Conditions: Crohn Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 147
Healthy volunteers: no

Brief summary:
Primary Objective:

The primary objective of this trial is to compare the clinical efficacy of BI 695501 with EU-approved Humira® in patients with active Crohn's disease (CD).

Secondary Objectives:

The secondary objectives of this trial are to compare the efficacy and safety of BI 695501 with EU-approved Humira® across the induction and maintenance phases.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: BI 695501 intervention 2: HUMIRA
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol
TITLE PAGE
Document Number:
c09542349-05
EudraCT No.:
EU Trial No:
2016-000612-14
BI Trial No.:
1297.4
BI Investigational 
Product(s):
BI 695501
Title:
BI 695501 versus Humira® in patients with active Crohn’s 
disease: a randomized, double-blind, multicenter, parallel group, 
exploratory trial comparing efficacy, endoscopic improvement, 
safety, and immunogenicity
Lay Title:
BI 695501 versus Humira in patients with active Crohn’s 
disease: a trial comparing efficacy, endoscopic improvement, 
safety, and immunogenicity
Clinical Phase:
III
Trial Clinical 
Monitor:
Tel.:
Coordinating 
Investigator:
Status:
Final Protocol (Revised Protocol (based on global amendment 
2))
Version and Date:
Version: 3.0
Date: 12 Dec 2017
Page 1 of 93
Proprietary confidential information.
2017 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:
30 May 2016
Trial number:
1297.4
Revision date:
12 Dec 2017
Title of trial:
BI 695501 versus Humira® in patients with active Crohn’s disease: a randomized, 
double-blind, multicenter, parallel-group, exploratory trial comparing efficacy,
endoscopic improvement, safety, and immunogenicity
Coordinating
Investigator:
Trial site(s):
Multinational, multicenter trial in approximately 125 clinical sites across 
approximately 15 countries in the US and the EU
Clinical phase:
III
Objective(s):
Primary Objective:
The primary objective of this trial is to compare the clinical efficacy of BI 695501 
with EU-approved Humira® in patients with active Crohn’s disease (CD).
Secondary Objectives:
The secondary objectives of this trial are to compare the efficacy and safety of
BI 695501 with EU-approved Humira across the induction and maintenance phases. 
Methodology:
This is an exploratory, randomized, 56-week, double-blind, parallel arm, multiple 
dose, active comparator trial of BI 695501 and EU-approved Humira, with a 48-
week treatment period and a 10-week follow-up period (starting after the last dose 
of trial medication at Week 46) in patients with moderately to severely active CD
and a primary endpoint assessment at Week 4.
The treatment phase of the trial will encompass 2 parts, the induction period, 
ranging from baseline to Week 4, and the maintenance period, from Week 4 to 
Week 48. 


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
30 May 2016
Trial number:
1297.4
Revision date:
12 Dec 2017
Patients who meet the inclusion and exclusion criteria will be randomly assigned in 
a blinded fashion to either BI 695501 or EU-approved Humira with a 1:1 allocation 
ratio in the first phase of this trial (induction). Each patient will receive a loading 
dose of 160 mg of BI 695501 or EU-approved Humira (Day 1), followed by 80 mg 
of BI 695501 or EU-approved Humira 2 weeks later (Day 15), thereafter 40 mg of 
BI 695501 or EU-approved Humira every second week.
Initial randomization will be stratified according to prior exposure to infliximab 
(yes/no) and to screening SES-CD (<16 or ≥16). No caps will be put on any of 
these strata.
At Week 4, clinical response will be assessed and only patients who are classified
as responders by achieving a decrease in CDAI ≥70 will continue on trial and enter 
the maintenance phase. The hematocrit value required to determine CDAI score at 
Week 4 will be assessed locally and confirmed via central laboratory assessment.
Patients who are originally randomized to EU-approved Humira will switch to
BI 695501 at Week 24.
In addition, every effort should be made for all patients who complete the total 
48-week treatment period or who discontinue the trial medication early during the 
maintenance phase, to have an End of Treatment Visit as soon as possible after 
completion/discontinuation and to return for a Safety Follow-up Visit 10 weeks 
after the last dose of trial medication.
No. of patients: 
total entered:
Approximately 130 evaluable patients will be randomized
each treatment:
Initially patients will be allocated to treatment in a 1:1 ratio to receive BI 695501 or 
EU-approved Humira
Diagnosis :
Moderately to severely active CD, for more than 4 months
Main criteria
for inclusion:
Adult patients, between 18 and 80 years of age, with moderately to severely active 
CD (CDAI 220-450), confirmed by endoscopy or radiologic evaluation for more
than 4 months. Evidence of mucosal ulceration has to be documented by recorded 
ileocolonoscopy during trial screening.
Test product:
BI 695501, solution for s.c. injection in single-use pre-filled syringe (PFS)
(40 mg/0.8 mL)
dose:
After randomization at Day 1: four PFS, corresponding to 160 mg of the test 
product
At Day 15: two PFS corresponding to 80 mg of the test product
At Day 29: one PFS corresponding to 40 mg of the test product and thereafter,
every 2 weeks, 40 mg of the test product via PFS
mode of 
administration:
subcutaneous injection


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
30 May 2016
Trial number:
1297.4
Revision date:
12 Dec 2017
Comparator product:
EU-approved Humira, solution for s.c. injection in single-use PFS (40 mg/0.8 mL 
or 40 mg/0.4 mL)
dose:
After randomization at Day1: four PFS, corresponding to 160 mg of the comparator 
product
At Day 15: two PFS corresponding to 80 mg of the comparator product
At Day 29: one PFS corresponding to 40 mg of the comparator product and 
thereafter, every 2 weeks, 40 mg of the comparator product via PFS
mode of 
administration:
subcutaneous injection
Duration of treatment:
The trial will consist of a screening period of up to a maximum of 28 days and a 
48-week treatment period. Each patient will be treated with either BI 695501 or 
EU-approved Humira for 4 weeks (induction) and responders will be treated in the 
maintenance phase for an additional 44 weeks. Patients who are originally 
randomized to EU-approved Humira will switch to BI 695501 at Week 24. A 
10-week safety follow-up period without treatment is implemented.
Endpoints
Primary endpoint:

Proportion of patients in each treatment group with a clinical response (CDAI 
decrease of ≥70 compared with baseline) at Week 4
Secondary endpoints:
Efficacy

Proportion of patients in each treatment group with a clinical response (CDAI 
decrease of ≥70 compared with baseline) at Week 24

Proportion of patients in each treatment group in clinical remission 
(CDAI <150) at Week 24


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
30 May 2016
Trial number:
1297.4
Revision date:
12 Dec 2017
Safety

Proportion of patients with AEs, SAEs, and AESIs

Proportion of patients with infections/serious infections (seriousness of 
infection defined as requirement of i.v. antibiotics for treatment and/or 
meeting seriousness criteria to be qualified as an SAE)

Proportion of patients who experience hypersensitivity reactions

Proportion of patients who experience DILI

Proportion of patients with injection-site reactions


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
30 May 2016
Trial number:
1297.4
Revision date:
12 Dec 2017
 
 
 
 
Safety criteria:
Safety assessments include continuous AE monitoring and local tolerability 
assessment, physical examination, vital signs (blood pressure, pulse rate, and body 
temperature), TB test (IGRA), 12-lead ECG, injection site reaction assessment, and 
laboratory tests.
Statistical methods:
This trial is intended to generate additional information for the comparison of 
BI 695501 with EU-approved Humira in patients with active Crohn’s disease.
The statistical model for the analysis of the primary endpoint will be a log-linked 
binomial regression model. The model will include the stratification factors (prior 
exposure to infliximab [yes/no] and baseline SES-CD [<16 or ≥16]) and treatment 
as fixed, categorical effects..
For the primary and secondary endpoints, point estimates (risk difference for binary 
endpoints) together with their 90% and 95% CIs will be calculated, but will be 
interpreted in a descriptive manner.
The safety population will consist of all patients who receive at least one (full or 
partial) dose of either of the trial treatments during any dosing period. The analysis 
of AEs will be based on the concept of treatment-emergent AEs. That means that all 
AEs with an onset 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 current treatment 
for evaluation. 


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
30 May 2016
Trial number:
1297.4
Revision date:
12 Dec 2017
Adverse events that start before first drug intake and deteriorate under treatment 
will also be considered as treatment-emergent. Other AEs will be assigned to the 
appropriate trial phases, i.e., screening or post-treatment. Safety endpoints and 
AESIs will be presented descriptively; in addition RR and risk difference together 
with 95% CIs will be presented.


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FLOW CHART A: SCREENING AND INDUCTION PERIOD
Trial Period
Screening
Induction
EoT2
SFU2
Visit
1
1.1
21
3
4
Week
-4 to -2
-1
0 
(Baseline)
2
4
-
14
Day
-28 to -14
-9
1
15
29
-
99
Permitted visit window (days)
-
±2
-1/+2
±1
±1
±3
+7
Informed consent
X
Assessment of eligibility 
X
X
X
Demographics
X
Medical and surgical history, 
incl. history of opportunistic 
infection
X
LABS/SAFETY ASSESSMENTS
Infection screen: hepatitis B 
(HBsAg), hepatitis C 
(antiHCV), and HIV test (where 
mandated by local authorities)
X
Chest X-ray3
X
TB testing (IGRA)4
X
X
CRP/fecal calprotectin
X
X
X
X
Pregnancy test5
X
X
X
X
Physical examination 
(incl. height and weight)6
X
X
X
X
Vital signs7
X
X
X
X
X
X
Laboratory tests (serum 
chemistry, hematology, 
urinalysis)8
X
X
X
X
X
Stool studies to evaluate for 
enteric pathogens
X
12-lead electrocardiogram
X
X
X
X
Previous and concomitant 
therapy
X
X
X
X
X
X
X
Adverse events9
X
X
X
X
X
X
X
EFFICACY ASSESSMENTS
CDAI evaluation10
X
X
X
X
Endoscopy (mucosal ulceration, 
SES-CD) 
X
TRIAL MEDICATION
Contact IRT12
X
X
X
X13
Randomization
X1
Trial medication 
administration14
X
X
X


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
; AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CDAI: 
Crohn’s disease activity index; SES-CD: Simple Endoscopic Score for Crohn’s Disease; CRP: C-reactive protein; EoT: End 
of Treatment; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HIV: human immunodeficiency virus; IGRA: 
interferon-gamma release assay; IRT: Interactive Response Technology; 
 
SFU: safety follow-up; TB: tuberculosis; ULN: upper limit of normal.
1
Patients will be randomized to each treatment in a 1:1 ratio (BI 695501: EU-approved Humira).
2
Patients who do not achieve a clinical response at Week 4 will be excluded from the maintenance period and will have 
their EoT visit at Week 4. Every effort should be made for all patients who discontinue to return for a Safety Follow-up 
Visit 10 weeks after their last dose of trial medication. 
3
A chest X-ray is to be taken at Screening. Alternatively, results from a chest X-ray taken within 12 weeks of Screening
can be used.
4
Patients must have a negative TB screening assessment, including an IGRA (e.g., QuantiFERON® TB Gold). In 
addition, a TB test will be performed at Week 24 before switch from EU-approved Humira to BI 695501, at EoT visit,
and may be performed at any time during the trial if the investigator considers it clinically necessary.
5
Females only: a serum pregnancy test at Screening and a urine pregnancy test on Day 1 (baseline); a urine pregnancy test 
will be performed at the applicable visits thereafter.
6
Height to be measured at Screening only; weight at every physical examination.
7
Includes measurement of blood pressure and pulse rate (both sitting after 5 minutes rest). The patient’s body temperature 
will also be recorded.
8
Findings of ALT or AST >1.5 times the ULN or hemoglobin <8.0 g/dL at Screening are criteria for exclusion.
9
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, new AEs will be captured until the end of the 10-week safety follow-up period.
10
CDAI determination: where applicable, exclude the day of bowel preparation for colonoscopy due to misleading impact 
on assessment of pain and liquid stool frequency. The CDAI evaluation at Visit 1.1 will be performed based on the 
CDAI diary provided to the patient at Visit 1 (a minimum of 7 days must be allowed between visits for completion of the 
diary). For subsequent CDAI evaluations, the diary will be provided to the patient at the previous planned visit. At 
Visit 4 (Week 4), the hematocrit value to determine CDAI score will be assessed locally and confirmed via central 
laboratory assessment. At visits where no physical examination is performed, weight must be measured for use in CDAI 
determination.
12
IRT will be contacted prior to every trial medication administration visit.
13
Contact IRT to confirm whether or not patient has achieved a clinical response (CDAI decrease ≥70). Patients who are 
non-responders will have an EoT visit and every effort should be made to ensure that they return for a Safety Follow-up 
visit 10 weeks after their last dose of trial medication. Patients achieving a clinical response at Week 4 will be eligible to 
continue in the trial (maintenance period) as shown in Flow Chart B.
14
Trial medication should be administered every 2 weeks (±1 day up to Visit 4). Patients will receive each dose of trial 
medication at the trial site until Week 22, trial medication will be administered by suitably qualified, designated 
unblinded trial personnel (Third party blinding). All assessments and procedures should be performed prior to trial 
medication administration, unless otherwise stated.


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FLOW CHART B: MAINTENANCE PERIOD
Visit
41
5
6
7
8
9
10
11
12
13
Week
4
6
8
10
12
14
16
18
20
22
Day
29
43
57
71
85
99
113
127
141
155
Permitted visit window (days)
±1
±3
±3
±3
±3
±3
±3
±3
±3
±3
LABS/SAFETY ASSESSMENTS
TB testing (IGRA)
CRP/fecal calprotectin
X
X
Pregnancy test3
X
X
Physical examination 
(incl. weight)
Vital signs4
X
X
X
X
X
Laboratory tests (serum 
chemistry, hematology, 
urinalysis)
X
X
X
12-lead electrocardiogram
X
X
Previous and concomitant therapy
X
X
X
X
X
Adverse events5
X
X
X
X
X
EFFICACY ASSESSMENTS
CDAI evaluation6
X
X
TRIAL MEDICATION
Contact IRT9
X
X
X
X
X
X
X
X
X
X
Switch from EU-approved 
Humira to BI 69550110
Trial medication administration11
X
X
X
X
X
X
X
X
X
X
 AE: adverse event; CDAI: Crohn’s disease activity index; SES-CD: Simple Endoscopic Score for 
Crohn’s Disease; CRP: C-reactive protein; EoT: End of Treatment; IGRA: interferon-gamma release assay; IRT: Interactive 
Response Technology; 
 SFU: safety follow-up; TB: tuberculosis; Wk: Week.
1
Visit 4 (Week 4) in this flow chart applies only for patients assessed as achieving a clinical response (CDAI decrease 
≥70). Non-responders will follow the visit schedule for Week 4, EoT, and SFU presented in Flow Chart A.
2
Patients who discontinue the trial early will, at discontinuation, have an EoT visit equivalent to the Week 48 
assessments, but without an endoscopy. A Safety Follow-up visit will be performed 10 weeks after the EoT visit. 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 56.
3
Females only: a serum pregnancy test at Screening and a urine pregnancy test on Day 1 (baseline); a urine pregnancy test 
will be performed at the applicable visits thereafter.
4
Includes measurement of blood pressure and pulse rate (all sitting after 5 minutes rest). The patient’s body temperature 
will also be recorded.
5
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, new AEs will be captured until the end of the 10-week safety follow-up period.


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FLOW CHART B: MAINTENANCE PERIOD (CONT’D)
Visit1
14
15
16
17
18
19, 20, 
21
22
23, 24, 
25
EoT2
SFU2
Week
24
26
28
30
32
34, 36, 
38
40
42, 44, 
46
48
56
Day
169
183
197
211
225
239, 253, 
267
281
295, 309, 
323
337
393
Permitted visit window 
(days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
LABS/SAFETY ASSESSMENTS
TB testing (IGRA)
X
X
CRP/fecal calprotectin
X
X
Pregnancy test3
X
X
X
X
X
Physical examination 
(incl. weight)
X
X
X
Vital signs4
X
X
X
X
X
X
Laboratory tests (serum 
chemistry, hematology, 
urinalysis)
X
X
X
X
X
12-lead electrocardiogram
X
X
X
Previous and concomitant 
therapy
X
X
X
X
X
X
Adverse events5
X
X
X
X
X
X
EFFICACY ASSESSMENTS
CDAI evaluation6
X
X
Endoscopy (mucosal 
ulceration, SES-CD) 
X7
TRIAL MEDICATION
Contact IRT9
X
X
X
X
X
X
X
X
Switch from EU-approved 
Humira to BI 69550110
X
Trial medication 
administration11
X
X
X
X
X
X
X
X
6
CDAI determination: exclude the day of bowel preparation for colonoscopy due to misleading impact on assessment of 
pain and liquid stool frequency. Patients will be required to complete a CDAI diary (provided at the previous visit) for 
the last 7 days prior to CDAI evaluation. At Visit 8 (Week 12), the hematocrit value from the central laboratory 
assessment at Visit 6 (Week 8) will be used to determine CDAI score. At visits where no physical examination is 
preformed, weight must be measured for use in CDAI determination.
7
Only applicable for patients who complete the 48-week treatment period
9
IRT will be contacted prior to every trial medication administration visit.
10
At Week 24, all patients on EU-approved Humira will switch to BI 695501.


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11
Trial medication should be administered every 2 weeks (±1 day up to Visit 4 and ±3 days from Visit 5 onwards). Patients 
will receive each dose of trial medication at the trial site until Week 22, trial medication will be administered by suitably 
qualified, designated unblinded trial personnel (Third party blinding); for remaining doses (Week 24 onwards), any 
suitably trained trial personnel may administer the trial medication since all patients will be receiving BI 695501. The 
last dose of BI 695501 will be at Week 46 for patients who remain on treatment throughout the trial. All assessments and 
procedures should be performed prior to trial medication administration, unless otherwise stated.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART A: SCREENING AND INDUCTION PERIOD .......................................8
FLOW CHART B: MAINTENANCE PERIOD.................................................................10
TABLE OF CONTENTS ......................................................................................................13
ABBREVIATIONS................................................................................................................17
1.
INTRODUCTION...............................................................................................19
MEDICAL BACKGROUND.............................................................................19
1.1
DRUG PROFILE................................................................................................20
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....22
RATIONALE FOR PERFORMING THE TRIAL.........................................22
2.1
TRIAL OBJECTIVES........................................................................................22
2.2
BENEFIT - RISK ASSESSMENT.....................................................................22
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
OVERALL TRIAL DESIGN AND PLAN .......................................................24
3.1
3.1.1
Administrative structure of the trial .................................................................25
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................26
SELECTION OF TRIAL POPULATION .......................................................26
3.3
3.3.1
Main diagnosis for trial entry ............................................................................26
3.3.2
Inclusion criteria .................................................................................................26
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Removal of patients from therapy or assessments...........................................29
Removal of individual patients .............................................................................29
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................31
3.3.4.2
4.
TREATMENTS...................................................................................................32
INVESTIGATIONAL TREATMENTS ...........................................................32
4.1
4.1.1
Identity of the Investigational Medicinal Products..........................................32
4.1.2
Selection of doses in the trial..............................................................................33
4.1.3
Method of assigning patients to treatment groups...........................................33
4.1.4
Drug assignment and administration of doses for each patient......................33
4.1.5
Blinding and procedures for unblinding...........................................................34
Blinding.................................................................................................................34
4.1.5.1
Unblinding and breaking the code ........................................................................35
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................35
4.1.7
Storage conditions...............................................................................................35
4.1.8
Drug accountability.............................................................................................36


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OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ................................................................................................36
4.2.1
Other treatments and emergency procedures..................................................36
4.2.2
Restrictions ..........................................................................................................37
Restrictions regarding concomitant treatment ......................................................37
4.2.2.1
Restrictions on diet and life style..........................................................................39
4.2.2.2
Restrictions regarding women of childbearing potential ......................................39
4.2.2.3
TREATMENT COMPLIANCE........................................................................39
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................40
TRIAL ENDPOINTS..........................................................................................40
5.1
5.1.1
Primary Endpoint(s)...........................................................................................40
5.1.2
Secondary Endpoint(s) .......................................................................................40
ASSESSMENT OF EFFICACY........................................................................41
5.2
5.2.1
CDAI ....................................................................................................................41
5.2.2
Endoscopy............................................................................................................43
SES-CD.................................................................................................................44
5.2.2.1
ASSESSMENT OF SAFETY.............................................................................45
5.3
5.3.1
Physical examination ..........................................................................................45
5.3.2
Vital Signs............................................................................................................45
5.3.3
Safety laboratory parameters ............................................................................45
5.3.4
Electrocardiogram ..............................................................................................46
5.3.5
Other safety parameters.....................................................................................47
Tuberculosis assessment .......................................................................................47
5.3.5.1
5.3.6
Assessment of adverse events.............................................................................47
Definitions of AEs ................................................................................................47
5.3.6.1
Adverse event collection and reporting ................................................................50
5.3.6.2
APPROPRIATENESS OF MEASUREMENTS..............................................55
5.7
6.
INVESTIGATIONAL PLAN.............................................................................56
VISIT SCHEDULE.............................................................................................56
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................56
6.2


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6.2.1
Screening and run-in period(s)..........................................................................56
6.2.2
Treatment period(s)............................................................................................57
6.2.3
Follow-up period and trial completion..............................................................60
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................62
STATISTICAL DESIGN - MODEL.................................................................62
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................62
7.2
PLANNED ANALYSES.....................................................................................62
7.3
7.3.1
Primary endpoint analyses.................................................................................62
7.3.2
Secondary endpoint analyses .............................................................................64
Secondary efficacy endpoints ...............................................................................64
7.3.2.1
Secondary safety endpoints...................................................................................64
7.3.2.2
7.3.4
Safety analyses.....................................................................................................64
INTERIM ANALYSES ......................................................................................66
7.4
7.4.1
Primary analysis..................................................................................................66
7.4.2
Final analysis .......................................................................................................66
HANDLING OF MISSING DATA ...................................................................66
7.5
7.5.1
Efficacy endpoints...............................................................................................66
7.5.2
Safety and other endpoints.................................................................................67
RANDOMIZATION...........................................................................................67
7.6
DETERMINATION OF SAMPLE SIZE .........................................................67
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................69
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT ...........................................................................................................69
DATA QUALITY ASSURANCE ......................................................................70
8.2
RECORDS...........................................................................................................70
8.3
8.3.1
Source documents ...............................................................................................70
8.3.2
Direct access to source data and documents.....................................................71
8.3.3
Storage period of records ...................................................................................71
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................72
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........72
8.5
8.5.1
Collection, storage, and future use of biological samples and corresponding 
data.......................................................................................................................72
TRIAL MILESTONES.......................................................................................72
8.6
9.
REFERENCES....................................................................................................74
PUBLISHED REFERENCES............................................................................74
9.1
UNPUBLISHED REFERENCES......................................................................76
9.2
10.
APPENDICES.....................................................................................................77


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MEDICATION BLINDING PROCEDURE FOR THIRD PARTY 
10.1
BLINDING ..........................................................................................................77
LIST OF LABORATORY TESTS....................................................................80
10.2
DETAILS ABOUT THE STATISTICAL CONSIDERATIONS...................82
10.3
CLINICAL EVALUATION OF LIVER INJURY ..........................................83
10.4
10.4.1
Introduction.........................................................................................................83
10.4.2
Procedures ...........................................................................................................83
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................85
GLOBAL AMENDMENT 1 ..............................................................................85
11.1
11.2
GLOBAL AMENDMENT 2 ..............................................................................90


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ABBREVIATIONS
5-ASA
5-aminosalicylic acid
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
anti-HBs
hepatitis B surface antibody
AST
aspartate aminotransferase
β-hCG
beta human chorionic gonadotropin
CD
Crohn’s disease
CDAI
Crohn’s disease activity index
CI
confidence interval
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
CRP
C-reactive protein
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
ECG
Electrocardiogram
eCRF
electronic Case Report Form
EoT
End of Treatment
EudraCT
European Clinical Trials Database
FAS
full analysis set
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HBsAg
Hepatitis B surface antigen
HCV
hepatitis C virus
HEV
hepatitis E virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
immunoglobulin
IGRA
interferon-gamma release assay
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
intrauterine device
i.v.
intravenous
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Drug Regulatory Activities


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MTX
methotrexate
nAb
neutralizing anti-drug antibody
NRI
non-responder imputation
PFS
pre-filled syringe
PK
pharmacokinetics
PPS
per-protocol set
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
RR
risk ratio
SAE
serious adverse event
SAF
safety analysis set
s.c.
subcutaneous
SES-CD
Simple Endoscopic Score for Crohn’s Disease
SmPC
summary of product characteristics
SOP
Standard Operating Procedure
sTNF
soluble tumor necrosis factor
SUSAR
Suspected Unexpected Serious Adverse Reaction
TB
tuberculosis
tmTNF
transmembrane tumor necrosis factor
TNF
tumor necrosis factor
TSAP
Trial Statistical Analysis Plan
ULN
upper limit of normal


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Crohn’s disease is a chronic relapsing, remitting inflammatory disease of the gastrointestinal 
tract characterized by abdominal pain, fever, and bloody or mucus-containing diarrhea
(R13-2231). The disease affects the gastrointestinal tract discontinuously from mouth to anus, 
but most commonly the ileum and colon (40%), followed by the small bowel only (30%), and 
the colon only (25%) (R13-2232, R13-2233). It occurs in a relatively young population, most 
commonly developing in people between the ages of 20 and 29, and there is no marked sex 
difference (R13-2231, R15-0886). Although the etiology of CD is still unknown, it is widely 
accepted that it is caused by a combination of environmental, immune, and bacterial factors 
in genetically susceptible individuals (R16-1919, R16-1918, R16-1917).
The incidence of CD in Europe and North America is approximately 161 to 319 cases per 
100,000 people (R13-2231) and is less common in Asia and Africa (R16-1920, R16-1923). 
Historically, CD has been more common in the developed world (R16-1922); however, rates 
have been increasing, particularly in the developing world, since the mid-1970s (R16-1923, 
R16-1922).
Because of myriad symptoms, clinical status is measured using clinical indexes. The most 
widely used in clinical trials is the CDAI (R97-2689). At the mucosal level, the extent of 
disease can be graded following ileocolonoscopy according to the SES-CD (R14-2969,
R15-6247).
Current treatment options
Medical treatment for CD has two main goals: achieving remission and, once that is 
accomplished, maintaining remission (prevention of flares). Treatment is, thus, aimed at 
controlling the ongoing inflammation in the intestine, the cause of IBD symptoms.
Medical therapy used in clinical practice includes 5-ASA and antibiotics (for colonic 
disease), corticosteroids, immunosuppressant drugs, and biologic agents. The latter is the 
newest class of drugs to be used in IBD and includes three of the available anti–TNF-alpha
agents (infliximab, adalimumab, certolizumab pegol), as well as vedolizumab (Entyvio®) and 
natalizumab (Tysabri®). Biologic therapies offer a distinct advantage in the treatment of IBD 
since their mechanism of action is targeted. Unlike corticosteroids, which tend to suppress the 
entire immune system and thereby produce major side effects, biologic agents act more 
selectively. However, immunosuppression-related side effects, such as an enhanced incidence 
of infections, are also described for biologic agents.
Nutritional support also has a role as primary therapy or as adjunct to other treatment. When 
medical treatment is unsuccessful or with certain complications, surgery is indicated. More 
than 70% of patients with ileal disease will require surgery at least once during the course of 
their disease. Due to therapeutic failures and serious side effects of present therapies, 
alternatives continue to be needed.


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DRUG PROFILE
1.2
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 humanized monoclonal IgG1 antibody specific to human 
TNF-alpha. It has human-derived heavy and light chain variable regions and human 
IgG1:kappa constant regions and is produced in a mammalian cell expression system 
(R15-5978, R15-4915).
For a more detailed description of the BI 695501 profile, please refer to the current IB, and 
for Humira, to the SmPC or US Prescribing Information.
Humira binds specifically to TNF-alpha (not to 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) (R15-5978).
In contrast to rheumatological indications, where binding and neutralization of soluble TNF 
is the prominent feature of adalimumab’s pharmacodynamic activity, clinical efficacy in IBD
requires additional effects attributable to interaction of adalimumab with tmTNF, 
subsequently leading to reverse signaling (T cell apoptosis, inhibition of cytokine release 
from macrophages) and induction of complement dependent cytotoxicity /
antibody-dependent cell-mediated cytotoxicity. The contribution of each of these effects is
still a matter of scientific debate.
Humira (adalimumab) has received regulatory approval for CD in the US, the EU, and many 
other countries (R15-5978, R15-4915).
Humira has a generally favorable clinical safety profile, and is not associated with AEs that 
would suggest a high risk to patients participating in this trial. In patients treated with 
Humira, most common adverse reactions (incidence >10%) include infections (e.g., upper 
respiratory, sinusitis), injection site reactions, headache, and rash, abdominal pain, 
musculoskeletal pain, nausea, and vomiting. Allergic reactions (e.g., allergic rash, 
anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been 
observed in approximately 1% of patients.
Cases of hepatitis B virus 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.
Tuberculosis 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.


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In the controlled portions of clinical trials of some TNF-blockers, including Humira, more 
cases of malignancies have been observed among TNF-blocker-treated adult patients 
compared to control-treated adult patients. Malignancies were rare side effects in clinical 
trials of Humira, with non-melanoma skin cancer and lymphoma most frequently reported; 
other malignancies included breast, colon, prostate, lung, and melanoma.
Humira was evaluated in over 1500 adult patients with moderately to severely active CD 
(CDAI ≥220 and ≤450) in trials that were performed prior to approval, with some patients 
followed for at least 3 years of open-label adalimumab. In the European Medicines Agency
SmPC, three randomized, double-blind, placebo-controlled studies were reported for Humira, 
which assessed the efficacy and safety of Humira for the treatment of CD (R15-4915).
The analytical similarity between BI 695501 and US-licensed Humira was assessed in a 
single-dose PK study in the cynomolgus monkey and a local tolerance study in rabbits. 
Additionally, the PK similarity between BI 695501, US-licensed Humira and EU-approved 
Humira was assessed in a Phase I clinical trial (1297.8) in healthy volunteers. The results of 
these studies are provided in the IB.
The PK similarity of BI 695501 to US-licensed Humira and EU-approved Humira was 
demonstrated in a healthy volunteer study (c03070713). Single s.c. doses of 40 mg 
BI 695501, US-licensed Humira and EU-approved Humira were generally well tolerated by 
healthy male subjects. There were no notable differences between the 3 treatment arms with 
respect to safety, tolerability, and immunogenicity. Including both Phase I studies, a total of 
175 subjects were exposed to BI 695501.
Overall, the AEs seen in healthy subjects for BI 695501 and both EU-approved Humira and
US-licensed Humira were in line with the known safety profile presented in the US 
prescribing information for Humira (R15-5978) and in the SmPC for EU-approved Humira 
(R15-4915).
A Phase III trial (1297.2) in patients with moderate to severe RA is ongoing. A total of 
645 patients with moderate to severe RA were included in this blinded trial and are being 
treated with either BI 695501 or US-licensed Humira, monitored by an IDMC.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
The CD trial 1297.4 is intended to generate comparative PK, efficacy, safety, and 
immunogenicity data in an indication where these modes of adalimumab’s action are 
important. The aim is to explore similarity of sTNF and tmTNF-related effects, initially 
established by the extrapolation approach which is based on comparative analytical testing 
and preclinical models, and has allowed extrapolation across indications.
The 1297.4 trial will also address switching between EU-approved Humira and BI 695501, as 
well as treatment of infliximab pre-treated patients after secondary resistance, both scenarios 
reflecting daily clinical practice in the future.
The primary outcome measure is defined as CDAI at Week 4,
 
 
 
TRIAL OBJECTIVES
2.2
The primary objective of this trial is to compare the clinical efficacy of BI 695501 with
EU-approved Humira in patients with active CD.
The secondary objectives of this trial are to compare the efficacy and safety of BI 695501 
with EU-approved Humira across the induction and maintenance phases, as covered by CDAI
and safety monitoring.
BENEFIT - RISK ASSESSMENT
2.3
Patients enrolled into this equivalence trial are expected to derive similar benefit and risk 
from the trial treatment across both arms. This is based on the similarity observed during 
preclinical, analytical, functional, and toxicological testing between the investigational 
medicinal product and the comparator.
Patient risk will be minimized in this trial by implementing conservative eligibility criteria.


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Adverse events, body temperature, vital signs, ECGs, and safety laboratory results as well as 
immunogenicity will be monitored at different time points during the trial and during the 
long-term safety follow-up period up to 10 weeks after the last administration of trial 
medication.
Although rare, a potential for DILI is under constant surveillance by sponsors and regulators. 
Therefore, this trial requires timely detection, evaluation, and follow-up of laboratory
alterations in selected liver laboratory parameters to ensure patients´ safety, see also 
Section 5.3.6.1.
All safety aspects will be regularly monitored by both the sponsor and a CRO during the 
Medical Quality Review Meetings.
To avoid a risk of reactivating TB and other infections, TB tests (IGRA), HBsAg
(qualitative), hepatitis B antibody (qualitative), hepatitis C antibodies (qualitative), HIV-1 
and HIV-2 antibody (qualitative) will be performed to exclude patients testing positive.
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, a possibly increased risk for the 
development of malignancies cannot be excluded.
The PK similarity of BI 695501 to US-licensed and EU-approved Humira was established in 
the Phase I trial 1297.8 (c03070713). Additionally, there were no notable differences with 
respect to safety, tolerability, and immunogenicity between BI 695501 and US-licensed and 
EU-approved Humira in this Phase I trial, and the dose of 40 mg BI 695501 was safe and 
well tolerated in healthy male volunteers. The observed blinded AE profile in the Phase III 
trial 1297.2 has thus far revealed no unexpected safety. The review of safety data by the 
IDMC to date has not suggested any clinically relevant differences in safety profile between 
Humira and BI 695501.
There have been no major clinically relevant findings with respect to clinical laboratory 
evaluation, vital signs, ECGs, or injection site reactions (including anaphylactic or allergic 
reactions). Based on extensive preclinical, analytical, functional, and toxicological testing 
carried out prior to initiation of this trial, and the Phase I data described above, BI 695501, as 
a proposed biosimilar to Humira, is expected to show a similar efficacy, safety, 
immunogenicity, and PK profile in patients with CD.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is an exploratory, randomized, 56-week, double-blind, parallel arm, multiple dose, 
active comparator trial of BI 695501 and EU-approved Humira, with a 48-week treatment 
period and a 10-week follow-up period (starting after last dose of trial medication at Week
46) in patients with moderately to severely active CD, and a primary endpoint assessment at 
Week 4.
The trial will consist of a Screening period of up to a maximum of 28 days, a 48-week 
treatment period consisting of an induction period from Baseline to Week 4 and a 
maintenance period from Week 5 to Week 48, and a 10-week safety follow-up period
(starting after last dose of trial medication at Week 46).
Approximately 130 evaluable patients with moderately to severely active CD will be 
randomized into the trial. Patients will be randomly assigned to receive either BI 695501 or 
EU-approved Humira according to the randomization ratio and the stratification factors as 
described in Section 7.6. Each patient will receive a loading dose of 160 mg of BI 695501 or 
EU-approved Humira (Day 1), followed by 80 mg of BI 695501 or EU-approved Humira
2 weeks later (Day 15), and thereafter 40 mg of BI 695501 or EU-approved Humira every 
2 weeks until the end of the treatment period (Week 46; with End of Treatment [EoT] 
evaluations at Week 48). Trial medication will be administered by s.c. injection.
At Week 4, patients will be assessed and those who are classified as responders (CDAI 
decrease of ≥70 compared to baseline) will continue on trial and enter the maintenance phase. 
Patients who are originally randomized to EU-approved Humira will switch to BI 695501 at 
Week 24.
Patients will undergo up to 27 visits (including 13 trial medication administration only visits) 
over the duration of the trial (56 weeks). The trial procedures to be undertaken at each visit 
are shown in Flow Chart A and Flow Chart B.
The primary endpoint of the trial is the proportion of patients in each treatment group with a 
clinical response (CDAI decrease of ≥70 compared to baseline) at Week 4. The primary 
analysis will take place when the last patient has completed the Week 4 assessments. For 
more details, please refer to Section 7.4.1.
Patients who discontinue the trial will, at discontinuation, have an EoT visit (see Flow 
Chart A and Flow Chart B). Every effort should be made for all patients who complete the 
total 48-week treatment period or who discontinue the trial medication early, to return for a 
Safety Follow-up Visit 10 weeks after their last dose of trial medication.
Patients may return for unscheduled visits should their medical condition warrant urgent 
attention at the discretion of the investigator.
An overview of the trial design is shown in Figure 3.1: 1.


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Figure 3.1: 1 Overview of trial design
wks: weeks.
Note: In the figure, Humira represents EU-approved Humira.
a
Screening period of 28 days to include 2 visits (Visit 1 during the period Day -28 to Day -14 and Visit 1.1 on 
Day -9 ± 2 days).
b
At Week 24, patients initially randomized to EU-approved Humira will switch to receive BI 695501 for the 
remainder of the treatment period.
c
Induction phase will comprise the following doses of trial medication: a loading dose of 160 mg on Day 1 and a 
second dose of 80 mg at Week 2 (Day 15). Evaluation of clinical response will be performed at the Week 4 visit 
and only responders will continue in the trial.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim. Boehringer Ingelheim has appointed a Trial 
Clinical Monitor, responsible for the planning, conduct, and reporting of the trial outsourced 
to a CRO in accordance with the applicable regulations and Boehringer Ingelheim/CRO 
SOPs.
The CRO will perform Project Management, Clinical Field Monitoring, Medical Monitoring,
Data Management, Statistical Evaluation, and Medical Writing according to CRO SOPs. A 
list of responsible persons and relevant local information can be found in the trial reference 
manual 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 
Week
0
Week
56
Week
24b
Week
46
Week
4
Screening
Inductionc
Maintenance phase
Safety follow-up
(10 wks)
28 daysa
4 wks
20 wks
24 wks
RANDOMIZATION (Day 1)
Humira
BI 695501
Humira
BI 
695501
BI 695501
Evaluate
response
Week
48
BI 695501


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(Principal) Investigators and other important participants, including their curricula vitae, will 
be filed in the electronic trial master file at the CRO.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in the IRT Manual and Central Laboratory Manual, available in the ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
The current trial is being performed to compare the clinical efficacy of BI 695501 with 
EU-approved Humira in patients with moderately to severely active CD. Additionally, the 
safety of BI 695501 will be assessed during long-term treatment and after switching from 
EU-approved Humira.
This is an exploratory, randomized, 56-week, double-blind, parallel arm, multiple dose, 
active comparator trial of BI 695501 and EU-approved Humira, with a 48-week treatment 
period and a 10-week follow-up period (starting from Week 46), in patients with moderately
to severely active CD.
Patients will be randomized according to a 1:1 ratio to either BI 695501 or EU-approved 
Humira in a blinded fashion. At Week 4, patients will be assessed and those who are 
classified as responders, by achieving a decrease in CDAI ≥70, will continue the trial and
enter the maintenance phase.
SELECTION OF TRIAL POPULATION
3.3
In view of the TNF-blocking mechanism of adalimumab, care has been taken to exclude 
patients likely to be at greater risk of severe infection, severe immunosuppression or severe 
heart failure (see Section 3.3.3).
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.
3.3.1
Main diagnosis for trial entry
Patients must have moderately to severely active CD (CDAI 220-450), confirmed by 
endoscopy or radiologic evaluation for more than 4 months, with evidence of mucosal 
ulceration documented by recorded ileocolonoscopy during trial screening.
Please refer to Section 8.3.1 (Source documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Males and females aged ≥18 and ≤80 years at Screening who have a diagnosis of 
moderate to severely active CD, confirmed by endoscopy or radiologic evaluation, for 


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more than 4 months with evidence of mucosal ulceration. Patients must have all of the 
following:
a.
CDAI score of ≥220 and ≤450
b. A diagnosis of CD confirmed by ileocolonoscopy during Screening
c.
Presence of mucosal ulcers in at least one segment of the ileum or colon and a 
SES-CD score ≥7 (for patients with isolated ileal disease SES-CD score ≥4), as 
assessed by ileocolonoscopy and confirmed by central independent reviewer(s) 
before randomization
2. Anti-TNF naïve patients or patients previously treated with infliximab who had initially 
responded and who meet one of the following criteria:
a.
Responded and developed secondary resistance due confirmed anti-infliximab 
ADA formation, which caused infliximab depletion
b. Responded and became intolerant
3. Willing to undergo up to 3 endoscopies
4. For participants of reproductive potential (males and females1), a reliable means of 
contraception has to be used throughout trial participation. Acceptable methods of birth 
control include, for example, birth control pills, IUDs, 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 childbearing potential) must also agree to use an 
acceptable method of contraception for 6 months following completion or discontinuation 
from the trial medication.
5. Signed and dated written informed consent in accordance with GCP and local legislation 
prior to admission to the trial
3.3.3
Exclusion criteria
1. Patients with ulcerative colitis or indeterminate colitis
2. Patients with symptomatic known obstructive strictures
3. Surgical bowel resection performed within 6 months prior to Screening or planned
resection at any time while enrolled in the trial
4. Patients with an ostomy or ileoanal pouch
5. Patients with short bowel syndrome
                                                
1 Women of childbearing potential are defined as: 
-
having experienced menarche,
-
not postmenopausal (12 months with no menses without an alternative medical cause), and
-
not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy).


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6. Patients currently receiving total parenteral nutrition
7. Patients who have received any investigational chemical agent in the past 30 days or 
5 half-lives prior to Screening (whichever is longer)
8. Patients who have received any biological treatment (other than TNF inhibitors) or 
investigational biological agent with the exception of infliximab within 6 months prior to 
Screening
9. Patients who have previously used infliximab and have never clinically responded
10. Patients who have previously received treatment with adalimumab, or who have 
participated in an adalimumab or adalimumab biosimilar clinical trial
11. Patients who have received systemic antibiotic, antiviral, or antifungal treatment(s) within 
3 weeks prior to Screening for any non-Crohn’s related infections
12. Patients taking combined budesonide and prednisone (or equivalent) at 4 weeks prior to 
randomization
13. Patients who have undergone therapeutic enemas within 2 weeks prior to Screening
14. Patients who have received cyclosporine (i.v. or oral), tacrolimus, sirolimus (rapamycin), 
thalidomide, or mycophenolate mofetil within 8 weeks prior to Screening
15. Patients who have received live vaccines within 3 months prior to Screening
16. Patients with a history of clinically significant drug or alcohol abuse within 1 year prior to 
Screening that, in the investigator’s opinion, makes them an unreliable trial subject or 
unlikely to complete the trial
17. History of severe allergy or hypersensitivity, including allergy to the trial medication, its 
excipients or device materials (e.g., natural rubber or latex)
18. Patients with a poorly controlled medical condition such as: uncontrolled diabetes with 
documented history of recurrent infections, unstable ischemic heart disease, congestive 
heart failure, recent cerebrovascular accidents, or any other condition which, in the 
opinion of the investigator or the sponsor, would put the patient at risk by participation in 
the trial
19. Have a stool culture or other examination positive for an enteric pathogen, including
Clostridium difficile toxin, in the last 4 months unless a repeat examination is negative 
and there are no signs of ongoing infection with that pathogen
20. Patients with a known history of lymphoproliferative disease, including lymphoma, or 
signs and symptoms suggestive of possible lymphoproliferative disease, such as 
lymphadenopathy and/or splenomegaly
21. Patients with any known malignancy or a history of malignancy (with the exception of 
basal cell carcinoma, squamous cell carcinoma in situ, or cervical carcinoma in situ that 
has been treated with no evidence of recurrence, within 5 years prior to Screening)
22. History or current evidence of listeria, HIV, an immunodeficiency syndrome, central 
nervous system demyelinating disease, or TB


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23. Positive serology for hepatitis B or hepatitis C, or a positive TB test (IGRA e.g.,
QuantiFERON® TB Gold) at Screening
24. Laboratory or other analyses at Screening (Visit 1) that show any of the following 
clinically relevant results, as assessed by the investigator:
a.
ECG with any clinically significant abnormalities
b. AST or ALT >1.5 times upper limit of the reference range
c.
Hemoglobin <8.0 g/dL
d. Platelets <100,000/μL
e.
Leukocyte count <4000/μL
f.
Total bilirubin ≥3 mg/dL
g. Creatinine clearance <60 mL/min
25. Patients who must or wish to continue the intake of restricted medications (see 
Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the 
trial
26. Previous enrolment and treatment in this trial
27. Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s), or receiving other 
investigational treatment(s)
28. Women who are pregnant at Screening (Visit 1), nursing, or who plan to become pregnant 
while in the trial and for 6 months after the last dose of trial medication
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An excessive withdrawal rate from the trial can have a severe negative impact on the 
scientific value of the trial. Every effort should be made to keep patients in the trial as 
scheduled. This includes careful patient selection and appropriate explanation of the trial 
requirements and procedures prior to enrolment as well as an explanation of the 
consequences of premature withdrawal.
Patients who do not meet all of the inclusion criteria or who meet one or more of the 
exclusion criteria will not be randomized, will be considered screen failures. The primary 
reason for the screen failure will be recorded on the eCRF. Patients may be rescreened if the 
investigator considers that the reason for screen failure may be resolved after a suitable 
period.
Patients have the right to withdraw from this trial at any time for any reason.


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Two situations can occur in this trial and need to be documented accordingly:
a)
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.
b)
Based on assessment by the investigator, an individual patient is to be discontinued 
from treatment with the investigational compound if:

Lack of efficacy: absence of a clinical response at Week 4, defined as a decrease in CDAI 
of ≥70.

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication.

Development of a toxicity or AE which warrants treatment discontinuation including, but 
not limited to, SAEs or SUSARs.

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, AEs, other diseases, or pregnancy).

The patient has an AE that is categorized as a serious infection (infections requiring i.v.
antibiotics or meeting the regulatory definition of an SAE [including, but not limited to 
systemic fungal infections, HIV, hepatitis B, hepatitis C]).

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to stick to the trial requirements in the future.
If a patient permanently discontinues from trial medication for any reason, every effort 
should be made for the patient to attend the EoT Visit as soon after trial discontinuation as 
possible. For patients who discontinue the trial medication early (and do not withdraw 
consent), every effort should be made to follow the patients for efficacy assessments Week 
48, wherever possible. In addition, 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.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow-up as outlined in Flow Chart A or Flow Chart B, as appropriate,
and Section 6.2.3.
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.


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Discontinuation of the trial by the sponsor
3.3.4.2
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).


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4.
TREATMENTS
INVESTIGATIONAL TREATMENTS
4.1
The trial medication will be provided by Boehringer Ingelheim or a designated CRO.
4.1.1
Identity of the Investigational Medicinal Products
BI 695501 and EU-approved Humira will be used in this trial. Details of the trial medication 
are provided in Table 4.1.1: 1 and Table 4.1.1: 2.
Table 4.1.1: 1
Test product
Substance:
BI 695501
Pharmaceutical formulation:
Solution for injection in PFS
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
40 mg / 0.8 mL
Posology
160 mg on Day 1 (after randomization);
80 mg on Day 15 (Week 2);
40 mg every 2 weeks from Week 4 to Week 46 inclusive
(and from Week 24 to Week 46 inclusive for patients 
switching from EU-approved Humira)
Route of administration:
subcutaneous injection
Table 4.1.1: 2
Reference product
Substance:
EU-approved Humira (adalimumab)
Pharmaceutical formulation:
Solution for injection in PFS
Source:
Unit strength:
40 mg / 0.8 mL or 40 mg / 0.4 mL
Posology
160 mg on Day 1 (after randomization);
80 mg on Day 15 (Week 2);
40 mg every 2 weeks from Week 4 to Week 22 inclusive
Route of administration:
subcutaneous injection
BI 695501 will be provided in sterile, preservative-free, non-pyrogenic, single-use PFS
containing 40 mg of BI 695501 per 0.8 mL. On Day 1, four PFS will be used (total of 
160 mg); on Day 15 (Week 2), two PFS will be used (total of 80 mg); and thereafter (Week 4, 
then every 2 weeks until Week 46 if patient is eligible to enter the maintenance phase; also 


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from Week 24 to Week 46 for patients who switch from EU-approved Humira), one PFS will 
be used per injection.
EU-approved Humira will be provided in sterile, preservative-free, non-pyrogenic, single-use 
PFS containing 40 mg of adalimumab per 0.8 mL or 40 mg of adalimumab per 0.4 mL (old 
and new formulations, respectively, approved to be comparable). On Day 1, four PFS will be 
used (total of 160 mg); on Day 15 (Week 2), two PFS will be used (total of 80 mg); and 
thereafter (Week 4, then every 2 weeks until Week 22 if patient is eligible to enter the 
maintenance phase), one PFS will be used per injection.
Any unused product or waste material will be disposed of in accordance with local 
requirements.
4.1.2
Selection of doses in the trial
In the US and EU, Humira has received health authority approval for the treatment of CD, 
RA, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and juvenile idiopathic 
arthritis. The doses of BI 695501 and EU-approved Humira selected for this trial follow the 
approved posology of Humira for the treatment of CD (a loading dose of 160 mg, followed 
2 weeks later by a dose of 80 mg, then 2 weeks later and subsequently every 2 weeks by 
40 mg, all by s.c. injection).
4.1.3
Method of assigning patients to treatment groups
Once patients have completed screening, have met all of the inclusion criteria and not met 
any of the exclusion criteria, randomization will occur on Day 1 through a standard 
randomization visit call, using the IRT system. Patients will be randomized to each treatment 
in a 1:1 ratio (BI 695501: EU-approved Humira) according to the stratification factors 
defined in Section 7.6.
Each PFS of trial medication will be labeled with the trial code and a unique medication 
identification number. The IRT system will be used for the randomization, allocation, and 
supply of trial medication throughout the trial. The IRT will assign each patient unique 
medication numbers for each drug administration (each syringe will have a unique 
medication number). Details of the IRT system will be provided in the ISF.
4.1.4
Drug assignment and administration of doses for each patient
Each patient will receive 160 mg (loading dose) of BI 695501 or EU-approved Humira at the 
Baseline Visit (Day 1) followed by 80 mg of BI 695501 or EU-approved Humira 2 weeks 
later (Day 15/Week 2), and then 40 mg of BI 695501 or EU-approved Humira at Week 4 
(primary endpoint).
At Week 4 (Day 29), patients achieving a clinical response (defined as a decrease in CDAI 
≥70) will continue receiving their randomized treatment (40 mg BI 695501 or EU-approved 
Humira every 2 weeks) in a blinded fashion. The hematocrit value required to determine 
CDAI score at Week 4 will be assessed locally and confirmed via central laboratory 


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assessment. At Week 24, patients originally randomized to EU-approved Humira will switch 
to receive 40 mg BI 695501 every 2 weeks. All patients will then continue to receive BI 
695501 at the same dose until Week 46.
Patients not achieving a clinical response at Week 4 will not receive any further treatment
with trial medication, but will be followed up for safety after 10 weeks (Safety Follow-up 
Visit).
Prefilled syringes will be used for the administration (see Section 4.1.1) and all patients will 
receive their injections at the trial site throughout the trial until Week 22, and 
BI 695501/EU-approved Humira will be administered by a dedicated, unblinded member of 
trial personnel (third party blinding). From Week 24 onwards, when all patients will be 
receiving BI 695501when all patients will be receiving BI 695501, any suitably trained trial 
personnel may administer the medication to the patient. However, patients and other trial 
personnel must remain blinded with respect to the initial assignment to EU-approved Humira 
or BI 695501.
After the first injection in the induction period (Visit 2) and the injection at Visit 14 (when 
patients originally randomized to EU-approved Humira will switch to receive BI 695501), 
patients will remain at the clinical site for at least 1 hour for observation of any AEs.
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, in accordance with the 
visit schedule presented in Flow Chart A and Flow Chart B. 
In the event of an anaphylactic or other serious allergic reaction, the administration of trial 
medication will be discontinued immediately and appropriate therapy instituted. Every effort 
should be made to ensure that patients who discontinue trial medication are followed up as 
described in Section 3.3.4.1.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
This is a double-blind trial, therefore patients, investigators, and everyone involved in trial 
conduct (except the trial personnel administering the trial medication – third party blinding) 
will remain blinded with regard to the randomized treatment assignments until after database 
lock. The unblinded trial personnel receiving, handling, and administering the trial 
medication will not be involved in any other trial assessments or procedures.
Details of blinding procedures are described in Appendix 10.1, Medication Blinding 
Procedures.
The randomization code will be kept secret by Clinical Trial Support up to database lock.
The secondary packaging (boxes containing PFS) will be identical for both BI 695501 and 
EU-approved Humira, allowing the blinding of the site pharmacy during the first 22 weeks of 


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treatment. Thereafter, all patients will receive BI 695501 and the drug supplies will not 
require blinding via secondary packaging.
The data will be unblinded at the time point of the primary analysis (see Section 7.4.1), only 
for individuals involved in the primary analysis and reporting.
Access to the randomization code will be controlled and documented. All persons directly 
involved in the conduct of the trial will have no access to the treatment allocation prior to 
final database lock.
Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the investigator / Pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. If unblinding is required in the 
interest of the safety of a patient, and time allows, the investigator will discuss the matter 
with the Medical Advisor before unblinding whenever possible. If the code is broken for a 
patient (via the IRT) the sponsor must be informed immediately. The reason for unblinding 
must be documented in the patient’s source documents and the appropriate eCRF along with 
the date and the initials of the person who broke the code.
The process for breaking the blind will be handled through the IRT. Instructions for this will 
be described in the IRT user manual that will be provided to each site.
Due to the requirements to report SUSARs, it may be necessary for a representative from the 
Boehringer Ingelheim Pharmacovigilance group to access the randomization code for 
individual patients during trial conduct. The access to the code will only be given to 
authorized Pharmacovigilance representatives and will not be shared further.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by Boehringer Ingelheim or a designated CRO. 
They will be packaged and labelled in accordance with the principles of GMP. Re-supply to 
the sites will be managed via an IRT system, which will also monitor expiry dates of supplies 
available at the sites.
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 with limited access under appropriate 
storage conditions and handled according to GMP 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 
temperature log will be kept at the trial site, and will be completed (with a minimum and 
maximum reading) on each working day. 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.


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If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
Drug supplies will be provided by the sponsor.
Pharmacy personnel 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 IRB/IECs

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

Availability of the proof of a medical license for the Principal Investigator

Availability of Form 1572 (for sites in the US)
The pharmacist or other designated person must maintain records of the product’s delivery to 
the trial site, the inventory at the site, the administration to each patient, and the return to the 
sponsor or warehouse/drug distribution center or alternative disposal of unused products. If 
applicable, the sponsor or warehouse/drug distribution center will maintain records of the 
disposal. Unused trial medication will be destroyed in accordance with local requirements.
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 
administered 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 appointed CRO, the 
designated person must verify that no remaining supplies are in the possession of the 
investigator.
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Patients will continue to take their usual prescribed concomitant medications, as allowed by 
this CTP, from their usual source.
There are no specific rescue drugs foreseen for the treatment of AEs. There are no special 
emergency procedures to be followed.
In case of AEs requiring treatment, the investigator can authorize an appropriate therapy. In 
such cases, patients will be treated as necessary and, if required, kept under supervision at the 


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trial site or transferred to a hospital until all medical evaluation results have returned to an 
acceptable level.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the trial or must refer them for appropriate ongoing care according to local 
guidelines and daily practice, respectively.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Restrictions on prior and concomitant medications during the course of the trial are described 
in Table 4.2.2.1: 1.
Patients must be instructed not to take any new medications or to change the dose regimen of 
any existing medication (including over-the-counter products, herbal medications, and 
complementary therapies) without first consulting the investigator. All changes must be noted 
in the concomitant medication section of the eCRF.
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 adhere to 
the restrictions listed in Table 4.2.2.1: 1.
All concomitant medications will be recorded in the appropriate sections of the eCRF, 
including dose and day of administration.


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Table 4.2.2.1: 1
Prior and concomitant treatments
Treatment
Restriction
Crohn’s-related concomitant 
treatments
No escalations are permitted during the trial.
No reductions are permitted with the exception of corticosteroids.
5-ASA, mesalamine, 
sulfasalazine, or Crohn’s-related 
antibiotics
If receiving treatment prior to entry to the trial, the dose must have been 
stable for a minimum of 4 weeks prior to randomization (Day 1) and must 
remain stable throughout the trial.
Corticosteroids
If receiving current treatment with corticosteroids, the dose must not exceed 
20 mg/day of prednisone or equivalent. The dose must have been stable for 
a minimum of 2 weeks prior to randomization (Day 1) and must remain 
stable throughout the induction period of the trial (i.e., until Week 4).
At Week 4, patients who are receiving prednisone or budesonide may begin 
a taper if qualifications are met.
Budesonide
If receiving current treatment with budesonide, the dose must not exceed 
6 mg/day and must have been stable for a minimum of 2 weeks prior to 
randomization (Day 1).
Budesonide and prednisone 
(combination therapy)
Not permitted throughout the trial.
Infliximab and other biologic 
therapies
Not permitted within 8 weeks (infliximab) and 6 months (other biologics)
prior to randomization (Day 1) and throughout the trial.
Adalimumab and other TNF
Treatment not permitted at any time.
Azathioprine, 6-mercaptopurine, 
or MTX
If receiving these treatments, the dose must have been stable for a minimum 
of 4 weeks prior to randomization (Day 1) and must remain stable 
throughout the trial.
Additionally, patients receiving these medications must have been on 
azathioprine, 6-mercaptopurine, or MTX for at least 12 weeks prior to 
randomization (Day 1).
Live/attenuated vaccine
Not permitted within 3 months prior to randomization (Day 1), for the 
duration of the trial, or for 70 days after the last dose of trial medication.
Cyclosporine, tacrolimus, and 
mycophenolate mofetil
Not permitted 8 weeks prior to Screening and throughout the trial.
Any drug/therapy that has not 
received regulatory approval for 
any indication
Not permitted within 6 months (or 30 days for chemical agents) or a 
minimum of five half-lives, whichever is longer, prior to randomization
(Day 1) and throughout the trial.
Enemas (except when related to 
routine endoscopy or 
radiographic studies)
Not permitted within 2 weeks prior to randomization (Day 1) and 
throughout the trial.
In addition to the above restrictions, adalimumab is prohibited throughout the safety 
follow-up period.


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Surgical bowel resection is not permitted within 6 months prior to randomization (Day 1), or 
at any time throughout the trial. If patients need surgery during the trial, they must 
discontinue.
Restrictions on diet and life style
4.2.2.2
Male patients with female partner(s) of childbearing potential must agree to use a medically 
acceptable method of contraception during the trial and for 6 months after the last dose of 
trial drug. 
Restrictions regarding women of childbearing potential 
4.2.2.3
A serum β-hCG test will be performed at Screening in women of childbearing potential. 
Thereafter, a local urine pregnancy test will be performed as indicated in the flow charts (see
Flow Chart A and Flow Chart B). Any woman with a confirmed positive pregnancy test 
during screening is not eligible for the trial. A positive urine pregnancy test during the 
treatment periods of the trial requires immediate interruption of trial treatment until a serum 
β-hCG test is performed and found to be negative. If the serum β-hCG test is positive, the 
patient must be discontinued from trial medication.
Women of childbearing potential must use the contraception methods described in the patient 
information and in Section 3.3.2.
TREATMENT COMPLIANCE
4.3
Compliance will be assured by administration of all trial medication by the dedicated trial 
personnel considered qualified to perform the s.c. injections. The measured plasma 
concentrations will provide additional confirmation of compliance.
Patients who are non-compliant (for instance, who do not attend scheduled visits or violate 
trial restrictions) may be discontinued from the trial treatment by the investigator after 
consultation with the sponsor or sponsor’s representative, and the eCRF will be completed 
accordingly.


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5.
VARIABLES AND THEIR ASSESSMENT
Please refer to Flow Chart A and Flow Chart B for the schedule of assessments for the trial.
The trial endpoints are listed in Section 5.1 below. Efficacy assessments are described in 
more detail in Section 5.2, safety assessments in Section 5.3, PK sample collection in 
Section 5.4, and immunogenicity assessments in Section 5.6.
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint(s)
The primary endpoint is:

Proportion of patients in each treatment group with a clinical response (CDAI decrease 
of ≥70 compared with baseline) at Week 4
5.1.2
Secondary Endpoint(s)
Secondary endpoints are:
Efficacy

Proportion of patients in each treatment group with a clinical response (CDAI decrease 
of ≥70 compared with baseline) at Week 24

Proportion of patients in each treatment group in clinical remission (CDAI <150) at 
Week 24
Safety

Proportion of patients with AEs, SAEs, and AESIs (e.g., serious infections, allergic 
reactions, abscesses, fistula, strictures)

Proportion of patients with infections/serious infections (seriousness of infection defined 
as requirement of i.v. antibiotics for treatment and/or meeting seriousness criteria to be 
qualified as an SAE)

Proportion of patients who experience hypersensitivity reactions

Proportion of patients who experience DILI

Proportion of patients with injection-site reactions


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ASSESSMENT OF EFFICACY
5.2
The assessments described in the following sections will be made at the time points indicated 
in Flow Chart A and Flow Chart B.
5.2.1
CDAI
Evaluation of CDAI will be performed by the investigator at the visits indicated in the 
Flow Chart A and Flow Chart B.
The CDAI is a validated instrument to measure disease severity in CD (R97-2689). It is the 
most widely used clinical index for the evaluation of disease activity and remission in 
inflammatory CD in clinical trials. It has been recommended by the International 
Organization for the study of IBD and the European Crohn’s and Colitis Organization for 


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defining CD activity (R02-0112, R15-4343) and has been accepted by the regulatory 
authorities (R13-2623).
The CDAI score is composed of eight factors as shown in Table 5.2.1: 1. The patient is 
required to keep a symptom diary for 4 of these 8 variables (number of liquid stools, 
abdominal pain, general well-being, and use of antidiarrheal drugs) for 7 consecutive days 
before each CDAI evaluation. Hematocrit results are integral to the CDAI calculation and 
will be assessed at each visit by the central laboratory as part of the safety laboratory analyses 
(see Section 5.3.3). The Visit 1 hematocrit results will be used for the calculation of CDAI at 
Visit 1.1 in order to determine eligibility of the patient to be included in the trial. At Week 4, 
the hematocrit value required to determine CDAI score will be assessed locally and 
confirmed via central laboratory assessment. At Visit 8 (Week 12), the hematocrit value from 
the central laboratory assessment at Visit 6 (Week 8) will be used to determine CDAI score.
At visits where CDAI evaluation is performed and no physical examination is planned, body 
weight must be measured for use in CDAI determination.
The CDAI score is a sum of the eight factors after adjustment with a weighting factor; CDAI 
scores range from 0 to approximately 600. The day of bowel preparation for colonoscopy and 
the day of colonoscopy will be excluded from the CDAI assessment. This is to prevent 
misleading influences (pain and liquid stool frequency) on CDAI evaluation.


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Table 5.2.1: 1
Calculation of CDAI
Variable
Description
Scoring
Multiplier
Number of liquid 
stools
Sum of 7 days
×2
Abdominal pain
Sum of 7 days' 
ratings
0 = none
1 = mild
2 = moderate
3 = severe
×5
General 
well-being
Sum of 7 days' 
ratings
0 = generally well
1 = slightly under par
2 = poor
3 = very poor
4 = terrible
×7
Extra-intestinal 
complications
Number of 
complications listed
Arthritis/arthralgia, iritis/uveitis, erythema nodosum, 
pyoderma gangrenosum, aphtous stomatitis, anal 
fissure/fistula/abscess, fever > 37.8°C
×20
Antidiarrheal
drugs
Use in the previous 
7 days
0 = no
1 = yes
×30
Abdominal mass
0 = no
2 = questionable
5 = definite
×10
Hematocrit
Expected–observed 
hematocrit
Men: 47 observed
Women: 42 observed
×6
Body weight
Ideal/observed ratio
[1 − (actual weight/standard weight)] × 100
×1 
(not < −10)
Adapted from R97-2689.
5.2.2
Endoscopy
Endoscopies will be performed for the evaluation of SES-CD and mucosal ulceration at the 
visits indicated in Flow Chart A
Lesions detected by endoscopy (ileocolonoscopy) will be scored by means of the validated 
SES-CD, as described below. The same endoscopist at the trial site will complete the 
SES-CD for each endoscopy immediately after the procedure. The investigator (or designate) 
will record each endoscopy and send the video to the central imaging laboratory. A central 
reading of all endoscopies will be performed by an independent blinded reviewer and the 
findings scored using SES-CD. Eligibility at Screening must be confirmed using the centrally 
read scores prior to randomization.


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The results for SES-CD and mucosal ulceration will be returned to the trial site from the 
central imaging laboratory for entry into the appropriate eCRF.
SES-CD
5.2.2.1
The SES-CD was developed as a reproducible measure that could be used to assess response 
to therapy in CD (R14-2969, R15-6247) using an endoscopic index capable of assessing the 
severity of mucosal lesions in colonic or ileocolonic CD. The scoring system is represented in 
Table 5.2.2: 1 below. The index is relatively complex and must be performed by an 
experienced endoscopist who has been trained in the precise and specific data recording 
procedure required.
Table 5.2.2.1: 1
Scoring system for SES-CD
Ileum
Right
colon
Transverse 
colon
Left
colon
Rectum
Total
Presence and size of ulcers (0-3)
0-3
0-3
0-3
0-3
0-3
0-15
Extent of ulcerated surface (0-3)
0-3
0-3
0-3
0-3
0-3
0-15
Extent of affected surface (0-3)
0-3
0-3
0-3
0-3
0-3
0-15
Presence and type of narrowings (0-3)
0-3
0-3
0-3
0-3
0-3
0-11
SES-CD =
0-56
Source: R14-2969.


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ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
A physical examination will be performed at the visits indicated in Flow Chart A and 
Flow Chart B.
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, and 
neurological systems, thyroid gland, musculoskeletal system/limbs, respiratory tract, and 
abdomen. Clinically relevant abnormal findings will be reported as baseline conditions or 
AEs.
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 Flow Chart A and Flow Chart B.
Blood pressure 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, urinalysis, and 
other tests will be taken at the times indicated in Flow Chart A and Flow Chart B.
The laboratory parameters listed in Appendix 10.2 will be measured.
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 


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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 and stool samples will be analyzed by a central laboratory. The central laboratory 
vendor will also provide the materials for blood sampling. Instructions for the labeling, 
storage, and shipment of the samples can be found in the Laboratory Manual. Details of all 
blood variable units, reference ranges, and blood sample volumes can be found in the 
Laboratory Manual.
At Week 4, in order to assess clinical response during the visit, the hematocrit value required 
to determine CDAI score will be assessed locally and subsequently confirmed via central 
laboratory assessment.
Pregnancy testing will be performed by a central laboratory using serum at Screening or by a 
local laboratory using urine at all applicable visits thereafter.
It should also be noted that additional samples may be required if medically indicated, e.g., at 
unscheduled visits to follow safety findings.
5.3.4
Electrocardiogram
A 12-lead ECG (I, II, III, aVR, aVL, aVF, V1 – V6) will be recorded using a computerized 
electrocardiograph at the visits indicated in Flow Chart A and Flow Chart B.
All ECGs will be recorded for 10-second duration after the patients have rested for at least 
5 minutes in a supine position. ECG assessment will always precede all other trial procedures 
at the same time point (except blood drawing from an i.v. cannula which is already in place) 
to avoid impact of sampling on the ECG quality.
The electronic version of the ECG is regarded as source data. Dated and signed printouts will 
be stored in the patient’s medical file.
The investigator or a designate will evaluate whether the ECG is normal or abnormal and 
whether it is clinically significant, if abnormal. Additionally, any occurrence of re- or 
depolarization disorders, arrhythmic disorders or other abnormalities will be assessed. ECGs 
may be repeated for quality reasons (like alternating current artefacts, muscle movements, 
electrode dislocation) and the repeated ECG will be used for analysis. Additional 
(unscheduled) ECGs may be collected by the investigator for safety reasons.
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 
removed from the trial and will receive the appropriate medical treatment. Additionally, 
evaluation of these ECGs will be performed by a board certified cardiologist.
Information about the details of ECG collection and the parameters assessed will be provided 
in the ISF.


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5.3.5
Other safety parameters
Tuberculosis assessment
5.3.5.1
A chest X-ray will be reviewed by the investigator or designee at Screening. If chest 
radiographs have been taken within 12 weeks of the Screening Visit then the chest 
radiographs do not need to be repeated (as long as they show no clinically significant 
abnormality and no signs or symptoms suggestive of lung disease that would exclude the 
patient from the trial). The results must be entered into the eCRF.
An IGRA (e.g., QuantiFERON®-TB Gold) will be used to assess TB status at Screening and, 
for patients who continue to the maintenance phase, at Visit 14 Week 24 (before switch from 
EU-approved Humira to BI 69550 and at EoT (Week 48 or earlier for patients who 
discontinued treatment during the maintenance phase). In the event of an indeterminate result 
at Screening, the test should be repeated. If a second indeterminate result is obtained then the 
patient must be excluded from the trial participation.
In the event of an indeterminate or positive result during the study, the test should be repeated 
and if a result is positive, then the patient will discontinue receiving the study treatment and 
followed up for safety. The patient will be referred to the specialist as required by local 
regulations.
5.3.6
Assessment of adverse events
Definitions of AEs
5.3.6.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal 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.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an AE is at least a reasonable possibility. Adverse reactions may arise from use 
of the product within or outside the terms of the marketing authorization or from occupational 
exposure. Conditions of use outside the marketing authorization include off-label use,
overdose, misuse, abuse, and medication errors.
Serious adverse event


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An SAE is defined as any AE which:

results in death,

is life-threatening, referring to an event in which the patient is at risk of death at the 
time of the event; it does not refer to an event that hypothetically might cause death if 
more severe,

requires inpatient hospitalization or 

prolongation of existing hospitalization,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect,
or

is 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.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization,
or development of dependency or abuse. Any suspected transmission via a medicinal product 
of an infectious agent is also considered a serious adverse reaction.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further 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.
The latest list of “Always Serious AEs” will be provided in the ISF. These events should 
always be reported as SAEs as described above.
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 Pharmacovigilance Department within the same 
timeframe that applies to SAEs (see above).


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The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

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

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.
For further details see Appendix 10.4.

Anaphylactic reactions

Serious infection (defined as infections requiring i.v. antibiotics or meeting the regulatory 
definition of an SAE)

Hypersensitivity reactions.
Protocol-specified AESIs can be classified as serious or non-serious but all AESIs must be 
reported in an expedited manner similar to SAEs on an SAE form (i.e., non-serious AESIs 
must be reported on the SAE form and follow SAE reporting timelines).
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
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an AE. An adverse reaction, in 
contrast to an AE, is characterized by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected.


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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.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative etiologies that could explain the event (e.g., pre-existing
or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g., Stevens-Johnson syndrome)

An indication of dose-response (i.e., greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g., after 5 half-lives). Of note, this 
criterion may not be applicable to events whose time course is prolonged despite 
removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g.,
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
Adverse event collection and reporting
5.3.6.2
AE Collection
The investigator shall maintain and keep detailed records of all AEs in their patient files.


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The following must be collected and documented on the appropriate eCRF(s) by the 
investigator:

From signing the informed consent onwards through the REP (defined as 10 weeks after 
last administration of trial medication), until the individual patient’s end of trial:
-
All AEs (serious and non-serious) and all AESIs
However, if an individual patient discontinues trial medication prematurely but stays in 
the trial (i.e., if further visits incl. telephone visits, or vital status assessments are planned)
from then on and until the individual patient’s end of the trial, the investigator must report 
related SAEs and related AESIs.

After the individual patient’s end of trial:
-
The investigator does not need to actively monitor the patient for AEs but should 
only report relevant SAEs and relevant AESIs of which the investigator may 
become aware.
The above instructions are summarized schematically below.
The REP 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 (see Section 7.3.4). Events which occurred 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’s unique entry point (specific contact details will be provided in 
the ISF). The same timeline applies if follow-up information becomes available. In 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.


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With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form. The investigator should determine the causal relationship 
to the trial medication and any possible interactions between the investigational drug(s) and a 
non-investigational medicinal product/auxiliary 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 trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the 
sponsor’s/sponsor’s designee’s unique entry point (specific contact details will be provided in 
the ISF). The Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.
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’s unique entry point on the 
Pregnancy Monitoring Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.


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APPROPRIATENESS OF MEASUREMENTS
5.7
The primary efficacy endpoint (CDAI decrease of ≥70 compared to baseline) is a standard 
outcome criterion that is widely accepted for regulatory purposes to demonstrate efficacy on 
signs and symptoms of CD.
 
Therefore, the appropriateness of all measurements applied in this trial is assured and is in 
line with guidance from regulatory authorities (R13-2623).


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
A schedule of assessments is provided in Flow Chart A and Flow Chart B.
Visits will be scheduled as close as possible to the preplanned schedule: 

A visit window of -1/+2 days is permitted for Visit 2 (Day 1)

A visit window of ±1 day is permitted for Visit 3 to Visit 4

A visit window of ±3 days is permitted for Visit 5 to Visit 25, and EoT 

A visit window of +7 days is permitted for safety follow-up Visit

Trial medication will be administered every 2 weeks (±1 day up to Visit 4 and ±3 days 
from Visit 5 onwards).
On trial medication administration days, all assessments should be performed prior to 
administration, unless otherwise specified. Laboratory samples must be drawn prior to trial 
medication injection.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
Study procedures to be performed at each visit are listed in Flow Chart A, Flow Chart B, and 
the respective protocol sections. Refer to Section 5 for explanations of procedures.
6.2.1
Screening and run-in period(s)
The Screening period in this trial will comprise two separate visits. Once the patient has 
provided informed consent (before any trial-specific procedures or assessments are 
performed), meets the inclusion criteria and does not meet any of the exclusion criteria (see 
Section 3.3), the trial site will enter the screened patient into the system using the IRT.
Screening Visit 1, Day -28 to Day -14
The following will be performed/collected:

Demographic information (including gender, date of birth, ethnicity, and race), and 
medical and surgical history (including CD history and history of opportunistic infection)

Infection screen (HBsAg, antiHCV, and HIV test, per the investigator’s discretion and/or
where mandated by local authorities)

Chest X-ray, unless taken within the previous 12 weeks (see Section 5.3.5.1)

TB test (IGRA e.g., QuantiFERON® Gold assay; see Section 5.3.5.1)

Stool studies to evaluate for enteric pathogens (see Section 5.3.3)

Serum pregnancy test for women of childbearing potential

Physical examination, including height (cm) and weight (kg) (see Section 5.3.1)

Vital signs (blood pressure, pulse rate, and body temperature; see Section 5.3.2)

Laboratory testing (serum chemistry, hematology, and urinalysis; see Section 5.3.3)


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
12-lead ECG (see Section 5.3.4)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)
Following completion of the above screening procedures at Visit 1, patients who are eligible 
to continue will receive a patient CDAI diary to complete their daily symptoms during the
7-day period immediately before Visit 1.1. Sites must ensure that sufficient time is allowed 
between Visit 1 and Visit 1.1 to allow completion of the CDAI diary.
Screening Visit 1.1, Day -9
At Visit 1.1, the patient CDAI diary will be reviewed by the investigator in order to assess the 
CDAI score. The hematocrit result and weight measurement from Visit 1 must be used to 
calculate the CDAI score at Visit 1.1 (see Section 5.2.1). Only patients with moderate to 
severe CD, defined as CDAI score ≥220 and ≤450 will undergo an endoscopy at Visit 1.1
(see Section 5.2.2). Evidence of mucosal ulcers in at least one segment of the ileum or colon
and a SES-CD score ≥7 (or ≥4 for patients with isolated ileal disease) must be confirmed by 
central independent reviewer(s) prior to randomization.
Once patients have completed screening at Visit 1.1, have met all the inclusion criteria and 
have not met any of the exclusion criteria, randomization will occur on Day 1 (-1/+2) through 
a standard randomization visit call, using the IRT system. Patients will be randomized to each 
treatment in a 1:1 ratio (BI 695501: EU-approved Humira) according to the stratification 
factors. Patients will be randomly assigned in a blinded fashion to BI 695501 or EU-approved 
Humira as described in Section 4.1.3 and Section 7.6.
6.2.2
Treatment period(s)
Prior to Week 24, BI 695501/EU-approved Humira will be administered by a suitably 
qualified, designated unblinded trial personnel. From Week 24 onwards, when all patients 
will be receiving BI 695501, it will not be necessary for the trial personnel administering the 
medication to be unblinded. However, patients and other trial personnel must remain blinded 
with respect to the initial assignment to EU-approved Humira or BI 695501. All 
administrations of trial medication will be performed at the trial site. Trial medication will be 
administered every 2 weeks (-1/+2 days at Visit 2, ±1 day up to Visit 4 and ±3 days from 
Visit 5 onwards).
Baseline, Visit 2 (Day 1)
Eligible patients will be randomized and 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)

Vital signs (blood pressure, pulse rate, and body temperature; see Section 5.3.2)


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
Laboratory testing (serum chemistry, hematology, and urinalysis; see Section 5.3.3)

Urine pregnancy test (in addition to a serum pregnancy test at Screening)

Evaluation of CDAI (see Section 5.2.1)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)

Contact IRT and administer first trial medication injection (see Section 4.1.4)
Visit 3 (Day 15)
The following will be performed/collected:

Vital signs (blood pressure, pulse rate, and body temperature; see Section 5.3.2)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)

Contact IRT and administer trial medication
Visits 4 and 14 (Days 29 and 169, respectively)
The following will be performed/collected:

Physical examination, including weight (kg) (Visit 14 only; see Section 5.3.1)

Vital signs (blood pressure, pulse rate, and body temperature; see Section 5.3.2)

Laboratory testing (serum chemistry, hematology, and urinalysis; see Section 5.3.3)

Urine pregnancy test for women of childbearing potential (Visit 14 only)

Local hematocrit testing (Visit 4 only; to be used for CDAI evaluation)

Evaluation of CDAI (see Section 5.2.1)

TB test (IGRA e.g., QuantiFERON Gold assay; at Visit 14 only)

12-lead ECG (see Section 5.3.4)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)

Contact IRT and administer trial medication
At Visit 14, patients initially randomized to EU-approved Humira will switch to receive 
BI 695501. From Visit 14 onwards, all patients will be receiving BI 695501.


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Visits 6, 10, 18 and 22 (Days 57, 113, 225 and 281, respectively)
The following will be performed/collected:

Vital signs (blood pressure, pulse rate, and body temperature; see Section 5.3.2)

Laboratory testing (serum chemistry, hematology, and urinalysis; see Section 5.3.3)

Urine pregnancy test for women of childbearing potential

12-lead ECG (Visit 6 only; see Section 5.3.4)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)

Contact IRT and administer trial medication
Visit 8 (Day 85)
The following will be performed/collected:

Vital signs (blood pressure, pulse rate, and body temperature; see Section 5.3.2)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)

Evaluation of CDAI (see Section 5.2.1)

Contact IRT and administer trial medication
At this visit, the hematocrit value from the central laboratory assessment at Visit 6 (Day 57) 
will be used to determine CDAI score.
Visits 12 and 16 (Days 141 and 197, respectively)
The following will be performed/collected:

Vital signs (blood pressure, pulse rate, and body temperature; see Section 5.3.2)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)

Contact IRT and administer trial medication
Trial medication administration only visits
Visits 5, 7, 9, 11, 13, 15, 17, 19, 20, 21, 23, 24, and 25 are for administration of trial 
medication only and the following will be performed:

Contact IRT and administer trial medication


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End of Treatment Visit
The following will be performed/collected:

TB test (IGRA e.g., QuantiFERON® Gold assay)

Physical examination, including weight (kg) (see Section 5.3.1)

Vital signs (blood pressure, pulse rate, and body temperature; see Section 5.3.2)

Laboratory testing (serum chemistry, hematology, and urinalysis; see Section 5.3.3)

Urine pregnancy test for women of childbearing potential

12-lead ECG (see Section 5.3.4)

Evaluation of CDAI (see Section 5.2.1)

CRP (see Section 5.2.3)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)
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 EoT Visit as soon after trial 
discontinuation as possible (except TB test, which is not required for those discontinuing 
before the maintenance phase, 
 which is only required for patients who 
complete the 48-week treatment period).
The patient who early discontinued from the trial will receive treatment as deemed 
appropriate by the investigator and in accordance with the applicable guidance.
6.2.3
Follow-up period and trial completion
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 last 
dose of trial medication (at Week 56 for patients who complete the full treatment period).
Safety follow-up visit
The following will be performed/collected:

Physical examination, including weight (kg) (see Section 5.3.1)

Vital signs (blood pressure, pulse rate, and body temperature; see Section 5.3.2)

Laboratory testing (serum chemistry, hematology, and urinalysis; see Section 5.3.3)

Urine pregnancy test for women of childbearing potential

12-lead ECG (see Section 5.3.4)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)


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
End of participation
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
STATISTICAL DESIGN - MODEL
7.1
This is a randomized, double-blind, parallel arm, multiple dose, multicenter, multinational,
active comparator trial of BI 695501 and EU-approved Humira.
The primary objective of this trial is to compare the clinical efficacy of BI 695501 with
EU-approved Humira in patients with active CD at the end of the induction phase at Week 4 
by means of the RR.
The primary endpoint (Section 5.1.1) will be analyzed using a log-linked binomial model, 
which will include stratification factors as covariates (i.e., prior exposure to infliximab 
[yes/no] and screening SES-CD (<16 or ≥16).
NULL AND ALTERNATIVE HYPOTHESES
7.2
This exploratory trial is intended to generate additional data in patients with active CD.
Therefore, no formal confirmatory hypotheses for the primary efficacy analysis are defined.
PLANNED ANALYSES
7.3
The primary analysis set will be the FAS according to the intention to treat principle. The
FAS will consist of all randomized patients who receive at least one dose of trial medication, 
and have all efficacy measures relevant for the CDAI, measured at baseline and at least once 
post-baseline.
A PPS of patients who have followed the CTP in all essential criteria will be created for 
sensitivity analyses. Patients included in the FAS who have important protocol violations 
relevant for efficacy prior or at Week 4 will be excluded from the PPS. Protocol violations 
will be assessed on a case-by-case basis. A protocol violation will be considered important if 
it can be expected to have a distorting influence on the assessment of the primary endpoint. 
Important protocol violations may include:

Incorrect trial medication taken until Week 4

Violation of treatment compliance until Week 4

Violation of inclusion/exclusion criteria

Further details on the definition of the different analysis sets will be provided in the 
TSAP.
All patients treated with at least one (full or partial) dose of either of the trial treatments 
during any dosing period will be included in the safety evaluation (SAF).
7.3.1
Primary endpoint analyses
Primary efficacy analysis:


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The primary analyses will be performed on the FAS. Patients will be assigned to the 
treatment they were randomized to receive.
The primary analysis of the observed proportion of patients with a clinical response (CDAI 
decrease of ≥70 compared with baseline) at Week 4 will be based on log-linked binomial 
model. No missing data imputation for primary analysis endpoint need to be taken into 
account due to FAS definition. However, for pre-specified criteria non-responder imputation 
(NRI) will be applied (see Section 7.5).
The statistical model can be described as follows:

(M1) Response to treatment at Week 4 = treatment + prior infliximab exposure + 
screening SES-CD
This model includes the stratification factor, prior exposure to infliximab, and treatment as 
fixed, categorical effects and it will be investigated whether the baseline SES-CD will be 
included as a continuous or as a categorical effect:

Treatment (BI 695501, EU-approved Humira)

Prior exposure to infliximab (Yes/No)

Baseline SES-CD (<16 or ≥16)
The relative risk estimate together with its 90% and 95% CI (ratio scale) will be produced.
Further efficacy analyses:
As sensitivity analyses to the primary analysis, the primary endpoint will also be analyzed on 
the PPS with NRI.
The following explorative hypotheses are not intended to support any biosimilarity claim for 
BI 695501; however, the framework of non-inferiority testing will be used to compare 
efficacy of BI 695501 versus EU-approved Humira in a descriptive way.
The following hypotheses will be investigated:

H0: RR of proportion of patients with a clinical response (CDAI decrease of ≥70 
compared with baseline) at Week 4 (BI 695501 versus EU-approved Humira) is less than 
or equal to 0.76

H1: RR of proportion of patients with a clinical response (CDAI decrease of ≥70 
compared with baseline) at Week 4 (BI 695501 versus EU-approved Humira) is greater 
than 0.76
Two-sided 90% CI will be used for the comparison.


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The applied margin (0.76 on the ratio scale for CDAI 70) does preserve 39% of the historical 
effect of adalimumab over placebo (based on a meta-analysis of GAIN and CLASSIC1; see 
Appendix 10.3 for further details). 
7.3.2
Secondary endpoint analyses
Secondary efficacy endpoints
7.3.2.1
To support the primary objective, the secondary efficacy endpoints detailed in Section 5.1.2
will be analyzed descriptively based on the FAS.
For the proportions, the risk difference will be computed and presented together with its 90% 
and 95% CI and interpreted in a descriptive manner.
Secondary safety endpoints
7.3.2.2
The secondary safety endpoints detailed in Section 5.1.2 will be based on the SAF and 
presented descriptively. In addition, RR and risk difference together with 95% CIs will be 
presented.
7.3.4
Safety analyses
Adverse events will be coded using the MedDRA coding dictionary.


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All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature. No hypothesis testing is planned. No formal inferential analyses are 
planned for safety comparison. The analyses will be based on the SAF.
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’. The REP is defined as 10 weeks after the last dose of trial medication. 
Adverse events that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’. Other AEs will be assigned to the appropriate trial 
phases, i.e., screening or post-treatment. For patients switching from EU-approved Humira to 
BI 695501, AEs occurring after the first dose of BI 695501 will be assigned to BI 695501 for 
the overall AE analysis. AEs occurring before the first dose of BI 695501 will be assigned to 
the ongoing treatment.
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 MedDRA. In addition, RR
and risk difference together with 95% CIs will be presented for the overall population (details 
will be specified in the TSAP).
Laboratory data will be analyzed quantitatively as well as qualitatively. The latter will be 
done via comparison of laboratory data with 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, physical examinations, 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 with findings before start of treatment.


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INTERIM ANALYSES
7.4
No classic interim analysis will be performed. Instead, an overview of the different analysis 
time points is given below.
7.4.1
Primary analysis
The primary analysis will take place when all primary efficacy endpoint data are available 
and cleaned (i.e., approximately 4 weeks after the last patient has been randomized). The 
cut-off date will be the date on which the last patient completes the Week 4 visit and will be
the same for all patients. A database snapshot will be taken with regard to this cut-off date; it 
will include all data available in the database up to and including the cut-off date and will be 
used for performing the analysis. Only cumulative results will be presented, i.e., patient level 
data will be excluded. Details regarding statistical analysis will be outlined in the TSAP. 
Only a selected team, not involved in any other trial activities, will have access to the 
unblinded snapshot data and will be required to sign a confidentiality agreement. Efficacy 
data will be included up to the Week 4 visit only and all available data for safety and other 
endpoints will be included up to the data cut-off date.
To ensure that the data integrity of the continuing trial will not be violated, a charter will be 
prepared in advance, outlining the procedures to be followed. This document will describe 
the measures to be implemented by the Sponsor to protect the integrity of the trial until the 
final database lock. Team members involved in the conduct of the trial as well as the site 
personnel and patients will remain blinded until the final database lock.
7.4.2
Final analysis
A final analysis (including all endpoints) will be performed when all trial data are available, 
i.e., approximately 56 weeks after the last patient has been randomized. In this analysis, all 
analyses performed for the primary analysis will be repeated with the (partially) updated data, 
in particular with respect to safety and efficacy endpoints collected until Week 56. The 
results of the final analysis will be summarized in a CTR.
HANDLING OF MISSING DATA
7.5
7.5.1
Efficacy endpoints
No missing data for the primary analysis endpoint are expected for the FAS, because Week 4 
is the first post-baseline visit for efficacy assessment and, in case of discontinuation prior to 
Week 4, the EoT efficacy assessments should be performed. However, all patients who 


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discontinue treatment, are lost-to-follow-up or have any major protocol deviation related to 
any therapy that may significantly impact efficacy assessment (Table 4.2.2.1: 1) prior to the 
primary endpoint assessment will be considered as non-responders. Patients without any 
available CDAI evaluation at Week 4 will also be considered as non-responders. This is 
referred to as ‘NRI’. Patients assessed as non-responders at Week 4 will be considered 
non-responders for all subsequent time points (LOCF).
For secondary efficacy endpoints, rules for handling of missing data will be specified in the 
TSAP, if necessary.
7.5.2
Safety and other endpoints
With respect to safety evaluations, it is not planned to impute missing values. For other 
endpoints, rules for handling of missing data will be specified in the TSAP, if necessary.
RANDOMIZATION
7.6
Patients who meet all the inclusion criteria and none of the exclusion criteria will be 
randomized 1:1 to either BI 695501 or EU-approved Humira over the 24-week (4-week 
induction and 20-week maintenance) treatment period after the screening period at Visit 2. 
The randomization will be stratified by prior exposure to infliximab (Yes/No) and screening
SES-CD (<16 or ≥16).
Randomization will occur on Day 1 (-1/+2) through a standard randomization visit call. 
Patients will be randomized to each treatment in a 1:1 ratio (BI 695501: EU-approved 
Humira) using an IRT system.
Boehringer Ingelheim Pharma GmbH & Co. KG, Clinical Trial Supply Unit or a third party 
appointed by the sponsor will provide the randomization list using a validated randomization 
number generating system. Access to the randomization code will be controlled and 
documented. All persons directly involved in the conduct of the trial have no access to the 
treatment allocation prior to final database lock. The block sizes of the randomization will be 
documented in the CTR.
DETERMINATION OF SAMPLE SIZE
7.7
The sample size determination is not based on a power calculation, but assures a precise
estimation of the relative risk difference. For this trial a precision (distance from observed 
difference to confidence limit) of 0.115 has been considered necessary and sufficient by the 
project team. Assuming a response rate of 80%, in both the Humira as well in the BI 695501 
treatment arm, the trial will need at least 130 patients (65 per treatment arm).


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Table 7.7: 1
Precision of 90% CI
Assumed true response rate 
Sample size
Precision$
Relative 
risk (RR)
90% CI
Humira
BI 695501
85%
85%
65
0.103
1
0.897-1.103
85%
80%
65
0.118
0.941
0.823-1.059
85%
75%
65
0.115
0.882
0.767-0.997
80%
80%
65
0.115
1
0.885-1.115
80%
75%
65
0.120
0.938
0.818-1.058
75%
75%
65
0.125
1
0.875-1.125
$Precision is defined as the distance from observed difference to confidence limit. Note that the precision is independent of 
the actual point estimate.
Calculations performed with nQuery Advisor® 7.0
Table 7.7: 2
Precision of 95% CI
Assumed true response rate 
Sample size
Precision$
Relative 
risk (RR)
95% CI
Humira
BI 695501
85%
85%
65
0.123
1
0.877-1.123
85%
80%
65
0.140
0.941
0.801-1.081
85%
75%
65
0.136
0.882
0.746-1.081
80%
80%
65
0.138
1
0.862-1.138
80%
75%
65
0.143
0.938
0.795-1.081
75%
75%
65
0.149
1
0.851-1.149
$Precision is defined as the distance from observed difference to confidence limit. Note that the precision is independent of 
the actual point estimate.
Calculations performed with nQuery Advisor® 7.0


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
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, relevant BI and CRO SOPs, the EU regulation 536/2014, and other relevant 
regulations.
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 subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. 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 general 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.
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
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 investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. The patient must be given sufficient time to consider 
participation in the trial. The investigator obtains written consent of the patient’s own free 
will with the informed consent form after confirming that the patient understands the contents. 
The investigator must sign (or place a seal on) and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by 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.
RECORDS
8.3
Case Report Forms for individual patients will be provided by the sponsor. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make three documented attempts to 
retrieve previous medical records. If this fails a verbal history from the patient, documented 
in their medical records, would be acceptable.
Before providing any copy of patients’ source documents to the sponsor, the investigator
must ensure that all patient identifiers (e.g., patient’s name, initials, address, phone number, 
social security number) have properly been removed or redacted to ensure patient 
confidentiality.
If the patient is not compliant with the protocol, any corrective action e.g., re-training, must 
be documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, date or year of birth (in accordance with local laws and 
regulations)


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
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it)

Prior to allocation of a patient to a treatment in a clinical trial, there must be documented 
evidence in the source data (e.g., medical records) that the trial participant meets all 
inclusion criteria and does not meet any exclusion criteria. The absence of records (either 
medical records, verbal documented feedback of the patient or testing conducted specific 
for a protocol) to support inclusion/exclusion criteria does not make the patient eligible 
for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and 
in-house data quality review. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology, and the 
degree of any deviations of the intervention from normal clinical practice.
The investigator /institution will allow on-site trial-related monitoring, audits, IRB/IEC 
review, and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor, and regulatory inspector 
(e.g., FDA). The CRA and auditor may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
ICH GCP.
8.3.3
Storage period of records
Trial site(s):
The trial sites must retain the source and essential documents (including ISF) according to the 
national or local requirements (whichever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
Boehringer Ingelheim is responsible to fulfil their legal regulatory reporting obligation and in 
accordance to the requirements defined in this CTP.
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
8.5
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage, and 
processing of patient data in accordance with principles 6 and 12 of the World Health 
Organization GCP handbook.
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.
8.5.1
Collection, storage, and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage, and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with 
the Principles of GCP as outlined in ‘Note For Guidance On Good Clinical Practice’
(CPMP/ICH/13 5/95)

The Boehringer Ingelheim internal facilities storing and analyzing biological samples 
and data from clinical trial participants as well as the laboratories’ activities for 
clinical trials sponsored by Boehringer Ingelheim are regularly audited. The analytical 
groups and the banking facility are therefore assessed to be qualified for the storage 
and use of biological samples and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment pf the first patient in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”), the date that the last patient in the trial dies, or the date that the last 
patient in the trial is lost to follow-up (whichever occurs last).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 


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prematurely). Individual investigators will be notified of SUSARs occurring with the trial 
medication until 10 weeks after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC/competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
R15-5978
Humira (adalimumab) injection, for subcutaneous use (AbbVie) (U.S. 
prescribing information, revised: 11/2015)
R15-4915
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: 08/2015).
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000481/WC500050870.pdf (2015)
R13-2232
Latella G, Papi C. Crucial steps in the natural history of inflammatory 
bowel disease. World J Gastroenterol 2012. 18(29):3790-9.
R13-2233
Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and 
natural history of inflammatory bowel diseases. Gastroenterology. 2011. 
140:1785-94.
R13-2264
Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione 
R et al. Adalimumab induction therapy for Crohn disease previously 
treated with infliximab: a randomized trial. Ann Intern Med. 2007. 
146(12):829-38.
R13-2267
Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, 
MacIntosh D et al. Human anti-tumor necrosis factor monoclonal antibody 
(adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology.
2006. 130(2):323-33.
R13-2231
Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012. 
380(9853):1590-605.
R14-2969
Daperno M, D'Haens G, Assche G van, Baert F, Bulois P, Maunoury V et 
al. Development and validation of a new, simplified endoscopic activity 
score for Crohn's disease: the SES-CD. Gastrointest Endosc. 2004. 
60(4):505-12.
R15-6247
Vuitton L, Marteau P, Sandborn WJ, Levesque BG, Feagan B, Vermeire S 
et al. IOIBD technical review on endoscopic indices for Crohn’s disease 


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clinical trials. Gut. 2015. Sep 9. doi: 10.1136/gutjnl-2015-309903. [Epub 
ahead of print]
R16-1918
Dessein R, Chamaillard M, Danese S. Innate immunity in Crohn's disease: 
the reverse side of the medal. J Clin Gastroenterol. 2008. 
42(Suppl 3):S144-7.
R16-1917
Stefanelli T, Malesci A, Repici A, Vetrano S, Danese S. New insights into 
inflammatory bowel disease pathophysiology: paving the way for novel 
therapeutic targets. Curr Drug Targets. 2008. 9(5):413-8.
R16-1919
Cho JH, Brant SR. Recent insights into the genetics of inflammatory 
bowel disease. Gastroenterology. 2011. 140(6):1704-12.
R15-0886
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G et 
al. Increasing Incidence and Prevalence of the Inflammatory Bowel 
Diseases With Time, Based on Systematic Review. Gastroenterology.
2012. 142(1):46-54.
R16-1920
Prideaux L, Kamm MA, De Cruz PP, Chan FKL, Ng SC. Inflammatory 
bowel disease in Asia: A systematic review. J Gastroenterol Hepatol.
2012. 27(8):1266-80.
R16-1923
Hovde Ø, Moum BA. Epidemiology and clinical course of Crohn's 
disease: Results from observational studies. World J of Gastroenterol.
2012. 18(15):1723-31.
R16-1922
Burisch J, Munkholm P. Inflammatory bowel disease epidemiology. Curr 
Opin Gastroenterol. 2013. 29(4):357-62.
R97-2645
Mary JY, Modigliani R. Development and validation of an endoscopic 
index of the severity for Crohn’s disease: a prospective multicentre study. 
Groupe d’Etudes Therapeutiques des Affections Inflammatoires du Tube 
Digestif (GETAID). Gut. 1989. 30(7): 983–9.
R97-2689
Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn's 
disease activity index. National Cooperative Crohn's Disease Study. 
Gastroenterology. 1976. 70(3):439-44.
R97-2688
Best WR, Becktel JM, Singleton JW. Rederived values of the eight 
coefficients of the Crohn's Disease Activity Index (CDAI). 
Gastroenterology. 1979. 77(4 Pt 2):843-6.
R02-0112
Sandborn WJ, Feagan BG, Hanauer SB, Lochs H, Löfberg R, Modigliani 
R et al. A review of activity indices and efficacy endpoints for clinical 
trials of medical therapy in adults with Crohn's disease. Gastroenterology.
2002. 122(2):512-30.


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R15-4343
Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M 
et al. The second European evidence-based Consensus on the diagnosis 
and management of Crohn's disease: Definitions and diagnosis. J Crohns 
Colitis. 2010. 4(1):7-27.
R13-2623
European Medicines Agency Committee for Medicinal Products for 
Human Use (CHMP): Guideline on the development of new medicinal 
products for the treatment of Crohn’s disease.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guid
eline/2009/09/WC500003265.pdf
R16-1921
Solem CA, Loftus EV Jr, Tremaine WJ, Harmsen WS, Zinsmeister AR, 
Sandborn WJ. Correlation of C-reactive protein with clinical, endoscopic, 
histologic, and radiographic activity in inflammatory bowel disease.
Inflamm Bowel Dis. 2005. 11(8):707-12.
R16-0167
Jones J, Loftus EV Jr, Panaccione R, Chen LS, Peterson S, McConnell J et 
al. Relationships between disease activity and serum and fecal biomarkers 
in patients with Crohn's disease. Clin Gastroenterol Hepatol. 2008. 
6(11):1218-24.
R16-1924
Gisbert JP, Bermejo F, Pérez-Calle JL, Taxonera C, Vera I, McNicholl AG 
et al. Fecal calprotectin and lactoferrin for the prediction of inflammatory 
bowel disease relapse. Inflamm Bowel Dis. 2009. 15(8):1190-8.
R16-1925
Burri E, Beglinger C. Faecal calprotectin -- a useful tool in the 
management of inflammatory bowel disease. Swiss Med Wkly. 2012. 
142:w13557.
UNPUBLISHED REFERENCES
9.2
c03070713
Pharmacokinetics and safety of BI 695501 in healthy subjects: a 
randomized, double-blind, single-dose, parallel-arm, active-comparator 
clinical Phase I study (BI Study 1297.8)


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10.
APPENDICES
MEDICATION BLINDING PROCEDURE FOR THIRD PARTY 
10.1
BLINDING
This is a double-blind trial, therefore patients, investigators, and trial personnel (except the 
trial personnel administering the trial medication at site) will remain blinded with regard to 
the randomized treatment assignments until after database lock.
The secondary packaging (boxes containing syringes) will be identical for both BI 695501 
and EU-approved Humira, allowing the blinding of the site pharmacy during the first 
22 weeks of treatment. Thereafter, all patients will receive BI 695501 and the drug supplies 
will not require blinding via secondary packaging.
A qualified unblinded designee will administer the trial medication until Week 22, as well as 
being responsible for preparation of unused trial medication for return to the sponsor or 
destruction in a blinded fashion and according to local SOPs.
Records of the product’s delivery to the trial site will include dates, quantities, batch/serial 
numbers, expiry (‘use by’) dates and the unique code numbers assigned to the investigational 
products and trial patients. The designated unblinded or blinded person will maintain records 
that document doses administered to patients and reconcile all investigational product 
received at site. At the time of return to sponsor or local destruction, the designated unblinded 
or blinded person must verify that no supplies remained at the trial site.
The unblinded trial personnel administering the trial medication will not be involved in any 
other trial assessments or procedures.
A description of the trial medication is provided in Table 4.1.1: 1 and Table 4.1.1: 2.
Patient blinding procedure
Trial medication will be administered by unblinded trial personnel until Week 22. To ensure 
patient’s blinding during the administration process, the following procedures are to be 
applied:

Syringes unpacked and prepared for injection are to be covered by a surgical drape at the 
time of patient preparation for dosing. The same procedure is to be applied to used 
syringes after injection.

During the dose administration, patients are to be separated from the unblinded designee 
who will administer the trial medication by, for example, a surgical drape or screen.

Used syringes should be discarded in a sharp container immediately after use .


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Site staff blinding procedure
Responsibilities for blinded and unblinded study site staff are defined below. At each site, a 
form with the name(s) of the staff members, blinded and unblinded, with their respective 
responsibilities will be filled in.
(NOTE: all personnel noted below will have signed the Site Personnel Signature Log, clearly 
outlining each individual’s responsibility).
In case of non-availability of blinded or unblinded study staff, the CRO and sponsor should 
be informed immediately.
Blinded Personnel
Main Responsibilities
Principal Investigator:
CANNOT ADMINISTER THE MEDICATION

Remains blinded to the medication assignment 
during the whole trial

Monitors patient status

Responsible for the delegation of tasks to 
appropriate staff and to ensure correctness of all 
assessments

Provides direct patient care

Works and communicates with blinded CRA

Ensures adequate unblinded trial site personnel 
and facilities for administration of trial medication

Contacts IXRS® to enter screen failures, screened 
patients, randomizations, and obtain subsequent 
medication assignments 
Blinded Sub-Investigator or Study Coordinator/Study 
Nurse:
CANNOT ADMINISTER THE MEDICATION

Remains blinded to the medication assignment 
during the whole trial

Contacts IXRS® to enter screen failures, screened 
patients, randomizations, and obtain subsequent 
medication assignments 

Monitors patient status

Provides direct patient care, if applicable

Works and communicates with blinded CRA

Can be involved in the receipt, storage control and 
return of IP (since secondary package is blinded)
Blinded CRA:
CANNOT MAKE SAFETY OR EFFICACY 
EVALUATIONS
CANNOT ADMINISTER THE MEDICATION

Remains blinded to the medication assignment 
during the whole trial

Acts as the primary point of contact for the blinded
and unblinded site team

Provides ongoing site support in all areas of trial 
conduct and performs accountability and 
reconciliation of trial medication (after disposal of 
the syringes by the unblinded trial medication 
administrator)

Conducts blinded site monitoring visits and 
performs source document verification
CRA = clinical research associate


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Unblinded Personnel 
Main Responsibilities 
Unblinded Trial Medication Administrator 
(Sub-Investigator or Study Nurse): 
CANNOT MAKE SAFETY OR EFFICACY 
EVALUATIONS

Prepares trial medication for dispensing

Performs the trial medication administration and 
ensures patient is blinded during IP administration

Discard used syringes in a blinded fashion after 
administration of trial medication according to 
local procedures such as local SOPs

Retains used unsealed/opened boxes (secondary 
packaging), which contained the syringes before 
administration of trial medication, for 
reconciliation by blinded CRA prior to destruction

Works and communicates with the blinded CRA in 
a way that does not reveal the treatment arm

Can be involved in the receipt, storage control, and 
return of trial medication
Training
All professional personnel taking part in the clinical trial are trained and aware of the need to 
respect study blinding principles as foreseen by the protocol. Blinded and unblinded trial site 
staff, as well as blinded CRAs, will be trained on trial blinding procedures before the start of 
any trial activities at site. Unblinded trial site staff is restricted to persons handling trial
medications including the injection of trial drug. Training in study blinding procedures for 
blinded trial CRAs will be provided during a CRA Meeting. Training in trial blinding 
procedures for blinded and unblinded site staff will be provided at the Investigators’ Meeting. 
For the remaining site staff, who do not participate in an Investigators’ Meeting, applicable 
training in trial blinding procedures will be provided by a blinded CRA during the Site 
Initiation Visit, based on information in the CTP, Medication Blinding Procedures, and 
Pharmacy Manual. Such training is a part of trial specific agenda for Site Initiation Visit, as 
well as the slide presentation prepared for the visit. All training will be documented.


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LIST OF LABORATORY TESTS
10.2
Category
Test name
Hematology
Hematocrit
Hemoglobin
RBC count / erythrocytes
Reticulocyte count
WBC / leukocytes
Platelet count
Differential automatic
(relative and absolute count)
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes
Differential manual
(relative and absolute count)
(if differential automatic is abnormal)
Neutrophils, bands
Neutrophils, polymorphonuclear
Eosinophils
Basophils
Monocytes
Lymphocytes
Coagulation
Partial thromboplastin time
Prothrombin time (Quick/INR)
Fibrinogen
Enzymes
AST
ALT
Alkaline phosphatase
Creatine kinase
CK-MB, only if CK is elevated
GGT
Lactic dehydrogenase
Lipase
Amylase
Specific gamma-globulin quantification
IgE (only in case of allergic reaction)
IgG
Electrolytes
Calcium
Sodium
Potassium
Chloride
Bicarbonate


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Category
Test name
Substrates
Glucose
Creatinine and creatinine clearance
Bilirubin total
Bilirubin direct
Total protein
Albumin
Uric acid
Cholesterol, total
High density lipoprotein cholesterol
Calculated low density lipoprotein
Cholesterol
Triglycerides
Hormones
TSH (Screening visit only)
Free T3, Free T4 if TSH <LLN or >ULN
Pregnancy test (only for female patients of 
childbearing potential)
β-hCG (serum or urine)
Urinalysis (dipstick)
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/Erythrocyte
Urine WBC/Leukocytes
Urine pH
Urine sediment (microscopic examination)
(if urine analysis is abnormal)
Urine Sediment Bacteria
Urine Casts in Sediment
Urine Squamous Epithelial Cells
Urine Sediment Crystals, Unspecified
Urine Sediment RBC/Erythrocytes
Urine Sediment WBC/Leucocytes
Infectious serology (only at Screening)
HBsAg
HBc antibody (IgM)
Hepatitis C antibody
HIV-1, and HIV-2 antibody (at the 
discretion of the investigator where 
clinically indicated or where mandated by 
local authorities)
TB screening for infections (at Screening, 
Visit 14 and EoT Visit)
TB test (IGRA e.g., QuantiFERON® Gold 
assay)


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Category
Test name
Stool studies to evaluate for enteric 
pathogens1 (only at Screening)
Salmonella
Shigella
Yersinia
Campylobacter
Vibrio
Escherichia coli O157/H7
Clostridium difficile toxin
Enteric parasites and their ova (including 
Cryptosporidia)
β-hCG: beta human chorionic gonadotropin; EoT: end of treatment; GGT: gamma-glutamyl transferase; HBc: hepatitis B 
core; HbsAg: hepatitis B surface antigen; HIV: human immunodeficiency virus; Ig: immunoglobulin;
IGRA: interferon-gamma release assay; INR: International Normalized Ratio; LLN: lower limit of normal; RBC: red blood 
cell; TB: tuberculosis; TSH: thyroid stimulating hormone; ULN: upper limit of normal; WBC: white blood cell.
1. The tests listed in the table are mandatory. If other pathogens are identified, the results will also be provided to the sites.
DETAILS ABOUT THE STATISTICAL CONSIDERATIONS
10.3
The purpose of this appendix is to detail the meta-analysis to estimate the expected treatment 
effect.
The historical treatment effect of Humira was established based on a meta-analysis of studies 
being representative for the treatment effect of Humira in the intended 1297.4 trial 
population:

CLASSIC 1 (R13-2267): a randomized, double-blind, placebo-controlled, dose-ranging 
trial performed to evaluate the efficacy of adalimumab induction therapies in patients 
with CD. In this trial, one endpoint was the percentage of patients achieving a 70-point 
response at Week 4.

GAIN (R13 2264): a 4-week, randomized, double-blind, placebo-controlled trial 
performed to determine whether adalimumab induces remission more frequently than 
placebo in adult patients with CD who have symptoms. One endpoint was also the 
decrease in CDAI score by 70 points.
The results are detailed in Table 10.3: 1.
Table 10.3: 1
CLASSIC I and GAIN study results
CLASSIC I
GAIN
Ada 160 mg/80 mg
Placebo
Ada 160 mg/80 mg
Placebo
Number and frequency of 
patients with 70 points 
CDAI decrease
45 (59.2%)
27 (36.5%)
82 (51.6%)
56 (33.7%)
Total number of patients 
per group
76
74
159
166
Ada: adalimumab; CDAI: Crohn’s Disease Activity Index.


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Response rate
The effect size was computed using the Freeman and Tukey method which is used to 
normalize and variance-stabilize the sampling distribution of proportions. Then the 
fixed-effects method was used to pool the response rates together. When back-transforming 
the results and considering inverse-variance weights, the pooled response rate was 54.1% 
(95% CI from 47.6% to 60.4%).
Non-inferiority margin
As this is an add-on study only, the standard rules for non-inferiority margin selection will 
not be applied. Instead, the magnitude of preserved historical treatment effect will be used 
(based on the point estimate rather than confidence interval).
The RRs of the two studies were pooled to determine the non-inferiority margin of the study. 
Log transformation was performed and a fixed-effect method (Mantel-Haenszel) was used to 
pool the RRs together. Using the inverse of the lower limit of the 90% CI of the RR, 
M1 = 1/1.31 (=0.76) preserves about 39% of the historical treatment effect of adalimumab 
over placebo (calculated as [ln{1.56}-ln{1.31}]/ln[1.56]=0.3928). The results are presented 
below:
Figure 10.3:1 Forest plot of the meta-analysis of CLASSIC I and GAIN studies
ADA: adalimumab; CI: confidence interval; RR: risk ratio.
Note: Forest plot produced with R 3.2.3 software.
CLINICAL EVALUATION OF LIVER INJURY
10.4
10.4.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.3.6.1 (AESIs), are to be 
further evaluated using the following procedures.
10.4.2
Procedures
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) within 48 to 
72 hours. If it is confirmed that ALT and/or AST values ≥3 times ULN occur in conjunction
with an elevation of total bilirubin of ≥2 times ULN, the laboratory parameters listed below 
(clinical chemistry, serology, hormones, hematology) must be determined and made available 
to the investigator and to Boehringer Ingelheim as soon as possible.


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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.
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
Serology

Hepatitis A (anti-IgM, anti-IgG), hepatitis B (HbsAg, anti-HBs, DNA), hepatitis C 
(anti-HCV, RNA if anti-HCV positive), hepatitis D (anti-IgM, anti-IgG), hepatitis E 
(anti-HEV, anti-HEV IgM, RNA if anti-HEV IgM positive), anti-smooth muscle antibody 
(titer), anti-nuclear antibody (titer), anti-liver-kidney microsomes antibody, 
anti-mitochondrial antibody
Hormones, tumor marker

Thyroid stimulating hormone
Hematology

Thrombocytes, eosinophils
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 (total 
and direct) at least weekly until the laboratory ALT and/or AST abnormalities stabilize or 
return to normal, then monitor further as specified in 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)
GLOBAL AMENDMENT 1
11.1
Date of amendment
15 Mar 2017
EudraCT number
EU number
2016-000612-14
BI Trial number
1297.4
BI Investigational Product(s)
BI 695501
Title of protocol
BI 695501 versus Humira® in patients with active 
Crohn’s disease: a randomized, double-blind, 
multicenter, parallel group, non-inferiority trial
comparing efficacy, endoscopic improvement, 
safety, and immunogenicity
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
Synopsis, Trial site(s)
Description of change
Approximate number of sites and countries 
updated per latest information.
Rationale for change
To reflect current trial status.
Section to be changed
Synopsis, Methodology
Description of change
Inserted text: “The hematocrit value required to 
determine CDAI score at Week 4 will be assessed 
locally and confirmed via central laboratory 
assessment.”
Rationale for change
To clarify that local hematocrit value will be used 
for CDAI evaluation at the Week 4 visit in order 
that clinical response can be determined 
immediately.
Section to be changed
Synopsis, Statistical methods
Description of change
Stratification factor for baseline SES-CD corrected 
to “<16 or ≥16” (previously “>16 or ≥ 16”).
Rationale for change
To correct a typographical error.
Section to be changed
Flow Chart A, footnote 10
Description of change
Text added: “At Visit 4 (Week 4), the hematocrit 
value to determine CDAI score will be assessed 


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locally and confirmed via central laboratory 
assessment. At visits where no physical 
examination is performed, weight must be 
measured for use in CDAI determination.”
Rationale for change
To clarify that local hematocrit value will be used 
for CDAI evaluation at the Week 4 visit in order
that clinical response can be determined 
immediately. Also, to clarify that weight must be 
measured at all visits where CDAI is evaluated.
Section to be changed
Flow Chart B, footnote 6
Description of change
Text added: “At Visit 8 (Week 12), the hematocrit 
value from the central laboratory assessment at 
Visit 6 (Week 8) will be used to determine CDAI 
score. At visits where no physical examination is 
performed, weight must be measured for use in 
CDAI determination.”
Rationale for change
To clarify that hematocrit value from prior central 
laboratory assessment (Visit 6) will be used to 
determine CDAI at Visit 8, and that weight must 
be measured at all visits where CDAI is evaluated.
Section to be changed
3.3.2
Description of change
Inclusion criterion 1c updated to “Presence of 
mucosal ulcers in at least one segment of the ileum 
or colon and a SES-CD score ≥7 (for patients with 
isolated ileal disease SES-CD score ≥4), as 
assessed by ileocolonoscopy and confirmed by 
central independent reviewer(s) before 
randomization”.
Rationale for change
To amend endoscopic eligibility to make severity 
of disease as defined by CDAI consistent with 
endoscopic evaluation (moderate to severely active 
Crohn’s disease implemented as primary inclusion 
criterion: CDAI 220-450).
Section to be changed
3.3.2
Description of change
Inclusion criterion 2 updated to remove text “or 
any other anti TNF agent (except adalimumab)”.
Rationale for change
To clarify that only infliximab is allowed as 
first-line anti-TNF therapy; previous treatment 
with other anti-TNF therapies (specifically 
certolizumab pegol) will not be permitted.
Section to be changed
Table 4.2.2.1: 1
Description of change
Table row #7: treatment column updated to add 


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“and other biologic therapies”.
Table row #10: treatment column updated to 
“Cyclosporine, tacrolimus, and mycophenolate 
mofetil”. Reference to “anakinra (Kineret®) and 
other biologic therapies” removed.
Rationale for change
To maintain consistency with restrictions
presented elsewhere in the protocol.
Section to be changed
5.2.1
Description of change
Text inserted into paragraph #2: “At Week 4, the 
hematocrit value required to determine CDAI 
score will be assessed locally and confirmed via 
central laboratory assessment. At Visit 8 
(Week 12), the hematocrit value from the central 
laboratory assessment at Visit 6 (Week 8) will be 
used to determine CDAI score. At visits where 
CDAI evaluation is performed and no physical 
examination is planned, body weight must be
measured for use in CDAI determination.”
Rationale for change
To clarify that local hematocrit value will be used 
for CDAI evaluation at the Week 4 visit in order 
that clinical response can be determined 
immediately. Also, to clarify that hematocrit value 
from Visit 6 will be used for Visit 8 CDAI 
determination and that weight must be measured at 
all visits where CDAI is evaluated.
Section to be changed
Table 5.2.1: 1
Description of change
CDAI scoring formula corrected for “Body 
Weight” variable on last row of table.
Rationale for change
To correct typographical error.
Section to be changed
5.3.3
Description of change
New paragraph added: “At Week 4, in order to 
assess clinical response during the visit, the 
hematocrit value required to determine CDAI 
score will be assessed locally and subsequently 
confirmed via central laboratory assessment.”
Rationale for change
To clarify that local hematocrit value will be used 
for CDAI evaluation at the Week 4 visit in order 
that clinical response can be determined 
immediately.
Section to be changed
6.2.1, Screening Visit 1.1, Day -9
Description of change
In paragraph #1, specified use of weight 
measurement from Visit 1 in addition to 


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hematocrit value. In same paragraph, also added 
that for patients to be eligible, evidence of mucosal 
ulcers must be in at least one segment of the ileum 
or colon. Also updated “initial isolate ileitis” to 
“isolated ileal disease”.
Rationale for change
To clarify use of Visit 1 weight for CDAI 
determination and to update requirements for 
eligibility to be consistent with inclusion criteria.
Section to be changed
6.2.2, Visits 4 and 14 (Days 29 and 169, 
respectively)
Description of change
Inserted text as new bullet #5: “Local hematocrit 
testing (Visit 4 only; to be used for CDAI 
evaluation)”
Rationale for change
To clarify that local hematocrit value will be used 
for CDAI evaluation at the Week 4 visit in order 
that clinical response can be determined 
immediately.
Section to be changed
7.4.1
Description of change
In paragraph #1:
1. Original text “A snapshot of the database 
will be taken and will be used for 
performing the analysis.” is replaced by 
“The cut-off date will be the date on which 
the last patient completes the Week 4 visit. 
The cut-off date will be the same for all 
patients. A database snapshot will be taken 
with regard to this cut-off date; it will 
include all data available in the database up 
to and including the cut-off date and will 
be used for performing the analysis.”
2. New text inserted at end of paragraph: 
“Efficacy data will be included up to the 
Week 4 visit only and all available data for 
safety and other endpoints will be included 
up to the data cut-off date.”
Rationale for change
To add further clarification of the process to be 
used for primary analysis.
Section to be changed
Appendix 10.1
Description of change
In paragraph #4, added clarification that 
designated person may be unblinded or blinded 
and that unused trial medication may be returned 
to sponsor as an alternative to local destruction.
Rationale for change
To bring protocol in line with instructions included 


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in trial Pharmacy Manual.
Section to be changed
Appendix 10.1, Patient blinding procedure
Description of change
Text added as new bullet #3: “Used syringes 
should be destroyed immediately at the local site 
after use and this should be documented in the 
related investigational product forms.”
Rationale for change
To bring protocol in line with instructions included 
in trial Pharmacy Manual.
Section to be changed
Appendix 10.1, Site staff blinding procedure
Description of change
In table listing blinded personnel, for Blinded 
Sub-Investigator or Study Coordinator/Study 
Nurse, text inserted as new bullet #6: “Can be 
involved in the receipt, storage control and return 
of IP (since secondary package is blinded)”
Rationale for change
To bring protocol in line with instructions included 
in trial Pharmacy Manual.
Section to be changed
Appendix 10.1, Site staff blinding procedure
Description of change
In table listing blinded personnel, for Blinded
CRA, in bullet #2 added that blinded and 
unblinded site teams will be supported.
Rationale for change
To bring protocol in line with instructions included 
in trial Pharmacy Manual.
Section to be changed
Appendix 10.1, Site staff blinding procedure
Description of change
In table of unblinded personnel for Unblinded 
Trial Medication Administrator, bullet list updated 
as follows:
1. New bullet #2 added: “Destroys used 
syringes in a blinded fashion after 
administration of trial medication 
according to local procedures such as local 
SOPs”
2. New bullet #3 added: Retains used 
unsealed/opened boxes (secondary 
packaging), which contained the syringes 
before administration of trial medication, 
for reconciliation by blinded CRA prior to 
destruction”
3. Original bullet #3 updated to: “Works and 
communicates with the unblinded CRA in 
a way that does not reveal the treatment 
arm”
4. Original bullet #4 replaced by: “Can be 


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involved in the receipt, storage control, and 
return of trial medication”
Rationale for change
To bring protocol in line with instructions included 
in trial Pharmacy Manual.
11.2
GLOBAL AMENDMENT 2
Date of amendment
12 Dec 2017
EudraCT number
EU number
2016-000612-14
BI Trial number
1297.4
BI Investigational Product(s)
BI 695501
Title of protocol
BI 695501 versus Humira® in patients with active 
Crohn’s disease: a randomized, double-blind, 
multicenter, parallel group, exploratory trial
comparing efficacy, endoscopic improvement, 
safety, and immunogenicity
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
Title page, Synopsis (Title of trial, Methodology, 
No. of patients, Statistical methods), Sections 2.1, 
3.1, 3.2, 7.1, 7.2, 7.3.1, 7.3.2.1, 7.7.
Description of change
The study methodology as well as related 
statistical method and sample size calculations 
have been updated
Rationale for change
Based on the fact that BI 695501 was already 
approved by the authorities for all Humira 
indications and an additional confirmatory trial is 
not necessary. 
Additionally, the patients with moderately to 
severely active CD (CDAI 220-450), confirmed by 
endoscopy or radiologic evaluation represent a 
relatively small proportion in a Crohn’s disease 
population. This fact causes enormous difficulties 
to find the patients for the study participation 
within a reasonable timeframe and therefore the 
trial was redesigned to an exploratory trial. 
Implementation of the updated statistical 
considerations will allow achieving the study 
objectives for the efficacy, 
as well as the 


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assessments of safety 
 with 
the number of evaluable subjects decreased to 65 
in each group and the total sample size of 
approximately 130.
Section to be changed
Flow Chart A, footnote 4
Description of change
Text added: “….TB test will be performed at 
Week 24 before switch from EU-approved Humira 
to BI 695501, at EoT visit and may be 
performed…..”
Flow Chart B: TB testing (IGRA) added on Visit 
14, Week 24.
Rationale for change
Additional TB testing added on Week 24, before 
switching from Humira to BI 695501, to clarify 
whether the incidence of possible positive TB tests 
is linked to the reference or investigational 
product. 
Section to be changed
3.3.3, 4.2.2.1:1
Description of change
Exclusion criterion 8 updated to “Patients who 
have received any biological treatment (other than 
TNF inhibitors), or investigational biological agent 
with the exception of infliximab within 6 months 
prior to Screening”.
4.2.2.1:1 Line 6 and 7 updated accordingly
Rationale for change
To emphasize that TNF inhibitors use is not 
allowed. 
Section to be changed
3.3.3
Description of change
Exclusion criterion 10 updated to remove text “or 
are positive for anti-adalimumab antibodies at 
baseline”
Rationale for change
To clarify that the results of the ADA are not 
available at the time of inclusion.
Section to be changed
5.2.1
Description of change
Text updated in paragraph #3: “The patient is 
required to keep a symptom diary for 4 of these 8 
variables (number of liquid stools, abdominal pain, 
general well-being, and use of antidiarrheal drugs)
for 7 consecutive days before each CDAI 
evaluation.”
Paragraph #4: The day of bowel preparation for 
colonoscopy and the day of colonoscopy will be 


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excluded from the CDAI assessment.
Rationale for change
To emphasize on which days the parameters for 
the CDAI score are to be captured. 
Section to be changed
5.3.5.1, 
Description of change
Paragraph 2, TB testing included at Visit 14 Week 
24 (before switch from EU- approved Humira to 
BI 695501.
New paragraph 3 added: “In the event of an 
indeterminate or positive result during the study, 
the test should be repeated and if a result is 
positive then the patient will discontinue receiving 
the study treatment and followed up for safety. 
The patient will be referred to the specialist as 
required by local regulations.”
Rationale for change
To clarify the TB testing procedure, evaluation 
and follow up.
Section to be changed
6.2.2, Visits 4 and 14 (Days 29 and 169), 10.2
Description of change
New bullet point added: TB test (IGRA e.g., 
QuantiFERON® Gold assay; at Visit 14 only)
Rationale for change
To clarify the TB testing procedure
Section to be changed
6.2.2, End of Treatment Visit
Description of change
Inserted new text added: “The patient who early 
discontinued from the trial will receive treatment 
as deemed appropriate by the investigator and in 
accordance with the applicable guidance”.
Rationale for change
To give a guidance how to proceed in case of early 
discontinuation.
Section to be changed
Appendix 10.1 
Description of change
Patient blinding procedure:
Text in the bullet #3 updated: “Used syringes 
should be discarded in a sharp container
immediately after use.
The following sentence was removed: “at the local 
site after use and this should be documented in the 
related investigational product forms.”
Site staff blinding procedure (Unblinded 
personnel): 
3rd bullet point updated to: “Discard used syringes 


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in a blinded fashion after administration of trial 
medication according to local procedures such as 
local SOPs.
Rationale for change
To correct the misleading wording on how to 
handle used syringes in accordance with medical 
requirements and to bring the protocol in line with 
instructions included in trial Pharmacy Manual.
Section to be changed
Appendix 10.2, List of laboratory tests, Stool 
studies
Description of change
Foot note 1 was added: “1. The tests listed in the 
table are mandatory. If other pathogens are 
identified, the results will also be provided to the 
sites.”
Rationale for change
To clarify that other pathogens might also be 
identified.
Section to be changed
Appendix 10.3, Non-inferiority margin
Description of change
Following paragraph was added:
As this is an add-on study only, the standard rules 
for non-inferiority margin selection will not be 
applied. Instead, the magnitude of preserved 
historical treatment effect will be used (based on 
the point estimate rather than confidence interval).
Rationale for change
To emphasize that the study design and
methodology was changed.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09542349
5.0
clinical-trial-protocol-revision-02
BI 695501 versus Humira in patients with active Crohn’s disease: a randomized,
double-blind, multicenter, parallel group, exploratory trial comparing efficacy,
endoscopic improvement, safety, and immunogenicity
Author-Trial Clinical Monitor
13 Dec 2017 11:42 CET
Approval-Translational Medicine
Expert
13 Dec 2017 11:44 CET
Author-Trial Statistician
13 Dec 2017 11:50 CET
Author-Trial Clinical
Pharmacokineticist
13 Dec 2017 12:31 CET
Approval-Team Member Medicine
13 Dec 2017 12:46 CET
Verification-Paper Signature
Completion
13 Dec 2017 13:37 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09542349
5.0

SAP_001.pdf: 
Statistical Analysis Plan 
 
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STATISTICAL ANALYSIS PLAN 
 
 
1297.4 
 
BI 695501 VERSUS HUMIRA® IN PATIENTS WITH ACTIVE CROHN’S DISEASE: A 
RANDOMIZED, DOUBLE‐BLIND, MULTICENTER, PARALLEL GROUP, EXPLORATORY 
TRIAL COMPARING EFFICACY, ENDOSCOPIC IMPROVEMENT, SAFETY, AND 
IMMUNOGENICITY 
 
 
 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: FINAL V4.0, 22MAY2019  
 
 


Statistical Analysis Plan 
 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan FINAL V4.0 (Dated 22MAY2019) for Protocol 1297.4. 
 
Name 
Signature 
Date 
Author: 
 
 
 
 
Position: 
Statistical Team 
 
 
Company: 
 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
 
 
 
 
Position: 
Senior Reviewer 
 
Company: 
 
 
Approved By: 
 
 
 
 
Position: 
Trial Statistician 
 
Company: 
Boehringer Ingelheim 
 
Approved By: 
 
 
 
 
Position: 
Medical Expert 
 
Company: 
Boehringer Ingelheim 
 
 


Statistical Analysis Plan 
 
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. 
 
Approved By: 
 
 
 
 
Position: 
Clinical Project 
 
 
Company: 
Boehringer Ingelheim 
 
Approved By: 
 
 
 
 
Position: 
Pharmacokineticist 
 
Company: 
Boehringer Ingelheim 
 
Approved By: 
 
 
 
 
 
Position: 
ADA/nAbs specialist 
 
Company: 
Boehringer Ingelheim 
 
 


Statistical Analysis Plan 
 
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Version Number: 
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Version Date:
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STATISTICAL ANALYSIS PLAN REVIEWED BY 
Boehringer Ingelheim 
Team Role
Trial Statistician 
Project Statistician
Project Programmer 
Medical Expert
Trial Clinical Monitor
Pharmacokineticist
ADA/nAb specialist
Regulatory
Regulatory
Project Medical Writer
Pharmacovigilance, Risk Management Physician 
Team Role
Senior Reviewer
 Programmer
Project 
Global Trial Medical Advisor
Medical Writer
 
 
OUTPUT TEMPLATES SIGNATURE PAGE 
Please refer to Output Templates Final V2.0 (Dated 22MAY2019) for Protocol 1297.4. 
 
 


Statistical Analysis Plan 
 
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Version Number: 
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MODIFICATION HISTORY 
Unique Identifier 
for this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
22MAR2017 
Not Applicable – First Version 
2.0 
09JAN2018 
Updated per Final Protocol – Version 
3.0 
Final Version 1.0 
07FEB2018 
Final edits based on review comments 
Final Version 1.1 
24MAY2018 
Update Periods per BI Request and 
minor text edits 
Final Version 1.2 
31MAY2018 
Final edits – revision of SAP per 
additional BI review comments of Final 
SAP V1.1 
Final Version 1.3 
12SEP2018 
Final edits – revision of SAP per 
additional BI review comments of Final 
SAP V1.2 
Final Version 1.4 
31OCT2018 
Update of the Appendix 2 – Partial Date 
Convention – Algorithm for Treatment 
Emergent Adverse Events 
Final Version 3.0 
29NOV2018 
Update versioning to 3.0 before 
signatures 
 
 
Final Version 4.0 
22MAY2019 
Update Section 5.4 – Per Protocol 
Analysis Set [PPS] for more clarity on 
the 2 Per Protocol Sets 
Update of PK measurement time points 
 
 


Statistical Analysis Plan 
 
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. 
 
TABLE OF CONTENTS 
Statistical Analysis Plan ........................................................................................................................................... 1 
Statistical Analysis Plan Signature Page .................................................................................................................. 2 
Modification History ............................................................................................................................................... 5 
Table of Contents .................................................................................................................................................... 6 
1. 
Introduction .............................................................................................................................................. 12 
2. 
Study Objectives ........................................................................................................................................ 12 
2.1. 
Primary Objective ...................................................................................................................................... 12 
2.2. 
Secondary Objectives ................................................................................................................................ 12 
3. 
Study Design .............................................................................................................................................. 13 
3.1. 
General Description ................................................................................................................................... 13 
3.2. 
Schedule of Events ..................................................................................................................................... 14 
3.3. 
Changes to Analysis from Protocol ............................................................................................................ 15 
4. 
Planned Analyses ....................................................................................................................................... 15 
4.1. 
Primary Analysis ........................................................................................................................................ 15 
4.2. 
Final Analysis ............................................................................................................................................. 15 
5. 
Analysis Sets .............................................................................................................................................. 16 
5.1. 
All Subjects Enrolled Set [ENR] .................................................................................................................. 16 
5.2. 
All Subjects Randomized Set [RND] ........................................................................................................... 16 
5.3. 
Full Analysis Set [FAS] ................................................................................................................................ 16 


Statistical Analysis Plan 
 
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5.4. 
Per Protocol Analysis Set [PPS] .................................................................................................................. 16 
5.5. 
Safety Analysis Set [SAF] ........................................................................................................................... 18 
6. 
General Considerations ............................................................................................................................. 18 
6.1. 
Reference Start Date and Study Day .......................................................................................................... 18 
6.2. 
Baseline ..................................................................................................................................................... 19 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 19 
6.4. 
Windowing Conventions ............................................................................................................................ 19 
6.5. 
Statistical Tests .......................................................................................................................................... 20 
6.6. 
Common Calculations ................................................................................................................................ 20 
6.7. 
Software Version ....................................................................................................................................... 20 
7. 
Statistical Considerations .......................................................................................................................... 20 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 20 
7.2. 
Multicenter Studies ................................................................................................................................... 20 
7.3. 
Missing data .............................................................................................................................................. 21 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 21 
7.5. 
Examination of Subgroups ......................................................................................................................... 21 
8. 
Output Presentations ................................................................................................................................ 21 
9. 
Disposition and Withdrawals ..................................................................................................................... 21 
9.1. 
Important Protocol Deviations .................................................................................................................. 23 
10. 
Demographic and other Baseline Characteristics ....................................................................................... 23 


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10.1.  Derivations ................................................................................................................................................ 25 
11. 
Surgical and Medical History ..................................................................................................................... 25 
12. 
Medications ............................................................................................................................................... 26 
13. 
Trial Medication Exposure ......................................................................................................................... 26 
13.1.  Derivations ................................................................................................................................................ 27 
14. 
Study Medication Compliance ................................................................................................................... 27 
14.1.  Derivations ................................................................................................................................................ 27 
15. 
Efficacy Outcomes ..................................................................................................................................... 28 
15.1.  Primary Efficacy ......................................................................................................................................... 28 
15.1.1. Primary Efficacy Variable & Derivation ...................................................................................................... 28 
15.1.2. Missing Data Methods for Primary Efficacy Variable ................................................................................. 28 
15.1.3. Primary Analysis of Primary Efficacy Variable ............................................................................................ 29 
15.2.  Secondary Efficacy ..................................................................................................................................... 30 
15.2.1. Secondary Efficacy Variables & Derivations ............................................................................................... 30 
15.2.1.1. 
CDAI clinical response .......................................................................................................................30 
15.2.1.2. 
CDAI clinical remission ......................................................................................................................30 
15.2.2. Missing Data Methods for Secondary Efficacy Variable ............................................................................. 31 
15.2.3. Analysis of Secondary Efficacy Variables.................................................................................................... 31 


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16. 
Safety Outcomes ....................................................................................................................................... 34 
16.1.  Adverse Events .......................................................................................................................................... 34 
16.1.1. Adverse Event Specific Derivation ............................................................................................................. 35 
16.1.1.1. 
Treatment Emergent Adverse Event ................................................................................................35 
16.1.1.2. 
Risk ratio ...........................................................................................................................................35 
16.1.1.3. 
Risk difference ..................................................................................................................................36 
16.1.2. All TEAEs .................................................................................................................................................... 36 
16.1.2.1. 
Intensity ............................................................................................................................................36 
16.1.2.2. 
Relationship to Trial Medication .......................................................................................................36 
16.1.3. TEAEs Leading to Discontinuation of Trial Medication ............................................................................... 37 
16.1.4. Serious Adverse Events .............................................................................................................................. 37 
16.1.5. Non‐Serious Adverse Events ...................................................................................................................... 37 
16.1.6. Adverse Events Leading to Death .............................................................................................................. 37 
16.1.7. Other Safety Endpoints and Adverse Events Of Special Interest ................................................................ 37 
16.1.7.1. 
Reported by Investigator ..................................................................................................................38 
16.1.7.2. 
Infections and Serious Infections ......................................................................................................38 
16.1.7.3. 
Hypersensitivity Reactions ................................................................................................................39 
16.1.7.4. 
Drug Induced Liver Injury (DILI) ........................................................................................................39 
16.1.7.5. 
Injection‐site reactions .....................................................................................................................39 
16.1.7.6. 
Anaphylactic reactions ......................................................................................................................40 
16.1.8. AEs Occuring After the Last Injection For Subjects Discontinued Due to Lack of Efficacy ........................... 40 


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16.2.  Deaths ....................................................................................................................................................... 41 
16.3.  Laboratory Evaluations .............................................................................................................................. 41 
16.3.1. Laboratory Specific Derivations ................................................................................................................. 42 
16.3.2. Laboratory Reference Ranges and Markedly Abnormal Criteria ................................................................ 43 
16.3.3. Other safety laboratory evaluations .......................................................................................................... 43 
16.3.3.1. 
Pregnancy test ..................................................................................................................................43 
16.3.3.2. 
Tuberculosis test ...............................................................................................................................43 
16.4.  ECG Evaluations ......................................................................................................................................... 43 
16.5.  Vital Signs .................................................................................................................................................. 43 
16.6.  Physical Examination ................................................................................................................................. 44 
19. 
References ................................................................................................................................................. 50 
APPENDIX 1. 
Programming Conventions for Outputs ...................................................................................... 50 


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APPENDIX 2. 
Partial Date Conventions ............................................................................................................ 56 
APPENDIX 3. 
EMA SOC order for presentation of the AE in the tables. ............................................................ 61 
APPENDIX 4. 
Files Attached to SAP .................................................................................................................. 62 
APPENDIX 5. 
Laboratory Assessments ............................................................................................................. 63 
 
 


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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy, safety, 
immunogenicity, and pharmacokinetics data for Protocol 1297.4. It describes the data to be summarized and 
analyzed, including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on Final Protocol, Protocol Version 3.0 (Revised Protocol (based on 
global amendment 2)), dated 12th of December 2017. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective of this trial is to compare the clinical efficacy of BI 695501 with EU‐approved Humira® in 
patients with active Crohn’s disease (CD). 
2.2. SECONDARY OBJECTIVES 
The secondary objectives of this trial are to compare the efficacy and safety of BI 695501 with EU‐approved Humira 
across the induction and maintenance phases, as covered by Crohn’s disease activity index (CDAI) and safety 
monitoring. 


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3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is an exploratory, randomized, 56‐week, double‐blind, parallel arm, multiple dose, active comparator trial of 
BI 695501 and EU‐approved Humira, with a 48‐week treatment period and a 10‐week follow‐up period (starting 
after last dose of trial medication at Week 46) in patients with moderately to severely active CD, and a primary 
endpoint assessment at Week 4.  
Approximately 130 patients with moderately to severely active CD, for more than 4 months will be randomized 
into the trial. 
The trial will consist of a Screening period of up to a maximum of 28 days and a 48‐week treatment period. The 
treatment period will consist of an induction period from Baseline to Week 4, a maintenance period from Week 5 
to Week 48, and a 10‐week safety follow‐up period (starting after last dose of trial medication at Week 46). 
At Week 4, patients with clinical response will be assessed and only patients who are classified as responders 
(CDAI decrease of ≥70 compared to baseline) will continue on trial and enter the maintenance phase. Patients 
who are originally randomized to EU‐approved Humira will switch to BI 695501 at Week 24. 
Patients will undergo up to 27 visits (including 13 trial medication administration only visits) over the duration of 
the trial (56 weeks). Every effort should be made for all patients who complete the total 48‐week treatment 
period or who discontinue the trial medication early, to return for a Safety Follow‐up Visit 10 weeks after their 
last dose of trial medication. 
Trial medication will be administered by subcutaneous (s.c.) injection.  
 
 


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Diagram of trial design 
 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Sections “FLOW CHART A: SCREENING AND INDUCTION PERIOD” and “FLOW 
CHART B: MAINTENANCE PERIOD” of the protocol. 


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3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
No change to analysis from protocol is planned. 
4. PLANNED ANALYSES 
The following analyses will be performed for this trial: 
 
Primary Analysis (after primary endpoint is available) 
 
Final Analysis (after Database lock, based on all available data) 
This document will provide details for Primary Analysis and Final Analysis. 
The analyses described in this SAP will be performed by 
 Biostatistics following Sponsor Authorization of 
this Statistical Analysis Plan, Sponsor Authorization of Analysis Sets and Data Snapshot/Database Lock. 
4.1. PRIMARY ANALYSIS 
The  primary  analysis  will  take  place  when  all  primary  efficacy  endpoint  data  are  available  and  cleaned  (i.e., 
approximately 4 weeks after the last patient has been randomized). The cut‐off date will be the date on which the 
last patient completes the Week 4 visit and will be the same for all patients. A database snapshot will be taken with 
regard to this cut‐off date; it will include data available in the database up to and including the cut‐off date of Week 
4 visit and will be used for performing the analysis (please refer to APPENDIX 4). Only cumulative results will be 
presented, i.e., patient level data will be excluded meaning that N, mean and SD will be displayed instead of usual 
summary statistics. Indeed, there may be a risk for unblinding when presenting individual data such as minimum or 
maximum values, quartiles together with the treatment groups. Only a selected team, not involved in any other trial 
activities, will have access to the unblinded snapshot data and will be required to sign a confidentiality agreement. 
Efficacy data and all available data for safety and other endpoints will be included up to the Week 4 visit only. 
To ensure that the data integrity of the continuing trial will not be violated, a charter will be prepared in advance, 
outlining  the  procedures  to  be  followed.  This  document  will  describe  the  measures  to  be  implemented  by  the 
Sponsor to protect the integrity of the trial until the final database lock. Team members involved in the conduct of 
the trial as well as the site personnel and patients will remain blinded until the final database lock. A separate clinical 
trial report (CTR) will not be prepared for this analysis; rather it will be attached to the final CTR. 
4.2. FINAL ANALYSIS  
A final analysis (including all endpoints) will be performed when all trial data are available, i.e., approximately 


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56 weeks after the last patient has been randomized. In this analysis, all analyses performed for the primary 
analysis will be repeated with the (partially) updated data, in particular with respect to safety and efficacy 
endpoints collected until Week 56. The results of the final analysis will be summarized in a CTR. 
5. ANALYSIS SETS 
Agreement and authorization of subjects included/excluded from each analysis set will be conducted prior to the 
unblinding of the dedicated staff for primary analysis (Week 4), and unblinding for final analysis (Week 56). The 
analysis sets will be checked at the time of final analysis and may be updated according to data entered in the 
database at the time of database lock. 
5.1. ALL SUBJECTS ENROLLED SET [ENR] 
The all subjects enrolled (ENR) set will contain all subjects who provide signed informed consent for this trial. 
5.2. ALL SUBJECTS RANDOMIZED SET [RND] 
The all subjects randomized (RND) set will contain all subjects in the ENR set who were randomized to trial 
medication. 
For analyses and displays based on RND, subjects will be classified according to randomized treatment. 
5.3. FULL ANALYSIS SET [FAS] 
The full analysis set (FAS) will contain all randomized patients who received at least 1 dose of trial medication, 
and have all efficacy measures relevant for the CDAI, measured at baseline and at least once post‐baseline (on 
Week 4). 
For analyses and displays based on FAS, subjects will be classified according to randomized treatment.  
5.4. PER PROTOCOL ANALYSIS SET [PPS] 
The per‐protocol analysis set (PPS) will contain all subjects in the FAS who did not experience any important 
protocol violations relevant for efficacy. Important protocol violations will be reviewed and approved prior to the 
Data Snapshot/Database Lock. However, additional unexpected protocol deviations may be added afterwards. 
Two Per Protocol Analysis Sets will be analyzed. One PPS for the Primary Analysis based on the week 4 data 


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(primary efficacy endpoint) (PPS) and one for the Final Analysis based on the week 24 data (secondary efficacy 
endpoint) (PPS2). 
The important protocol violations may include but are not limited to: 
 
Incorrect trial medication taken. Kit numbers which were actually used for the preparation of the 
trial drug will be recorded on the eCRF. Defined as, on the patient level, at least one kit number 
used before Week 4 – for Primary Analysis PPS – and before Week 24 – for Final Analysis PPS – does 
not correspond to the initial randomized treatment group. 
 
Important violation of treatment compliance prior to Week 4 – for Primary Analysis PPS – and prior 
to Week 24 – for Final Analysis PPS: medical team will review subjects with treatment compliance 
outside 80% and 120% (refer to section 14.1) and decide if the violation is severe. 
 
Important violation of inclusion/exclusion criteria 
o 
IC1 
o 
IC2 
o 
EC1 
o 
EC7 
o 
EC8 
o 
EC9 
o 
EC10 
o 
EC14 
o 
EC21 
o 
EC25 
o 
EC27 
o 
EC28 
 


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5.5. SAFETY ANALYSIS SET [SAF] 
The safety analysis set (SAF) will contain all subjects in the RND set who receive at least one dose (full or partial) 
of trial medication.  
If there is any doubt whether a subject was treated or not, they will be assumed treated for the purposes of 
analysis. 
For analyses and displays based on SAF: 
‐ 
In case the subject was fully incorrectly treated, the subject will be classified according to treatment 
received 
‐ 
In case the subject was partially incorrectly treated, the subject will be classified according to treatment 
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/stop day of 
assessments and events. It will appear in every listing where an assessment date or event date appears. 


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Reference start date is defined as the day of the first dose of study medication, (Day 1 is the day of the first dose 
of trial medication), or for subjects randomized but not treated it is the day of randomization. 
 
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1. 
 
 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, Study Day, and any corresponding durations will 
appear partial or missing in the listings. 
6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non‐missing measurement taken prior to reference 
start date (including unscheduled assessments). In the case where the last non‐missing measurement and the 
first dose of trial medication date coincide, that measurement will be considered as baseline. 
6.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by‐visit summaries, data recorded at the nominal visit will be presented. In the case of a retest, an 
unscheduled assessment will be created. For laboratory assessments as described in APPENDIX 5, the latest 
available measurement within acceptable timeframe  after the planned assessment will be used for by‐visit 
summaries. Unless assigned to a planned visit number, unscheduled measurements will not be included in by‐
visit summaries. 
Treatment early termination data will be included in End‐of‐Treatment visit in by‐visit table summaries and by‐
visit graphs, according to the protocol. 
Listings will include scheduled, unscheduled, and retest data as collected in the eCRF database. 
6.4. WINDOWING CONVENTIONS  
Unless otherwise specified, visit data as recorded in the database will be used for the analysis. No visit 
windowing recalculation will be performed for this trial. 


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6.5. STATISTICAL TESTS 
The default significance level will be 10%; confidence intervals will be 90% and 95% and all tests will be two‐
sided, unless otherwise specified in the description of the analyses. 
6.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 
Test Value at Visit X – Baseline Value 
6.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher. 
7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN ANALYSES 
The following covariates and factors are used in the primary and secondary efficacy analyses. For details of their 
inclusion in the models, see the specific analysis section. 
 
Treatment (BI 695501 versus EU‐approved Humira) 
 
Prior exposure to infliximab (Yes/No). 
 
Baseline SES‐CD (<16 or ≥16) 
7.2. MULTICENTER STUDIES 
This trial will be conducted by multiple investigators at multiple centers internationally, approximately 128 
clinical sites across approximately 13 countries. Randomization to treatment arms is stratified by prior exposure 
to infliximab (Yes/No) and screening SES‐CD (<16 or ≥16). No stratification by site was planned because of the 
small number of subjects to be randomized per site. 


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7.3. MISSING DATA 
Missing safety data will not be imputed, unless otherwise specified in section 16. 
Missing efficacy data will be handled as described in section 15. 
Calculation for a partial date is described in APPENDIX 2. 
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
No multiplicity consideration is required in this trial. 
7.5. EXAMINATION OF SUBGROUPS 
There is no examination of subgroups. 
8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this trial and therefore the format and 
content of the summary tables, figures, and listings to be provided by 
 Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this trial. 
The counts of the analysis sets will be presented: 
 
All Subject Enrolled Set (ENR) 
 
All Subjects Randomized Set (RND) 
 
Full Analysis set (FAS) 
 
Per Protocol Analysis Set (PPS, PPS2) 
 
Safety Analysis Set (SAF) 


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The reasons for exclusion from the analysis sets will be listed. 
The following subject disposition and withdrawals will be presented for the ENR set: 
 
Screened 
 
Screen failure (defined as withdrawn from trial prior to randomization) 
 
Primary reason for non‐inclusion 
 
Randomized 
 
Randomized but not treated 
 
Treated 
 
Subjects with CDAI decrease ≥ 70 at Day 29 (Week 4) 
 
Subjects treated after Day 29 (Week 4) 
 
Completed treatment at Day 337 (Week 48) 
 
Completed the trial per the protocol 
 
Discontinued from treatment strictly before Day 29 (Week 4), primary reason for premature 
discontinuation from treatment before Day 29 (Week 4) 
 
Discontinued from treatment (before Week 48), primary reason for premature discontinuation from 
treatment 
 
Discontinued from trial (after Week 48), primary reason for premature discontinuation from trial 
The following subject disposition and withdrawals will be presented for the ENR set per site: 
 
Screened 
 
Screen failure (defined as withdrawn from trial prior to randomization) 
 
Randomized 
 
Randomized but not treated 


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 
Treated 
 
Subjects with CDAI decrease  ≥ 70 at Day 29 (Week 4) 
 
Subjects treated after Day 29 (Week 4) 
 
Completed treatment at Day 337 (Week 48) 
 
Completed the trial (Week 56) 
9.1. IMPORTANT PROTOCOL DEVIATIONS 
Protocol violations (as defined in section 5.4), as well as inclusion and exclusion criteria violators will be 
tabulated and listed for the FAS. 
Important protocol violations are defined as: 
 
entering the study even though the subject did not fulfill the entry criteria;  
 
developing withdrawal criteria during the study but the subject did not withdraw;  
 
receiving the wrong treatment or incorrect dose;  
 
receiving a prohibited concomitant treatment. 
Important protocol violations confirmed by a clinical and medical review as recorded in the protocol deviations 
log will be tabulated and listed for the FAS. These violations are not the ones excluding subjects from either one 
of the PPSs (refer to section 5.4). 
The full protocol deviations log will be attached to the clinical trial report. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic characteristics will be reported at Primary Analysis for the FAS, PPS and SAF, and at 
Final Analysis for RND, FAS, PPS, PPS2 and SAF: 
 
Age (years) at Informed Consent 
 
Gender (Male/Female) 


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 
Childbearing potential (Post‐Menopausal/Surgically Sterile/Childbearing Potential (tubal ligation at 
least 6 weeks before screening is considered not of childbearing potential) 
 
Race (American Indian or Alaska Native/Asian/Black or African American/Native Hawaiian or Other 
Pacific Islander/White/Other) 
 
Ethnicity (Hispanic or Latino/Not Hispanic or Latino/Not reported/Unknown) 
 
Country 
 
Weight at baseline (kg) 
 
Height at baseline (cm) 
 
BMI at baseline (kg/m2) 
The randomization stratification categories (Prior exposure to infliximab Yes/No, screening SES‐CD <16/≥16) 
based on eCRF data, will be presented at Primary and Final Analyses for the FAS. Any differences between 
stratification data in the eCRF and IVRS will be documented. 
 
The following baseline disease characteristics will be presented at Primary Analysis for the FAS, PPS, SAF, and at 
Final Analysis for FAS, PPS2, and SAF: 
 
CDAI score at baseline as collected in the eCRF 
 
Mucosal ulceration at baseline as collected in the SES‐CD under the item: Extent of ulcerated 
surface subscore. The second reading will be taken into account in case there were two readings. 
Other baseline characteristics will be presented on FAS and SAF: 
 
Infection screen (for HBsAg, HCV and HIV test) 
 
Chest X‐Ray result 
 
Tuberculosis (TB) test 
 
CRP at baseline 
 
Fecal calprotectin at baseline 


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 
Stool studies at baseline (Salmonella, Shigella, Yersinia, Campylobacter, Vibrio, Escherichia coli 
O157/H7, Clostridium difficile toxin, Enteric parasites and their ova including Cryptosporidia), and 
other identified pathogens. 
Accountability for missing data will be displayed in case of any missing entries. 
10.1. DERIVATIONS 
 
Conversion factors: 
o 
1 lbs=0,453592 kg 
o 
1 in=2,54 cm 
 
BMI (kg/m2) = weight (kg)/height (m)2 
 
Age (years) = (date of consent– date of birth)/365.25 
11. SURGICAL AND MEDICAL HISTORY 
Surgical and Medical History information will be presented at Primary Analysis for the SAF, and at Final Analysis 
for the FAS and SAF. 
Surgical and Medical History will be coded using MedDRA version 19.1 or higher. 
The system organ classes will be sorted by internationally agreed EMA SOC (System Organ Class) order (refer to 
APPENDIX 3), preferred terms will be sorted by decreasing frequencies (within system organ class). 
Data captured on the “Medical History and Previous surgical procedures” page of the eCRF will be assigned to prior 
or concomitant. 
See APPENDIX 2 for handling of partial dates for medical history, surgeries and procedures; if it is not possible to 
define a history, surgery or procedure as prior, concomitant, or post‐treatment, it will be classified by the worst case; 
i.e., concomitant. 
 
Prior medical history, surgeries, and procedures are defined as those conditions or procedures 
which stop prior to or at Screening.  
 
Concomitant medical history, surgeries, and procedures  are defined as those conditions or 
procedure which: 


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o 
started prior to or at Screening and are ongoing or active at the date of Screening 
or 
o 
started after Screening during the treatment period. 
Prior and concomitant surgical and medical history will be presented by SOC and PT (Preferred Term) in two 
separate tables. 
12. MEDICATIONS 
Medications will be presented at Primary Analysis for the SAF, at Final Analysis for the FAS and SAF. They will be 
coded using the WHO Drug Dictionary (WHO‐DD) version SEP2016 or higher. 
No ATC class coding will be performed. The medical terms will be summarized by WHO‐DD Preferred Name. The 
WHO‐DD Preferred Name will be sorted by decreasing frequencies. 
See APPENDIX 2 for handling of partial dates for medications, in the case where it is not possible to define a 
medication as prior, concomitant, or post treatment, the medication will be classified by the worst case; i.e., 
concomitant.  
 
‘Prior’ medications are medications which started and stopped prior to the first dose of trial 
medication.  
 
‘Concomitant’ medications are medications which:  
o 
started prior to, on, or after the first dose of trial medication and started no later than end of trial 
medication,  
o 
AND ended on or after the date of first dose of trial medication or were ongoing at the end of the 
trial. 
 
‘Post’ medications are medications which started after the last dose of trial medication. 
Prior, concomitant, and post medications will be presented in separate tables. 
 
13. TRIAL MEDICATION EXPOSURE 
Exposure to trial medication will be presented at Primary Analysis for the SAF, at Final Analysis for the FAS and 


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SAF. 
The proportion of subjects treated at each planned visit (administration on Day 1 and every other week until Day 323) 
and per treatment group will be presented.  
Descriptive statistics for the number of injections from Day 1 up to Week 4 (included) and from Week 4 
(excluded) up to Week 46 per subjects will be presented. 
Number of subjects per duration of exposure categories, patient time (years) per duration of exposure 
categories, and descriptive statistics for duration of exposure will be presented. 
Exposure categories will be the following cumulative categories: ≥ 1 day, ≥ 2 weeks, ≥ 4 weeks, ≥ 12 weeks, ≥ 16 
weeks, ≥ 24 weeks, ≥ 48 weeks. 
13.1. DERIVATIONS 
The date of first and last trial medication administration will be taken from the eCRF page “Trial Medication 
Injection”. 
Duration of exposure (days) = (date of last injection ‐ date of first injection + 1). 
Duration of exposure (weeks) = Duration of exposure (days)/7. 
Patient Year Exposure (year) = cumulative duration of exposure in days per subject/365.25. 
14. STUDY MEDICATION COMPLIANCE  
Compliance to trial medication will be presented at Primary Analysis for the SAF, at Final Analysis for the FAS, and 
SAF. 
14.1. DERIVATIONS 
Compliance with trial medication will be based on the eCRF page “Trial Medication Injection”. An administered 
injection is considered when the question “Was full dose given” is answered “Yes”. 
Compliance will be based on the comparison of actual administered injections and the planned usage. 
Compliance will include visits until treatment discontinuation. 
 
“Per visit” compliance will be calculated as follows: 
Compliance (%) = 100% if the injection occurred at the specific visit 


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= 0% otherwise 
Note: One administration is planned at each visit. 
 
“Overall” compliance will be calculated as follows: 
Compliance (%) = (Number of administered injections)*100/Planned number of injections 
 
“Week 4” compliance will be calculated considering the injections until Week 4 (visit 4) (included). 
 
“Week 24” compliance will be calculated considering the injections until Week 24 (visit 14) 
(included). 
15. EFFICACY OUTCOMES  
15.1. PRIMARY EFFICACY 
15.1.1. PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy endpoint is: 
 
The proportion of patients in each treatment group with a clinical response (CDAI decrease of ≥70 
compared with baseline) at Week 4 
CDAI decrease at Week 4 is assessed as the decrease relative to baseline measurement: 
 
Decrease = CDAI at Baseline ‐ CDAI at Week 4 
In case of baseline value equal to 0 or missing post‐baseline value recorded, then the change is set to 0 for the 
corresponding visit (no decrease). 
Subjects with a decrease greater or equal to 70 are responders. Other subjects are considered as non‐
responders. 
15.1.2. MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE 
No missing data for the primary analysis endpoint are expected for the FAS, because Week 4 is the first post‐
baseline visit for efficacy assessment and, in case of discontinuation prior to Week 4, the EoT efficacy 
assessments should be performed. 
The non‐responder imputation principle will be followed for the FAS. CDAI evaluation will be set to non‐


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responder at Week 4 if the subject:  
 
discontinues treatment prior to Week 4 
 
is lost‐to‐follow‐up (according to eCRF record for “End of Treatment” or “Trial Completion”) prior to 
Week 4 
15.1.3. PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The primary efficacy analysis will be performed for the FAS. Patients will be assigned to the treatment they were 
randomized to receive. 
The primary objective of this trial is to compare the clinical efficacy of BI 695501 with EU‐approved Humira in 
patients with active CD at the end of the induction phase at Week 4 by means of the Relative Risk (RR). 
The primary analysis of the observed proportion of patients with a clinical response (CDAI decrease of ≥70 
compared with baseline) at Week 4 will be based on log‐linked binomial model. 
The statistical model can be described as follows: 
 
(M1) Response to treatment at Week 4 = treatment + prior infliximab exposure + screening SES‐CD 
This model includes the stratification factor, prior exposure to infliximab, and treatment as fixed effects and 
screening SES‐CD will be included as a categorical effect: 
 
Treatment (BI 695501, EU‐approved Humira) 
 
Prior exposure to infliximab (Yes/No) 
 
Screening SES‐CD (<16 or ≥16) 
The relative risk estimate together with its 90% and 95% CI (ratio scale) will be produced. The following SAS code 
will be used: 
proc genmod data=data_CDAI70 descend; 
class CDAI70(ref="N") TRTP(ref="HUMIRA") EXP_PRIO(ref=”N”) BAS_SES 
(ref=”<16”) / param=GLM; 
model CDAI70=TRTP EXP_PRIO SCR_SES/ dist=binomial link=logit; 
lsmeans TRT / ilink; 
run; 


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15.2. SECONDARY EFFICACY 
15.2.1. SECONDARY EFFICACY VARIABLES & DERIVATIONS 
The following parameters are based on an imputation of CDAI described in Section 15.2.2: 
15.2.1.1. CDAI clinical response 
The proportion of patients in each treatment group with a clinical response (CDAI decrease of ≥70 compared 
with baseline) will be assessed at Week 24. 
The derivation of CDAI decrease is detailed in section 15.1.1. Subjects with a decrease greater or equal to 70 are 
responders. Other subjects are considered as non‐responders. 
In addition, RR and risk difference together with 90% and 95% CIs will be presented. 
15.2.1.2. CDAI clinical remission 
The proportion of patients in each treatment group in clinical remission (CDAI <150) will be assessed at Week 24. 
Subjects with CDAI <150 at Week 24 will be considered as clinical remission cases. 
In addition, RR and risk difference together with 90% and 95% CIs will be presented. 


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15.2.2. MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE 
Missing CDAI at Week 24 will be imputed using the combination of NRI and LOCF methods. Only the data up to 
Week 24, inclusive, will be considered. 
The following table details exactly where the NRI / LOCF imputation method will be applied for the sensitivity 
analysis. 
Table 1: Application of LOCF / NRI for the secondary analysis on the FAS  
 
prior to/on Week 24 
Secondary analysis (FAS) 
Discontinued treatment#  
Did NOT discontinue treatment 
CDAI computable using observed data at Week 24 
Observed 
Observed 
CDAI NOT computable using observed data at Week 24 
NRI applied 
LOCF applied 
 
# lost to follow‐up (according to eCRF record for “End of Treatment” or “Trial Completion”) is also included here, or patients who took a therapy 
that may significantly impact efficacy assessment prior to this time‐point.  
 
The following steps will be followed: 
STEP 1: 
Missing CDAI score will be imputed using LOCF method and CDAI will be calculated based on the imputed scores.  
Last observation will be carried forward as many times as needed. 
STEP 2: 
NRI principle will be considered at Week 24 as detailed in section 15.1.2. 
15.2.3. ANALYSIS OF SECONDARY EFFICACY VARIABLES 
Secondary efficacy endpoints will be presented with descriptive statistics for FAS and PPS2. The relative risk of 
the proportions will be computed and presented together with its 90% and 95% CI and risk difference and 
interpreted in a descriptive manner. 


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16. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF for overall and Period output.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise 
specified with the relevant section.  
Safety will be assessed as a secondary objective in this trial. 
The safety endpoints considered as secondary endpoints are defined as: 
 
Proportion of patients with AEs, SAEs, and AESIs (e.g., serious infections) 
 
Proportion of patients with infections/serious infections (seriousness of infection defined as 
requirement of i.v. antibiotics for treatment and/or meeting seriousness criteria to be qualified as 
an SAE) 
 
Proportion of patients who experience hypersensitivity reactions 
 
Proportion of patients who experience DILI (Drug Induced Liver Injury) 
 
Proportion of patients with injection‐site reactions 
Another safety endpoint is the proportion of patients who discontinue due to drug‐related AEs and AESIs (e.g., 
serious infections and allergic reactions). 
16.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA central coding dictionary, Version 19.1 or higher. The SOCs will 
be sorted by internationally agreed EMA SOC order (refer to APPENDIX 3); PTs will be sorted by decreasing 
frequencies (within system organ class). 
A summary of the number of subjects and percentages within each of the categories described in the sub‐section 
below will be provided.  
In case of worsening in intensity, a new entry is created with start date equal to start of worsening. 
Listings will include Treatment‐Emergent Adverse Events (TEAEs) and Non‐TEAEs. 


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16.1.1. ADVERSE EVENT SPECIFIC DERIVATION 
16.1.1.1. Treatment Emergent Adverse Event 
Treatment‐Emergent Adverse Events (TEAEs) are defined as AEs that started or worsened on or after the first 
dose of trial medication and prior to the last date of trial medication + 10 weeks (70 days) inclusive. 
There are two specific periods of interest: 
Period 1 Treatment‐Emergent Adverse Events (P1 TEAEs) are defined as AEs that started or worsened on or 
after the first dose of trial medication and prior to the date of Week 24 visit or within 10 weeks (70 days, 
inclusive) after the last dose of IMP for patients who discontinued the treatment before Week 24. 
Period 2 Treatment‐Emergent Adverse Events (P2 TEAEs) are defined as AEs that started or worsened on Week 
24 visit and prior to or on the Week 56 visit or within 10 weeks (70 days, inclusive) after the last dose of IMP for 
patients discontinuing treatment prior to Week 46. 
Non‐TEAEs will be classified as “Screening” if AE start date is strictly prior to the first injection date. Non‐TEAEs 
will be classified as “Post treatment” if AE start date is strictly after the last injection date + 70 days. 
See APPENDIX 2 for handling of partial dates for AEs. In the case where it is not possible to define an AE as 
treatment‐emergent or not, the AE will be classified by the worst case, i.e., treatment‐emergent in the period of 
the last injection of trial medication. 
16.1.1.2. Risk ratio 
Risk ratios and associated 95% exact confidence interval will be presented for all adverse events. 
Risk ratio will be defined as: [a/(a+b)]/[c/(c+d)] 
where: 
‐ 
a is the number of subjects with AE within treatment group BI 695501 
‐ 
a+b is the total number of subjects in treatment group BI 695501 
‐ 
c is the number of subjects with AE within treatment Humira 
‐ 
c+d is the total number of subjects in treatment group Humira 
 
PROC FREQ with option RELRISK will be used for programming purpose. 
proc freq data=data; 
tables trt*ae_overall; 
exact relrisk(method=score); 
weight count; 
run; 


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16.1.1.3. Risk difference 
The risk difference between both treatment groups will be displayed together with its 95% confidence interval 
(CI) using the same SAS code as in section 16.1.1.2. 
16.1.2. ALL TEAES  
Number of subjects, percentages, and number of events overall and for period 1 and period 2 will be presented 
by SOC and PT and also broken down further by maximum intensity and relationship to trial medication. 
Periods for TEAE’s: 
Period 1 
Visit date within  
 
[first injection date; Week 24 Visit] or 
 
[first injection date; last injection date + 10 weeks (70 days)] (for 
patients that discontinued the treatment before week 24)]. 
Period 2 
Visit date within  
 
[Week 24 Visit; Week 56 Visit[ or 
 
[Week 24 visit; last injection date + 10 weeks (70 days)] (for 
patients that discontinued the treatment before week 56)]. 
 
16.1.2.1. Intensity 
Intensity is classed as mild/ moderate/ severe (increasing intensity). TEAEs starting after the first dose of trial 
medication with a missing intensity will be classified as severe. If a subject reports a TEAE more than once within 
that SOC/ PT, the AE with the worst case intensity will be used in the corresponding intensity summaries. 
16.1.2.2. Relationship to Trial Medication 
A related AE is defined as a TEAE with the item “Causal Relationship between the event and the trial drug” ticked 
“Related” on the AE form of the eCRF according to the investigator. 
TEAEs with a missing relationship to trial medication will be regarded as related to trial medication. If a subject 
reports the same TEAE more than once for the given period within that SOC/ PT and at least 1 episode was 
assessed as related, the TEAE will be regarded as related in the corresponding relationship summaries. 
All drug related AEs will be listed. 
In addition, the number and percentages of subjects who discontinue due to drug‐related TEAEs will be prepared 


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overall by SOC and PT. 
16.1.3. TEAES LEADING TO DISCONTINUATION OF TRIAL MEDICATION 
TEAEs leading to permanent discontinuation of trial medication will be identified by using the “Action taken with 
trial drug due to AE” equal to “Drug Withdrawn” from AEs eCRF pages. 
The number and percentages of subjects with TEAEs leading to permanent discontinuation of trial medication 
will be prepared overall and for period by SOC and PT. 
The AEs causing treatment modification or drug withdrawal will be listed. 
16.1.4. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as ”Serious” on the Adverse Events page of the eCRF. A 
summary of serious TEAEs by SOC and PT will be prepared overall and for period including the number of 
subjects, percentages and number of events. 
A summary of related SAEs by SOC and PT will also be prepared overall and for period. 
The SAEs and Non‐SAEs will be listed. 
16.1.5. NON‐SERIOUS ADVERSE EVENTS 
Non‐Serious TEAEs with incidence in preferred terms strictly greater than 5% in at least one of treatment groups 
by SOC and PT will also be displayed overall and for period. 
 
16.1.6. ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as ”Fatal” on the Adverse Events page of the eCRF. A 
summary of TEAEs leading to death by SOC and PT will be prepared overall including the number of subjects, 
percentages and number of events. 
16.1.7. OTHER SAFETY ENDPOINTS AND ADVERSE EVENTS OF SPECIAL INTEREST  
A summary of the number of subjects, percentages, and number of events within each of the categories 
described in the sub‐section below will be provided by SOC and PT. 


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In addition, the number and percentages of subjects who discontinue due to drug‐related AESI (as reported by 
investigators and CTP specified) will be prepared overall by SOC and PT. 
The below table describes the allocation of adverse events to AESI group and Other safety endpoints group: 
 
Adverse Event : 
AESI 
Other safety 
endpoint 
     Serious infections 
√ 
√ 
     Infections 
 
√ 
     Hypersensitivity reactions 
√ 
√ 
     Drug induced liver injury 
√ 
√ 
     Injection site reactions 
 
√ 
     Anaphylactic reactions 
√ 
√ 
16.1.7.1. Reported by Investigator 
AESI reported by Investigators are those events recorded as “Adverse Event of Special Interest” equal to “Yes” on 
the Adverse Events page of the eCRF. 
AESI reported by investigators and CTP specified are detailed in the following sections. 
16.1.7.2. Infections and Serious Infections 
Infections are those events with a SOC equal to “Infections and infestations". 
Serious infections are: 
 
AEs which are both infections and SAEs as reported on the Adverse Events page of the eCRF. 
 
AEs which are both infections and identified by the medical advisor as requiring class IV 
(intravenous) antibiotics. 
Serious infection events of special interest (Serious infection AESI) are those events both identified as serious 
infection adverse events and recorded as “Adverse Event of Special Interest” equal to “Yes” on the Adverse 
Events page of the eCRF. 
Infections and Serious Infections will be summarized. Infections / Serious Infections will also be listed. The listing 
will include the “Adverse Event of Special Interest” equal to “Yes” information from the Adverse Events page of 


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the eCRF as a flag. 
16.1.7.3. Hypersensitivity Reactions 
Hypersensitivity reactions are those events recorded as MedDRA code in the pre‐defined Standardized MedDRA 
Queries (SMQ) “Hypersensitivity” (narrow). 
Hypersensitivity reaction adverse events of special interest (Hypersensitivity reactions AESI) are those events 
both identified as Hypersensitivity reaction adverse events and recorded as “Adverse Event of Special Interest” 
equal to “Yes” on the Adverse Events page of the eCRF. 
Hypersensitivity reactions will also be listed. The listing will include the “Adverse Event of Special Interest” equal 
to “Yes” information from the Adverse Events page of the eCRF as a flag. 
16.1.7.4. Drug Induced Liver Injury (DILI) 
Drug Induced Liver Injury (DILI) are those events identified by medical advisor on the subset of AEs for subjects 
presenting laboratory potential DILI findings (refer to section 16.3). 
DILI events of special interest (DILI AESI) are those events both identified as DILI adverse events and recorded as 
“Adverse Event of Special Interest” equal to “Yes” on the Adverse Events page of the eCRF. 
Drug Induced Liver Injury (DILI) will be listed. The listing will include the “Adverse Event of Special Interest” equal 
to “Yes” information from the Adverse Events page of the eCRF as a flag. 
16.1.7.5. Injection‐site reactions 
Injection‐site reactions are those events recorded with MedDRA high level terms (as listed in BIcMQs 
Administration site reaction subsearches 1,2,4 and 5, with a version consistent with the MedDRA version, refer to 
APPENDIX 4): 
 
Administration site reactions NEC  
 
Application and instillation site reactions  
 
Infusion site reactions  
 
Injection site reactions 
These will be presented by period and treatment.  
There are 2 periods: 


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Period 1 
Visit date within [first injection date; Week 24 Visit[ +10 weeks (70 days) 
inclusive (for patients that discontinued the treatment before week 24). 
Period 2 
Visit date within  
 
[Week 24 Visit; Week 56 Visit[ or 
 
[Week 24 visit; last injection date + 10 weeks (70 days)] (for 
patients that discontinued the treatment before week 56)]. 
 
Injection‐site reactions will be listed. 
16.1.7.6. Anaphylactic reactions 
Anaphylactic reactions are those events recorded as MedDRA code in the pre‐defined Standardized MedDRA 
Queries (SMQ) = “Anaphylactic reactions” (narrow) 
Anaphylactic reaction adverse events of special interest (Anaphylactic reaction AESI) are those events both 
identified as Anaphylactic reactions and recorded as “Adverse Event of Special Interest” equal to “Yes” on the 
Adverse Events page of the eCRF. 
Anaphylactic reactions will also be listed. The listing will include the “Adverse Event of Special Interest” equal to 
“Yes” information from the Adverse Events page of the eCRF as a flag. 
 
16.1.8. AES OCCURING AFTER THE LAST INJECTION FOR SUBJECTS DISCONTINUED DUE TO LACK OF 
EFFICACY 
Subjects who discontinued treatment due to lack of efficacy will be identified from “End of treatment visit” eCRF 
page, where “Reason for End of Treatment” is “Progressive Disease”. 
Number of subjects, percentages, and number of events occurring after the last injection and prior to the last 
injection + 10 weeks for subjects discontinued due to lack of efficacy by SOC and PT will be prepared. 
AEs occurring after the last injection and prior to the last injection + 10 weeks for subjects discontinued due to 
lack of efficacy will be listed. 


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16.2. DEATHS 
If any subjects die during the trial as recorded on the “End of Treatment” page or the “Trial Completion” page or 
the AE page (SAE which “Results in death” or AE with “Fatal” outcome) or the “Death” form, the information will 
be presented in a summary table and a data listing. 
16.3. LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this trial for Serum Chemistry, Hematology 
and Urinalysis. A list of laboratory assessments to be included in the outputs is included in APPENDIX 5. 
Presentations will use SI and US Units.  
Quantitative laboratory measurements reported as “< X”, i.e., below the lower limit of quantification (BLQ), or 
“> X”, i.e., above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, i.e., as “< X” or “> X” in the listings. 
Qualitative laboratory urinalysis results measured by central laboratory will be classified to the categories 
“Positive” and “Negative” based on the central laboratory normal reference. 
The handling of retests, unscheduled, and end of trial measurements is described in Section 6.3. However, 
laboratory values taken after the first dose of trial medication up to the end of a period (i.e. up to 10 weeks after 
the last dose of the trial medication) will be assigned to the treatment phase for evaluation. All available data will 
be listed.  
The following summaries will be provided for laboratory data: 
 
Actual and change from baseline by visit (for quantitative measurements) 
 
Shifts from baseline category (Low/ Normal/ High) by visit (except for urinalysis) 
 
Shift from baseline category (Negative/ Positive) by visit (for urinalysis) 
 
Listing of subjects meeting abnormal criteria 
 
Proportion of possible Hy’s law subjects 
 
Proportion of possible Drug Induced Liver Injuries (DILIs) 
 
The time course of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total 
bilirubin (TBL) for all possible Hy’s law subjects, all parameters shown on a logarithm to base 10 


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scale of the multiple of the upper limit of normal (ULN) (Y axis) versus days since treatment start (X 
axis). 
 
Scatter plots for Evaluation of Potentially Drug‐Induced Liver Injury: 
o 
log ALT on the X axis and log TBL on the Y axis, both shown on a logarithm to base 10 scale of 
the multiple of the ULN 
o 
log AST on the X axis and log TBL on the Y axis, both shown on a logarithm to base 10 scale of 
the multiple of the ULN. 
Baseline is described in section 6.2. 
16.3.1. LABORATORY SPECIFIC DERIVATIONS 
 
Log ALT = logarithm to base 10 scale of the multiple of the ULN of ALT 
 
Log AST = logarithm to base 10 scale of the multiple of the ULN of AST 
 
Log TBL = logarithm to base 10 scale of the multiple of the ULN of TBL. Note: Bilirubin value instead 
of TBL will be used. 
 
Potential Hy’s law categories: 
o 
Category 1: ALT or AST ≥ 3xULN and TBL ≥ 2xULN within the same sample 
o 
Category 2: TBL ≥ 2xULN within 30 days after transaminase peak (ALT or AST ≥ 3 ULN) 
 
Potential Hy’s Law subjects are defined as subjects with laboratory data in at least one Potential 
Hy’s law categories at any time point of the trial. 
 
Drug induced liver injury (DILI): 
o 
Normal liver function at Baseline is defined as AST and ALT and Total Bilirubin values measured 
at baseline are each ≤ respective ULN. 
o 
For post baseline visits: 
 
Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN for all 
subjects with normal liver function at baseline. 


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16.3.2. LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in SI units 
and categorized as: 
 
Low: Strictly below the lower limit of the laboratory reference range.  
 
Normal: Within the laboratory reference range (upper and lower limit included). 
 
High: Strictly above the upper limit of the laboratory reference range. 
16.3.3. OTHER SAFETY LABORATORY EVALUATIONS 
16.3.3.1. Pregnancy test 
Descriptive table will present pregnancy results for females by visit on SAF. 
The pregnancy results will be listed as well. 
16.3.3.2. Tuberculosis test 
Descriptive table will present Tuberculosis (TB) test results by visit on SAF. 
The TB test results will be listed as well. 
16.4. ECG EVALUATIONS 
Results from ECGs will be summarized by visit to the categories as recorded in the eCRF page “12‐Lead‐ECG” 
(“Normal”, “Abnormal, not clinically significant” and “Abnormal, clinically significant”). 
ECG evaluations will also be listed. 
16.5. VITAL SIGNS 
The following Vital Signs measurements will be reported: 
 
Sitting Systolic Blood Pressure (mmHg) 
 
Sitting Diastolic Blood Pressure (mmHg) 


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 
Sitting Pulse Rate (bpm) 
 
Temperature (°C). Conversion: Temperature(°C)=[Temperature (F)‐32]/1.8  
Weight will be presented along with vital signs. 
 
Weight (kg) 
The handling of retests, unscheduled, and end of trial measurements is described in Section 6.3. 
The summary of actual and change from baseline by visit will be provided for vital sign data. In case of multiple 
measurement timepoints at one visit, the pre‐injection data will be used for summary tables. 
Vital signs data will be listed. 
16.6. PHYSICAL EXAMINATION 
Incidence of evaluation categories (Normal, Abnormal) at baseline and post‐baseline visits will be provided for 
physical examination data. 
The handling of retests, unscheduled, and end of trial measurements is described in Section 6.3. 
Baseline is described in Section 6.2. 


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19. REFERENCES  
ICH E9 – Statistical Principles for Clinical Trials (Issued 1998) 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
OUTPUT CONVENTIONS 
Output File Naming Conventions 
File names should only consist of lowercase letters, digits (0 to 9) and hyphens. A period should only be used to 
indicate a separator between the file name and the extension. No spaces, other special characters or 
punctuation marks are permitted.  
The program, program log and output file name should reflect the type of the statistical output. The output files 
will contain the output number in addition. If this is not possible, then the output name should be at least as 
descriptive as possible. A prefix can be used to distinguish between a Table, Listing and Figure document (‘t’ for 
table, ‘l’ for listing and ‘f’ for figure). If there is only 1 digit in the number of the table, listing or figure in the place 
where 2 digits are possible, a leading zero should be added in the file name to make sorting consistent with the 
sequence (eg t‐14‐3‐01‐1.RTF) 
As far as possible, output files should be in RTF format. 
The outputs will be provided in pdf format. 
PAPER SIZE, ORIENTATION AND MARGINS 
The size of paper will be Letter. 
The page orientation should preferably be landscape, but portrait is also permitted. 
Margins should provide at least 1 inch (2.54 centimeters) of white space all around the page, regardless of the 
paper size. 
The number of columns per page (linesize) should 134 for Letter. 
The number of rows per page (pagesize) should be 40 for Letter. 
FONTS 
The font type ‘Courier New’ should be used as a default for tables and listings, with a font size of 8. The font 
color should be black. No bolding, underlining, italics or subscripting should be permitted. Try to avoid using 


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superscripts, unless absolutely necessary. Single spacing should be used for all text. 
Figures should have a default font of “Times New Roman”, “Helvetica”, or “Courier New”. 
This can be achieved by using the following options in SAS: 
goptions 
gunit = pct 
cback = white 
colors = (black) 
hby = 2.4 
ftext = “TimesRoman” 
htext = 2.5; 
HEADER INFORMATION 
Headers should be defined as follows: 
 
The header should be placed at the top of the page (same place on each page) regardless of the size or 
orientation of the table or listing 
 
The customer name and protocol number should appear in row 1, left‐aligned 
 
The output identification number should appear in row 2, left‐aligned 
 
The  output  title  should  start  in  row  2  after  output  identification  number  separated  by  a  double  dot, 
left‐aligned 
 
The output population should appear in row 2 after output title separated by a dash, left‐aligned. The 
population should not be spelled out in full, e.g. FAS in preference to Full analysis set. 
 
Row 3 should be a continuous row of underscores (‘_’) (the number of underscores should equal the linesize) 
 
Row 4 should be a blank line 
 
Mixed case should be used for titles 
 
The output titles should be designed so that they are arranged consistently through all outputs. For example, 
content (e.g., Vital Signs) followed by metric (e.g., Change from Baseline) e.g. Vital Signs – Change from 
Baseline. 
 
Titles should not contain quotation marks or footnote references 
 
The column headings should be underlined with a row of underscores (‘_’) 
 
Column headings spanning more than one column should be underlined and have underscores on either 
side of the title and should be centered 
 
Column headings containing numbers should be centered 
 
Column headings should be in sentence case 
 
In general, the population count should appear in the column header in the form “(N=XXX)” 
 
“Statistic” should be the column header over n, Mean, SE, n (%) etc. 
 
As a rule, all columns should have column headings. 
 
 


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TABLE AND LISTING OUTPUT CONVENTIONS 
General: 
 
The first row in the body of the table or listing should be blank 
 
The left hand column should start in column 1. No indenting or centering of the output should occur. 
 
Rounding should be done with the SAS function ROUND, if no further specification. 
 
Numbers in tables should be rounded, not truncated, if no further specification. 
 
Alphanumeric output should be left aligned. 
 
Numbers should be decimal point aligned. 
 
Whole numbers should be right aligned. 
 
Text values should be left aligned. 
 
The first letter of a text entry should be capitalized 
 
Listings of adverse events, concomitant medications, medical histories etc. should be sorted in chronological 
order, with earliest adverse event, medication or history coming first. 
 
The trial drug should appear first in tables with treatments as columns 
 
In general, only present totals (across treatment groups) at baseline/randomization, and do not present 
them post randomization. 
 
If possible, include  100%  frequencies in  the table  shell, so that it  is clear what the denominator is  for 
percentage calculations. 
 
All listing outputs should be sorted (preferably by Treatment, Site Number and Subject Number). 
 
Do not use superscripts and subscripts 
 
The width of the entire output should match the linesize option 
Univariate Statistics: 
 
Statistics should be presented in the same order across tables (i.e., n, Mean, SD, Median, IQR, Minimum, 
Maximum or n, gMean, gCV, Mean, CV, SD, Median, Minimum, Maximum) 
 
Table statistics should line up under the N part of the (N=XXX) in the table header. All decimal points should 
line up. If the minimum and maximum are output on one line as Minimum, Maximum then the comma 
should line up with the decimal point. 
 
If the original data has N decimal places, then the summary statistics should have the following decimal 
places: 
o 
Minimum and maximum: N 
o 
Mean, gMean, median, gCV% and CV%: N + 1 
o 
SD, IQR: N + 2 
Frequencies and percentages (n and %): 
 
Percent values should be reported inside parentheses, with one space between the count and the left 
parenthesis of the percentage. Parentheses should be justified to accept a maximum of 100.0 as a value and 
padded with blank space if the percent is less than 100.0. An example is given below: 
77 (100.0%) 


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50 ( 64.9%) 
0 ( 0.0%) 
 
Percentages will be reported to one decimal place, except percents <100.0% but >99.9% will be presented 
as ‘>99.9%’ (e.g., 99.99% is presented as >99.9%); and percents < 0.1% will be presented as ‘<0.1%’ (e.g., 
0.08% is presented as <0.1%). Rounding will be applied after the <0.1% and >99.9% rule.  
E.g., ( <0.1%) 
( 6.8%) 
(>99.9%) 
 
Percentages may be reported to 0 decimal places as appropriate (for example, where the denominator is 
relatively small). 
 
Where counts are zero, percentages of 0.0% should appear in the output.  
Confidence Intervals: 
 
As a rule confidence intervals are output to one place more than the raw data, and standard deviations and 
standard errors to two places more than the raw data 
 
Confidence intervals should be justified so that parentheses displayed on consecutive lines of a table “line 
up”. 
 
Boundary values of confidence intervals should be separated by a comma. 
 
Boundary values should be padded as necessary to accept negative values and to allow alignment of the 
decimal place. 
 
An example is given below: 
(‐0.12, ‐0.10) 
( 9.54, 12.91) 
P‐values: 
 
P‐values should be reported to three decimal places, except values <1.000 but >0.999 will be presented as 
‘>0.999’ (e.g., 0.9998 is presented as >0.999); and values <0.001 will be presented as ‘<0.001’ (e.g., 0.0009 
is presented as <0.001). Rounding will be applied after the <0.001 and >0.999 rule 
Ratios: 
 
Ratios should be reported to one more decimal place than the original data.  
Spacing: 
 
There must be a minimum of 1 blank space between columns (preferably 2) 
Denominators: 
 
If a different count other than the population count is used for a denominator (within the table) to calculate 
percentages, there should be a row in the table that identifies that number “n”. 
 
Alternatively, a footnote should be included in each table with percentages to indicate the denominator for 
percentages. 
Missing values 
 
A “0” should be used to indicate a zero frequency. 


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 
A blank will be used to indicate missing data in an end‐of‐text table or subject listing. 
FIGURE OUTPUT CONVENTIONS 
 
Figures will be provided in PDF files using the SAS Output Delivery System (ODS) as generated by SAS. 
 
The image should be clear and of high quality when viewed in the Word document, and when printed. 
 
In general, boxes around the figures should be used. 
FOOTNOTE INFORMATION 
Footers should be defined as follows: 
 
A continuous line of underscores (‘_’) will follow the body of the table or listing prior to any footnotes at the 
bottom of the page 
 
Table footnotes should be defined using compute statements in the proc report, and should appear directly 
after the body of the table 
 
The program path and name and version number (if applicable) should appear as footnote 1 at the bottom 
of the page 
 
The date/time stamp should appear as footnote 2 at the bottom of the page 
 
Footnotes should be left‐aligned. 
 
Footnotes should be in sentence case. 
 
Only “typewriter” symbols are permitted – e.g., “*”, “$”, “#”, “@”, “&” and “+”. 
 
The  choice  of  footnote  symbols  should  be  consistent.  E.g.,  if  you  have  the  footnote  “#  indicates  last 
observation carried forward” for one table, the same symbol and footnote should indicate LOCF for all 
tables. 
 
If text wraps across more than one line (for a note), the first letter for all lines of text after the first one will 
be indented to align beneath the first letter of the text in the first line. 
 
The page identification in the format Page X of Y (where Y is the total number of pages for the output) should 
appear in the footer, right aligned. 
Ordering of footnotes should be as follows: 
1.) Source data listing reference, if necessary 
2.) Abbreviations and definitions 
3.) Formulae 
4.) P‐value significance footnote 
5.) Symbols 
6.) Specific notes 
 
Common notes from table to table should appear in the same order. 
The symbols should appear in the same order as they are defined in the table or listing, from left to right. 


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DATES & TIMES 
Depending on data available, dates and times will take the form yyyy‐mm‐ddThh:mm:ss. 
SPELLING FORMAT 
English US. 
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment Group 
For Tables and Graphs 
BI 695501 
BI 695501 
EU‐approved Humira 
Humira 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Visits as per protocol 
Day ‐28 to ‐14 
D‐28 to ‐14 
 
Day 1 
D1 
Baseline 
Day 15 
D15 
Day 15 (Week 2) 
… 
… 
… 
Day 337 
D337 
…. 
 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
 
randomized treatment group (or treatment received if it’s a safety output) 


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 
center‐subject ID 
 
date including Study Day (where applicable), 
 
For listings where non‐randomized subjects are included, these will appear in a category after the 
randomized treatment groups labeled ‘Not Randomized’. 
The visit as recorded in the eCRF will be displayed in the listings (and not the remapped visit). 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR PRIOR / ACTIVE MEDICAL HISTORY, SURGERIES AND PROCEDURES 
Partial date to be imputed as: 
Start date 
Earliest possible date 
first day of month if day unknown 
or 1st January if day and month are 
unknown 
 
Stop date 
Latest possible date 
last day of month if day unknown 
or 31st December if day and month 
are unknown, if not resulting in a 
date later than the date of subject's 
death. In the latter case the date of 
death will be used for imputation.  
General rules: 
 
If stop date < screening date, assign as prior  
If stop date >= screening date and start date <= end of treatment, assign as concomitant 
If stop date >= screening date and start date > end of treatment, assign as post Treatment 
If Missing stop date: (Rules 2) 
If stop date is missing could never be assumed as prior  
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
If Missing Start date: (Rules 3) 
If stop date < screening date, assign as prior 
If stop date >= screening date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 


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START DATE 
STOP DATE 
ACTION 
Known 
Known 
General rules 
 
Partial 
General rules 
 
Missing 
Rules 2 
 
 
 
Partial 
Known 
General rules 
 
Partial 
General rules 
 
Missing 
Rules 2 
 
 
 
Missing 
Known 
Rules 3 
 
Partial 
Rules 3 
 
Missing 
Assign as concomitant 
 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
Partial  
Missing 
If start date < trial med start date or start date> trial med stop 
date +70 days, then not TEAE 
If start date >= trial med start date and start date <= trial 
med stop date +70 days, then TEAE 
 
 
 
Partial, but known 
components show that it 
cannot be on or after trial 
med start date 
Known 
Partial  
Missing 
Not TEAE 
 
 
 
Partial, could be on or after 
trial med start date and 
prior to trial med stop date 
+ 70 days 
Known 
Impute start date as earliest possible date, (i.e., first day of 
month if day unknown or 1st January if day and month are 
unknown), except if only day is missing and month and year 
of start date are the same as for trial med start date or if day 
and month are missing and year of start date is the same as 
for trial med start date. In the latter cases, the trial med start 
date will be used for the imputation. 
 


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START DATE 
STOP DATE 
ACTION 
If start date <= stop date, then: 
If stop date < trial med start date, then not TEAE 
If start date > trial med end date +70 days, then not TEAE 
If stop date >= trial med start date and start date <= trial 
med end date +70 days, then TEAE 
If start date > stop date, then: 
Consider the start date as Missing and apply the algorithms 
for missing start date 
 
Partial 
Impute start date as above.
Impute stop date as latest possible date (i.e., last day of 
month if day unknown or 31st December if day and month are 
unknown), if not resulting in a date later than the date of 
subject's death. In the later case the date of death will be 
used for imputation.  
 
If start date <= stop date, then: 
If stop date < trial med start date, then not TEAE 
If start date > trial med end date +70 days, then not TEAE 
If stop date >= trial med start date and start date <= trial 
med end date +70 days, then TEAE 
If start date > stop date, then: 
Consider the start and stop dates as Missing and apply the 
algorithms for missing start date 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < trial med start date, then not TEAE 
If stop date >= trial med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If stop date < trial med start date, then not TEAE 
If stop date >= trial med start date, then TEAE 


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START DATE 
STOP DATE 
ACTION 
 
Missing 
Assumed TEAE 
 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
Partial date to be imputed as: 
Start date 
Earliest possible date 
first day of month if day unknown 
or 1st January if day and month are 
unknown 
 
Stop date 
Latest possible date 
last day of month if day unknown 
or 31st December if day and month 
are unknown, if not resulting in a 
date later than the date of subject's 
death. In the latter case the date of 
death will be used for imputation. 
 
 
General rules: 
 
If stop date < trial med start date, assign as prior  
If stop date >= trial med start date and start date <= end of treatment, assign as concomitant  
If stop date >= trial med start date and start date > end of treatment, assign as post treatment 
 
If Missing stop date: (Rules 2) 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
If Missing Start date: (Rules 3) 
If stop date < trial med start date, assign as prior 
If stop date >= trial med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
General rules 


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START DATE 
STOP DATE 
ACTION 
 
Partial 
General rules 
 
Missing 
Rules 2 
 
 
 
Partial 
Known 
General rules 
 
Partial 
General rules 
 
Missing 
Rules 2 
 
 
 
Missing 
Known 
Rules 3 
 
Partial 
Rules 3 
 
Missing 
Assign as concomitant 


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


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APPENDIX 5. LABORATORY ASSESSMENTS 
Laboratory parameter 
SI unit 
US unit 
Serum chemistry 
 
 
Creatinine 
umol/L 
mg/dL 
Alkaline phosphatase 
IU/L 
U/L 
Aspartate aminotransferase (AST) 
U/L 
U/L 
Alanine aminotransferase (ALT) 
U/L 
U/L 
Gamma glutamyl transpeptidase (GGT) 
U/L 
U/L 
Lactic dehydrogenase 
U/L 
U/L 
Lipase 
U/L 
U/L 
Amylase 
U/L 
U/L 
IgE 
kUL 
kUL 
IgG 
g/L 
ng/dL 
Total bilirubin 
umol/L 
mg/dL 
Direct bilirubin 
umol/L 
mg/dL 
Glucose 
mmol/L 
mg/dL 
Total cholesterol 
mmol/L 
mg/dL 
Total protein 
g/L 
g/dL 
Sodium  
mmol/L 
mEq/L 
Potassium  
mmol/L 
mEq/L 
Chloride 
mmol/L 
mEq/L 
Calcium  
mmol/L 
mg/dL 
Albumin 
g/L 
g/dL 
Bicarbonate 
mmol/L 
nEq/L 
Uric acid 
umol/L 
mg/dL 
High density lipoprotein cholesterol 
mmol/L 
mg/dL 
Calculated low density lipoprotein 
mmol/L 
mg/dL 
Triglycerides 
mmol/L 
mg/dL 
Hematology 
 
 
Hemoglobin 
g/L 
g/dL 
Hematocrit 
V/V 
% 
Erythrocyte 
10^12/L 
10^6/uL 
Platelets 
10^9/L 
10^3/uL 
White blood cells 
10^9/L 
10^3/uL 
Lymphocytes 
10^9/L 
10^3/uL 
Neutrophils 
10^9/L 
10^3/uL 


Statistical Analysis Plan 
 
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Laboratory parameter 
SI unit 
US unit 
Reticulocyte 
% 
% 
Eosinophils 
% 
% 
Basophils 
% 
% 
Monocytes 
% 
% 
Partial thromboplastin time 
seconds 
seconds 
Prothrombin time 
seconds 
seconds 
Fibrinogen 
g/L 
ng/dL 
Urinalysis 
 
 
Protein 
‐ 
‐ 
Glucose 
‐ 
‐ 
Nitrite 
‐ 
‐ 
Ketone 
‐ 
‐ 
Urobilinogen 
‐ 
‐ 
Bilirubin 
‐ 
‐ 
Erythrocyte 
‐ 
‐ 
Leukocyte 
‐ 
‐ 
pH 
‐ 
‐