth control pills, intrauterine devices, surgical sterilization, 
vasectomized partner and double barrier method (for example male condom in 
combination with female diaphragm/cervical cap plus spermicidal 
foam/gel/film/cream/suppository). All patients (males and females of child-bearing 
potential*) must also agree to use an acceptable method of contraception for 6 months 
following completion or discontinuation from the trial medication.
*Women of childbearing potential are defined as:

Any female who has experienced menarche and does not meet the criteria for "women not 
of childbearing potential" as described below
Women not of childbearing potential are defined as:

Women who are postmenopausal (12 months with no menses without an alternative 
medical cause) or who are permanently sterilized (e.g., tubal occlusion, hysterectomy, 
bilateral oophorectomy or bilateral salpingectomy)
3.3.3
Exclusion criteria
1. Patients who experienced Investigator-reported drug-related serious adverse events 
(SAEs) in Trial 1297.2.
2. ACR functional Class IV (see Appendix 10.1) or wheelchair/bed bound.
3. Primary or secondary immunodeficiency (history of, or currently active).
4. Positive QuantiFERON test. 


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5. Known clinically significant coronary artery disease or significant cardiac arrhythmias or 
severe congestive heart failure (New York Heart Association Classes III or IV), or 
interstitial lung disease observed on chest X-ray. 
6. Anaphylactic reaction or hypersensitivity to adalimumab received in Trial 1297.2.
7. History or recent evidence of cancer including solid tumors, hematologic malignancies, 
and carcinoma in situ (except participants with previous resected and cured basal or 
squamous cell carcinoma, treated cervical dysplasia, or treated in situ Grade I cervical 
cancer within 5 years prior to the Screening Visit). 
8. Positive serology for HBV or hepatitis C virus (HCV).
9. Patients who are expecting to receive any live virus or bacterial vaccinations during the 
trial, or up to 3 months after the last dose of trial drug.
10. Any treatment (including biologic therapies) that, in the opinion of the Investigator, may 
place the patient at unacceptable risk during the trial.
11. Patients with a significant disease other than RA and/or a significant uncontrolled disease 
(such as, but not limited to, nervous system, renal, hepatic, endocrine, or gastrointestinal 
disorders). A significant disease is defined as a disease which, in the opinion of the 
Investigator, may (i) put the patient at risk because of participation in the trial, or (ii) 
influence the results of the trial, or (iii) cause concern regarding the patient's ability to 
participate in the trial. 
12. Premenopausal (last menstruation 1 year prior to screening), sexually active women who 
are pregnant or nursing, or are of child-bearing potential and not practicing an acceptable 
method of birth control, or do not plan to continue practicing an acceptable method of 
birth control throughout the trial (acceptable methods of birth control are intrauterine 
devices, surgical sterilization, double barrier, or vasectomized partner).
13. Current inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic 
arthritis, seronegative spondyloarthropathy, Lyme disease) or other systemic autoimmune 
disorder (e.g., systemic lupus erythematosus, inflammatory bowel disease, pulmonary 
fibrosis, or Felty’s syndrome, scleroderma, inflammatory myopathy, mixed connective 
tissue disease, or any overlap syndrome). Secondary Sjögren’s syndrome or secondary 
limited cutaneous vasculitis with RA is permitted. 
14. Any planned surgical procedure, including bone/joint surgery/synovectomy (including 
joint fusion or replacement) for the duration of the trial.
15. Known active infection of any kind (excluding fungal infections of nail beds), or any 
major episode of infection requiring hospitalization or treatment with intravenous (i.v.) 
anti-infectives within 4 weeks of the Screening Visit or completion of oral anti-infectives 
within 2 weeks of the Screening Visit. 
16. Serious infection or opportunistic infection during the 1297.2 trial.
17. Any acquired neurological, vascular, systemic or demyelinating disorder that might affect 
any of the efficacy assessments, in particular, joint pain and swelling (e.g., Parkinson’s 
disease, cerebral palsy, diabetic neuropathy) that occurred during the 1297.2 trial. 
18. Currently active alcohol or drug abuse.


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19. Treatment with i.v. Gamma Globulin or the Prosorba® Column during the 1297.2 trial.
20. Planned treatment with i.v. intramuscular, intra-articular and parenteral corticosteroids.
21. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 times upper 
limit of normal (ULN). 
22. Hemoglobin <8.0 g/dL. 
23. Platelets <100,000/µL.
24. Leukocyte count <4000/µL.
25. Creatinine clearance <60 mL/min.
26. Patients who are currently participating in another clinical trial other than Trial 1297.2.
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
Patients who do not meet all of the inclusion criteria or who meet one or more of the 
exclusion criteria will not be enrolled in this extension trial. The primary reason for the 
screen failure will be recorded on the electronic Case Report Form (eCRF).
Patients have the right to withdraw from this trial at any time for any reason. 
Two situations can occur in this trial and need to be documented accordingly, as follows:
1.
An individual patient is to be withdrawn from the trial if:

The patient decides to discontinue participation in the trial by withdrawal of consent. In 
this case, no more investigations will be performed. The patient does not have to justify 
the decision.
2.
Based on assessment by the Investigator, and after consultation with the trial medical 
advisor, an individual patient may be discontinued from treatment with the investigational 
compound if:

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse or drug-related events, other diseases, or pregnancy)

Repeated protocol violation after documented discussion with the medical monitor

Lack of efficacy 

The patient has an AE that is categorized as a serious infection. A serious infection is 
defined as infections requiring i.v. antibiotics or those that meet the regulatory definition 
of a SAE (including, but not limited to, systemic fungal infections, human 
immunodeficiency virus [HIV], HBV, HCV, infected joint prosthesis)

Patient lost to follow-up despite reasonable efforts to make contact with the patient


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If a patient permanently discontinues trial medication for any reason, every effort should be 
made for the patient to attend the EoT Visit as soon after trial treatment discontinuation as
possible. Every effort should be made for all patients who discontinue the trial treatment
early, to return for a safety follow-up visit 10 weeks after the last dose of trial medication.
For details of assessments to be performed at the Week 48 visit and the Week 58 visit, see
Sections 6.2.2 and 6.2.3, respectively.
For all patients the reason for withdrawal (e.g., AEs) must be recorded in the eCRF. These 
data will be included in the trial database and reported.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-risk
assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial
The Investigator/the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason above).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of BI investigational product(s) and comparator product(s)
Details of the trial medication are provided in Table 4.1.1: 1.
Table 4.1.1: 1
Trial medication
Trial Medication
Dosage form (concentration)
Manufacturer
BI 695501, sterile solution consisting of:
sodium acetate, acetic acid, trehalose, 
polysorbate 80 and water for injection.
Solution for SC injection 
(40 mg/0.8 mL)
Boehringer Ingelheim 
Pharma GmbH & Co KG, 
Germany
SC: subcutaneous.
BI 695501 will be provided in sterile, preservative-free, non-pyrogenic, single-use prefilled 
glass syringes containing 40 mg of BI 695501 per 0.8 mL. One syringe will be used per 
injection. 
Any unused product or waste material will be disposed of in accordance with local 
requirements.
4.1.2
Method of assigning patients to treatment groups
This is an open-label, single-arm trial. Once patients have completed screening, have met all 
the inclusion criteria and none of the exclusion criteria, they will all be treated with 
BI 695501. 
4.1.3
Selection of doses in the trial
The dose of BI 695501 for the treatment of RA in this trial is the same dose used in 
Trial 1297.2, and is based on the clinically effective dose of currently available forms of 
US-licensed Humira® and EU-approved Humira®. The recommended dose for use in patients 
with RA is 40 mg by SC injection every 2 weeks and therefore BI 695501 will be 
administered at 40 mg by SC injection every 2 weeks.
4.1.4
Drug assignment and administration of doses for each patient
Each patient will receive up to 25 SC drug injections (40 mg/0.8 mL) of BI 695501 during 
the treatment period. 
Prefilled syringes will be used for the injections (see Section 4.1.1). Injections will be 
administered subcutaneously. 
At the Screening visit (Week 48 visit of Trial 1297.2), trial medication will be administered 
by a suitably qualified, designated trial personnel. This will be the last administration of trial 


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medication in Trial 1297.2. Detailed training and instruction on self-administration will be 
provided to the patient at this visit and a self-administration guide will be provided to the 
patient. Patients will be instructed to accurately record the dates and times of BI 695501 
dosing, and the occurrence of any AEs and use of concomitant medications, on the provided 
diary cards between the ambulatory visits.
The first administration of trial medication in this extension trial will be at the Baseline visit 
(Day 1). After the first injection (Baseline, Day 1), the patient will remain at the clinical site 
for at least 1 hour for observation of any AEs.
All subsequent injections of BI 695501 will be administered by the patients themselves, these
injections may be performed at the site or at the patients home, as specified in the
Flow Chart.
At each visit, 1 to 5 syringes will be dispensed to the patient so that patients can continue to 
self-administer trial medication at home until the next site visit.
Handling and administration of trial medication will be described in detail in the handling 
instructions, which will be provided in the ISF.
Dose modification is not permitted during this trial. If a patient misses a dose of trial 
medication, then the dose should be administered as soon as possible. The 2-week regimen 
for trial medication administration should resume from the time the dose is administered.
In the event of an anaphylactic or other serious allergic reaction, the administration of trial 
medication will be discontinued immediately, and appropriate therapy instituted.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is an open-label, single-arm trial. No blinding of BI 695501 will be performed. The 
patients, Investigators, and site staff will know that the patients are receiving treatment with 
BI 695501. 
4.1.5.2
Unblinding and breaking the code
Not applicable. 
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
All trial medications must be kept in a secure place under appropriate storage conditions and 
handled according to Good Manufacturing Practice and GCP. The medication must be stored 
in a refrigerator at a controlled temperature (2 to 8°C [36 to 46°F]) and must not be frozen. A 


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temperature log will be kept at the trial site, and will be completed (with a minimum and 
maximum reading) on each business date. Syringes will be kept in the outer carton in order to 
protect from light. Detailed storage conditions will be described on the trial medication 
labels.
Patients will be instructed on the correct storage of the trial medication at home, and will be 
required to document storage conditions in the patient diary.
4.1.8
Drug accountability
Drug supplies will be provided by the Sponsor.
The designated person at each trial site will receive the investigational drugs delivered by the 
Sponsor when the following requirements are fulfilled:

Approval of the CTP by the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)

Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of the investigational site

Approval/notification of the regulatory authority, e.g., competent authority

Availability of the curriculum vitae of the principal Investigator

Availability of a signed and dated CTP or immediately imminent signing of the CTP

Availability of the proof of a medical license for the principal Investigator

Availability of Form 1572 for sites in the US
The designated person must maintain records of the product’s delivery to the trial site, the 
inventory at the site, the use by each patient, and the preparation of the trial medication. 
Unused trial medication will be destroyed as per local standard operating procedures.
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product and trial patients. The 
designated person will maintain records that document adequately that the patients were 
provided the doses specified by the CTP and reconcile all investigational products received 
from the Sponsor. At the time of return to the Sponsor and/or the Clinical Research 
Organization, the designated person must verify that all unused or partially used drug 
supplies have been returned by the clinical trial patient and that no remaining supplies are in
the Investigator’s possession.
Patients will be instructed to return all unused drug supplies to the site.


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Patients will continue to take their usual prescribed concomitant medications as allowed by 
the CTP, including MTX (within the dose range of the 1297.2 trial, up to Week 12) from their 
usual source. After Week 12, the dosing regimen for MTX and associated folic acid or folinic 
acid intake may be adjusted at the Investigator’s discretion. In this case, MTX treatment can 
be combined with or replaced by other non-biologic DMARDs (as described in Table 4.2.2.1: 
1). Non-biologic DMARD therapy may be modified during the trial, per Investigator 
assessment. Certain side effects are commonly associated with MTX treatment and therefore 
patients are required to take folic acid (a stable dose of at least 5 mg/week or as per local 
practice) or folinic acid (at least 1 mg/week or as per local practice), from their usual source, 
to minimize MTX-related toxicity. 
All patients should also continue to receive any oral nonsteroidal anti-inflammatory drugs 
(NSAIDs) at a stable dose or background oral corticosteroids as required throughout the trial. 
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Restrictions on prior and concomitant medications during the course of the trial are described 
in Table 4.2.2.1: 1.
Other medication that is considered necessary for the patient’s safety (e.g., as a result of an 
AE) may be given at the Investigator’s discretion. Investigators are encouraged to discuss the 
introduction of any of the medications listed in Table 4.2.2.1: 1 with the Sponsor’s physician 
representative. 
Any concomitant medications will be recorded in the appropriate sections of the eCRF.


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Table 4.2.2.1: 1
Prior and concomitant treatments
Treatment
Restriction
DMARD therapy
Patients may continue receiving or have previously received 
conventional DMARD therapy, for the treatment of RA. Non-biologic 
DMARD therapy may be modified during the trial, per Investigator 
assessment
MTX 
Patients must continue to receive and tolerate oral or parenteral MTX
within the dose range of the 1297.2 trial up to Week 12. After Week 12, 
MTX therapy may be adjusted based on Investigator assessment.
Folic acid/folinic acid
Patients must be taking oral folic acid (at least 5 mg/week or as per local 
practice) or folinic acid (at least 1 mg/week or as per local practice) 
during treatment with MTX. The dosing regimen is at the Investigator’s 
discretion.
Intravenous, intramuscular, intra-
articular or parenteral 
corticosteroids
Parenteral administration of corticosteroids should be avoided to the 
extent possible.  
Oral corticosteroids
If receiving current treatment with oral corticosteroids (other than 
intra-articular or parenteral corticosteroids), the dose should not exceed 
10 mg/day prednisolone or equivalent. 
NSAIDs
At the discretion of the Investigator. 
Leflunomide
Not permitted.  
Hydroxychloroquine/chloroquine
Patients may take oral hydroxychloroquine provided that the dose is not 
>400 mg/day or chloroquine provided that the dose is not >250 mg/day. 
Dose and route of administration must remain throughout the entire trial 
period where possible.
Analgesics (other than NSAIDs)
Analgesics up to the maximum recommended doses may be used for 
pain as required. However, patients must not take analgesics within 
24 hours prior to a visit where clinical efficacy assessments are 
performed and recorded.
Prosorba® Column
Not permitted.
IV Gamma Globulin 
Not permitted.
Live/attenuated vaccine
Not permitted for the duration of the trial, and up to 3 months after the 
last dose of trial drug
Anti-infective agents
At the discretion of the Investigator.
Any drug/therapy that has not 
received regulatory approval for 
any indication
Not permitted.
Non-pharmacological treatments 
(e.g., physical therapy)
Permitted freely.
It is recommended that, in case of an unplanned surgical procedure, including bone/joint 
surgery/synovectomy (including joint replacement or fusion), the Investigator should consult 
with the trial medical advisor to discuss issues surrounding cessation of trial medication
administration.


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4.2.2.2
Restrictions on diet and life style
Not applicable. 
4.3
TREATMENT COMPLIANCE
Compliance will be assessed by a count of syringe boxes and/or labels by a Clinical Research 
Associate. 
The prescribed dosage, timing, and mode of administration of trial medication may not be 
changed. Any deviation from the intended regimen must be recorded in the eCRF. 
For all injections patients will be asked to complete a patient diary documenting the date and 
time of the injections. All used and unused syringes must be returned to the site at each visit.
Patients showing poor compliance as assessed by missing their allocated days for trial drug 
administration must be counseled on the importance of good compliance to the trial dosing 
regimen.


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5.
VARIABLES AND THEIR ASSESSMENT 
Please refer to the Flow Chart for the schedule of assessments for the trial.  
The primary endpoint is described in Section 5.1.1 below. Secondary endpoints are described 
in Section 5.1.2, and other endpoints are described in Section 5.1.3. 
Unless otherwise specified, all endpoints will be assessed using the 1297.2 baseline 
values.
5.1
TRIAL ENDPOINTS
5.1.1
Primary Endpoint
The primary endpoint is the number (proportion) of patients with drug-related AEs during the 
treatment phase (refer to Section 7.3.1 for the definition of treatment phase).
5.1.2
Secondary Endpoints
Long-term efficacy will be assessed as a secondary objective in this trial. 

The change from Baseline in DAS28 (ESR) at Week 48 

The proportion of patients meeting ACR20 response criteria at Week 48

The proportion of patients who meet the ACR/European League Against Rheumatism 
(EULAR) definition of remission at Week 48 

The proportion of patients with EULAR response (good response, moderate response, or 
no response) at Week 48.


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5.2
ASSESSMENT OF EFFICACY
The following assessments will be made at the time points indicated in the Flow Chart for the 
purposes of calculating the DAS28 (ESR and CRP) and ACR response scores.
5.2.1
Joint assessments
Wherever possible, the same person will perform the joint assessment throughout the trial 
(i.e., for all patients at each trial site). Standardized training will be provided to the 
independent joint assessor via the training modules provided in the specific study portal. This 
training will be documented and filed in the ISF.
Each of the 66/68 joints will be evaluated for tenderness and swelling, respectively (prior to 
taking any required analgesic that day if possible). The 66/68 joint count includes the 
metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints of the 
hands, the metatarsal phalangeal and distal interphalangeal joints of the feet, and the 
shoulder, elbow, wrist, hip, knee, ankle, tarsus, and temporomandibular, sternoclavicular, and 
acromio-clavicular joints. Artificial, missing, and ankylosed joints, and data from joints 
following intra-articular injections are excluded from both tenderness and swelling 
assessments (R11-4385).
5.2.2
Patient’s global assessment of disease activity VAS
Patients will mark on a visual analogue scale (VAS) their overall assessment of how their RA 
affects them, rating how they are managing from 0 (very well) to 100 (very poor). This is 
equivalent to the General Health component of the Disease Activity Score (DAS) (see 
Appendix 10.2).


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5.2.3
Patient’s assessment of pain
Patient’s assessment of pain will be assessed using the VAS provided in the HAQ-DI 
questionnaire (see Appendix 10.3).
5.2.4
Physician’s global assessment of disease activity VAS
The physician’s global disease assessment will be documented on a VAS, ranging from no 
arthritis activity (0) to extremely active arthritis (100) (see Appendix 10.2).
5.2.5
Patient’s assessment of disability
The physical functioning of the patient will be assessed using the HAQ-DI questionnaire. 
This is a widely used patient self-report tool which assesses the degree of difficulty a person 
has had in accomplishing tasks in eight functional areas, over the previous week, taking into 
account any aids or help required. It consists of eight component sets: (1) dressing and 
grooming, (2) rising, (3) eating, (4) walking, (5) hygiene, (6) reach, (7) grip and (8) common 
daily activities. In addition, patients will mark on a VAS the severity of pain that they have 
had because of their RA in the past week, ranging from 0 (no pain) to 100 (severe pain) (see 
Appendix 10.3).
5.2.6
SF-36 v2
Patients will complete the SF-36 v2, a generic health survey consisting of 36 questions, 
yielding eight health-related quality of life domains (physical functioning, role-physical, 
bodily pain, general health, vitality, social function, role-emotional and mental health) as well 
as a psychometrically-based physical component score and mental component score (see 
Appendix 10.4).
5.2.7
Systemic inflammation: CRP level and ESR
A blood sample for CRP and ESR assessments will be taken at the visits indicated in the 
Flow Chart. 
Analysis of CRP will be conducted by a suitably qualified laboratory using validated 
methods. 
A whole blood sample (2 mL) will be collected for the ESR values to be measured locally.
5.2.8
Calculation of DAS28 and ACR scores
The DAS28 score will be derived using the following formulas:
DAS28 (ESR) = 0.56*√(TJC28) + 0.28*√(SJC28) + 0.014*(GH) + 0.7*ln(ESR) 
DAS28 (CRP) =  0.56*√(TJC28) + 0.28*√(SJC28) + 0.014*(GH) + 0.36*ln(CRP+1) + 0.96


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Where:

TJC28 = 28 joint count for tenderness

SJC28 = 28 joint count for swelling

Ln(ESR) = natural logarithm of ESR

Ln(CRP) = natural logarithm of CRP

GH = the General Health component of the DAS (see Section 5.2.2)
Improvement in DAS28 will also be categorized using the EULAR response criteria (see 
Table 5.1.2.8: 1).  
Table 5.1.2.8: 1
DAS28 EULAR response
DAS28 Improvement
DAS28 at Endpoint
≥1.2
>0.6 and <1.2
≤0.6
≤3.2
Good Response
Moderate response
No Response
>3.2 and ≤5.1
Moderate response
Moderate response
No Response
>5.1
Moderate response
No Response
No Response
Low disease activity is defined as a DAS28 score of ≤3.2 and DAS28 remission is defined as 
a DAS28 score of <2.6. A clinically relevant change in DAS28 score is defined as an 
improvement in DAS28 score of at least 1.2.
A patient has an ACR20 response if all of the following occur:

A ≥20% improvement in the SJC (66 joints)

A ≥20% improvement in the TJC (68 joints)

A ≥20% improvement in at least three of the following assessments:
o
Patient’s assessment of pain
o
Patient’s global assessment of disease activity
o
Physician’s global assessment of disease activity
o
Patient’s assessment of physical function, as measured by the HAQ-DI
o
Acute phase reactant (CRP)
Patients will be considered to have had an ACR50 or ACR70 response if a 50% or 70% 
improvement from Baseline of Trial 1297.2, respectively, was observed in the criteria 
specified above for ACR20.


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5.2.9
Definition of ACR/EULAR remission
Boolean-based definition:
At any time point, the patient must satisfy all of the following: 

TJC ≤1a

SJC ≤1a

CRP ≤1 mg/dL

Patient global assessment of disease activity ≤10 (on a 0 to 100 scale) (see 
Appendix 10.2)
a For TJC and SJC, use of a 28-joint count may miss actively involved joints, especially in the 
feet and ankles, and it is preferable to include feet and ankles also when evaluating remission.
5.3
ASSESSMENT OF SAFETY
5.3.1
Physical examination
A physical examination will be performed at the visits indicated in the Flow Chart.
Whenever possible, the same person should perform the physical examination throughout the 
trial (i.e., for all patients at each trial site). The physical examination will include assessment 
of general appearance, skin, head, neck, throat, lymph nodes, cardiovascular, neurological, 
thyroid, musculoskeletal/extremities, respiratory and abdomen. Body weight will also be 
measured. Height will be measured at Screening only.
5.3.2
Vital Signs
Vital signs will be assessed at the visits indicated in the Flow Chart.
Blood pressure, respiratory rate and pulse rate measurements should be taken following at 
least 5 minutes rest while the patient is in a sitting position. The patient’s body temperature 
will also be recorded.
The Investigator must assess all vital signs findings at each visit. If the Investigator finds any 
clinically relevant abnormalities, these must be reported as AEs/SAEs as appropriate (see 
Section 5.3.6).
5.3.3
Safety laboratory parameters
Blood and urine samples for determination of serum chemistry, hematology and urinalysis 
will be taken at the times indicated in the Flow Chart.
The following laboratory parameters will be measured:

Serum chemistry: creatinine, alkaline phosphatase, AST, ALT, gamma glutamyl 
transpeptidase, bilirubin (total and direct), glucose, total cholesterol, total protein, 
albumin, sodium, potassium, chloride, calcium


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
Hematology: hemoglobin, hematocrit, platelets, white blood cells, lymphocytes, 
neutrophils

Urinalysis: protein, glucose, blood
In addition, the following parameters will be analyzed at the visits indicated in the 
Flow Chart:

Infection screen: patients must have a negative serological test for hepatitis B surface 
antigen (HBsAg), for hepatitis C serology 

HIV screen (at the discretion of the Investigator where clinically indicated, and per local 
regulations)

TB test (QuantiFERON® Gold assay)

ESR and CRP

Pregnancy testing for females of child-bearing potential only (serum human chorionic 
gonadotropin or urine)

ADAs and nADAs
Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies will be 
analyzed at Baseline (Day 1) and Week 48.
The Investigator must assess all laboratory results. The Investigator will evaluate any change 
in laboratory values and all clinical laboratory tests will be reviewed for potential clinical 
significance at all time points throughout the trial. The Investigator should endeavor to 
provide a reason for all results deemed not clinically significant. If the Investigator
determines a laboratory abnormality to be clinically significant, it will be considered an 
AE/SAE (see Section 5.3.6); however, if the laboratory value abnormality is consistent with a 
current diagnosis, it will be documented accordingly.
Blood samples will be analyzed by a central laboratory (except ESR). The central laboratory 
provider will also provide the materials for blood sampling. Instructions for the labelling, 
storage and shipment of the samples can be found in the Laboratory Manual. Details of all 
blood variable units and reference ranges can be found in the Laboratory Manual.
Pregnancy testing will be performed by a central laboratory using serum at Screening or local 
laboratory using urine at all applicable visits thereafter. 
Estimated blood volumes are shown in Section 6.1.
5.3.4
Electrocardiogram
A resting 12-lead ECG will be performed at the visits indicated in the Flow Chart. 
Patients should rest for at least 5 minutes in a supine position before ECG evaluations. Two 
consecutive recordings will be made.
The original ECG traces and variables must be stored in the patients’ medical record as 
source data. The Investigator or designee will evaluate the ECG from a clinical perspective 


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and the result (whether the ECG result is normal or abnormal) will be recorded on the 
appropriate section of the eCRF.
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the Investigator. Any ECG abnormalities, judged 
as clinically relevant, will be monitored carefully and, if necessary, the patient will be 
discontinued from the trial medication and will receive the appropriate medical treatment.
5.3.5
Other safety parameters
Tuberculosis Assessment
A QuantiFERON®-TB Gold test will be used to assess TB status at Screening and at 
Week 48.
5.3.6
Assessment of adverse events
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A SAE is defined as any AE which:

results in death

is life-threatening

requires inpatient hospitalisation or prolongation of existing hospitalisation

results in persistent or significant disability or incapacity

is a congenital anomaly/birth defect
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
Every new occurrence of cancer will be reported as a SAE regardless of the duration between 
discontinuation of the drug and the occurrence of the cancer.


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AEs considered “Always Serious”
In accordance with the EMA initiative on Important Medical Events, Boehringer Ingelheim 
has set up a list of AEs, which by their nature, can always be considered to be “serious” even 
though they may not have met the criteria of an SAE as given above.
A copy of the latest list of “Always Serious AEs” can be found in the ISF. These events 
should always be reported as SAEs as described in Section 5.3.7. 
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g., the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the Sponsor’s/Sponsor’s designee Pharmacovigilance 
Department within the same timeframe that applies to SAEs, see Section 5.3.7.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
o
An elevation of AST and/or ALT >3 fold ULN combined with an elevation of 
total bilirubin >2 fold ULN measured in the same blood draw sample, and/or
o
Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These laboratory findings constitute a hepatic injury alert and the patients showing these 
laboratory abnormalities need to be followed up according to the “DILI checklist” provided 
in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without laboratory
results (ALT, AST, total bilirubin) available, the Investigator should make sure these 
parameters are analyzed, if necessary in an unscheduled blood test. Should the results meet 
the criteria of hepatic injury alert, the procedures described in the DILI checklist should be 
followed.

Anaphylactic reactions

Serious infection (defined as infections requiring i.v. antibiotics or meeting the regulatory 
definition of a SAE)

Hypersensitivity reactions.
Protocol-specified AESIs can be classified as serious or nonserious, but all AESIs must be 
reported in an expedited manner similar to SAEs on an SAE form (i.e., nonserious AESIs 
must be reported on the SAE form and follow SAE reporting timelines).


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Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE
The causal relationship must be provided by the Investigator for the trial drug (BI 695501).
The reason for the decision on causal relationship needs to be provided in the eCRF and on 
the SAE form (if applicable).
5.3.7
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate eCRF by the 
Investigator:
-
From signing the informed consent onwards through the Residual Effect Period 
(REP), all AEs (serious and non-serious), and AESIs
-
After the individual patient’s end of trial:  the Investigator does not need to actively 
monitor for AEs but should only report relevant SAEs and relevant AESIs of which 
the Investigator may become aware of


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The REP for BI 695501 is defined as 10 weeks after the last trial medication application. All 
AEs which occurred through the treatment phase and throughout the REP will be considered 
as on treatment. Events that occur after the REP will be considered as post-treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
Sponsor’s/Sponsor’s designee unique entry point (specific contact details will be provided in 
the ISF). The same timeline applies if follow-up information becomes available. On specific 
occasions the Investigator could inform the Sponsor/Sponsor’s designee upfront via 
telephone. This does not replace the requirement to complete and fax the BI SAE form.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug(s). The Investigator 
should determine the causal relationship to the trial medication and any possible interactions 
between the investigational drug and a Non-Investigational Medicinal Product.
The following should also be recorded as an (S)AE in the eCRF and SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator. If such abnormalities already 
pre-exist prior to trial inclusion, they will be considered as baseline conditions
All (S)AEs, including those persisting after trial completion, must be followed up until they 
have resolved, have been sufficiently characterized, or no further information can be 
obtained.
Pregnancy
In rare cases, pregnancy might occur in a trial. Once a patient has been enrolled into the 
clinical trial after having taken trial medication the Investigator must report any drug 
exposure during pregnancy which occurred in a female patient or in a partner to a male 
patient to the Sponsor/Sponsor’s designee by means of Part A of the Pregnancy Monitoring 
Form to the Sponsor’s unique entry point. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s/Sponsor’s designee unique entry point on the 
Pregnancy Monitoring Form for Clinical Trials (Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 


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completed. If there is an SAE associated with the pregnancy, then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Blood samples for the determination of concentrations of BI 695501 will be obtained from 
each patient at the visits specified in the Flow Chart and Table 5.4: 1.
Table 5.4: 1
Pharmacokinetic estimated sample time points
Visit
Week
Day
PK Samplea
ADA/nADA sampleb
2
Baseline
1
X (predose)
X (predose)
X (between 1 and 6 hours after dosing)
4
12
85
X
X
6
24
169
X
X
9
48/EoT
337
X
X
10
58/SFU
407
X
X
ADA = antidrug antibody; EoT = End of Treatment; nADA = neutralizing antidrug antibody; PK = pharmacokinetics; SFU = 
Safety Follow-up.
a.
PK samples collected from Visit 4 onwards can be taken at any time during each designated visit.
b.
ADA and nADA samples will be collected at the same time as PK samples.
5.4.1
Assessment of Pharmacokinetics
The PK analysis will be based on a population-based approach. Therefore, although samples 
may be taken at any time during each designated visit starting at Visit 4, it will be essential 
for the Investigator or designated staff to document the exact time each sample is taken. The 
exception is at Visit 2. At that visit, one sample must be taken from each patient before 
dosing begins. A second sample should be taken between 1 and 6 hours after dosing. If the 
sample on the visit day is taken after the dose on that visit day, the dosing time will be
collected in the eCRF as well as in the diary.
5.4.2
Methods of sample collection
Full instructions for collection, labeling, storage and shipment of samples are provided in the 
Laboratory Manual.
Plasma sampling for pharmacokinetic analysis
Samples of whole blood (2.7 to 3 mL) will be taken (in tubes containing K2EDTA 
anticoagulant) at the time points shown in Table 5.4: 1 for the determination of the 
concentration of BI 695501. 


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Immediately after blood sampling, the drawing tubes will be transferred into ice water or on 
ice until centrifugation. 
 
 
 
 
 
After completion of the trial, 
selected PK samples may be retained and used for further methodological investigations, e.g.,
stability testing. The PK samples will be discarded after the completion of the additional 
investigations upon the Sponsor´s written approval. The PK samples may be destroyed
5 years after the final Clinical Trial Report (CTR) has been signed, and in accordance with 
local regulation.
Wherever possible, PK blood samples will be taken at the same time as blood is drawn for 
other analyses to limit repeated venipuncture. 
In the event of early withdrawal from the trial, every effort should be made to take a PK 
sample as part of the early withdrawal procedures, if possible, with date and time of sample 
and time of dose prior to this sample recorded.
Estimated blood volumes are shown in Section 6.1.
5.4.3
Analytical determinations
Analyte concentrations in plasma samples for all patients that receive active drug will be 
determined by a fully validated enzyme-linked immunosorbant assay. Detailed descriptions 
of the assay methods will be available prior to the start of sample analysis.
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
Not applicable. 
5.5
ASSESSMENT OF EXPLORATORY BIOMARKER(S)
Not applicable. 


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5.6
OTHER ASSESSMENTS
5.6.1
Immunogenicity – Antidrug antibodies
Blood samples (2.7 to 3 mL) will be taken at the visits shown in the Flow Chart and 
Table 5.4: 1 to determine the number (proportion) of patients with ADAs.
Plasma sampling for ADA characterization
For characterization of human anti-BI 695501 antibodies (ADAs), 2.7 to 3 mL of blood will 
be collected from a forearm vein in a dipotassium ethylendiaminetetraacetic acid (K2EDTA) 
anticoagulant blood drawing tube at time points indicated in the Flow Chart. Immediately 
after blood sampling, the drawing tubes should be placed in ice water or on ice until 
centrifugation.
 
 
 
 
 
Antidrug 
antibody will be detected in human plasma samples by a validated method. A screen positive 
response in a patient will be confirmed in a drug-competition assay. Confirmed positive 
samples will be further characterized in a titer assay and in a neutralizing antibody assay.
After completion of the trial, selected PK and immunogenicity samples may be retained and 
may be analyzed for the presence of species (e.g., soluble proteins or small molecule entities) 
potentially interfering with the analysis method or for generation of ADA positive control 
material and stability testing for use in future assays. Retained samples may also be used to 
further characterize the immune response (e.g., isotyping of ADA) if required and as 
additional assay methods are developed. The results of any additional ADA analyses of the 
retained samples (i.e., analyses not already specified in this protocol) will be reported 
separately from the CTR. The ADA samples will be discarded after the completion of the 
additional investigations upon the Sponsor´s written approval. The ADA samples may be 
destroyed 5 years after the final CTR has been signed, and in accordance with local 
regulation.
Plasma sampling for Neutralizing Antibody characterization
For characterization of human neutralizing anti-BI 695501 antibodies (nADA), 6 mL of 
blood will be collected from a forearm vein in a K2EDTA-anticoagulant blood drawing tube 
at the same time points as ADA samples are collected. Immediately after blood sampling, the 
drawing tubes will be placed in ice water or on ice until centrifugation.
 
 
 


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Neutralizing antibodies will be detected in human plasma samples by a validated method.
Full instructions for collection, labeling, analysis, storage and shipment of samples are 
provided in the Laboratory Manual.
5.6.2
Lack of efficacy
Discontinuation due to lack of efficacy, as judged by the Investigator, will be captured in the 
eCRF.
5.6.3
Adverse Event leading to discontinuation
Discontinuation due to a drug-related AE will be captured in the eCRF.
5.7
APPROPRIATENESS OF MEASUREMENTS
The efficacy endpoints (ACR20) are standard outcome criteria that are widely accepted for 
regulatory purposes to demonstrate efficacy on signs and symptoms of RA. 
These endpoints were chosen to comply with the recommendations of both the EU and US 
regulatory authorities for studies in RA (R11-4337, R03-1444).


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
A schedule of assessments is provided in the Flow Chart.
Visits will be scheduled as close as possible to the pre-planned schedule: 

The first dose is to be administered approximately 2 weeks after the Screening visit
(Week 48 of Trial 1297.2). A visit window of ±1 day is permitted for Visit 2; trial 
medication will be administered on the day of the Baseline visit

A visit window of ±2 days is permitted for Visits 4, 6, 9 and 10

Trial medication should be administered every 2 weeks (±2 days after the Baseline visit)

No visit window will apply to Visits 3, 5, 7, and 8
On ambulatory visit (outpatient) days, all assessments should be performed prior to trial 
medication administration, unless otherwise specified. Laboratory samples must be drawn 
prior to trial medication injection.
Questionnaires will be completed at the site by the patient before any investigations or 
discussions about their disease with the clinic staff and may only be recorded by a trial 
nurse/Investigator on behalf of the patient if the patient has difficulty writing during the visit 
or is unable to read. This must be documented clearly in the patient notes.
The total estimated volume of blood that will be drawn from each patient during the course of 
the trial is shown in Table 6.1: 1.
Table 6.1: 1
Estimated blood sample volumes per patient
Parameter
Sample volume (mL)
Number of samples
Total volume (mL)
Laboratory tests (including serum 
chemistry, CRP)
3
6
18
Hematology
2
6
12
ADAs
3
5
15
nADAs
6
5
30
ESR (local)
2
6
12
Pharmacokinetics
3
6
18
RF, anti-CCP
1
2
2
Infection screen
4
1
4
TB test
3
2
6
Approximate total
117
ADAs: antidrug antibodies; anti-CCP: anti-cyclic citrullinated peptide; CRP: C-reactive protein; ESR: erythrocyte 
sedimentation rate; nADAs: neutralizing ADAs; RF: rheumatoid factor; TB: tuberculosis.
It should also be noted that additional samples may be required if medically indicated, e.g. at 
unscheduled visits to follow safety findings.


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
Screening Period (Day -14)
Once the patient has provided informed consent (before any 1297.2 or 1297.3 trial-specific 
procedures or assessments are performed) and meets all inclusion criteria and none of the
exclusion criteria (see Section 3.3), the trial site will enter the screened patient into the 
system using the Interactive Response Technology (IRT).
The following will also be performed/collected:

Demographic information (including gender, date of birth, ethnicity and race), and 
medical and surgical history (including RA history and history of opportunistic infection)

Evaluation of patient’s willingness and ability to self-administer trial medication

Physical examination, including height (cm) and weight (kg) (see Section 5.3.1)

Infection screen (HBsAg, HCV and HIV test, per the Investigator’s discretion)

Urine pregnancy test for women of child-bearing potential

Patient questionnaires: global VAS, HAQ-DI and SF-36 v2 (see Section 5.2)

Joint assessment (see Section 5.2)

TB test (QuantiFERON®-TB Gold test)

ESR and CRP

Physician questionnaire: global VAS (see Section 5.2)

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.3.2)

Laboratory testing (serum chemistry, hematology and urinalysis; see Section 5.3.3)

12-lead ECG (see Section 5.3.4)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)
Once patients have signed the ICF, completed screening, and eligibility is confirmed, the
Investigator will contact IRT and patients will be assigned to treatment with BI 695501. As 
part of the Trial 1297.2 Week 48 assessments, trial medication is administered. This is the 
last trial medication administration of the 1297.2 trial. During this visit, the 
Investigator/designee will train the patient on how to self-administer the trial medication. See 
Section 4.1.4 for details.


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6.2.2
Treatment period(s)
For the duration of the trial, BI 695501 will be administered by the patients themselves. Trial
medication will be administered every 2 weeks (±2 days). 
Baseline, Visit 2 (Day 1) 
Eligible patients will receive their first administration of trial medication on Day 1.
The following will also be performed/collected:

Physical examination, including weight (kg) (see Section 5.3.1)

RF and anti-CCP antibodies

Patient questionnaires: global VAS, HAQ-DI and SF-36 v2 (see Section 5.2)

Joint assessment (see Section 5.2)

ESR and CRP

Physician questionnaire: global VAS (see Section 5.2)

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.3.2)

Urine pregnancy test for women of child-bearing potential

Laboratory testing (serum chemistry, hematology and urinalysis; see Section 5.3.3)

12-lead ECG (see Section 5.3.4)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)

Blood PPK samples (see Section 5.4)

Blood samples for the level of ADAs and nADAs (see Section 5.6.1)

Contact IRT and administration of trial medication

Dispense trial medication
Patients will be instructed to accurately record the dates and times of BI 695501 dosing, and 
the occurrence of any AEs and use of concomitant medications, on the provided diary cards 
between the ambulatory visits.
The Investigator should plan with the patient when Visit 3 (Week 6) will occur and 3 syringes 
will be dispensed to the patient.
Visits 3, 5, 7, and 8 (Days 43, 127, 225 and 281, respectively) 
The patient may choose to attend the site to self-inject the trial medication with the support of 
the suitably qualified, designated trial personnel or may self-inject the trial medication at 
home. 
At all visits, the Investigator/designee will contact IRT and will dispense trial medication to 
the patient (see Section 4.1.4 for details). The Investigator should plan with the patient when 
administration only visits will occur and 1 to 5 syringes will be dispensed to the patient at 
each visit. Patients may choose to administer the trial medication at home for these visits and 
collect dispensed medication at a later date. The Investigator/designee will review the patient 
diary card entries.


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Visits 4 and 6 (Days 85 and 169, respectively) 
The following will be performed/collected:

Physical examination, including weight (kg) (see Section 5.3.1)

Patient questionnaires: global VAS, HAQ-DI and SF-36 v2 (see Section 5.2)

Joint assessment (see Section 5.2)

ESR and CRP

Physician questionnaire: global VAS (see Section 5.2)

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.3.2)

Urine pregnancy test for women of child-bearing potential

Laboratory testing (serum chemistry, hematology and urinalysis; see Section 5.3.3)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)

Review of patient diary card entries

Blood PPK samples (see Section 5.4)

Blood samples for the level of ADAs and nADAs (see Section 5.6.1)

Contact IRT and administration of trial medication

Dispense trial medication
Visit 9 (Day 337): End of Treatment Visit
The following will be performed/collected:

Physical examination, including weight (kg) (see Section 5.3.1)

RF and anti-CCP antibodies

Patient questionnaires: global VAS, HAQ-DI and SF-36 v2 (see Section 5.2)

Joint assessment (see Section 5.2)

TB test (QuantiFERON®-TB Gold test)

ESR and CRP

Physician questionnaire: global VAS (see Section 5.2)

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.3.2)

Urine pregnancy test for women of child-bearing potential

Laboratory testing (serum chemistry, hematology and urinalysis; see Section 5.3.3)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)

Review of patient diary card entries

Blood PPK sample (see Section 5.4)

Blood samples for the level of ADAs and nADAs (see Section 5.6.1)

Administration of trial medication


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Visit 10 (Day 407): Safety follow-up Visit
The following will be performed/collected:

Physical examination, including weight (kg) (see Section 5.3.1)

ESR and CRP

Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature; see 
Section 5.3.2)

Urine pregnancy test for women of child-bearing potential

Laboratory testing (serum chemistry, hematology and urinalysis; see Section 5.3.3)

12-lead ECG (see Section 5.3.4)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)

Review of patient diary card entries

Blood PPK sample (see Section 5.4)

Blood samples for the level of ADAs and nADAs (see Section 5.6.1)

End of participation
6.2.3
Follow-Up Period and Trial Completion
End of Treatment Visit
Patients who discontinue the trial at any time after Day 1 (but do not withdraw their consent) 
will be required to have all of the evaluations for the Week 48 Visit as soon after trial 
discontinuation as possible. 
Every effort should be made for all patients who complete the total 48-week treatment period 
or who discontinue the trial early, to return for a safety follow-up visit 10 weeks after the last 
dose of trial medication.
End of trial definition
The trial will be considered to be complete once the last patient in the trial meets one of the 
following:

Completes the last trial visit (Week 58 or safety follow-up visit 10 weeks after the last 
trial medication administration); or

Dies; or

Is lost to follow-up
The Sponsor may also elect to discontinue clinical investigations under this trial for any 
reason at any time.
Unscheduled Visit Assessments
Patients may attend the trial site for unscheduled visits at any time for additional safety 
monitoring at the discretion of the Investigator.  


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a Phase IIIb, open-label, single arm extension of Trial 1297.2. 
The objective of this trial is to provide long-term efficacy, safety, PK and immunogenicity 
data on BI 695501 administered via prefilled syringe in patients with RA who have 
completed the trial 1297.2.
No formal hypothesis testing will be performed. The analysis of the data will be performed 
descriptively.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No formal hypothesis testing will be performed. If confidence intervals or p-values are 
presented, they will be interpreted in an exploratory fashion only.
7.3
PLANNED ANALYSES
All patients treated with at least one dose of trial medication during the 1297.3 trial (Safety 
Analysis Set) will be included in the safety evaluations. 
The Full Analysis Set (FAS) will be the basis for efficacy analyses. The FAS consists of all 
patients who received at least one dose of trial medication in Trial 1297.3 and had at least one 
DAS28 (ESR or CRP) or ACR20 measured during the 1297.3 trial.
The “All Enrolled Patients” analysis set will include all patients who provide informed 
consent for this trial.
For presentation of results in the report, three groups of patients will be created depending on 
treatments assigned in Trial 1297.2. The first group will consist of patients who were 
randomized to BI 695501 in Trial 1297.2 and will continue to receive BI 695501 in
Trial 1297.3 but via self-administration. The second group will consist of patients who were 
initially randomized to receive US-licensed Humira® in Trial 1297.2, continue to receive 
US-licensed Humira® after Week 24 re-randomization in Trial 1297.2 and will transition to 
BI 695501 via self-administration in the Trial 1297.3. The third group will consist of patients 
who were initially randomized to receive US-licensed Humira® in Trial 1297.2, transitioned 
to BI 695501 following the re-randomization at Week 24 in the Trial 1297.2 and continue to 
receive BI 695501 in Trial 1297.3 but via self-administration. Table 7.3: 1 gives an overview 
of the above-defined patient groups.


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Table 7.3: 1
Patient groups for presentation of analysis results
Patient group
1
2
3
Randomized treatment in 
Trial 1297.2
BI 695501
US-licensed
Humira®
US-licensed
Humira®
Re-randomized treatment 
in Trial 1297.2 (Week 24)
BI 695501
US-licensed
Humira®
BI 695501
The descriptive statistics for safety, efficacy and other endpoint will be presented for these 
three groups and overall for all patients combined.
Unless otherwise specified, baseline for this trial (1297.3) is defined as the baseline of 
Trial 1297.2 and all endpoints are those assessed in Trial 1297.3.
7.3.1
Primary endpoint analyses
The primary endpoint is defined as the number (proportion) of patients with drug-related AEs
during the treatment phase.
The primary safety analysis will be performed using the Safety Analysis Set.
All AEs with an onset date between start of treatment and end of the REP, a period of 
10 weeks after the last dose of trial medication, will be assigned to the treatment phase for 
evaluation. Adverse events will be classified by system organ class and term using the 
Medical Dictionary of Regulatory Activities (MedDRA) coding dictionary. 
The proportion of patients with drug-related AEs during the treatment phase will be analyzed 
descriptively by MedDRA system organ class and preferred term. In addition, patient 
incidence and/or event incidence per 1000 patient-years exposure will be provided. No 
formal inferential analyses are planned.
7.3.2
Secondary endpoint analyses
The secondary efficacy endpoints (see Section 5.1.2) will be summarized descriptively for the 
FAS.


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7.3.4
Safety analyses
Adverse events will be coded using the MedDRA coding dictionary. Standard BI summary 
tables and listings will be produced. All AEs with an onset between start of treatment and end 
of the residual effect period (REP), a period of 10 weeks after the last dose of trial 
medication, will be assigned to the treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be presented by MedDRA system organ class and preferred 
term. No hypothesis testing is planned.
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs. To this 
end, all AEs occurring between start of treatment and end of the REP will be considered 
‘treatment-emergent’.  Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of the MedDRA.
In addition, for infections/serious infections, hypersensitivity reactions, drug-induced liver 
injury (DILI) and injection-site reactions, patient incidence and/or event incidence per 
1000 patient-years exposure will be displayed.
Laboratory values taken after the first dose of trial medication up to a period of 10 weeks
after the last dose of the trial medication will be assigned to the treatment phase for 
evaluation. Laboratory data will be analyzed both quantitatively as well as qualitatively. The 
latter will be done via comparison of laboratory data to their reference ranges. Values outside 
the reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs (blood pressure, pulse rate, respiratory rate and body temperature), physical 
examinations, 12-lead ECGs, or other safety-relevant data observed at screening, baseline, 
during the course of the trial and at the end-of-trial evaluation will be assessed with regard to 
possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic analyses
A PPK analysis with sparse blood sampling throughout the treatment period and at follow-up 
will be carried out to assess the PK of BI 695501. The PK analysis might involve combining 
data with data from other BI 695501 studies. If relevant, a relationship will be investigated 
between selected safety and efficacy parameters including the development of ADA/nADA. 
The population PK will be described in a separate analysis plan and will be reported 
separately to the CTR. Raw concentration data will be reported in the CTR. Reporting of the 
raw concentration data will be described in the trial statistical analysis plan (TSAP).


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7.3.6
Immunogenicity analyses
If data allow, the antibody response, antibody titer and neutralizing antibody response will be 
summarized as appropriate (frequency/proportions for ADA positive samples, descriptive 
statistics for titer and frequency/proportions of characterization of the neutralizing potential 
of the ADA for ADA positive samples assayed) by scheduled assessments (Week 12, 
Week 24 and Week 48) and overall (for ADA positive patients only). Further, the potential 
relationship between safety and antibody response will be explored if appropriate. Details of 
the analyses will be described in the TSAP.
7.4
INTERIM ANALYSES
No formal interim analysis will be performed for this trial. However, based on regulatory 
requirements safety snapshots may be provided. 
7.5
HANDLING OF MISSING DATA
7.5.1
Safety and other endpoints
For the aim of primary and secondary analyses, in case of missing AE relationship status, the 
AE will be considered as related.
For other endpoints, rules for the handling of missing data will be specified in the TSAP if 
necessary.
7.5.2
Efficacy endpoints
Missing ACR20 data will be imputed using the last observation carried forward (LOCF) 
method. However, all patients who discontinue treatment, are lost-to-follow-up or have any 
severe violation related to any therapy that may significantly impact efficacy assessment 
(Table 4.2.2.1: 1) prior to the secondary endpoint assessment will be considered as a 
non-responder. This is referred to as ‘NRI’ (missing data imputation of primary analysis in 
1297.2).
. For missing data, LOCF will be applied on the component variables prior to the 
DAS28(ESR) score.
Other missing efficacy data will not be imputed.
Further details will be given in the TSAP. 
7.6
RANDOMISATION
This is an open-label, single-arm trial. No randomization will be performed.


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7.7
DETERMINATION OF SAMPLE SIZE
All patients from the initial randomized controlled Trial 1297.2 willing and able to 
self-administer BI 695501 pre-filled syringe, and who are eligible for further treatment 
courses will be offered an additional treatment course with BI 695501. Patients are deemed 
eligible for further treatment courses if they have not experienced Investigator-reported 
drug-related SAEs during the 1297.2 trial, and in the Investigator’s assessment can benefit 
from receiving BI 695501. It is anticipated that approximately 300 to 400 patients will be 
eligible to participate in this roll-over extension trial.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for GCP and relevant BI Standard Operating Procedures.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, and also of any serious breaches of the 
protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. As a rule, no trial results should be 
published prior to finalization of the CTR.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB/IEC and competent authority (CA) according to national and 
international regulations. The same applies for the implementation of changes introduced by 
amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH/GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his/her medical records may be examined by authorized 
monitors (Clinical Research Associate/on site monitor) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.


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8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, the IRB/IEC or by regulatory authorities. The quality assurance auditor will have 
access to all medical records, the Investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial.
8.3
RECORDS
Electronic CRFs for individual patients will be provided by the Sponsor. For drug 
accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data entered in the eCRFs must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For eCRFs, all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The Investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. Electronic 
CRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g., FDA). The Clinical Research 
Associate/on site monitor and auditor may review all eCRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfill the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular AE is "listed", i.e. is a known side effect of the drug or not. Therefore, a 
unique reference document for the evaluation of listedness needs to be provided. For 
BI 695501, this is the current version of the IB. 
For non-investigational medicinal products, for both MTX and folic acid, the reference 
document is the Summary of Product Characteristics. 
The current versions of these reference documents are provided in the ISF. No AEs are 
classified as listed for trial design, or invasive procedures.


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8.4.2
Expedited reporting to health authorities and IEC/IRB
Expedited reporting of SAEs, e.g., suspected unexpected serious adverse reactions (SUSARs) 
to health authorities and IECs/IRBs, will be done according to local regulatory requirements.
Further details regarding this reporting procedure are provided in the ISF.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities.
8.6
END OF TRIAL
The IEC/competent authority in each participating EU member state needs to be notified 
about the end of the trial (last patient/patient out, unless specified differently in the CTP) or
early termination of the trial.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R11-4384
Ku IA, Imboden JB, Hsue PY, Ganz P. Rheumatoid arthritis: model of 
systemic inflammation driving atherosclerosis. Circ J 2009. 73(6): 977-85.
R11-4383
Scott DL. Early rheumatoid arthritis. Br Med Bull 2007. 81-82: 97-114.
R07-0637
Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid 
arthritis. Arthritis Res 2002. 4: 265-72.
R15-0739
Humira® (adalimumab) injection, for subcutaneous use (AbbVie) (U.S. 
prescribing information, revised: 12/2014
website rxabbvie.com/pdf/humira.pdf
R15-3225
Humira® 40 mg/0.8 mL solution for injection for paediatric use, 40 mg 
solution for injection in pre-filled syringe, 40 mg solution for injection in 
pre-filled syringe with needleguard, 40 mg solution for injection in 
pre-filled pen (AbbVie) (summary of product characteristics, 
manufacturer(s) of the biological active substance and manufacturer(s) 
responsible for batch release, conditions or restrictions regarding supply 
and use, other conditions and requirements of the marketing authorisation, 
conditions or restrictions with regard to the safe and effective use of the 
medicinal product, labelling and package leaflet, last updated:12/05/2015).
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000481/WC500050870.pdf (access date: 26 
June 2015) (2015)
R11-4385
Sokka T and Pincus T. Quantitative joint assessment in rheumatoid 
arthritis. Clin Exp Rheumatol 2005. 23(Suppl. 39): S58-62.
R11-4337
Points to consider on clinical investigation of medicinal products other 
than NSAIDs for treatment of rheumatoid arthritis. CPMP/EWP/556/95 
rev 1/Final. 17 December 2003. 
ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/0
9/WC500003439.pdf.
R03-1444
Food and Drug Administration. Guidance for Industry: Clinical 
development programs for drugs, devices, and biological products for the 
treatment of rheumatoid arthritis (RA). February 1999. 
R12-2515
Kukar M, Petryna O, Efthimiou P. Biological targets in the treatment of 
rheumatoid arthritis: a comprehensive review of current and in-
development biological disease modifying anti-rheumatic drugs. Biologics 
2009. 3:443-57.


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9.2
UNPUBLISHED REFERENCES
Not applicable. 


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10.
APPENDICES
10.1
FUNCTIONAL CLASS 
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)
Class II
Able to perform 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 in ability to perform usual self-care, vocational, and avocational 
activities
* 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.


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10.2
PATIENT AND PHYSICIAN GLOBAL ASSESSMENT VAS 
Patient’s Global Assessment VAS
Considering all the ways that your arthritis affects you, rate how you are doing on the
following scale by placing a single vertical mark ()׀on the line.
VERY WELL
    VERY POOR
0
    100
24.Feb.06
©Stanford University
2953


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Physician’s Global Assessment VAS
Global assessment of rheumatoid arthritis activity today.
NO 
    EXTREMELY
RHEUMATOID 
    ACTIVE 
ARTHRITIS 
    RHEUMATOID 
ACTIVITY 
    ARTHRITIS
0
     100
24.Feb.06
©Stanford University
2953


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10.3
HAQ DISABILITY INDEX
HEALTH ASSESSMENT QUESTIONNAIRE
Name_________________________________
Date___________________________
PATKEY#
QUESTDAT
In this section we are interested in learning how your illness affects your ability to function in daily life. Please 
feel free to add any comments on the back of this page.
Please check the response which best describes your usual abilities OVER THE PAST WEEK:
HAQADMIN
QUESTYPE
DRESSING & GROOMING
Are you able to:
Without
ANY
Difficulty
With
SOME
Difficulty
With
MUCH
Difficulty
UNABLE
To Do
PMSVIS
RASTUDY
QUESTNUM
- Dress yourself, including tying shoelaces 
and doing buttons?
_____
_____
_____
_____
- Shampoo your hair?
_____
_____
_____
_____
DRESSNEW
ARISING
Are you able to:
- Stand up from a straight chair?
_____
_____
_____
_____
- Get in and out of bed?
_____
_____
_____
_____
RISENEW
EATING
Are you able to:
- Cut your meat?
_____
_____
_____
_____
- Lift a full cup or glass to your mouth?
_____
_____
_____
_____
- Open a new milk carton?
_____
_____
_____
_____
EATNEW
WALKING
Are you able to:
- Walk outdoors on flat ground?
_____
_____
_____
_____
- Climb up five steps?
_____
_____
_____
_____
WALKNEW
Please check any AIDS OR DEVICES that you usually use for any of these activities:
_____ Cane
_____ Devices used for dressing (button 
hook, zipper pull,
long-handled shoe horn, etc.)
_____ Walker
_____ Built up or special utensils
_____ Crutches
_____ Special or built up chair
_____ Wheelchair
_____ Other (Specify:______________)
DRSGASST
RISEASST
Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
_____ Dressing and Grooming
_____ Eating
_____ Arising
_____ Walking
EATASST
WALKASST
____________________________________________________________________________________________________________________________________________
STANFORD-RA (MAY99 - Phase 31) – English, USA
-1-
Stanford University
HAQ-DI - United States/English
f:\institut\cultadap\project\5008\study5008\questionnaire\original\forproject\haq-di_au1.0-eng-usori.doc-10/12/2008-co
Please check the response which best describes your usual abilities OVER THE PAST WEEK:


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HYGIENE
Are you able to:
Without
ANY
Difficulty
With
SOME
Difficulty
With
MUCH
Difficulty
UNABLE
To Do
- Wash and dry your body?
_____
_____
_____
_____
- Take a tub bath?
_____
_____
_____
_____
- Get on and off the toilet?
_____
_____
_____
_____
HYGNNEW
REACH
Are you able to:
- Reach and get down a 5 pound object
(such as a bag of sugar) from just above your 
head?
_____
_____
_____
_____
- Bend down to pick up clothing from the floor?
_____
_____
_____
_____
REACHNEW
GRIP
Are you able to:
- Open car doors?
_____
_____
_____
_____
- Open jars which have been previously opened?
_____
_____
_____
_____
- Turn faucets on and off?
_____
_____
_____
_____
GRIPNEW
ACTIVITIES
Are you able to:
- Run errands and shop?
_____
_____
_____
_____
- Get in and out of a car?
_____
_____
_____
_____
- Do chores such as vacuuming or yardwork?
_____
_____
_____
_____
ACTIVNEW
Please check any AIDS OR DEVICES that you usually use for any of these activities:
_____Raised toilet seat
_____ Bathtub bar
_____Bathtub seat
_____ Long-handled appliances for reach
_____ Jar opener (for jars
_____ Long-handled appliances in bathroom
previously opened)
_____Other (Specify: 
______________________)
Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
_____Hygiene
_____ Gripping and opening things
_____Reach
_____Errands and chores
HYGNASST
RCHASST
GRIPASST
ACTVASST
We are also interested in learning whether or not you are affected by pain because of your illness.
How much pain have you had because of your illness IN THE PAST WEEK:
PLACE A VERTICAL (I) MARK ON THE LINE TO INDICATE THE SEVERITY OF THE PAIN.
NO
PAIN
0
SEVERE
PAIN
100
PAINSCAL
__________________________________________________________________________________________________________STANFOR
D-RA (MAY99 - Phase 31) – English, USA-2-
Stanford University
HAQ-DI - United States/English
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10.4
SF-36 V2


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10.5
CLINICAL EVALUATION OF LIVER INJURY
Alterations of liver laboratory parameters, as described in Section 5.3.6 (AESIs), are to be 
further evaluated using the following procedures.
Repeat the following laboratory tests: ALT, AST and bilirubin (total and direct) within 48 to 
72 hours and provide the additional blood sample to the central laboratory for automatic 
reflex testing of the below listed laboratory parameters. 
Only in cases whereby the central laboratory is not immediately available (e.g. if the logistics 
are such that the patient’s repeat specimen would not reach the central laboratory in a 
reasonable timeframe), ALT, AST and bilirubin (total and direct) will be evaluated by a local 
laboratory and the results made available to the Investigator and to Boehringer Ingelheim as 
soon as possible. If in such a case it is confirmed that ALT and/or AST are ≥3 times ULN 
combined with an elevation of total bilirubin ≥2 times ULN, results of the laboratory 
parameters described below must be made available to the Investigator and to Boehringer 
Ingelheim as soon as possible.
In addition:

Obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF

Obtain history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets 
according to the “DILI checklist” provided in the ISF

Obtain a history of exposure to environmental chemical agents (consider home and work 
place exposure) according to the “DILI checklist” provided in the ISF
and report these via the eCRF.
The Investigator is to follow the laboratory testing and assessments as noted in the DILI 
checklist in the ISF. These assessments include but are not limited to:
Clinical chemistry

Alkaline phosphatase, albumin, prothrombin time or International Normalized Ratio, 
creatine kinase, creatine kinase muscle-brain, coeruloplasmin, α-1 antitrypsin, transferin, 
amylase, lipase, fasting glucose, cholesterol, triglycerides, cholinesterase
Serology

Hepatitis A (Anti-IgM, total Ig), hepatitis B (hepatitis B surface antigen, antiHBs, DNA), 
hepatitis C (antiHCV, RNA if antiHCV positive), hepatitis D (anti-IgM, total Ig), 
hepatitis E (antihepatitis E virus [HEV], antiHEV IgM, RNA if antiHEV IgM positive), 
antiSmooth Muscle antibody (titer), antinuclear antibody (titer), antiliver-kidney 
microsomes antibody, antimitochondrial antibody, Epstein Barr Virus (virus capsid 
antigen [VCA] IgG, VCA IgM), cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, 
IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), toxoplasmosis (IgG, IgM)
Hormones, tumor marker

Thyroid stimulating hormone


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Hematology

Complete blood count (including differential counts)
Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic pathology, 
e.g. bile duct stones or neoplasm.
Initiate close observation of patients by repeat testing of ALT, AST, and total bilirubin (with 
fractionation by total and direct) at least weekly until the laboratory ALT and or AST 
abnormalities stabilize or return to normal, then according to the protocol. Depending on 
further laboratory changes, additional parameters identified e.g. by reflex testing, will be 
followed up based on medical judgment and GCP.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
01
Date of CTP revision
19. February 2016
EudraCT number
2015-002634-41
BI Trial number
1297.3
BI Investigational Product(s)
BI695501
Title of protocol
Long-term assessment of safety, efficacy, 
pharmacokinetics and immunogenicity of BI 
695501 in patients with rheumatoid arthritis (RA): 
an open-label extension trial for patients who have 
completed trial 1297.2 and are eligible for long-
term treatment with adalimumab
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities

To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval

Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only

Section to be changed
Clinical Trial Protocol Synopsis -  Trial Clinical 
Monitor
Description of change
Change of the name and contact details (phone and 
fax number) regarding the Trial Clinical Monitor 
from 
to 
.
Rationale for change
The responsibility as Trial Clinical Monitor for this 
trial has been transferred.
Section to be changed
Clinical Trial Protocol Synopsis -  Flow Chart
Description of change
The following three changes are made to the flow 


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chart:
1. Change of the permitted visit window for the 
Screening Visit from ±1 day to ±3 days.
2. Inclusion of the following sentence in the 
footnotes: 
‘VAS assessments and completion of the HAQ-
DI and SF-36 v2 questionnaires must be done 
prior to any visit procedures at this day. Patient 
questionnaires completed for the 1297.2 trial will 
be used as baseline questionnaires for the 1297.3 
trial.’
3. Inclusion of the following footnote regarding 
ECG: 
‘Two consecutive recordings need to be taken.’
Rationale for change
Ad 1) The visit window for the screening visit for 
study 1297.3 is changed to ±3 days to be in line 
with the permitted visit window for the End of 
Treatment Visit (Week 48) of the parent trial 
1297.2, as these two visits coincide.
Ad 2) Emphasis of the order of the assessments to 
be performed at the visits to avoid that the patients 
are biased before doing the questionnaires.
Ad 3) Emphasis that in study 1297.3 two ECGs are 
to be taken (as in the parent study 1297.2).
Section to be changed
3.3.3:  Exclusion Criteria
Description of change
Deletion of exclusion criteria #2
Original text:
Patients with major protocol deviations in Trial 
1297.2
Rationale for change
The term “major protocol deviations” was not 
further defined in the clinical study protocol (CTP). 
The vast majority of currently known major 
protocol deviations is of administrative nature and 
not relevant for safety of the patients. As judged by 
BI, these administrative deviations do not justify 
exclusion of patients who would be otherwise 
eligible for participation in 1297.3 based on the 
clinical and safety assessments performed at the 
screening/baseline visit and are expected to have a 
continued benefit from further treatment in the 
1297.3 study.


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Patients having any major protocol violations in 
study 1297.2 related to safety will be excluded 
from the study 1297.3 based on the other specific 
exclusion criteria listed in the CTP.
Section to be changed
5.2.1  Joint assessments
Description of change
Correction of the text regarding training of 
independent joint assessor
Original text:
Wherever possible, the same person will perform 
the joint assessment throughout the trial (i.e., for 
all patients at each trial site). Standardized training 
will be provided to the independent joint assessor 
during the Investigator Meeting via the training
portal. This training will be documented and filed 
in the ISF.
Amended text: 
Wherever possible, the same person will perform 
the joint assessment throughout the trial (i.e., for 
all patients at each trial site). Standardized training 
will be provided to the independent joint assessor 
via the training modules provided in the specific
study portal. This training will be documented and 
filed in the ISF.
Rationale for change
The original CTP states that standardized training 
will be provided to the independent joint assessor 
(IJA) during the Investigator Meeting via the 
training portal. Based on the fact that no 
investigator meeting will take place for this 
extension study, training of the IJAs will be 
conducted via the respective training modules
posted in the study portal.  
Section to be changed
5.4.2   Methods of sample collection
Description of change
Revision of wording regarding storage of PK
samples
Original text:
After completion of the trial, selected PK samples 
may be retained and used for further 
methodological investigations, e.g., stability 
testing. The PK samples will be discarded after the 
completion of the additional investigations and 
after the Sponsor has approved this in writing, but 
not earlier than 5 years after the final Clinical Trial 


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Report (CTR) has been signed.
Amended text: 
After completion of the trial, selected PK samples 
may be retained and used for further 
methodological investigations, e.g., stability 
testing. The PK samples will be discarded after the 
completion of the additional investigations upon 
the Sponsor´s written approval. The PK samples 
may be destroyed 5 years after the final Clinical 
Trial Report (CTR) has been signed, and in 
accordance with local regulation.
Rationale for change
Reworded for clarity and because the storage of 
samples for PK analyses at the central laboratory 
should be limited to 5 years, where possible. The 
storage time needs to be in line with the local 
regulations.
Section to be changed
5.6.1   Immunogenicity – Antidrug antibodies
Description of change
Amendment of wording regarding storage of ADA
samples
Original text:
The ADA samples will be discarded after the 
completion of the additional investigations and the 
Sponsor has approved this in writing, but not 
earlier than 5 years after the final CTR has been 
signed.
Amended text: 
The ADA samples will be discarded after the 
completion of the additional investigations upon 
the Sponsor´s written approval. The ADA samples 
may be destroyed 5 years after the final CTR has 
been signed, and in accordance with local 
regulation.
Rationale for change
Reworded for clarity and because the storage of 
samples for biological analyses at the central 
laboratory should be limited to 5 years, where 
possible. The storage time needs to be in line with 
the local regulations.
Section to be changed
7.3.1  Primary endpoint analysis
7.3.4  Safety Analysis
Description of change
Correction of patient incidence


Boehringer Ingelheim
19 Feb 2016
BI Trial No.: 1297.3
c03635799-02
Trial Protocol
Page 78 of 79
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Original text (section 7.3.1):
In addition, patient incidence and/or event 
incidence per 100 patient-years exposure will be 
provided. No formal inferential analyses are 
planned.
Corrected text: 
In addition, patient incidence and/or event 
incidence per 1000 patient-years exposure will be 
provided. No formal inferential analyses are 
planned.
Corrected text (section 7.3.4):
In addition, for infections/serious infections, 
hypersensitivity reactions, drug-induced liver 
injury (DILI) and injection-site reactions, patient 
incidence and/or event incidence per 1000 patient-
years exposure will be displayed.
Rationale for change
Correction of an error in the original protocol to be 
in line with the protocol for the 1297.2 study.
Section to be changed
7.5.2  Efficacy endpoints
Description of change
Revision of 
Original text:
For DAS28 secondary endpoint, off-treatment 
assessments will not be taken into account. For 
missing data, LOCF will be applied on the 
component variables prior to the DAS28(ESR) 
score.
Other missing efficacy data will not be imputed.
Further details will be given in the TSAP, 
including an additional analysis strategy using 
patients’ off-treatment results.
Corrected text: 
For missing data, LOCF will be applied on the 
component variables prior to the DAS28(ESR) 
score.
Other missing efficacy data will not be imputed.
Further details will be given in the TSAP.
Rationale for change
Correction of an error in the original protocol. No 
off-treatment efficacy data will be collected and no 
analysis regarding off-treatment efficacy will be 


Boehringer Ingelheim
19 Feb 2016
BI Trial No.: 1297.3
c03635799-02
Trial Protocol
Page 79 of 79
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
done for study 1297.3.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number:  
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03635799
2.0
clinical-trial-protocol-revision-01
Long-term assessment of safety, efficacy, pharmacokinetics and immunogenicity of
BI 695501 in patients with rheumatoid arthritis (RA): an open-label extension trial
for patients who have completed trial 1297.2 and are eligible for long-term treatment
with adalimumab
Approval-Team Member Medicine
19 Feb 2016 15:28 CET
Author-Clinical Monitor
19 Feb 2016 15:35 CET
Approval-Therapeutic Area 
19 Feb 2016 15:40 CET
Approval-Clinical Pharmacokinetics
19 Feb 2016 17:44 CET
Approval-Biostatistics
22 Feb 2016 08:32 CET
Verification-Paper Signature
Completion
24 Feb 2016 09:31 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
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(Continued) Signatures (obtained electronically) 
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.0

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1297.3 
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STATISTICAL ANALYSIS PLAN 
 
 
1297.3 
LONG-TERM ASSESSMENT OF SAFETY, EFFICACY, PHARMACOKINETICS AND 
IMMUNOGENICITY OF BI 695501 IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA): 
AN OPEN-LABEL EXTENSION TRIAL FOR PATIENTS WHO HAVE COMPLETED TRIAL 
1297.2 AND ARE ELIGIBLE FOR LONG-TERM TREATMENT WITH ADALIMUMAB 
 
 
 
 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: V1.0, 22JUN2016 
 
 
 
 


 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V1.0 (Dated 22JUN2016) for Protocol 1297.3. 
 
Name 
Signature 
Date 
Author: 
 
 
DDMMMYYYY 
 
Position: 
Statistical Team 
 
 
Company: 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
 
 
DDMMMYYYY 
 
Position: 
Senior Reviewer 
 
Company: 
 
 
Approved By: 
 
 
DDMMMYYYY 
 
Position: 
Trial Statistician 
 
Company: 
 
 
Approved By: 
 
 
DDMMMYYYY 
 
Position: 
Clinical Program 
 
 
Company: 
Boehringer Ingelheim 
 
Approved By: 
 
 
DDMMMYYYY 
 
Position: 
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Company: 
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Approved By: 
 
 
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Company: 
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Statistical Analysis Plan Reviewed By 
Boehringer Ingelheim 
Team Role 
Trial Statistician 
Project Statistician 
Project Programmer  
Data 
 
Project Data 
 
Project Medical Writer 
Clinical Program 
 
Clinical Project 
 
Pharmacokineticist 
ADA/nABs specialist 
ADA/nABS specialist 
Global Drug Regulatory Affairs (DRA) 
Global Drug Regulatory Affairs (DRA) 
Pharmacovigilance (PV) 
Global Pharmacovigilance (GPV) 
Statistical Expert Group member 
Therapeutic Area 
 
Team Role 
Senior Reviewer 
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Global Project 
 
Global Medical Monitor 
Medical Writer 
  
 


 
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OUTPUT TEMPLATES SIGNATURE PAGE 
Please refer to Output Templates V1.0 (Dated 22JUN2016) for Protocol 1297.3. 
MODIFICATION HISTORY 
Unique 
Identifier 
for 
this 
Version 
Date of the 
Document 
Version 
Author 
Significant 
Changes 
from  
Previous Authorized Version 
1.0 
22JUN2016 
 
Not Applicable – First Version 
 
 
 


 
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reproduction is strictly prohibited. 
TABLE OF CONTENTS 
1. INTRODUCTION ............................................................................................................................. 11 
2. TRIAL OBJECTIVES ....................................................................................................................... 11 
3. TRIAL DESIGN ................................................................................................................................ 11 
3.1. 
General Description ................................................................................................................................... 11 
3.2. 
Schedule of Events..................................................................................................................................... 11 
3.3. 
Changes to Analysis from Protocol ............................................................................................................ 12 
4. PLANNED ANALYSES .................................................................................................................... 12 
4.1. 
Data Monitoring Committee (DMC) ........................................................................................................... 12 
4.2. 
Final Analysis ............................................................................................................................................. 12 
5. ANALYSIS SETS .............................................................................................................................. 12 
5.1. 
All Subjects Enrolled Set [ENR] .................................................................................................................. 12 
5.2. 
All Subjects Assigned Set [ASD] ................................................................................................................. 12 
5.3. 
Full Analysis Set [FAS] ................................................................................................................................ 13 
5.4. 
Per Protocol Analysis Set [PPAS] ................................................................................................................ 13 
5.5. 
Safety Analysis Set [SAF] ........................................................................................................................... 13 
5.6. 
Pharmacokinetic Full Analysis Set [PKFS] ................................................................................................... 13 
6. GENERAL CONSIDERATIONS ..................................................................................................... 14 
6.1. 
Reference Start Date and Study Day .......................................................................................................... 14 
6.2. 
Baseline ..................................................................................................................................................... 14 


 
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6.3. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 15 
6.4. 
Windowing Conventions ............................................................................................................................ 15 
6.5. 
Statistical Tests .......................................................................................................................................... 15 
6.6. 
Common Calculations ................................................................................................................................ 15 
6.7. 
Software Version ....................................................................................................................................... 15 
7. STATISTICAL CONSIDERATIONS ............................................................................................. 16 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 16 
7.2. 
Multicenter Studies ................................................................................................................................... 16 
7.3. 
Missing data .............................................................................................................................................. 16 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 16 
7.5. 
Examination of Subgroups ......................................................................................................................... 17 
8. OUTPUT PRESENTATIONS ......................................................................................................... 17 
9. DISPOSITION AND WITHDRAWALS ....................................................................................... 17 
9.1. 
Important Protocol Deviations .................................................................................................................. 18 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .......................................... 18 
10.1. 
Derivations ............................................................................................................................................ 20 
11. SURGICAL AND MEDICAL HISTORY ........................................................................................ 22 
12. MEDICATIONS ................................................................................................................................ 22 
13. TRIAL MEDICATION EXPOSURE............................................................................................... 23 
13.1. 
Derivations ............................................................................................................................................ 23 


 
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14. TRIAL MEDICATION COMPLIANCE ......................................................................................... 24 
14.1. 
Derivations ............................................................................................................................................ 24 
15. EFFICACY OUTCOMES .................................................................................................................. 25 
15.1. 
Primary Efficacy ..................................................................................................................................... 25 
15.2. 
Secondary Efficacy ................................................................................................................................. 25 
15.2.1. 
Secondary Efficacy Variables & Derivations .............................................................................................26 
15.2.1.1. 
DAS28 endpoint ................................................................................................................................26 
15.2.1.2. 
ACR20 endpoint ................................................................................................................................26 
15.2.1.3. 
ACR/EULAR remission .......................................................................................................................28 
15.2.1.4. 
EULAR response ................................................................................................................................28 
15.2.2. 
Missing Data Methods for Secondary Efficacy Variables ..........................................................................29 
15.2.2.1. 
Missing data method for DAS28 .......................................................................................................29 
15.2.2.2. 
Missing data method for ACR20 .......................................................................................................29 
15.2.2.3. 
Missing data method for ACR/EULAR remission and EULAR response ............................................30 
15.2.3. 
Analysis of Secondary Efficacy Variables ..................................................................................................30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16. SAFETY OUTCOMES ...................................................................................................................... 34 
16.1. 
Adverse Events ...................................................................................................................................... 35 
16.1.1. 
Adverse Event Specific Derivation ............................................................................................................36 
16.1.1.1. 
Treatment Emergent Adverse Event ................................................................................................36 
16.1.1.2. 
Person-Year incidence rate ...............................................................................................................36 
16.1.2. 
All TEAEs ...................................................................................................................................................36 
16.1.2.1. 
Intensity ............................................................................................................................................36 
16.1.2.2. 
Relationship to Trial Medication .......................................................................................................37 


 
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16.1.3. 
TEAEs Leading to Discontinuation of Trial Medication .............................................................................37 
16.1.4. 
Serious Adverse Events .............................................................................................................................37 
16.1.5. 
Related Serious Adverse Events ...............................................................................................................37 
16.1.6. 
Adverse Events Leading to Death .............................................................................................................37 
16.1.7. 
Adverse Events Of Special Interest ...........................................................................................................38 
16.1.7.1. 
Reported by investigator ..................................................................................................................38 
16.1.7.2. 
Infections and Serious Infections ......................................................................................................38 
16.1.7.3. 
Hypersensitivity reactions ................................................................................................................38 
16.1.7.4. 
Drug Induced Liver Injury (DILI) ........................................................................................................38 
16.1.7.5. 
Injection-site reactions .....................................................................................................................39 
16.1.7.6. 
Anaphylactic reactions ......................................................................................................................39 
16.1.8. 
AEs occurring after the last injection for subjects discontinued due to lack of efficacy. .........................39 
16.1.9. 
Non-serious adverse events leading to discontinuation of treatment .....................................................40 
16.1.10. 
Further selected adverse events ..........................................................................................................40 
16.1.10.1. 
Hepatitis B Virus (HBV) reactivation ................................................................................................40 
16.1.10.2. 
Haematological disorders ................................................................................................................40 
16.1.10.3. 
Neurological events (Demyelinating disorders) ...............................................................................40 
16.1.10.4. 
Systemic lupus erythematosus ........................................................................................................41 
16.1.10.5. 
Sarcoidosis .......................................................................................................................................41 
16.1.10.6. 
Stevens-Johnson syndrome .............................................................................................................41 
16.1.10.7. 
Erythema multiforme .......................................................................................................................41 
16.1.10.8. 
Autoimmune hepatitis .....................................................................................................................41 
16.1.10.9. 
Malignancies ....................................................................................................................................42 
16.1.10.10. 
Chronic heart failure ......................................................................................................................42 
16.2. 
Deaths ................................................................................................................................................... 42 
16.3. 
Laboratory Evaluations .......................................................................................................................... 42 
16.3.1. 
Laboratory Specific Derivations ................................................................................................................43 
16.3.2. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ..............................................................44 
16.3.3. 
RCTC Grading for Laboratory Data ...........................................................................................................44 
16.4. 
ECG Evaluations ..................................................................................................................................... 44 
16.5. 
Vital Signs .............................................................................................................................................. 45 
16.6. 
Physical Examination ............................................................................................................................. 45 
16.7. 
Other Safety Assessments ..................................................................................................................... 46 
16.7.1. 
Immunogenicity ........................................................................................................................................46 
16.7.2. 
Pregnancy Test .........................................................................................................................................46 
16.7.3. 
Tuberculosis test .......................................................................................................................................47 
17. PHARMACOKINETIC DATA ........................................................................................................ 47 


 
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17.1. 
Pharmacokinetic Endpoints ................................................................................................................... 47 
17.2. 
General Consideration ........................................................................................................................... 47 
17.3. 
Plasma Concentrations Presentation ..................................................................................................... 47 
18. REFERENCES ................................................................................................................................... 49 
APPENDIX 1. 
Programming Conventions for Outputs ...................................................................................... 50 
APPENDIX 2. 
Partial Date Conventions ............................................................................................................ 56 
APPENDIX 3. 
EMA SOC order for presentation of the AE in the tables. ............................................................ 61 
APPENDIX 4. 
Laboratory Assessments ............................................................................................................. 62 
APPENDIX 5. 
BIcMQs ....................................................................................................................................... 63 
 
 


 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of safety, efficacy, 
pharmacokinetics and immunogenicity data for Protocol 1297.3. It describes the data to be summarized and 
analyzed, including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version 2.0, dated 19 February 2016. 
2. TRIAL OBJECTIVES 
The objective of this trial is to provide long-term safety, efficacy, PK, and immunogenicity data on BI 695501 
administered via prefilled syringe in patients with RA who have completed Trial 1297.2. 
3. TRIAL DESIGN 
3.1. 
GENERAL DESCRIPTION 
This is a single-dose, open-label trial of BI 695501 with a 48-week treatment period in patients with RA continuing 
to receive methotrexate (MTX) within the dose range of the 1297.2 trial for at least 12 weeks after which point the 
MTX dose will be at the Investigators discretion. The trial will consist of a Screening visit 14 days prior to Day 1, a 
48-week treatment period and a 10-week safety follow-up period (Week 58 visit). The Screening visit will be the 
Week 48 visit in Trial 1297.2. Patients will undergo up to 10 visits over the duration of the trial (58 weeks). 
Patients who discontinue the trial medication early (and do not withdraw consent) should return to the site for an 
End of Treatment (EoT) visit equivalent to the Week 48 assessments as soon as possible after last trial medication 
administration. For patients who discontinue treatment early, a safety follow-up visit should be performed 10 
weeks after the last administration of BI 695501. 
It is anticipated that approximately 300 to 400 patients with moderately to severely active RA who have completed 
Trial 1297.2 will be eligible and willing to participate in this extension trial. Each patient who provides informed 
consent and meets all the inclusion criteria and none of the exclusion criteria will self-administer 40 mg of BI 695501 
every 2 weeks by subcutaneous (SC) injection. 
3.2. 
SCHEDULE OF EVENTS 
Schedule of events can be found in Section “FLOW CHART” of the protocol. 


 
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3.3. 
CHANGES TO ANALYSIS FROM PROTOCOL 
No change is planned. 
4. PLANNED ANALYSES 
4.1. 
DATA MONITORING COMMITTEE (DMC)  
There will be no DMC for this trial. 
4.2. 
FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by 
 Biostatistics following Sponsor 
Authorization of this Statistical Analysis Plan, Database Lock, and Sponsor Authorization of Analysis Sets. 
5. ANALYSIS SETS 
Agreement and authorization of subjects included/ excluded from each analysis set will be conducted prior to the 
database lock of the trial.  
 
5.1. 
ALL SUBJECTS ENROLLED SET [ENR] 
The all subjects enrolled (ENR) set will contain all subjects who provide informed consent for this trial. 
5.2. 
ALL SUBJECTS ASSIGNED SET [ASD] 
The all subjects assigned (ASD) set will contain all subjects in the ENR set who were assigned to trial medication in 
1297.3. 
For analyses and displays based on ASD, subjects will be classified according to randomized / re-randomized 
treatments of trial 1297.2. 


 
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5.3. 
FULL ANALYSIS SET [FAS] 
The full analysis set (FAS) will contain subjects from the ASD set, who received at least one dose of trial medication 
in Trial 1297.3, and had data recorded for at least one DAS28 (Erythrocyte Sedimentation Rate [ESR] or C-reactive 
protein [CRP]) or ACR20 during the 1297.3 trial (for at least one composite variable at least one non-missing value 
should be present on at least one post-baseline visit. It is not required that all composite variables must be non-
missing at the same post-baseline visit). Subjects will be classified according to randomized / re-randomized 
treatments of trial 1297.2. 
5.4. 
PER PROTOCOL ANALYSIS SET [PPAS] 
No per protocol analysis set (PPAS) is defined in this trial. 
5.5. 
SAFETY ANALYSIS SET [SAF] 
The safety analysis set (SAF) will contain all subjects who received at least one dose of trial medication during the 
1297.3 trial. Subjects will be classified according to randomized / re-randomized treatments received in trial 
1297.2.  
If there is any doubt whether a subject was treated or not, they will be assumed treated for the purposes of 
analysis. Subjects will be classified according to randomized / re-randomized treatments group allocated in trial 
1297.2 safety outputs.  
5.6. 
PHARMACOKINETIC FULL ANALYSIS SET [PKFS] 
The pharmacokinetic full analysis set PKFS analysis set for the summary of PK concentrations consists of all subjects 
who receive at least one dose of trial medication and have at least one post-treatment valid PK concentration 
value. 
The following are considered as non-valid PK concentration measurement: 
• 
Sampling date or time missing 
• 
Dosing date or time missing 
• 
No valid result (NOR), No sample available (NOS), Not Analyzed (NOA) 


 
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6. GENERAL CONSIDERATIONS 
6.1. 
REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/stop day of assessments 
and events.  
Reference start date is defined as the day of the first dose of trial medication in 1297.3 trial, (Day 1 is the day of 
the first dose of trial medication), or for subjects assigned to treatment but not treated it is the day of treatment 
assignment. This will appear in every listing where an assessment date or event date appears.  
• 
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1. 
 
• 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, and 
Study Day, and any corresponding durations will be presented based on the imputations specified in Appendix 2; 
Partial Date Conventions. 
6.2. 
BASELINE 
Unless otherwise specified, baseline in Trial 1297.3 is defined as the last non-missing measurement taken prior to 
reference start date (including unscheduled assessments). In the case where the last non-missing measurement 
and the reference start date coincide, that measurement will be considered pre-baseline. Adverse Events (AEs) 
and medications commencing on the reference start date will be considered post-baseline. 
For the analysis referring to the 1297.2 baseline, the baseline value as derived in 1297.2 will be used. All endpoints 
will be assessed using the 1297.2 baseline values. In addition, the following further endpoints will be assessed 
using the 1297.3 baseline values: 
• 
DAS28 (ESR) 
• 
ACR20 response criteria 
• 
SF-36 v2 


 
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6.3. 
RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. In the case of a retest, an 
unscheduled assessment will be created. For laboratory assessments, the latest available measurement within 2 
days after the planned assessment will be used for by-visit summaries.  
Unscheduled measurements will not be included in by-visit table summaries and by-visit graphs, but will contribute 
to the last observation carried forward (LOCF) values.  
Treatment Early termination data will not be included in by-visit table summaries and by-visit graphs, but will 
contribute to the last observation carried forward (LOCF) values and be present in the listing and individual data 
graphs.  
Listings will include all scheduled, unscheduled, retest and early discontinuation data collected in the eCRF 
database. 
6.4. 
WINDOWING CONVENTIONS  
Unless other specified, visit data as recorded in the database will be used for the analysis. No visit windowing 
recalculation will be performed for this trial. 
6.5. 
STATISTICAL TESTS 
No formal hypothesis testing will be performed. The analysis of the data will be performed descriptively. If 
confidence intervals or p-values are presented, they will be interpreted in an exploratory fashion only. In this case, 
the default significant level will be (5%); confidence intervals will be 95% and all tests will be two-sided, unless 
otherwise specified in the description of the analyses.  
6.6. 
COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 
• 
Test Value at Visit X – Baseline Value 
6.7. 
SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher.  


 
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7. STATISTICAL CONSIDERATIONS 
7.1. 
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN 
ANALYSES 
No covariates adjustment is required in this trial. 
7.2. 
MULTICENTER STUDIES 
This trial will be conducted by multiple investigators at multiple centers internationally depending on the inclusions 
of trial 1297.2. No specific analyses based on (pooled) centers are planned.  
Geographic region will be categorized using country information as follows: 
 
Geographic Region 
Country 
Asia 
Republic of Korea, Malaysia, New Zealand, Thailand 
Europe (EU) 
Bulgaria, Estonia, Germany, Hungary, Poland, 
Russian Federation, Serbia, Spain, Ukraine 
Latin America 
Chile 
United States of America 
United States 
 
7.3. 
MISSING DATA 
Missing safety data will not be imputed, unless otherwise specified in section 16. 
Missing efficacy data will be handled as described in section 15.2.2 of this analysis plan.  
For duration of disease and birth date, the missing date will not be imputed. Calculation for the partial date is 
described in APPENDIX 2. 
7.4. 
MULTIPLE COMPARISONS/ MULTIPLICITY 
No multiplicity consideration is required in this trial. 


 
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7.5. 
EXAMINATION OF SUBGROUPS 
No subgroup analysis is required in this trial. 
8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows conventions for presentation of data in outputs, unless other specified within the document 
(e.g. plasma concentration). In particular, for presentation of results, three groups of patients will be created 
depending on treatments assigned in Trial 1297.2. 
The templates provided with this SAP describe the presentations for this trial and therefore the format and content 
of the summary tables, figures and listings to be provided by 
 Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this trial.  
The counts of the analysis sets will be presented: 
• 
All Subject Enrolled (ENR) 
• 
All Subjects Assigned (ASD) 
• 
Safety Analysis Set (SAF) 
• 
Full Analysis Set (FAS) 
• 
Pharmacokinetic Full Analysis Set (PKFS) 
The following subject disposition and withdrawals will be presented for the ENR set: 
• 
Screened 
• 
Screen failure (defined as subjects who do not enter the trial and are not assigned treatment), 
reason for non-inclusion 
• 
Assigned to treatment 
• 
Assigned to treatment but not treated 
• 
Treated 
• 
Completed treatment 


 
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• 
Completed trial 
• 
Discontinued from treatment, reason for premature discontinuation from treatment 
• 
Discontinued from trial, reason for premature discontinuation from trial 
• 
Discontinued from safety follow-up, reason for premature discontinuation from safety follow-up 
Subjects enrolment will also be summarized by country and by age group (18-64, 65-84, >=85). 
9.1. 
IMPORTANT PROTOCOL DEVIATIONS 
Important protocol violations defined below will be listed for the ASD set: 
• 
Trial drug not administered at all 
• 
Severe violation of treatment compliance  
o 
Medical team will review subjects with treatment compliance outside 80% and 120% (refer 
to section 14.1) and decide if the violation is severe. 
• 
Any deviation of inclusion/exclusion criteria should be considered as important violations. 
• 
A severe violation to the restricted DMARD therapy (protocol table 4.2.2.1:1), as assessed by the 
medical team. 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic characteristics will be reported for ASD, FAS, SAF and PKFS: 
• 
Age (years) at Inform Consent 
• 
Age groups at Informed Consent  
o 
Adolescent (12-17 years): 12 <= AGE < 18 – no patient expected 
o 
Adults (18-64 years): 18<= AGE < 65 
o 
Adults (65-84 years): 65<= AGE < 85 
o 
Adults (Over 85 years): 85<= AGE – no patient expected 


 
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• 
First age subgroup at Informed Consent 
o 
AGE < 65 years 
o 
AGE >= 65 years 
• 
Second age subgroup at Informed Consent 
o 
AGE < 65 years 
o 
65 <= AGE < 76 
o 
76 <= AGE <85 
o 
AGE >= 85 
• 
Gender (Male/Female) 
• 
Childbearing potential (Post-Menopausal / Surgically Sterile / Childbearing Potential (includes tubal 
ligation)) 
• 
Race (American Indian or Alaska Native / Asian / Black or African American / Native Hawaiian or 
Other Pacific Islander / White / Other) 
• 
Ethnicity (Hispanic or Latino / Not Hispanic or Latino / Not reported) 
• 
Height at baseline (cm) 
• 
Weight at baseline (kg) 
• 
BMI at baseline (kg/m²) 
• 
Country (please refer to section 7.2) 
• 
Region (please refer to section 7.2) 
 
The following baseline disease characteristics will be presented for FAS and SAF: 
• 
Duration of rheumatoid arthritis (years) at Informed Consent. 
• 
Individual parameters of ACR improvement criteria at baseline:  
1. Swollen joint counts (66 joints) at baseline 


 
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2. Tender joint counts (68 joints) at baseline 
3. Patient’s assessment of pain at baseline 
4. Patient’s global assessment of disease activity at baseline 
5. Physician’s global assessment of disease activity at baseline 
6. Patient’s assessment of physical function, as measured by the HAQ-DI, at baseline 
7. C-reactive protein (CRP) at baseline  
• 
Erythrocyte sedimentation rate (ESR) at baseline 
• 
Disease Activity Score 28-Erythrocyte sedimentation rate (DAS28-ESR) at baseline  
• 
Disease Activity Score 28-Erythrocyte sedimentation rate (DAS28-CRP) at baseline  
Other baseline characteristics will be presented on FAS, and SAF: 
• 
Immunogenicity (proportion of subjects with positive ADAs result) at baseline 
• 
Neutralizing anti-drug antibodies results at baseline 
• 
Infection screen (for hepatitis B, hepatitis C, HIV test) 
• 
Tuberculosis (TB) test 
• 
Rheumatoid factor (RF) and anti-CCP antibodies 
Accountability for missing data will be displayed in case of any missing entries. 
10.1. 
DERIVATIONS 
• 
Age (years) = (date of consent– date of birth)/365.25 
• 
BMI (kg/ m2) = weight (kg)/ height (m)2 
• 
Duration of rheumatoid arthritis (years) = (date of informed consent - date of first diagnosis + 1)/ 
365.25 
• 
Joint counts:  
o 
Swollen joint counts (66 joints) 
o 
Tender joint counts (68 joints) 


 
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Refer to section 15.2.1.2 for further calculation details 
• 
DAS28 
o 
DAS28 (CRP) = 0.56*√(TJC28) +0.28*√(SJC28)+0.014*GH+0.36*ln(CRP+1)+0.96 
o 
DAS28 (ESR) = 0.56*√(TJC28) + 0.28*√(SJC28) + 0.70*ln(ESR) + 0.014*(GH) 
Where: 
 
 
TJC28 = 28 joint count for tenderness 
 
 
SJC28 = 28 joint count for swelling 
 
 
ln(CRP) = natural logarithm of CRP 
 
 
ln(ESR) = natural logarithm of ESR 
GH = the General Health component of the DAS, which is the patient’s global 
assessment of disease activity.  
ESR local value will be used for the DAS28 (ESR) calculation. 
The following 28 joints will be evaluated for swelling and tenderness based on the eCRF entry  
• 
8 proximal interphalangeal (PIP) joints of the fingers (eCRF: right and left PIP2, PIP3, PIP4, PIP5)  
• 
the interphalangeal (IP) joints of the thumbs (eCRF: right and left IP thumb) 
• 
the 10 metacarpophalangeal (MCP) joints (eCRF: right and left MCP 1 – MCP 5) 
• 
the wrists (eCRF: right and left wrist)  
• 
elbows (eCRF: right and left elbow)  
• 
shoulders (eCRF: right and left shoulder)  
• 
knees (eCRF: right and left knee) 
In determining the TJC28 and SJC28, if a joint evaluation is missing or ‘Not done’ at baseline (please refer to section 
6.2 for baseline definition), it will not contribute to the joint counts at baseline and all subsequent visits (i.e., will be 
treated as ‘Not Done’). If at least half but not all joints are evaluable (at least 14 joints for the 28 joint count with 
eCRF values ‘present’ or ‘absent’), then the observed prorated tender/swollen joint count will be calculated. The 
prorated scores will be adjusted based upon the number of evaluable joints: the counted score will be multiplied by 
28 and divided by the number of joints evaluated. For example, if only 25 of the 28 joints are assessed at a visit and 
8 of those 25 are tender/swollen (eCRF value ‘present’), the prorated joint count is 8/25×28 = 8.96. This value, 8.96 
(not 8) will be used for DAS28 (ESR) score calculation. If less than half of the joints are evaluable (eCRF value ‘not 
done’ or missing), the number of tender/swollen joints is missing.  
The General Health component of the DAS28(ESR) is Patient’s global assessment of disease activity visual analysis 
scale (VAS) as collected in the eCRF and the ESR values provided by the local laboratory will be used for the 


 
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DAS28(ESR) calculation.  
In the situation where the diagnosis date is partial or missing, the corresponding durations will be presented based 
on the imputations specified in APPENDIX 2. 
11. 
SURGICAL AND MEDICAL HISTORY 
Surgical and Medical History information will be presented for the SAF. Medical History conditions are defined as 
those conditions which stop prior to or at Screening.  
The system organ classes will be sorted by internationally agreed European Medicines Agency System Organ Class 
(EMA SOC) order (refer to APPENDIX 3), preferred terms (PT) will be sorted by decreasing frequencies (within 
system organ class). 
Data captured on the “Medical and surgical history” page of the eCRF and on the “Concomitant Surgical Procedures” 
page of the eCRF will be merged together and assigned to prior, concomitant, or post-treatment phase.  
Surgical and Medical History will be coded using MedDRA version 18.1 or higher. 
See APPENDIX 2 for handling of partial dates for medical history, surgeries and procedures; if it is not possible to 
define an history, surgery or procedure as prior, concomitant, or post-treatment, it will be classified by the worst 
case; i.e. concomitant. 
• 
Prior medical history, surgeries and procedures are defined as those conditions or procedures which 
stop prior to or at Screening (prior only).  
• 
Concomitant medical history, surgeries and procedures  are defined as those conditions or 
procedure which: 
o 
started prior to or at Screening and are ongoing or active at the date of Screening 
 or 
o 
started after Screening during the treatment period (prior and concomitant).  
Prior and concomitant surgical and medical history will be presented by SOC and PT in two separate tables.  
12. 
MEDICATIONS 
Medications will be presented for the SAF and coded using WHO Drug Dictionary version SEP2015 or higher. 
No ATC class coding will be performed. 
The medical terms will be summarized by generic medication name. 
The generic medication name will be sorted by decreasing frequencies. 
See APPENDIX 2 for handling of partial dates for medications; if it is not possible to define a medication as prior, 


 
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concomitant, or post treatment, the medication will be classified by the worst case; i.e. concomitant.  
• 
‘Prior’ medications are medications which started and stopped prior to the first dose of trial 
medication.  
• 
‘Concomitant’ medications are medications which:  
o 
started prior to, on or after the first dose of trial medication or started no later than end of trial 
medication,  
o 
AND ended on or after the date of first dose of trial medication or were ongoing at the end of the 
trial. 
• 
‘Post’ medications are medications which started after the last dose of trial medication. 
In addition all prior (respectively concomitant) prohibited/restricted medications outlined in CTP table 4.2.2.1:1, 
taken by at least one subject which may significantly impact efficacy assessment as determined by the trial medical 
advisor will be summarized in tables (overall for the FAS). 
 
13. 
TRIAL MEDICATION EXPOSURE 
Exposure to trial medication will be presented for the FAS and SAF. 
The proportion of subjects treated at each planned visit (administration every two weeks from Day 1 to Day 337) 
will be presented. 
Descriptive statistics for the number of injections from Day 1 up to Week 48 per subjects will be presented.  
Number of subjects per duration of exposure categories, Patient time (years) per duration of exposure, categories 
and descriptive statistics for duration of exposure will be presented. 
Exposure categories will be the following: >= 1 day, >= 2 weeks, >= 4 weeks, >=12 weeks, >=24 weeks, , >=52 
weeks. 
13.1. 
DERIVATIONS 
The date of first and last trial medication administration will be taken from the eCRF “Self-Administration of trial 
medication” page. Interruptions, compliance, and dose changes are not taken into account for duration of 
exposure.  
Duration of exposure (weeks) = (date of last injection - date of first injection + 1)/ 7. 
Duration of exposure (days) = (date of last injection - date of first injection + 1). 


 
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Patient Year Exposure (year) = cumulative duration of exposure in days per subjects / 365.25 
14. 
TRIAL MEDICATION COMPLIANCE  
Compliance to trial medication will be presented for the FAS and SAF.  
A first calculation will be based on the count of syringe boxes and/or labels in the eCRF. A second calculation will 
take into account the approximate left-over percentage of the pre-filled syringe volume in case the full volume 
was not injected. 
Descriptive statistics for drug accountability compliance overall, overall until Week 12 and overall until Week 24 
will be presented.  
Descriptive statistics for pre-filled syringe volume compliance will be presented at each planned visit, overall, 
overall until Week 12 and overall until Week 24.  
14.1. 
DERIVATIONS 
Compliance will be calculated for subjects having attended the visit. A subject is considered having attended the 
visit if the indicated visit is captured in the eCRF database. Two types of compliances will be computed: drug 
accountability compliance and compliance (based on the left-over percentage of the pre-filled syringe volume). 
Drug accountability compliance 
Compliance with trial medication—based on the drug accountability data—will be calculated as the number of 
syringes injected (total dispensed – total unused + administered at site) divided by the prescribed number of 
syringes expressed as a percentage, see calculations below. The number of syringes will be captured in the two 
eCRF pages: Self-Administration of trial medication (if the administration was on site) and Trial medication 
Dispensation and collection (if the administration was at patient’s home). The number of syringes required to be 
taken per week is 0.5. 
• 
Overall Compliance by Week 12 and Overall Compliance by Week 24 will include unscheduled visit 
data and will be calculated by: 
1. Summing the number of syringes dispensed until 12 (resp. 24) Weeks  exclusively and the 
number of syringes administered on site until 12 (resp. 24) Weeks inclusively, and subtracting 
the number of syringes unused until 12 (resp. 24) Weeks inclusively 
2. Multiplying by two the above quantity and dividing by the number of weeks between the 
first administration date and visit date Week 12 (resp. 24) plus 2 weeks 
3. Multiplying by 100 to express compliance as a percentage. 
For subjects who permanently stop the trial medication prior to Week 12 (resp. 24), the ”Date of Visit X(n)“ will be 
replaced by the date of last administration of trial medication. 


 
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• 
Overall Compliance to trial medication will include unscheduled visit data and will be calculated by: 
1. Summing the number of syringes dispensed over the study, the number of syringes 
administered on site over the study, and subtracting the number of syringes unused over the 
study 
2. Multiplying by two the above quantity and dividing by the number of weeks between the 
first and last administration date plus 2 week 
3. Multiplying by 100 to express compliance as a percentage. 
Compliance 
Compliance with trial medication will be based on the “Self-Administration of trial medication” eCRF data. 
The amount of drug to be administered is 0.8mL. The compliance will be based on the approximated left-over 
percentage of the pre-filled syringe volume in % (eCRF data) and the total volume (0.8mL considered as 100%) and 
calculated as amount of drug administered divided by the amount of drug to be administered expressed as a 
percentage, see calculations below. If the administration of trial medication occurred at home, one will assume 
100% of the volume was administered if the administration occurred (i.e. “Was trial drug administered?” reported 
as “Yes”). 
• 
”Per Visit” Compliance to trial medication will be calculated  at every administration timepoint as 
follows: 
Compliance (%) = 100 – Approximated left-over percentage of the pre-filled syringe volume as 
indicated in eCRF.  
• 
Overall Compliance by Week 12 and Overall Compliance by Week 24 will be calculated as mean of 
the “per visit” compliance until Week 12 (resp. Week 24). 
• 
Overall Compliance to trial medication will be calculated as mean of the “per visit” compliance.  
15. 
EFFICACY OUTCOMES  
15.1. 
PRIMARY EFFICACY 
No primary efficacy endpoint. 
15.2. 
SECONDARY EFFICACY 
The secondary efficacy analyses will be performed for the FAS and are summarized below: 


 
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Secondary endpoints  
Population, imputation method 
Analysis 
Change from Baseline of DAS28(ESR) at 
Week 48 
FAS, LOCF 
Descriptive 
Proportion of subjects meeting the ACR20 
response criteria at Week 48 
FAS, NRI/LOCF 
Descriptive 
Proportion of subjects who meet the 
ACR/EULAR definition of remission at 
Week 48 
FAS, no imputation method 
Descriptive 
Proportion of subjects with EULAR 
response at Week 48 
FAS, no imputation method 
Descriptive 
 
15.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
15.2.1.1. 
DAS28 endpoint 
A secondary endpoint is: 
• 
The change from Baseline in trial 1297.2 in DAS28 (ESR) at Week 48 of trial 1297.3 
DAS28 (ESR) score will be derived at every planned efficacy assessment visit using the formula described in section 
10.1. The change from Baseline in DAS28 (ESR) (baseline-post baseline) will be calculated for every planned post-
baseline efficacy assessment visit. 
15.2.1.2. 
ACR20 endpoint 
A secondary efficacy endpoint is  
• 
The proportion of subjects meeting the ACR20 response criteria (based on improvement since 
Baseline in trial 1297.2) at Week 48 of trial 1297.3. 
ACR20 response will be calculated at every planned efficacy assessment visit. 
A subject has an ACR20 response if all of the following occur: 
• 
A ≥ 20% improvement in the swollen joint count (66 joints)  
• 
A ≥ 20% improvement in the tender joint count (68 joints) 
• 
A ≥ 20% improvement in at least three of the following assessments: 
o 
Patient’s assessment of pain 
o 
Patient’s global assessment of disease activity 
o 
Physician’s global assessment of disease activity (see below for more details). 
o 
Patient’s assessment of physical function, as measured by the Health Assessment 


 
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Questionnaire – Disability Index (HAQ-DI) 
o 
Acute phase reactant (CRP). 
Improvement is assessed as the decrease in a component relative to baseline, (100×(baseline - post 
baseline)/baseline). 
The handling of retests, unscheduled and end of trial measurements is described in Section 6.3. 
If a joint evaluation is missing or ‘Not done’ at baseline (please refer to section 6.2 for baseline definition), it will 
not contribute to the joint counts at baseline and all subsequent visits (i.e., will be treated as ‘Not Done’). If at least 
half but not all joints are evaluable (at least 33 joints for the 66 joint count for swelling with eCRF values ‘present’ 
or ‘absent’, at least 34 joints for the 68 joint count for tenderness with eCRF values ‘present’ or ‘absent’), then the 
observed prorated tender/swollen joint count will be calculated.  
The prorated scores will be evaluated based upon the number of evaluable joints: the counted score will be 
multiplied by 66 for swelling or 68 for tender joint count and divided by the number of joints evaluated. For 
example, for tender joint count, if only 45 of the 68 joints are assessed at a visit and 18 of those 45 are tender 
(eCRF value ‘present’), the prorated tender joint count is 18/45×68 = 27.2. This exact value, 27.2 (and not 18) will 
be used for ACR20 score calculation. For swollen joint count, if only 45 of the 66 joints are assessed at a visit and 
18 of those 45 are swelling (eCRF value ‘present’), the prorated swollen joint count is 18/45×66 = 26.4. This exact 
value, 26.4 (and not 18) will be used for ACR20 score calculation. 
If less than half of the joints are evaluable (eCRF value ‘not done’ or missing), the number of tender/swollen joints 
is missing. 
The central laboratory data for CRP and eCRF data for all other ACR20 components will be used for the calculation. 
Patient’s assessment of pain as well as patient’s and physician’s global assessment of disease activity accessed 
using the VAS of 100 mm.  
Patient’s assessment of physical function will be assessed using HAQ-DI. The calculation of this index is described 
below. The HAQ-DI is composed of 20 items. There are eight categories, each of which has at least two component 
questions: 
1. 
Dressing and grooming 
2. 
Arising 
3. 
Eating 
4. 
Walking 
5. 
Hygiene 
6. 
Reach 
7. 
Grip 
8. 
Common daily activities. 
For each of the categories, subjects report the amount of difficulty they have in performing two or three specific 
sub-category items, or also known as components, or component variables. 


 
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0 = without ANY difficulty  
1 = with SOME difficulty  
2 = with MUCH difficulty  
3 = UNABLE to do. 
If a component question is left blank, then the score for that category is determined by the remaining completed 
question(s).  
The subject must have a score for at least 6 of the 8 categories. If there are less than 6 categories completed, a 
HAQ-DI cannot be computed, whether the missing categories are due to missing values or they do not apply to the 
respondent.  
Calculation of HAQ-DI score: 
1. 
Sum the eight category scores*  
*A category score is determined from the highest score of the sub-categories, or components, in that category, 
except when aids or devices are taken into account (see below). For example, if there are three sub-category items 
(as in the category ARISING), and the subject responds with a 1, 2, and 0, respectively, to the three sub-category 
items, the score for the ARISING category will be a 2.  
2. 
Divide the sum by the number of categories answered (range - 6-8)  
Scoring AIDS OR DEVICES or help companion variables:  
1. 
When there are NO aids or devices, or help indicated for a category, the category’s score is not modified.  
2. 
When aids or devices or help ARE indicated by the subject, the score for the category item is raised from 
a 0 or a 1 to a 2, but if the subject’s highest score for that sub-category is a 2, it stays a 2 (the same for 3) 
15.2.1.3. 
ACR/EULAR remission 
A secondary efficacy endpoint is  
• 
The proportion of subjects who meet the ACR/EULAR definition of remission (based on 
improvement since Baseline in trial 1297.2) at Week 48 of trial 1297.3. 
To have the ACR/EULAR Remission, the subject must satisfy all of the following criteria: 
- 
Tender joint count (TJC) (68) ≤ 1 
- 
Swollen joint count (SJC) (66) ≤ 1 
- 
CRP ≤ 1mg/dL 
- 
Patient global assessment ≤ 10 (on a 0-100 scale) 
15.2.1.4. 
EULAR response 
A secondary efficacy endpoint is  


 
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• 
The proportion of subjects with EULAR response (good response, moderate response or no 
response) (based on DAS28 (ESR) improvement since Baseline in trial 1297.2) at Week 48 of trial 
1297.3. 
Improvement in DAS28 (ESR) will also be categorized using the EULAR response criteria: 
 
DAS28 Improvement 
DAS at endpoint 
≥1.2 
>0.6 and <1.2 
≤0.6 
≤3.2 
Good Response 
Moderate response 
No Response 
>3.2 and ≤5.1 
Moderate response 
Moderate response 
No Response 
>5.1 
Moderate response 
No Response 
No Response 
 
Where DAS28(ESR) improvement is computed as:  
o DAS28(ESR) at 1297.2 baseline – DAS28(ESR) at Week X.  
 
15.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLES 
15.2.2.1. 
Missing data method for DAS28 
Last observation carried forward (LOCF) will be used for imputation of missing component variables prior to DAS28 
(ESR) score calculation.  
15.2.2.2. 
Missing data method for ACR20 
Missing ACR20 data will be imputed at Week 48 using a combination of non-responder imputation and LOCF 
methods. 
Table 1 details exactly where the LOCF / NRI imputation will be applied. 
Table 1: Application of LOCF/NRI for the primary analysis on the FAS – possible outcomes 
 
…prior to week X 
Analysis (FAS) 
Discontinued treatment#  
Did NOT discontinue treatment 
ACR20 computable using observed data at week X 
No (NRI applied) 
Yes/No (observed) 
ACR20 NOT computable using observed data at week X 
No (NRI applied) 
Yes/No (LOCF applied)$ 
 
# lost to follow-up from trial is also included here, or patients who took a therapy that may significantly impact efficacy assessment prior to this 
time-point.  
The following steps will be followed: 
Step 1: Missing ACR20 component data will be imputed using the last observation carried forward (LOCF) method 


 
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and ACR20 will be calculated based on the imputed component data. 
Last observation will be carried forward as many time as needed.  
Step 2: The imputed ACR20 will be set to non-responder at Week 48, if the subject  
• 
discontinue treatment prior to Week 48 
• 
are lost-to-follow-up prior to Week 48 
• 
have any severe violation related to any therapy that may significantly impact efficacy assessment 
prior to Week 48  
Severe violation related to any therapy (according to CTP Table 4.2.2.1: 1) that may significantly impact efficacy 
assessment will be assessed by: 
• 
providing to the trial medical advisor 
o 
a list of medication codes (WHO Drug Dictionary version SEPR2015 or higher) presented in CTP 
Table 4.2.2.1: 1 and taken by at least one subject during trial conduct. 
o 
full individual concomitant medication information including dose, frequency and Study day at start 
of medication.  
• 
Trial medical advisor will then identify the medications and start date of severe violation which may 
impact efficacy assessment 
15.2.2.3. 
Missing data method for ACR/EULAR remission and EULAR response 
Efficacy data for ACR/EULAR remission and EULAR response will not be imputed. 
15.2.3. 
ANALYSIS OF SECONDARY EFFICACY VARIABLES 
Secondary efficacy endpoints will be presented for FAS. 
Descriptive statistics will be provided for each secondary endpoint. 
 
  
 
 
 
 
 


 
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16. 
SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise specified 
with the relevant section. 
The primary endpoint is defined as: 


 
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• 
The number (proportion) of patients with drug-related AEs during the treatment phase (with onset 
date between start of treatment and 10 weeks after the last dose of trial medication, i.e. treatment-
emergent AE, refer to Section 16.1.1.1). 
Other safety endpoints will be: 
• 
The proportion of patients with infections/serious infections (seriousness of infection defined as 
requirement of i.v. antibiotics for treatment and/or meeting seriousness criteria to be qualified as 
an SAE) 
• 
The proportion of patients who experience hypersensitivity reactions 
• 
The proportion of patients who experience DILI 
• 
The proportion of patients with injection-site reactions 
• 
The proportion of patients with antidrug antibodies (ADAs) at Week 12, Week 24, and Week 48 
• 
The proportion of patients with neutralizing antidrug antibodies (nABs) at Week 12, Week 24, and 
Week 48 
• 
The proportion of patients who discontinue due to a drug-related AE 
Other safety evaluations will include: physical examination, vital signs (blood pressure, pulse rate, respiratory rate, 
body temperature), 12-lead ECGs, laboratory tests, and continuous AE monitoring. 
16.1. 
ADVERSE EVENTS 
Adverse Events (AEs) will be coded using the MedDRA central coding dictionary, Version 18.1 or higher. The system 
organ classes will be sorted by internationally agreed EMA SOC order (refer to APPENDIX 3), preferred terms will 
be sorted by decreasing frequencies (within system organ class).  
An overall summary of the number of subjects, percentages, number of events and patient-year incidence rate 
within each of the categories described in the sub-section below will be provided. 
In case of worsening in severity, a new entry is created with start date equal to start of worsening. 
All the outputs described in this section will be presented according to the initial randomization and re-
randomization of trial 1297.2 unless specified otherwise. 
Listings will include treatment-emergent adverse events (TEAEs) and Non-TEAEs. 


 
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16.1.1. 
ADVERSE EVENT SPECIFIC DERIVATION 
16.1.1.1. 
Treatment Emergent Adverse Event 
Treatment-emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity on or after 
the first dose of 1297.3 trial medication and prior to the last date of 1297.3 trial medication + 10 weeks inclusive. 
Non-TEAEs will be classified as “Prior treatment” if AE start date is strictly prior the first injection date. Non-TEAEs 
will be classified as “Post treatment” if AE start date is strictly after the last injection date + 70 days. 
See APPENDIX 2 for handling of partial dates for AEs. In the case where it is not possible to define an AE as 
treatment-emergent or not, the AE will be classified by the worst case; i.e. treatment-emergent. 
16.1.1.2. 
Patient-Year incidence rate 
Patient-year incidence rate per 1000 years for AEs will be calculated as follows: 
(Number of subjects with at least one AE) / (Patient-Year) * 1000 
where Patient-Year is the sum of time at risk for each subject (days) in the treatment group divided by 365.25. 
The time at risk (years) per subject is derived as following: 
• 
subject had at least one AE with specific criterion:  
time at risk (days) = start date of first AE meeting the specific criterion – start of treatment +1 
• 
subject without AE with specific criterion:  
time at risk (days) = end of treatment + 70 – start of treatment +1 
Patient-year incidence rate per 1000 years for TEAEs, SAEs, related TEAEs, TEAEs leading to discontinuation of trial 
medication, TEAEs leading to Death and AEs of special interest (AESI) will be calculated using the above algorithm. 
16.1.2. 
ALL TEAES  
Number of subjects, percentages, number of events and patient-year incidence rate of TEAEs will be presented by 
System Organ Class (SOC) and Preferred Term (PT) and also broken down further by maximum severity, 
relationship to trial medication and subgroups (refer to section 7.5.1). 
A summary of 1297.2 trial TEAEs occurring during the 1297.3 screening phase will be prepared. 
16.1.2.1. 
Intensity 
Intensity is classified as mild/ moderate/ severe (increasing intensity). TEAEs starting after the first dose of trial 
medication with a missing intensity will be classified as severe. If a subject reports a TEAE more than once within 
that SOC/ PT, the AE with the worst case intensity will be used in the corresponding intensity summaries. 


 
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16.1.2.2. 
Relationship to Trial Medication 
An investigator-assessed drug-related AE is defined as an AE with a relationship to trial medication ticked “yes” 
according to the investigator. TEAEs with a missing relationship to trial medication will be regarded as related to 
trial medication. If a subject reports the same AE more than once within that SOC/PT, and at least 1 episode is 
related, the AE will be considered related for the corresponding relationship summaries. 
All drug related AEs will be listed. 
16.1.3. 
TEAES LEADING TO DISCONTINUATION OF TRIAL MEDICATION 
TEAEs leading to permanent discontinuation of trial medication will be identified by using the “Action taken with 
trial drug due to AE?” equal to “Drug Withdrawn” from AEs eCRF pages. 
For TEAEs leading to permanent discontinuation of trial medication, number of subjects, percentages, number of 
events and patient-year incidence rate by SOC and PT will be prepared. 
The AEs causing treatment modification or Drug Withdrawn will be listed. 
16.1.4. 
SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as ”Serious” on the AEs page of the eCRF. A summary of 
serious TEAEs by SOC and PT will be prepared. 
Number of subjects, percentages, number of events and patient-year incidence rate of Serious TEAEs by SOC and 
PT will be prepared. 
Number of subjects, percentages, number of events and patient-year incidence rate of Non-Serious TEAEs with 
incidence in preferred terms strictly greater than 5% in at least one of treatment groups by SOC and PT will be 
prepared. 
The SAEs and Non-SAEs will be listed. 
16.1.5. 
RELATED SERIOUS ADVERSE EVENTS 
Number of subjects, percentages, number of events and patient-year incidence rate of Related Serious TEAEs by 
SOC and PT will be prepared. 
16.1.6. 
ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as ”Results in death” or with outcome ”Fatal” on the 
AEs page of the eCRF. Number of subjects, percentages, number of events and patient-year incidence rate of TEAEs 
leading to death by SOC and PT will be prepared. 
All AEs leading to death will be listed. 


 
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16.1.7. 
ADVERSE EVENTS OF SPECIAL INTEREST 
An overall summary of the number of subjects, percentages, number of events and patient-year incidence rate 
within each of the categories described in the sub-section below will be provided by SOC and PT. 
16.1.7.1. 
Reported by investigator 
AESI reported by investigators are those events recorded as “Adverse Event of Special Interest” equal to “Yes” on 
the AEs page of the eCRF. 
16.1.7.2. 
Infections and Serious Infections 
Infections are those events with a SOC equal to “Infections and infestations". 
Serious infections are: 
 
• 
AEs which are both infections and SAEs as reported on the AEs page of the eCRF. 
• 
AEs which are both infections and identified by medical advisor as requiring class IV (intravenous) 
antibiotics. 
Serious infections events of special interest are those events both identified as serious infections adverse events 
and recorded as “Adverse Event of Special Interest” equal to “Yes” on the Adverse Events page of the eCRF. 
Treatment Emergent Infections / Serious Infections will be tabulated separately. 
Infections / Serious Infections will be listed. 
16.1.7.3. 
Hypersensitivity reactions 
Hypersensitivity reactions are those events recorded as MedDRA code in the pre-defined Standardized MedDRA 
Queries (SMQ) “Hypersensitivity” (narrow). 
Hypersensitivity reactions adverse events of special interest are those events both identified as Hypersensitivity 
reactions adverse events and recorded as “Adverse Event of Special Interest” equal to “Yes” on the Adverse Events 
page of the eCRF. 
Treatment Emergent Hypersensitivity reactions will be tabulated separately. 
Hypersensitivity reactions will be listed. 
16.1.7.4. 
Drug Induced Liver Injury (DILI) 
Drug Induced Liver Injury (DILI) are those events identified by medical advisor on the subset of AEs for subjects 
presenting laboratory potential DILI findings (refer to section 16.3). 
DILI events of special interest are those events both identified as DILI adverse events and recorded as “Adverse 
Event of Special Interest” equal to “Yes” on the Adverse Events page of the eCRF. 


 
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Treatment Emergent DILI will be tabulated separately. 
Drug Induced Liver Injury (DILI) will be listed. 
16.1.7.5. 
Injection-site reactions 
Injection-site reactions are those events recorded with MedDRA high level terms (as listed in BI SMQs 
Administration site reaction subsearches 1,2,4 and 5, refer to APPENDIX 5): 
• 
Administration site reactions NEC  
• 
Application and instillation site reactions  
• 
Injection site reactions  
• 
Infusion site reactions  
The number and percentage of subjects with injection site reactions will be summarized by treatment for each 
injection site reaction (swelling, induration, heat, redness, pain, itching, bruising, other). 
Treatment Emergent Injection-site reactions as well as injections site reactions types will be tabulated separately. 
Treatment Emergent Injection-site reactions as well as injections site reactions types will be listed. 
16.1.7.6. 
Anaphylactic reactions 
Anaphylactic reactions are those events recorded as MedDRA code in the pre-defined Standardized MedDRA 
Queries (SMQ) = “Anaphylactic reactions” (narrow). 
Anaphylactic reactions adverse events of special interest are those events both identified as Anaphylactic reactions 
and recorded as “Adverse Event of Special Interest” equal to “Yes” on the Adverse Events page of the eCRF. 
Treatment Emergent Anaphylactic reactions will be tabulated separately. 
Anaphylactic reactions will be listed. 
16.1.8. 
AES OCCURRING AFTER THE LAST INJECTION FOR SUBJECTS DISCONTINUED DUE TO LACK OF 
EFFICACY. 
Subjects who discontinued treatment due to lack of efficacy will be identified from “End of treatment visit” eCRF 
page, where “Reason for End of Treatment” is “Lack of Efficacy”. 
Number of subjects, percentages, number of events and patient-year incidence rate of AEs occurring after the last 
injection and prior to the last injection + 10 weeks for subjects discontinued due to lack of efficacy by SOC and PT will 
be prepared. 
AEs occurring after the last injection and prior to the last injection + 10 weeks for subjects discontinued due to lack 
of efficacy will be listed. 


 
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16.1.9. 
NON-SERIOUS ADVERSE EVENTS LEADING TO DISCONTINUATION OF TREATMENT 
Non-serious adverse events leading to discontinuation of treatment (recorded as “Is this a serious adverse event?” 
equal to “No” and “Action taken with trial drug due to AE?” equal to “Drug Withdrawn” on the Adverse Events 
page of the eCRF). 
Number of subjects, percentages, number of events and patient-year incidence rate of treatment emergent non-
serious adverse events leading to discontinuation of treatment by SOC and PT tables will be prepared. 
Non-serious adverse events leading to discontinuation of treatment will be listed. 
16.1.10. FURTHER SELECTED ADVERSE EVENTS 
Further selected adverse events were not defined in the CTP and were identified to support a project-level integrated 
safety summary of additional important safety topics of the class. 
16.1.10.1. 
Hepatitis B Virus (HBV) reactivation 
Hepatitis B Virus (HBV) reactivation are those events recorded as MedDRA LLT search “reactivation of hepatitis B”. 
Number of subjects, percentages, number of events and patient-year incidence rate of Treatment Emergent 
Hepatitis B Virus (HBV) reactivation by SOC and PT tables will be prepared. 
Hepatitis B Virus (HBV) reactivation will be listed. 
16.1.10.2. 
Haematological disorders 
Haematological disorders are those events recorded as: 
• 
BIcMQ “Haematologic disorders” (narrow and broad)(refer to APPENDIX 5) 
Number of subjects, percentages, number of events and patient-year incidence rate of Treatment Emergent 
Haematological disorders by SOC and PT tables will be prepared 
Haematological disorders will be listed. 
16.1.10.3. 
Neurological events (Demyelinating disorders) 
Neurological events (Demyelinating disorders) are those events recorded as: 
• 
SMQ “Demyelination” (narrow)  
Number of subjects, percentages, number of events and patient-year incidence rate of Treatment Emergent 
Neurological events (Demyelinating disorders) by SOC and PT tables will be prepared. 
Neurological events (Demyelinating disorders) will be listed. 
 


 
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16.1.10.4. 
Systemic lupus erythematosus 
Systemic lupus erythematosus are those events recorded as: 
• 
SMQ “Systemic lupus erythematosus” (narrow) 
Number of subjects, percentages, number of events and patient-year incidence rate of Treatment Emergent 
Systemic lupus erythematosus by SOC and PT tables will be prepared. 
Systemic lupus erythematosus will be listed. 
16.1.10.5. 
Sarcoidosis 
Sarcoidosis are those events recorded as: 
• 
BIcMQ “Sarcoidosis” (narrow) 
Number of subjects, percentages, number of events and patient-year incidence rate of Treatment Emergent 
Sarcoidosis by SOC and PT tables will be prepared. 
Sarcoidosis will be listed. 
16.1.10.6. 
Stevens-Johnson syndrome 
Stevens-Johnson syndrome are those events recorded as: 
• 
PT “Stevens-Johnson syndrome” 
Number of subjects, percentages, number of events and patient-year incidence rate of Treatment Emergent 
Stevens-Johnson syndrome by SOC and PT tables will be prepared. 
Stevens-Johnson syndrome will be listed. 
16.1.10.7. 
Erythema multiforme 
Erythema multiforme are those events recorded as: 
• 
PT “Erythema multiforme” 
Number of subjects, percentages, number of events and patient-year incidence rate of Treatment Emergent 
Erythema multiforme by SOC and PT tables will be prepared. 
Erythema multiforme will be listed. 
16.1.10.8. 
Autoimmune hepatitis 
Autoimmune hepatitis are those events recorded as: 
• 
SMQ “Hepatitis, noninfectious” (narrow) 
Number of subjects, percentages, number of events and patient-year incidence rate of Treatment Emergent 
Autoimmune hepatitis by SOC and PT tables will be prepared. 


 
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Autoimmune hepatitis will be listed. 
16.1.10.9. 
Malignancies 
Malignancies are those events recorded in BIcMQ “Malignancies” (narrow and broad) (refer to APPENDIX 5). 
Number of subjects, percentages, number of events and patient-year incidence rate of Treatment Emergent 
Malignancies by SOC and PT tables will be prepared. 
Malignancies will be listed. 
16.1.10.10. 
Chronic heart failure 
Chronic heart failure are those events recorded in SMQ “Cardiac failure” (narrow). 
Number of subjects, percentages, number of events and patient-year incidence rate of Treatment Emergent 
Chronic heart failure by SOC and PT tables will be prepared. 
Chronic heart failure will be listed. 
16.2. 
DEATHS 
If any patients die during the trial as recorded on the completion or safety follow-up page of eCRF, the information 
will be summarized and listed.  
16.3. 
LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this trial for Serum Chemistry, Hematology 
and Urinalysis. A list of laboratory assessments to be included in the outputs is included in APPENDIX 4.  
Presentations will use SI and US Units.  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), or 
“> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
Qualitative laboratory urinalysis results measured by central laboratory will be classified to the categories 
“Positive” and “Negative” based on the central laboratory normal reference. 
The handling of retests, unscheduled and end of trial measurements is described in Section 6.3. However, 
laboratory values taken after the first dose of trial medication up to a period of 10 weeks after the last dose of the 
trial medication will be assigned to the treatment phase for evaluation. All available data will be listed. 
The following summaries will be provided for laboratory data: 
• 
Actual and change from baseline in trial 1297.2 by visit (for quantitative measurements) 


 
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• 
Shifts in Rheumatology Common Toxicity Criteria (RCTC) grading, from baseline in trial 1297.2 by 
visit (for gradable parameters, see APPENDIX 4) 
• 
Shifts from baseline category (Low/ Normal/ High) in trial 1297.2 by visit (for non-gradable 
parameters except urinalysis parameters and ADA)  
• 
Shift from baseline category (Negative/ Positive) in trial 1297.2 by visit (for urinalysis non-gradable 
parameters) 
• 
Box plots for ESR, CRP, hemoglobin, leukocytes (equivalent to white blood cells), platelets, AST, ALT, 
bilirubin, creatinine, cholesterol 
• 
Plots for time course of gradable safety parameters for subjects having at least one value with 
toxicity grade 3 or 4 (RCTC grading is described section 16.3.3) 
• 
Proportion and frequency of possible Hy’s law subjects 
• 
Proportion and frequency of possible Drug Induced Liver Injuries 
• 
The time course of ALT, AST and total bilirubin (TBL) for all possible Hy’s law subjects, all parameters 
shown on a logarithm to base 10 scale of the multiple of the upper limit of normal (ULN) (Y axis) 
versus days since treatment start (X axis). 
• 
Scatter plots for Evaluation of Potentially Drug-Induced Liver Injury: 
1. log ALT on the X axis and log TBL on the Y axis, both shown on a logarithm to base 10 scale of 
the multiple of the ULN 
2. log AST on the X axis and log TBL on the Y axis, both shown on a logarithm to base 10 scale of 
the multiple of the ULN. 
Baseline is described in Section 6.2. 
16.3.1. 
LABORATORY SPECIFIC DERIVATIONS 
• 
Log ALT = logarithm to base 10 scale of the multiple of the ULN of ALT 
• 
Log AST = logarithm to base 10 scale of the multiple of the ULN of AST 
• 
Log TBL = logarithm to base 10 scale of the multiple of the ULN of TBL. Note: Bilirubin value instead 
of TBL will be used. 
• 
Potential Hy’s law categories: 


 
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1. Category 1: ALT or AST >=3xULN and TBL >=2xULN within the same sample 
2. Category 2: TBL >=2xULN within 30 days after transaminase peak ( ALT or AST >=3 ULN ) 
• 
Potential Hy’s Law subjects are defined as subjects with laboratory data in at least one Potential 
Hy’s law categories at any time point of the trial. 
• 
Drug induced liver injury : 
1. Category 1 : AST and/or ALT ≥3 times ULN and TBL ≥2 times ULN within the same sample 
2. Category 2: AST and/or ALT ≥3 times the Baseline value and TBL ≥2 times the Baseline value 
within the same sample. 
3. Category 3 : marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN 
16.3.2. 
LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges and 
categorized as: 
• 
Low: Below the lower limit of the laboratory reference range.  
• 
Normal: Within the laboratory reference range (upper and lower limit included). 
• 
High: Above the upper limit of the laboratory reference range. 
16.3.3. 
RCTC GRADING FOR LABORATORY DATA 
Laboratory results will be classified according to the Rheumatology Common Toxicity Criteria v.2.0. 
Only programmable parts of definitions will be performed. 
The “Grade 0” will be introduced to indicate that a certain laboratory value can be seen as “normal” and does not 
fulfill the criteria of RCTC grading. For uncertain cases (for example when the values can be assigned to grade 0 
based on the normal range and grade 1 or 2 based on the toxicity criteria), a medical check will be performed, to 
determine the correct grade. 
16.4. 
ECG EVALUATIONS 
Results from ECGs will be summarized by visit to the categories as recorded in the eCRF page “12-Lead-ECG” 
(“normal”, “abnormal, not clinical significant” and “abnormal, clinical significant”). 


 
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ECG evaluations will also be listed. 
16.5. 
VITAL SIGNS 
The following Vital Signs measurements will be reported: 
• 
Sitting Systolic Blood Pressure (mmHg) 
• 
Sitting Diastolic Blood Pressure (mmHg) 
• 
Sitting Pulse Rate (bpm) 
• 
Sitting Respiratory Rate (breaths/min) 
• 
Temperature (⁰C) 
The weight will be presented along with vital signs. 
• 
Weight (kg) 
The handling of retests, unscheduled and end of trial measurements is described in Section 6.3. 
The summary of actual and change from baseline by visit will be provided for vital sign data. In case of multiple 
measurement timepoints at one visit the pre-injection data will be used for summary tables. 
Vital signs data will be listed. 
16.6. 
PHYSICAL EXAMINATION 
Proportion of evaluation categories (normal, abnormal) at baseline and post-baseline visits will be provided for 
physical examination data. 
The handling of retests, unscheduled and end of trial measurements is described in Section 6.3. 
Baseline is described in Section 6.2. 
Physical examination data will be listed. 


 
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16.7. 
OTHER SAFETY ASSESSMENTS 
16.7.1. 
IMMUNOGENICITY  
The following summaries will be provided for ADAs and nABs samples by visit (Week 12, Week 24 and Week 48) 
and overall: 
• 
Number and proportion of subjects with ADA/nAB sampling results by visit: 
o 
Negative 
o 
Positive 
o 
Total reportable (= sum of Negative and Positive)o 
o 
Not Reportable (=samples which should have been taken per protocol but no result is available 
(due to many reasons). Samples from patient that discontinued (drop-outs) or patients that have 
not reached a defined time-point yet, are not considered non-reportable but reduce the number 
of total samples available.) 
o 
Total (= sum of Total Reportable and Not Reportable) 
• 
Descriptive statistics of ADA titer will be provided by visit when available. 
The ADA and nABs results will be listed as well.  
The following summaries figures will be provided for Immunogenicity data: 
• 
Time course of ADA development (percent positive subjects) over time (by planned visit day) for all 
treatment groups  
• 
Box plot (with whiskers) of titer within ADA positive subjects over time (by planned visit day) (one 
graph) – the log2 scale will be used. 
• 
Box plot (with whiskers) of titer within ADA positive subjects at each ADA-timepoint (multiple 
graphs) – the log2 scale will be used. 
• 
Time course of nAB development (percent positive subjects) over time (by planned visit day) for all 
treatment groups 
• 
Time course of ADA titer for each patient with ADA-titer over time (by actual visit day) 
16.7.2. 
PREGNANCY TEST 
Pregnancy, described as a patient with at least one pregnancy result Plus, will be summarized.  


 
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Descriptive table will be presented by treatment group according to the initial and re-randomization in trial 1297.2 
on SAF. 
The pregnancy results will be listed as well. 
16.7.3. 
TUBERCULOSIS TEST 
Descriptive table will present Tuberculosis (TB) test results by treatment group on SAF. 
The TB test results will be listed as well. 
17. 
PHARMACOKINETIC DATA 
17.1. 
PHARMACOKINETIC ENDPOINTS 
The PK analysis will be based on a population based approach, which is not a part of this SAP. 
This SAP contains the description of the planned presentation of the measured plasma concentrations. 
17.2. 
GENERAL CONSIDERATION  
Missing data will not be replaced. 
For data presentation the following conventions will apply: 
Sampling visits performed outside the allowed time window will be reported and flagged in the table. The flagged 
sampling results will be excluded from the descriptive statistics and from the figures (with exception of the scatter 
plot of individual plasma concentrations per treatment group over time). 
Descriptive statistics of concentrations at specific visits will be calculated only when at least 2/3 of the individuals 
have concentrations measurements within the validated concentration range of the assay (that means between 
lower and upper limit of quantification as reported in the BA transfer). The overall sample size to decide whether 
the “2/3 rule” is fulfilled will be based on the total number of samples actually drawn. 
The individual values as well as descriptive statistics are reported with 3 significant digits. 
17.3. 
PLASMA CONCENTRATIONS PRESENTATION  
The PK concentration data will be based on PKFS set. 
Descriptive statistics will contain at least N, geometric mean (gMean), geometric coefficient of variation (gCV, given 
in %), arithmetic mean, SD, coefficient of variation (CV, given in %), minimum, median, and maximum of a 
parameter.  


 
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CV: The coefficient of variation (CV) will be calculated by the formula: 
CV  = (SD/mean)x100 
gMean, gCV: The geometric mean (gMean) and geometric coefficient of variation (gCV, given in %), will be 
calculated by the formulae: 
[
])
ln(x
exp
)
ln(x
 
exp
gMean
i
n
1
i
i
n
1
=




=
∑
=
 
[
] 1
))
Var(ln(x
 
exp
  
100
gCV(%)
i
−
⋅
=
 
where 
[
]
2
n
1
i
i
i
i
)
ln(x
)
ln(x
1
n
1
))
Var(ln(x
∑
=
−
−
=
 
The following summaries will be provided for plasma concentration data: 
• 
All measured plasma concentrations will be listed by 1297.2 treatment sequence and overall and planned 
time point and descriptive statistics per time point. 
• 
A spaghetti plot of individual and gMean plasma concentrations over time by 1297.2 treatment sequence 
and overall (gMeans shown per planned time points connected by a line)  
• 
A scatter plot of individual plasma concentrations after the preceding dose over time by 1297.2 treatment 
sequence and overall.  


 
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18. 
REFERENCES  
Ware JE Jr., Kosinski M, Bjorner JB, et al. 2008. SF-36v2® Health Survey: Administration guide for clinical trial 
investigators. Lincoln, RI: QualityMetric Incorporated. 
 
 
 


 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
OUTPUT CONVENTIONS 
OUTPUT FILE NAMING CONVENTIONS 
File names should only consist of lowercase letters, digits (0 to 9) and hyphens. A period should only be used to 
indicate a separator between the file name and the extension. No spaces, other special characters or punctuation 
marks are permitted.  
The program, program log and output file name should reflect the type of the statistical output. The output files 
will contain the output number in addition. If this is not possible, then the output name should be at least as 
descriptive as possible. A prefix can be used to distinguish between a Table, Listing and Figure document (‘t’ for 
table, ‘l’ for listing and ‘f’ for figure). If there is only 1 digit in the number of the table, listing or figure in the place 
where 2 digits are possible, a leading zero should be added in the file name to make sorting consistent with the 
sequence (eg t-14-3-01-1.RTF) 
As far as possible, output files should be in RTF format. 
The outputs will be provided in pdf format. 
PAPER SIZE, ORIENTATION AND MARGINS 
The size of paper will be Letter. 
The page orientation should preferably be landscape, but portrait is also permitted. 
Margins should provide at least 1 inch (2.54 centimeters) of white space all around the page, regardless of the 
paper size. 
The number of columns per page (linesize) should 134 for Letter. 
The number of rows per page (pagesize) should be 40 for Letter. 
FONTS 
The font type ‘Courier New’ should be used as a default for tables and listings, with a font size of 8. The font color 
should be black. No bolding, underlining italics or subscripting should be permitted. Try to avoid using super-
scripts, unless absolutely necessary. Single spacing should be used for all text. 
Figures should have a default font of “Times Roman”, “Helvetica”, or “Courier New”. 
This can be achieved by using the following options in SAS: 


 
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goptions 
gunit = pct 
cback = white 
colors = (black) 
hby = 2.4 
ftext = “TimesRoman” 
htext = 2.5; 
HEADER INFORMATION 
Headers should be defined as follows: 
• 
The header should be placed at the top of the page (same place on each page) regardless of the size or 
orientation of the table or listing 
• 
The customer name and protocol number should appear in row 1, left-aligned 
• 
The output identification number should appear in row 2, left-aligned 
• 
The output title should start in row 2 after output identification number separated by a double dot, left-
aligned 
• 
The output population should appear in row 2 after output title separated by a dash, left-aligned. The 
population should not be spelled out in full, e.g. FAS in preference to Full analysis set. 
• 
Row 3 should be a continuous row of underscores (‘_’) (the number of underscores should equal the linesize) 
• 
Row 4 should be a blank line 
• 
Mixed case should be used for titles 
• 
The output titles should be designed so that they are arranged consistently through all outputs. For example, 
content (eg Vital Signs) followed by metric (eg Change from Baseline) e.g. Vital Signs – Change from Baseline. 
• 
Titles should not contain quotation marks or footnote references 
• 
The column headings should be underlined with a row of underscores (‘_’) 
• 
Column headings spanning more than one column should be underlined and have underscores on either 
side of the title and should be centered 
• 
Column headings containing numbers should be centered 
• 
Column headings should be in sentence case 
• 
In general, the population count should appear in the column header in the form “(N=XXX)” 
• 
“Statistic” should be the column header over n, Mean, SE, n (%) etc. 
• 
As a rule, all columns should have column headings. 
TABLE AND LISTING OUTPUT CONVENTIONS 
General: 
• 
The first row in the body of the table or listing should be blank 
• 
The left hand column should start in column 1. No indenting or centering of the output should occur. 
• 
Rounding should be done with the SAS function ROUND, if no further specification. 


 
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Author: 
 
Version Number: 
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Version Date: 
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Effective Date: 01May2012 
 
Copyright © 2012 
. All rights reserved. 
The contents of this document are confidential and proprietary to 
. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
• 
Numbers in tables should be rounded, not truncated, if no further specification. 
• 
Alphanumeric output should be left aligned. 
• 
Numbers should be decimal point aligned. 
• 
Whole numbers should be right aligned. 
• 
Text values should be left aligned. 
• 
The first letter of a text entry should be capitalized 
• 
Listings of adverse events, concomitant medications, medical histories etc. should be sorted in chronological 
order, with earliest adverse event, medication or history coming first. 
• 
The trial drug should appear first in tables with treatments as columns 
• 
In general, only present totals (across treatment groups) at baseline/randomization, and do not present 
them post randomization. 
• 
If possible, include 100% frequencies in the table shell, so that it is clear what the denominator is for 
percentage calculations. 
• 
All listing outputs should be sorted (preferably by Treatment, Site Number and Subject Number). 
• 
Do not use superscripts and subscripts 
• 
The width of the entire output should match the linesize 
Univariate Statistics: 
• 
Statistics should be presented in the same order across tables (i.e., n, Mean, SD, Median, IQR, Minimum, 
Maximum or n, gMean, gCV, Mean, CV, SD, Median, Minimum, Maximum) 
• 
Table statistics should line up under the N part of the (N=XXX) in the table header. All decimal points should 
line up. If the minimum and maximum are output on one line as Minimum, Maximum then the comma 
should line up with the decimal point. 
• 
If the original data has N decimal places, then the summary statistics should have the following decimal 
places: 
o 
Minimum and maximum: N 
o 
Mean, gMean, median, gCV% and CV%: N + 1 
o 
SD, IQR: N + 2 
Frequencies and percentages (n and %): 
• 
Percent values should be reported inside parentheses, with one space between the count and the left 
parenthesis of the percentage. Parentheses should be justified to accept a maximum of 100.0 as a value and 
padded with blank space if the percent is less than 100.0. An example is given below: 
77 (100.0%) 
50 ( 64.9%) 
0 ( 0.0%) 
• 
Percentages will be reported to one decimal place, except percents <100.0% but >99.9% will be presented 
as ‘>99.9%’ (e.g., 99.99% is presented as >99.9%); and percents < 0.1% will be presented as ‘<0.1%’ (e.g., 
0.08% is presented as <0.1%). Rounding will be applied after the <0.1% and >99.9% rule.  
Eg ( <0.1%) 
( 6.8%) 
(>99.9%) 
• 
Percentages may be reported to 0 decimal places as appropriate (for example, where the denominator is 
relatively small). 


 
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Document: 
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Author: 
 
Version Number: 
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Version Date: 
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Copyright © 2012 
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. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
• 
Where counts are zero, percentages of 0.0% should appear in the output.  
Confidence Intervals: 
• 
As a rule confidence intervals are output to one place more than the raw data, and standard deviations and 
standard errors to two places more than the raw data 
• 
Confidence intervals should be justified so that parentheses displayed on consecutive lines of a table “line 
up”. 
• 
Boundary values of confidence intervals should be separated by a comma. 
• 
Boundary values should be padded as necessary to accept negative values and to allow alignment of the 
decimal place. 
• 
An example is given below: 
(-0.12, -0.10) 
( 9.54, 12.91) 
P-values: 
• 
P-values should be reported to three decimal places, except values <1.000 but >0.999 will be presented as 
‘>0.999’ (e.g., 0.9998 is presented as >0.999); and values <0.001 will be presented as ‘<0.001’ (e.g., 0.0009 
is presented as <0.001). Rounding will be applied after the <0.001 and >0.999 rule 
Ratios: 
• 
Ratios should be reported to one more decimal place than the original data.  
Spacing: 
• 
There must be a minimum of 1 blank space between columns (preferably 2) 
Denominators: 
• 
If a different count other than the population count is used for a denominator (within the table) to calculate 
percentages, there should be a row in the table that identifies that number “n”. 
• 
Alternatively, a footnote should be included in each table with percentages to indicate the denominator for 
percentages. 
Missing values 
• 
A “0” should be used to indicate a zero frequency. 
• 
A blank will be used to indicate missing data in an end-of-text table or subject listing. 
FIGURE OUTPUT CONVENTIONS 
• 
Figures will be provided in PDF files using the SAS Output Delivery System (ODS) as generated by SAS. 
• 
The image should be clear and of high quality when viewed in the Word document, and when printed. 
• 
In general, boxes around the figures should be used. 
FOOTNOTE INFORMATION 


 
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Author: 
 
Version Number: 
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Version Date: 
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Effective Date: 01May2012 
 
Copyright © 2012 
. All rights reserved. 
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. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
Footers should be defined as follows: 
• 
A continuous line of underscores (‘_’) will follow the body of the table or listing prior to any footnotes at the 
bottom of the page 
• 
Table footnotes should be defined using compute statements in the proc report, and should appear directly 
after the body of the table 
• 
The program path and name and version number (if applicable) should appear as footnote 1 at the bottom 
of the page 
• 
The date/time stamp should appear as footnote 2 at the bottom of the page 
• 
Footnotes should be left-aligned. 
• 
Footnotes should be in sentence case. 
• 
Only “typewriter” symbols are permitted – eg “*”, “$”, “#”, “@”, “&” and “+”. 
• 
The choice of footnote symbols should be consistent. E.g. if you have the footnote “# indicates last 
observation carried forward” for one table, the same symbol and footnote should indicate LOCF for all 
tables. 
• 
If text wraps across more than one line (for a note), the first letter for all lines of text after the first one will 
be indented to align beneath the first letter of the text in the first line. 
• 
The page identification in the format Page X of Y (where Y is the total number of pages for the output) should 
appear in the first footnote, right aligned 
Ordering of footnotes should be as follows: 
1.) Source data listing reference, if necessary 
2.) Abbreviations and definitions 
3.) Formulae 
4.) P-value significance footnote 
5.) Symbols 
6.) Specific notes 
• 
Common notes from table to table should appear in the same order. 
The symbols should appear in the same order as what they are defined in the table or listing, from left to right. 
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
SPELLING FORMAT 
English US.  
PRESENTATION OF TREATMENT GROUPS 
Treatment Groups will depend on treatment assignment in Trial 1297.2 (randomization/re-randomization) and will 


 
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Version Date: 
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be named as follows: 
• 
BI 695501 to BI 695501 
• 
US-licensed Humira® to US-licensed Humira® 
• 
US-licensed Humira® to BI 695501 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment Group 
For Tables and Graphs 
For Listings  
BI 695501 to BI 695501 
 
BI 695501 to BI 695501 
 
BI 695501 to BI 695501 
 
US-licensed Humira® to US-
Licensed Humira® 
Humira to Humira 
Humira to Humira 
US-licensed Humira® to BI 695501 
Humira to BI 695501 
Humira to BI 695501 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Day -14 
D-14 
Day 1 
D1 
Day 43 
D43 
… 
… 
Day 337 
D337 
In addition, the corresponding weeks will be added for each pre-specified visit in protocol flow chart to long name 
(Day 43, 85, 127, 169, 225, 281, 337). E.g.:  Day 43 (Week 6). 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the shell): 
• 
treatment group 
• 
center-subject ID 
• 
date including Study day (where applicable) 
 


 
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Version Date: 
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. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR DISEASE DURATION 
DATE 
ACTION 
Partial 
Impute date as earliest possible date (i.e. first day of month if day unknown 
or 1st January if day and month are unknown) 
ALGORITHM FOR BIRTH DATE 
DATE 
ACTION 
Partial 
Impute date as earliest possible date (i.e. first day of month if day unknown 
or 1st January if day and month are unknown) 
ALGORITHM FOR PRIOR / ACTIVE MEDICAL HISTORY, SURGERIES AND PROCEDURES 
Partial date to be imputed as: 
Start date 
Earliest possible date  
first day of month if day unknown 
or 1st January if day and month 
are unknown 
 
Stop date 
Latest possible date  
last day of month if day unknown 
or 31st December if day and 
month are unknown 
General rules: 
 
If stop date < trial med start date, assign as prior  
If stop date >= trial med start date and start date <= end of treatment, assign as concomitant 
If stop date >= trial med start date and start date > end of treatment, assign as post Treatment 
 
 


 
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Version Date: 
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. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
 
If Missing stop date: (Rules 2) 
If stop date is missing could never be assumed as prior  
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
If Missing Start date: (Rules 3) 
If stop date < trial med start date, assign as prior 
If stop date >= trial med start date, assign as active 
Cannot be assigned as ‘post treatment’ 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
General rules 
 
Partial 
General rules 
 
Missing 
Rules 2 
 
 
 
Partial 
Known 
General rules 
 
Partial 
General rules 
 
Missing 
Rules 2 
 
 
 
Missing 
Known 
Rules 3 
 
Partial 
Rules 3 
 
Missing 
Assign as concomitant 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known  
Partial  
Missing 
If start date < trial med start date or start date> trial med 
stop date +70 days, then not TEAE 
If start date >= trial med start date and start date <= trial 
med stop date +70 days, then TEAE 
 
 
 
Partial, 
but 
known 
components show that it 
cannot be on or after trial 
med start date 
Known  
Partial  
Missing 
Not TEAE 
 
 
 


 
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Document: 
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Author: 
 
Version Number: 
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Version Date: 
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Template No:  CS_TP_BS016 – Revision 3 
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Effective Date: 01May2012 
 
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. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
START DATE 
STOP DATE 
ACTION 
Partial, could be on or after 
trial med start date 
Known 
Impute start date as earliest possible date, (i.e. first day of 
month if day unknown or 1st January if day and month are 
unknown), except if only day is missing and month and year 
of start date are the same as for trial med start date or if day 
and month are missing and year of start date is the same as 
for trial med start date. In the later cases, the trial med start 
date will be used for the imputation. 
 
If start date <= stop date, then : 
If stop date < trial med start date, then not TEAE 
If start date > trial med end date +70 days, then not TEAE 
If stop date >= trial med start date and start date <= trial 
med end date +70 days, then TEAE 
If start date > stop date, then : 
Consider the start date as Missing and apply the algorithms 
for missing start date 
 
Partial 
Impute start date as above. 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month are 
unknown), if not resulting in a date later than the date of 
subject's death. In the later case the date of death will be 
used for imputation.  
 
If start date <= stop date, then : 
If stop date < trial med start date, then not TEAE 
If start date > trial med end date +70 days, then not TEAE 
If stop date >= trial med start date and start date <= trial 
med end date +70 days, then TEAE 
If start date > stop date, then : 
Consider the start and stop dates as Missing and apply the 
algorithms for missing start date 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < trial med start date, then not TEAE 
If stop date >= trial med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 


 
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Version Date: 
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reproduction is strictly prohibited. 
START DATE 
STOP DATE 
ACTION 
are unknown), then: 
If stop date < trial med start date, then not TEAE 
If stop date >= trial med start date, then TEAE 
 
Missing 
Assumed TEAE 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
Partial date to be imputed as: 
Start date 
Earliest possible date  
first day of month if day unknown or 
1st January if day and month are 
unknown 
 
Stop date 
Latest possible date  
last day of month if day unknown or 
31st December if day and month are 
unknown 
 
 
 
General rules: 
 
If stop date < trial med start date, assign as prior  
If stop date >= trial med start date and start date <= end of treatment, assign as concomitant  
If stop date >= trial med start date and start date > end of treatment, assign as post Treatment 
 
If Missing stop date: (Rules 2) 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
If Missing Start date: (Rules 3) 
If stop date < trial med start date, assign as prior 
If stop date >= trial med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
General rules 
 
Partial 
General rules 
 
Missing 
Rules 2 


 
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reproduction is strictly prohibited. 
START DATE 
STOP DATE 
ACTION 
 
 
 
Partial 
Known 
General rules 
 
Partial 
General rules 
 
Missing 
Rules 2 
 
 
 
Missing 
Known 
Rules 3 
 
Partial 
Rules 3 
 
Missing 
Assign as concomitant 
 
 


 
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APPENDIX 3. EMA SOC ORDER FOR PRESENTATION OF THE AE IN THE TABLES.  
Order System Organ Class                                                                    
0 Uncoded                   
1 Infections and infestations                                            
2 Neoplasms benign, malignant and unspecified (incl cysts and polyps)    
3 Blood and lymphatic system disorders                                   
4 Immune system disorders                                                
5 Endocrine disorders                                                    
6 Metabolism and nutrition disorders                                     
7 Psychiatric disorders                                                  
8 Nervous system disorders                                                
9 Eye disorders                                                          
10 Ear and labyrinth disorders                                            
11 Cardiac disorders                                                      
12 Vascular disorders                                                     
13 Respiratory, thoracic and mediastinal disorders                        
14 Gastrointestinal disorders                                             
15 Hepatobiliary disorders                                                
16 Skin and subcutaneous tissue disorders                                 
17 Musculoskeletal and connective tissue disorders                        
18 Renal and urinary disorders                                            
19 Pregnancy, puerperium and perinatal conditions                         
20 Reproductive system and breast disorders                               
21 Congenital, familial and genetic disorders                             
22 General disorders and administration site conditions                   
23 Investigations                                                         
24 Injury, poisoning and procedural complications                         
25 Surgical and medical procedures                                        
26 Social circumstances                                                   
 
 
 


 
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APPENDIX 4. LABORATORY ASSESSMENTS 
Laboratory parameter 
Gradable with RCTC 
US unit 
SI unit 
Serum chemistry 
 
 
 
Creatinine 
X 
mg/dL 
umol/L 
Alkaline phosphatase 
X 
U/L 
IU/L 
Aspartate aminotransferase (AST) 
X 
U/L 
U/L 
Alanine aminotransferase (ALT) 
X 
U/L 
U/L 
Gamma glutamyl transpeptidase 
(GGT) 
 
U/L 
U/L 
Total bilirubin 
X 
mg/dL 
umol/L 
Direct bilirubin 
X 
mg/dL 
umol/L 
Glucose 
X 
(Hypoglycemia) 
mg/dL 
mmol/L 
Total cholesterol 
 
mg/dL 
mmol/L 
Total protein 
 
g/dL 
g/L 
Albumin 
 
g/dL 
g/L 
Sodium  
X 
(Hyponatremia) 
mEq/L 
mmol/L 
Potassium  
X 
(Hypokalemia/Hyperkalemia) 
mEq/L 
mmol/L 
Chloride 
 
mEq/L 
mmol/L 
Calcium  
X 
Hypocalcemia/Hypercalcemia) 
mg/dL 
mmol/L 
Hematology 
 
 
 
Hemoglobin 
X 
g/dL 
g/L 
Hematocrit 
 
% 
V/V 
Platelets 
X 
10^3/uL 
10^9/L 
White blood cells 
X 
10^3/uL 
10^9/L 
Lymphocytes 
X 
10^3/uL 
10^9/L 
Neutrophils 
X 
10^3/uL 
10^9/L 
Urinalysis 
 
 
 
Protein 
 
g/dL 
g/L 
Glucose 
 
mg/dL 
mmol/L 
Blood 
 
N/A 
N/A 
 
 
 
 


 
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APPENDIX 5. BICMQS 
BIcMQ_19.0_Admini
stration_site_reactio
BIcMQ_19.0_Haema
tologic disorders
BIcMQ_19.0_Sarcoi
dosis