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
Phase: PHASE3
Conditions: Arthritis, Rheumatoid
Sponsor: Boehringer Ingelheim

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
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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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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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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
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Page 78 of 79
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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
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done for study 1297.3.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
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Title: 
 
 
 
 
                                                                                                                   
 
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c03635799
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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

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(Continued) Signatures (obtained electronically) 
 
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c03635799
2.0