Clinical trial NCT02899338
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2016-09-21; Completion date: 2017-02-23
Enrollment: 162 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To characterize and compare the pharmacokinetics and to assess the safety of BI 695501 after single injection using either auto injector or prefilled syringe.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI695501 Prefilled syringe intervention 2: BI695501Autoinjector
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Boehringer Ingelheim 
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CTR Appendices – Section 16   
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16.1 STUDY INFORMATION 
16.1.1 Protocol and Protocol Amendments 
Version 1.0, 23 August 2016 
 
 
 
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Clinical Trial Protocol
TITLE PAGE
Document Number:
c11534380-01
EudraCT No.:
EU Trial No:
2016-003158-34
BI Trial No.:
1297.13
BI Investigational 
Product(s):
BI 695501
Title:
Randomized, single-dose, parallel-arm, open-label Phase I trial to 
compare the pharmacokinetics, safety and tolerability of BI 695501 
administered subcutaneously via prefilled syringe or autoinjector
Clinical Phase:
I
Trial Clinical 
Monitor:
 
Phone: 
Fax: 
Coordinating 
Investigator:
,
Phone: 
Fax: 
Status:
Final Protocol
Version and Date:
Version:1.0
Date:23 August 2016
Page 1 of 58
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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:
23 Aug 2016
Trial number:
1297.13
Revision date:
Title of trial:
Randomized, single-dose, parallel-arm, open-label Phase I trial to compare 
the pharmacokinetics, safety and tolerability of BI 695501 administered 
subcutaneously via prefilled syringe or autoinjector
Coordinating
Investigator:
, 
Trial sites:
Multicenter trial to be conducted in three two countries:
SGS Life Science Services – Clinical Research
Clinical Pharmacology Unit Antwerpen
Lange Beeldekenstraat 267
B-2060 Antwerpen, Belgium
PRA HealthSciences
Van Swietenlaan 6, 
9728 NZ Groningen. 
PO Box 8144, 
9702 KC Groningen
Clinical phase:
I
Objective(s):
The primary objective of this trial is to characterize and compare the 
pharmacokinetics of BI 695501 after subcutaneous injection using either a 
prefilled syringe or an autoinjector. Additionally, safety, tolerability and 
immunogenicity will be assessed.
Methodology:
This is a randomized, single-dose, open-label trial in healthy volunteers in two 
sites. This trial will consist of two parallel arms receiving BI 695501 by either a 
prefilled syringe or an autoinjector.
No. of patients: 
160 healthy male and female subjects with evaluable PK data for primary analysis. 
At least 30% of each gender will be included in the study.
total entered:
Consisting of:

subjects with a baseline body weight ≤ 60.0 kg,

subjects with a body weight >60.0 - <90.0 kg,

subjects with a body weight ≥90.0 kg
each treatment:
BI 695501/ prefilled syringe – up to 80 subjects 
BI 695501/ autoinjector – up to 80 subjects 
Diagnosis :
Not applicable
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Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
23 Aug 2016
Trial number:
1297.13
Revision date:
Main criteria
for inclusion:
Healthy male and female subjects aged 18 to 65 years and body mass 
index range: >17.5 to < 35.0
Test product(s):
dose:
mode of 
administration:
BI 695501 solution for injection/autoinjector
40 mg (0.8 mL)
Subcutaneous injection via autoinjector
Comparator products:
dose:
mode of 
administration:
BI 695501 solution for injection/pre-filled syringe
40 mg (0.8 mL)
Subcutaneous injection via prefilled syringe
Duration of treatment:
Single dose administration trial followed by a 57-day observation period and up 
to 70 days safety follow up period
Endpoints
Criteria for pharmacokinetics:
Primary endpoints:
The following primary endpoints will be determined for BI 695501 administered 
via prefilled syringe and autoinjector:

AUC0-1368 (area under the concentration-time curve of the analyte in 
plasma over the time interval from 0 to 1368 hours after dose)

Cmax (maximum measured concentration of the analyte in plasma)

AUC0-∞(area under the concentration-time curve of the analyte in plasma 
over the time interval from 0 extrapolated to infinity)
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Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
23 Aug 2016
Trial number:
1297.13
Revision date:
Safety criteria:
Criteria for safety:
Secondary endpoints: 
The number (proportion) of subjects with drug-related treatment emergent 
adverse events (TEAEs) occurring from Day 1 through Day 70.
Statistical methods:
Primarily, all PK endpoints will be presented descriptively.
Cmax, AUC0-∞and AUC0-1368 will be evaluated descriptively using scatterplots and 
boxplots for prefilled syringe versus autoinjector administration of BI 695501, by 
baseline body weight, and overall.
Additionally, and in an exploratory manner, the relative bioavailability of BI 
695501 using autoinjector compared to BI 695501 using prefilled syringe will be 
estimated using an analysis of variance (ANOVA) model on the logarithmic 
transformed primary PK parameters (Cmax, AUC0-∞and AUC0-1368), adjusting for 
baseline body weight (continuous). In addition to the ratio of the geometric means, 
the 90% confidence intervals will also be presented.
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FLOW CHART
Treatment period
Visit
Day
Planned time
[h:min]
Approx. time (actual 
time) [h:min]
Event and comment
Laboratory/
Urinalysis4
Injection Site Reaction 
Assessment
PKblood
Anti-drug antibodies
Neutralizing antibodies
Physical Exam3
12-lead ECG
Vital signs 
(BP, PR and 
Temperature3)
AE/Concomitant 
Mediation
1
-28 
to 
-2
Screening
X
X
X
X
▲
│
▼
1
21,2
-1
Admission to 
trial center
X
X
X
X
X
1
-1:00
7:00
Predose
X
X
X
X
X
0:00
8:00
Drug 
administration
│
0:30
8:30
X
X
1:00
9:00
X
X
4:00
12:00
X
X
X
X
8:00
16:00
X
12:00
20:00
X
X
2
24:00
8:00
X
X
X
3
48:00
8:00
X
X
▲
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
60:00
20:00
X
4
72:00
8:00
X
84:00
20:00
X
5
96:00
8:00
X
108:00
20:00
X
6
120:00
8:00
X
132:00
20:00
X
7
144:00
8:00
X
8
168:00
8:00
Discharge from 
trial site
X
X
X
X
X
31,2
10
216:00
8:00
Ambulatory 
visit
X
41,2
15
336:00
8:00
Ambulatory 
visit
X
51,2
22
504:00
8:00
Ambulatory 
visit
X
X
X
X
X
X
X
61,2
29
672:00
8:00
Ambulatory 
visit
X
71,2
36
840:00
8:00
Ambulatory 
visit
X
81,2
43
1032
8:00
Ambulatory 
visit 
X
9
57
1368
8:00
Ambulatory 
e.o.t.
End of 
Treatment
X
X
X
X
X
X
X
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Treatment period
Visit
Day
Planned time
[h:min]
Approx. time (actual 
time) [h:min]
Event and comment
Laboratory/
Urinalysis4
Injection Site Reaction 
Assessment
PKblood
Anti-drug antibodies
Neutralizing antibodies
Physical Exam3
12-lead ECG
Vital signs 
(BP, PR and 
Temperature3)
AE/Concomitant 
Mediation
10
70
Safety Follow-
up5
End of Trial
│
▼
X
Note:  Please refer to table 1 for specific planned time points.  
1.
Days -1 to 8 will be inpatient visits. Days 10 to 57 (e.o.t.) will be outpatient/ambulatory visits.
2.
Subjects who discontinue the trial early will have all assessments completed as identified for the e.o.t visit. 
3.
Temperature may be measured orally or aurally; however, should be consistent for all assessments at a given trial 
site.
4.
Full laboratory testing as outlined in Table 5.3.3:1 inclusive IGRA-T will be performed at screening and e.o.t.; 
Abbreviated laboratory testing as outlined in section 5.3.3 will be performed on Day -1, 8, 22 and at the 
investigator’s discretion. 
5.
Day 70: subjects will be contacted to collect safety data.
6.
Flowchart represents an example based on a drug administration time of 8:00 in the morning. If the drug 
administration time is shifted, all other measurements specified in the flowchart have to be shifted accordingly.
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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................10
1.
INTRODUCTION...............................................................................................12
MEDICAL BACKGROUND.............................................................................12
1.1
DRUG PROFILE................................................................................................12
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....14
RATIONALE FOR PERFORMING THE TRIAL.........................................14
2.1
BENEFIT - RISK ASSESSMENT.....................................................................14
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................17
OVERALL TRIAL DESIGN AND PLAN .......................................................17
3.1
3.1.1
Administrative structure of the trial .................................................................17
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................18
SELECTION OF TRIAL POPULATION .......................................................19
3.3
3.3.1
Main diagnosis for trial entry ............................................................................19
3.3.2
Inclusion criteria .................................................................................................19
3.3.3
Exclusion criteria ................................................................................................20
3.3.4
Removal of subjects from therapy or assessments...........................................21
Removal of individual subjects.............................................................................21
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................21
3.3.4.2
3.3.5
Replacement of subjects .....................................................................................22
4.
TREATMENTS...................................................................................................23
INVESTIGATIONAL TREATMENTS ...........................................................23
4.1
4.1.1
Identity of the Investigational Medicinal Products..........................................23
4.1.2
Selection of doses in the trial..............................................................................24
4.1.3
Method of assigning subjects to treatment groups ..........................................24
4.1.4
Drug assignment and administration of doses for each subject .....................24
4.1.5
Blinding and procedures for unblinding...........................................................25
Blinding.................................................................................................................25
4.1.5.1
Unblinding and breaking the code ........................................................................25
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................25
4.1.7
Storage conditions...............................................................................................25
4.1.8
Drug accountability.............................................................................................26
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ................................................................................................27
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4.2.1
Other treatments and emergency procedures..................................................27
4.2.2
Restrictions ..........................................................................................................27
Restrictions regarding concomitant treatment ......................................................27
4.2.2.1
Restrictions on diet and life style..........................................................................27
4.2.2.2
Restrictions regarding women of childbearing potential ......................................28
4.2.2.3
TREATMENT COMPLIANCE........................................................................28
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................29
TRIAL ENDPOINTS..........................................................................................29
5.1
5.1.1
Primary Endpoint(s)...........................................................................................29
5.1.2
Secondary Endpoints..........................................................................................29
...........................................................................................29
ASSESSMENT OF EFFICACY........................................................................30
5.2
ASSESSMENT OF SAFETY.............................................................................30
5.3
5.3.1
Physical examination ..........................................................................................30
5.3.2
Vital Signs............................................................................................................30
5.3.3
Safety laboratory parameters ............................................................................31
5.3.4
Electrocardiogram ..............................................................................................33
5.3.5
Other safety parameters.....................................................................................34
5.3.6
Immunogenicity evaluation................................................................................34
5.3.7
Assessment of adverse events.............................................................................34
Definitions of AEs ................................................................................................34
5.3.7.1
Adverse event collection and reporting ................................................................37
5.3.7.2
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................39
5.4.1
Assessment of Pharmacokinetics.......................................................................39
5.4.2
Methods of sample collection .............................................................................39
5.4.3
Analytical determinations ..................................................................................40
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................40
ASSESSMENT OF BIOMARKER(S) ..............................................................40
5.5
OTHER ASSESSMENTS...................................................................................40
5.6
5.6.1
Assessment of immunogenicity ..........................................................................40
Plasma sampling for Anti-Drug-antibodies characterization................................40
5.6.1.1
Plasma sampling for neutralizing antibody characterization................................41
5.6.1.2
APPROPRIATENESS OF MEASUREMENTS..............................................41
5.7
6.
INVESTIGATIONAL PLAN.............................................................................42
VISIT SCHEDULE.............................................................................................42
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................42
6.2
6.2.1
Screening Period .................................................................................................42
6.2.2
Treatment period(s)............................................................................................43
6.2.3
Follow Up Period and Trial Completion...........................................................43
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................44
STATISTICAL DESIGN - MODEL.................................................................44
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................44
7.2
PLANNED ANALYSES>...................................................................................44
7.3
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7.3.1
Primary endpoint analyses.................................................................................45
...............................................46
...............................................46
7.3.4
Analysis of Safety endpoints...............................................................................46
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................47
INTERIM ANALYSES ......................................................................................47
7.4
HANDLING OF MISSING DATA ...................................................................47
7.5
7.5.1
Safety....................................................................................................................47
7.5.2
Plasma drug concentration - time profiles........................................................47
7.5.3
Pharmacokinetic parameters.............................................................................47
RANDOMISATION ...........................................................................................48
7.6
DETERMINATION OF SAMPLE SIZE .........................................................48
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................51
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
8.1
CONSENT ...........................................................................................................51
DATA QUALITY ASSURANCE ......................................................................52
8.2
RECORDS...........................................................................................................52
8.3
8.3.1
Source documents ...............................................................................................52
8.3.2
Direct access to source data and documents.....................................................52
8.3.3
Storage period of records ...................................................................................53
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................53
8.4
STATEMENT OF CONFIDENTIALITY........................................................53
8.5
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................53
TRIAL MILESTONES.......................................................................................54
8.6
9.
REFERENCES....................................................................................................55
PUBLISHED REFERENCES............................................................................55
9.1
UNPUBLISHED REFERENCES......................................................................56
9.2
10.
APPENDICES.....................................................................................................57
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................58
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ABBREVIATIONS
ACR
American College of Rheumatology
ADA
Anti-drug antibody
AE
Adverse event
AI
Autoinjector
AESI
Adverse event of special interest
ANCOVA
Analysis of covariance
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AP/ALP
Alkaline phosphatase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC0-1368
Area under the concentration curve of the analyte in plasma from time 
zero to 1368 hours
AUC0-
Area under the concentration-time curve of the analyte in plasma over the 
time interval from zero to infinity
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CI
Confidence interval
CL/F
Apparent clearance of the analyte in plasma following extravascular 
administration
CK
Creatine kinase
Cmax
Maximum measured concentration of the analyte in plasma
CPM
Clinical Project Manager
CRA
Clinical Research Associate
CRP
C-reactive protein
eCRF
Electronic Case Report Form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CTSU
Clinical Trial Supplies Unit
DILI
Drug-induced liver injury
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
e.o.t.
end of treatment
FDA
Food and Drug Administration
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GGT
Gamma glutamyl transferase
Hep B
Hepatitis B
Hep C
Hepatitis C
HIV
Human immunodeficiency virus
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
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IGRA
Interferon-gamma release assay
IGRA-T
Interferon-gamma release assay testing
INR
International Normalized Ratio
IRB
Institutional Review Board
ISF
Investigator Site File
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regualtory Activities
nAb
Neutralizing antibody
NOA
Not analyzed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic analysis set
PFS
Prefilled syringe 
PR
Pulse rate
RA
Rheumatoid arthritis
RBC
Red Blood Cell(s)
RDC
Remote data capture
REP
Residual effects period
SAE
Serious adverse event
s.c.
Subcutaneous
SOP
Standard operating procedure
SPC
Summary of Protocol Characteristics
SUSAR
Serious unexpected suspected adverse reactions
TB
Tuberculosis
tmax
Time to reach maximum concentration
TSAP
Trial Statistical Analysis Plan
TNF
Tumor necrosis factor
t1/2
Terminal half-life of the analyte in plasma
ULN
Upper limit of normal
US
United States
Vz/F
Apparent volume of distribution during the terminal phase λz following 
an extravascular dose
WBC
λz
White Blood Cell(s)
Terminal rate constant in plasma
Vz/F
Apparent volume of distribution during the terminal phase λz following 
an extravascular dose
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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by 
synovial inflammation in the joints and consequently, progressive joint destruction. The 
prevalence of RA varies with factors such as gender, race, and smoking status, and ranges 
from 0.5% to 1% (R07-0637). 
The biologic tumor necrosis factor (TNF) antagonists, including the human monoclonal 
antibody (mAb) adalimumab (Humira®, Abbott), are generally preferred as first-line biologic 
therapy. Tumor necrosis factor is a naturally occurring cytokine that is involved in normal 
inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid 
of patients with inflammatory joint disease (e.g., RA and psoriatic arthritis).
The use of adalimumab (Humira®) and other TNF antagonists in RA therapy are endorsed in 
the current RA treatment recommendations of the American College of Rheumatology 
(ACR) (R13-3614) and the European League Against Rheumatism (R14-3385). Humira has 
also gained approval for the treatment of polyarticular juvenile idiopathic arthritis, psoriatic 
arthritis, ankylosing spondylitis, Crohn’s disease, and moderate to severe chronic plaque 
psoriasis.
DRUG PROFILE
1.2
BI 695501 is a monoclonal antibody being developed as a proposed biosimilar to the TNF-
alpha blocker US-licensed and EU-approved Humira (adalimumab). Adalimumab is a 
recombinant human monoclonal immunoglobulin (Ig) GI antibody specific to human 
TNF-alpha. Humira binds specifically to TNF-alpha (and not TNF-beta) and blocks its 
interaction with the TNF receptors, TNFR1 and TNFR2. It has human derived heavy and 
light chain variable regions and human IgG1:k constant regions and is produced in a 
mammalian expression system (R15-0739 and R15-3225).
The preclinical studies that support the clinical program included: 

A comparative 5-week toxicology trial with an 8-week recovery in cynomolgus 
monkeys comparing BI 695501 and EU-approved Humira. There was no difference in
systemic exposure between BI 695501 and EU-approved Humira with repeated 
dosing. This trial demonstrated the similarity of the toxicology profile for BI 695501
and EU-approved Humira.

A single dose pharmacokinetic (PK), subcutaneous (s.c.) trial in cynomolgus monkeys 
comparing BI 695501 to EU-approved Humira. There were no differences in the 
exposure or antidrug antibody (ADA) response in cynomolgus monkeys to BI 695501 
and EU-approved Humira.

A comparative human tissue cross-reactivity trial of BI 695501, US-licensed and 
EU-approved Humira. This trial showed that the patterns of staining of BI 695501, 
US-licensed and EU-approved Humira were similar with minor differences 
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attributable to section to section variation, rather than any true staining differences. 
All of the tissue cross-reactivity staining was consistent with reported sites of TNF
expression and/or previously reported sites of reference product cross-reactivity.

A determination of the potential other cytokines to bind to BI 695501 or inhibit 
binding of BI 695501 to TNF compared to US-licensed and EU-approved Humira. 
None of the three antibodies bound to any of the 8 other cytokines that were tested. 
Additionally, there was no difference in the effect of these cytokines on the binding of 
TNF between BI 695501, US-licensed and EU-approved Humira. 

The potential for BI 695501 to induce in vitro cytokine release or directly activate 
complement compared to EU-approved Humira. The results from this trial 
demonstrated that BI 695501 and EU-approved Humira are not anticipated to induce 
cytokine release in humans and do not directly activate complement.

An irritation potential trial in rabbits with BI 695501 demonstrated that BI 695501 did 
not cause irritation.
To date, a total of 175 male healthy subjects were treated with 40 mg s.c. of BI 695501
administered via prefilled glass syringe in two healthy subject trials 1297.1 and 1297.8
(U13-1096-01 and c03070713). The PK similarity of BI 695501 to US-licensed Humira and 
EU-approved Humira was demonstrated in a healthy volunteers study using the final 
commercial formulation (c03070713) in study 1297.8. 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.
Additionally, 71 healthy volunteers were treated in a Phase I trial (1297.6, c02715841), 
comparing the PK of BI 695501 administrated using an autoinjector or a prefilled syringe
following s.c. injection in the abdominal area. Preliminary results of 66 completed subjects 
showed no clinically relevant differences in PK, safety and immunogenicity.Overall, the 
adverse events (AEs) seen in three healthy subject trials 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 US-licensed Humira (R16-2901) and in the summary of 
product characteristics (SPC) for EU-approved Humira (R16-2926).
A phase III trial (1297.2) in patients with moderate to severe RA is ongoing and recruitment 
has been completed; 645 patients with moderate to severe RA were included and randomized 
to treatment with BI 695501 or US-licensed Humira in a blinded manner. The observed 
blinded AE profile revealed no unexpected safety findings and showed no clinically relevant 
safety concerns. The extension trial to the RA trial (1297.3) is ongoing where patients with 
benefit on the pivotal trial are treated with Bi 695501 in an open label fashion.
In addition, 77 patients with RA were enrolled in an open label real life handling study 
(1297.11) and received 4 doses of BI 695501 by AI. Patients completing the AI part of the 
study are being continued in an extension phase and will self-inject BI 695501 via PFS for 
additional 42 weeks. No unexpected safety concerns have been observed in this study till 
date.
For further details see ‘Investigator’s Brochure’ (c01843589).
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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
BI 695501 is being developed in two different presentations – prefilled syringe and 
autoinjector, both containing the same drug product of 40 mg BI 695501 per 0.8 mL solution.
Pursuant to the draft guidance published by the FDA (R13-5230), additional considerations 
for drug products developed as a drug-device combination for the treatment of RA should be 
addressed throughout the entire development program. Changes in the device components 
may affect the drug product delivery characteristics and clinical performance of the drug-
device combination product. 
This PK bridging trial aims to demonstrate similar delivery of the drug product to the same 
biospace across a range of body weights for the two delivery devices for BI 695501 in 
development (a prefilled syringe and an autoinjector); additionally, clinical data to support 
the safety, including immunogenicity and local tolerability will be evaluated. Humira is 
approved for administration in abdomen and thigh as injection sites. In contrast to 1297.6 
study which evaluated abdomen as an injection site, this study is designed to compare the PK 
between BI 695501 PFS vs AI, when administered in the thigh. 
The primary objective of this trial is to compare the PK of 40 mg of BI 695501 administered
using an autoinjector and 40 mg of BI 695501 administered using a prefilled syringe
following a single s.c. injection in the thigh. In particular: Cmax, AUC0-1368 and AUC0-∞.
The assessment of safety (proportion of subjects with drug-related TEAEs) will be the 
secondary objective of this trial.
BENEFIT - RISK ASSESSMENT
2.3
Participation in this trial is without any (therapeutic) benefit for healthy subjects. Their 
participation in the trial, however, is of major importance to the development of the 
BI 695501 autoinjector. The subjects are exposed to the risks of the trial procedures and the 
risks related to the exposure to the trial medication. 
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Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venepuncture for blood sampling.
The total volume of blood withdrawn during the entire trial per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
The needle cap on the prefilled syringe contains dry natural rubber. In rare cases this may 
cause severe allergic reactions. However, since the injection will be performed by the 
experienced medical personnel, the risks will be minimized. Subjects with a known history of 
allergic reactions will not be included into the trial. 
Drug-related risks and safety measures
Adalimumab (Humira) has a generally favorable clinical safety profile, and is not associated 
with AEs that would suggest a high risk to subjects 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 (HBV) reactivation have been reported in patients receiving 
anti-TNF therapy. Some cases have been fatal, the majority of which were in patients 
concomitantly receiving other immunosuppressive medications.
Tuberculosis (TB) reactivation or new TB infections have been observed in patients receiving 
Humira and other TNF-inhibitors, including patients who had previously received treatment 
for latent or active TB. 
To avoid a risk of reactivating TB and other infections, TB tests (interferon-gamma release 
assay [IGRA]), Hepatitis B Surface Antigen (qualitative), Hepatitis B Antibody (qualitative), 
Hepatitis C Antibodies (qualitative), human immunodeficiency virus (HIV)-1 and HIV-2 
Antibody (qualitative) will be performed prior to dosing to exclude subjects tested positive. 
Risk to subjects will also be minimized in this trial by implementing conservative eligibility 
criteria. 
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 when treated with multiple doses. However, the 
possible risk for the development of malignancies cannot be excluded. 
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Further information regarding relevant contraindications, special precautions, adverse 
reactions and other recommendations for the use of US-licensed Humira and EU-approved 
Humira are described in the prescribing information (R16-2901 and R16-2926). 
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 the three groups in this phase I 
trial and the dose of 40 mg BI 695501 was safe and well tolerated in young healthy 
volunteers. The AE with the highest incidence in the 108 subjects who received BI 695501 
in trial 1297.8 was headache (25 subjects, 23.1%), followed by upper respiratory tract
infections (19 subjects, 17.6%). However, there was no difference in the AE profile between 
BI 695501 to US-licensed and EU-approved Humira®. There were no clinically relevant 
findings with respect to clinical laboratory evaluation, vital signs, electrocardiograms 
(ECGs), or injection site reactions.
The subjects will be kept in a Phase I unit for 8 days after trial medication administrationfor 
safety evaluations and blood samples draws. A careful clinical examination will be performed 
before the subjects are discharged from the clinic, during the trial and at the end of trial visit.
Subjects will be followed up during outpatient ambulatory visits. The ambulatory visits will 
occur on Days 10, 15, 22, 29, 36, 43 and 57 (End-of-Treatment [e.o.t.]) and will allow for 
collection of safety signs and symptoms that may occur or arise following trial treatment. 
Adverse events, body temperature, vital signs, ECGs and safety laboratories as well as 
immunogenicity will be monitored at different time points during the trial. During the long 
term safety follow-up period all AEs, regardless of relatedness, will be collected until 10
weeks after the administration of trial medication.
Although rare, a potential for drug-induced liver injury (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 subjects´ 
safety, see also section 5.3.7.1.
In addition, hypersensitivity reactions, anaphylaxis, and serious infections are considered as 
adverse events of special interest (AESI), see Section 5.3.7.1.
Based upon preclinical and clinical information available to date, healthy subjects in this trial 
will not be exposed to undue safety risks.
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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
The trial will be performed as a randomized, single-dose, open-label, parallel arm trial in 
healthy male and female subjects aged 18 to 65 years, in order to evaluate and to compare 
the PK and safety of the test treatment (A/BI 695501 in autoinjector) to the reference 
treatment (B/ BI 695501in prefilled syringe) in a broad weight range . The subjects will be 
allocated to 3 weight groups: ≤ 60.0 kg, >60.0 - <90.0 kg, ≥90.0 kg. The subjects will be 
randomly allocated to one of the two treatments (A or B). The treatments will be one 40 mg 
BI 695501/ autoinjector (A) or one 40 mg BI 695501 / prefilled syringe (B) followed by 
approximately 57 days of observation period.  
It is planned to include 160 healthy male and female subjects (at least 30% of each gender 
will be included in the study) with a broad range of weight for the primary analysis report 
describing the PK profiles of BI 695501 given in a prefilled syringe and an autoinjector as 
well as the assessments of safety and immunogenicity. All efforts will be made to enroll 
subjects in all subgroups, in order to ensure a wide distribution of weight in the study.
This trial will have a screening period of up to 28 days. The subject will check-in to the trial
center on Day -1, will be dosed on Day 1 and be resident until the Day 8 discharge 
procedures are complete. All subjects will remain in the clinic until day 8 after dosing. The 
subject will then return to the clinic for 7 ambulatory visits on Days 10, 15, 22, 29, 36, 43 and 
57 (e.o.t.).
Additionally, all AEs, regardless of relatedness, will be collected until 10 weeks after the 
administration of trial medication. Adverse events not fully resolved at the Safety Follow-up 
visit will be followed until recovery or in case of persistency, sufficient characterization has 
been achieved and the investigator and medical monitor agree to not pursue them further.
For details for treatments to be administered refer to Section 4.1.
An overview of all relevant trial activities is provided in Flow Chart. For visit schedule and 
details of trial procedures at selected visits, refer to Section 6.1 and Section 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) International GmbH.
A Coordinating Investigator is responsible to coordinate Investigators at different centres 
participating in this multicentre trial. 
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating 
the activities required to manage the trial in accordance with applicable regulations and 
Standard Operating Procedures (SOPs). 
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma
GmbH & Co. KG, Biberach, Germany.
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The trial will be conducted at two clinical sites in two countries:
-
Clinical Pharmacology Unit Antwerpen of SGS Life Science Services – Clinical Research, 
Antwerpen, Belgium under the supervision of the principal investigator.
-
PRA Health Sciences, Van Swietenlaan 6, 9728 NZ Groningen. PO Box 8144, 9702 KC 
Groningen
Details of the investigators and other personnel whose participation may materially affected 
the conduct of the trial, including their curricula vitae are provided in Clinical Trial Master 
File.
Safety laboratory tests will be performed by the local laboratory of the trial sites. ZNA 
Klinisch Laboratorium, Lange Beeldekensstraat 267, 2060 Antwerpen, Belgium and 
PRA HS Clinical Chemistry Lab, Van Swietenlaan, 6 9728 NZ Groningen.
The analyses of BI 695501 PK, ADA and neutralizing antidrug antibody (nAb) samples will 
be performed by
. 
The organisation of the trial (including but not limited by Project Management, Clinical Field 
Monitoring, Medical Monitoring, On-site monitoring, Data Management) in the participating 
countries will be performed by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
This is a 14-week, open-label, randomized, single dose, parallel arm trial to investigate and 
compare the PK, safety, tolerability and immunogenicity of BI 695501 administered 
subcutaneously in the thigh via prefilled syringe or autoinjector.
Due to the long half-life of BI 695501, a parallel group design was selected, with 
administration of BI 695501 as a single dose only. Additionally, randomization minimizes 
selection bias between the treatment groups.
Blinding is not possible because the BI 695501 presentations are visually distinguishable. 
The open-label treatment is not expected to bias the PK results, since the trial endpoints are 
derived from measurement of plasma concentrations of the analyte provided by a 
bioanalytical laboratory which is blinded to treatment allocation.
It is not expected that the device itself, being a prefilled syringe or an autoinjector, has an 
influence on the bioavailability in terms of rate and extent of absorption especially 
considering the long half-life of the compound. The most likely important variable is the
reliability of the injection with regards the depth of the injection and thus the tissue reached 
as well as the amount of drug being injected by the device. The injection characteristics are 
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more likely influenced by the amount of s.c. fat tissue. Body mass index and weight have a 
good correlation with s.c. fat tissue thus the inclusion of healthy subjects having a broad 
range of weight would give a better estimation of the reliability and performance of the 
devices.
The group size of up to 80 subjects per treatment group is considered adequate for an
evaluation of the PK, safety, tolerability, and immunogenicity for the primary analysis report 
to support the primary objective of the study. 
SELECTION OF TRIAL POPULATION
3.3
It is planned that in total up to 160 healthy male and female subjects will enter the trial. All 
efforts will be made to enroll in all 3 weight categories, in order to ensure a wide distribution 
of weight in the study. 
Subjects, who prematurely discontinue the trial due to any reason, may be replaced to ensure 
sufficient numbers complete the trial. Thus the planned number of subjects entered may 
exceed a total of 160. They will be recruited from the volunteers’ pool of the trial sites.
Male and female healthy subjects with a weight in the indicated weight groups will be 
included into the trial. This will ensure that performance of the devices is tested in a wide 
range of weight ranges and is representative of wider patient population.
A log of all subjects 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
The trial will be performed in healthy male and female subjects.
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. Age between 18 and 65 years (inclusive)
2. BMI of >17.5 to <35.0 kg/m2
3. Healthy male or female subjects, according to the investigator’s assessment, based on a 
complete medical history including a physical examination, vital signs (blood pressure 
[BP], pulse rate [PR]), 12-lead ECG, and clinical laboratory tests.
4. Subjects who meet any of the following criteria:
-
Surgically sterilized (confirmed 6 month prior to enrollment)
-
Have surgically sterilized sexual partner (confirmed 6 month prior to enrollment)
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Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable 
cases a blood sample with simultaneous levels of FSH above 40 U/L and estradiol below 
30 ng/L is confirmatory)
5. Subjects agree to use an adequate contraception, starting from the begin of the trial and 
until 6 months after the dose of the trial drug: e.g. any of the following methods plus 
condom: implants, injectables, combined oral or vaginal contraceptives, intrauterine 
device
6. 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. Previous exposure to adalimumab or proposed adalimumab biosimilar drugs.
2. Any finding in the medical examination (including BP, PR or ECG) that deviates from 
normal and judged as clinically relevant by the investigator.
3. Any evidence of a concomitant disease judged as clinically relevant by the investigator
including gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, 
immunological, hormonal disorders or diseases of the central nervous system (including 
but not limited to any kind of seizures or stroke), and other relevant neurological or 
psychiatric disorders.
4. History of relevant orthostatic hypotension, fainting spells, or blackouts.
5. Chronic or relevant acute infections.
6. Positive result for HIV, HBV, and hepatitis C (Hep C) at screening.
7. History of relevant allergy or hypersensitivity including allergy to the trial medication, its 
excipients or device materials (e.g. natural rubber or latex).
8. Within 10 days prior to administration of trial medication, use of drugs that might 
reasonably influence the results of the trial.
9. Intake of an investigational drug in another trial within 2 months or 5 half-lives 
(whichever longer) prior to planned administration of the trial medication in this trial or 
intake of an investigational drug during the course of this trial.
10. Alcohol abuse (consumption of more than 28 units/week).
11. Unwillingness/inability to refrain from intake of alcoholic beverages from 48 hours prior 
to the trial medication administration and until Day 14 post trial medication 
administration; and/or to limit alcohol intake to a maximum of 3 units per day until e.o.t.
12. Drug abuse or positive drug screening.
13. Blood donation of more than 500 mL within 30 days prior to administration of trial 
medication or intended donation during the trial.
14. Intention to perform excessive physical activities within 4days prior to administration of 
trial medication or contact sport during the entire trial and unwilling to avoid vigorous 
exercise for 14 days post dosing.
15. Inability to comply with dietary regimen of trial site.
16. Any out-of-range laboratory values considered clinically significant by the investigator; 
(subjects with creatine kinase (CK) values 2 times the upper limit of normal (ULN) at 
Day -1 are to be) excluded from participation).
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17. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because he 
is considered not able to understand and comply with trial requirements, or has a 
condition that would not allow safe participation in the trial.
18. Subjects with any immunological disorders or auto-immune disorders, (e.g., RA, lupus 
erythematosus, scleroderma, etc.).
19. Subject has received a live vaccine within 12 weeks prior to enrolling in the trial.
20. History of TB or positive finding in IGRA.
21. Evidence of skin irritation or infection at the planned injection place.
22. Currently enrolled in another investigational device or drug study
23. Any condition that, in the investigator’s opinion, makes them an unreliable study subject 
or unlikely to complete the trial
24. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
3.3.4
Removal of subjects from therapy or assessments
Removal of individual subjects
3.3.4.1
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep subjects in the trial as scheduled. This includes 
careful subject selection and appropriate explanation of the trial requirements and procedures 
prior to enrolment.
An individual subject is to be withdrawn from trial if:

The subject withdraws consent for trial participation, without the need to justify the 
decision. In this case, no more assessments/investigations will be performed.

The subject needs to take concomitant drugs that interfere with the investigational product 

The subject can no longer participate for other medical reasons (such as surgery, adverse 
events, other diseases, or pregnancy)

The subject 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.
Given the subject’s agreement, the subject will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart (FC) and section 6.2.3.
For all subjects, the reason for withdrawal (e.g. adverse events) must be recorded in the CRF. 
These data will be included in the trial database and reported.
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 reasons including but not restricted to:
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
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In case the planned number of subjects cannot be randomized, the trial clinical monitor 
together with the trial pharmacokineticist and the trial statistician are to decide if the available 
sample size is sufficient to complete 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).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. A replacement subject will be assigned a unique trial subject number, and will be 
assigned to the same treatment as the subject he replaces.
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4.
TREATMENTS
INVESTIGATIONAL TREATMENTS 
4.1
The investigational products have been manufactured and will be provided by BI Pharma 
GmbH & Co. KG. 
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test products are given below:
Substance:
BI 695501 
Pharmaceutical formulation: Solution for injection in autoinjector
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
40 mg / 0.8 mL
Posology:
1-0-0*
Route of administration:
s.c.
Duration of use:
single dose
Substance:
BI 695501 
Pharmaceutical formulation: Solution for injection in prefilled syringe
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
40 mg / 0.8 mL
Posology:
1-0-0*
Route of administration:
s.c.
Duration of use:
single dose
*administered in the morning 
BI 695501 autoinjector will be provided as sterile, preservative-free, non-pyrogenic, 
single-use prefilled syringes in autoinjectors containing 40 mg of BI 695501 per 0.8 mL. One 
autoinjector will be used per injection. The needle cap of the autoinjector syringe contains 
dry, natural rubber. BI is the final manufacturer of the BI 695501 autoinjector. 
BI 695501 prefilled syringe will be provided as sterile, preservative-free, non-pyrogenic, 
single-use prefilled glass syringes containing 40 mg of BI 695501 per 0.8 mL. One syringe 
will be used per injection. The needle cap of the syringe contains dry, natural rubber.
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Any unused product or waste material will be disposed of in accordance with local 
requirements.
4.1.2
Selection of doses in the trial
The dose selected for this trial reflects the standard clinical dose, and established similarity to 
the originator compound (see Section 1.2). The design and handling of the BI 695501
prefilled syringe and autoinjector do not significantly differ from the originator products as 
well and both presentations are intended to be marketed.
4.1.3
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted and informed about the planned visit 
dates.
Once subjects have completed screening, have met all the inclusion criteria and none of the 
exclusion criteria, randomization can occur prior to the planned dosing on Day 1. Subjects
will be stratified by weight and site, and randomized sequentially.
Each prefilled syringe and autoinjector of the trial medication will be labeled with the trial 
code and a unique medication identification number. 
The randomisation procedure is described in Section 7.6.
4.1.4
Drug assignment and administration of doses for each subject
This is a single dose trial. All subjects will receive one of two possible treatments in a 
randomized order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
A
BI 695501
Solution for 
injection in
autoinjector
40 mg
0.8 mL
40 mg
B
BI 695501
Solution for 
injection in 
prefilled 
syringe
40 mg
0.8 mL
40 mg
The autoinjector and prefilled syringe should be removed from refrigeration approximately 
30 minutes before administration, to permit the medication to warm. Injecting cold 
medication can cause discomfort.
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Trial medication will be administered as a single, s.c. injection while the subject is in a supine 
position by the trained investigator or designee. The time, injection location, and any 
difficulties with injection of the trial medication administration will be recorded in the eCRF. 
The location for the injection is the front of the thigh. Detailed “Instructions for use” for 
autoinjector and prefilled syringe will be provided in the ISF. Subjects will be kept under 
close medical surveillance until 24 hours following trial medication administration. 
Standardized meals will be served during the residential period.
For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
No blinding will be performed because the treatments are distinguishable from each other. 
This Phase I trial will be handled in an open-label fashion throughout (that is, during the 
conduct, including data cleaning and preparation of the analysis). This is considered 
acceptable because the potential for bias is low and does not outweigh practical 
considerations.
Emergency envelopes will not be provided, since all subjects will receive the same dose of 
the same drug via different presentations in an open-label design.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site and the bioanalyst will remain blinded.
Unblinding and breaking the code
4.1.5.2
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI. They will be packaged and labelled in 
accordance with the principles of Good Manufacturing Practice (GMP).
For details of packaging, retention sampling, and description of the labels refer to the ISF. 
Re-supply of the trial medication may occur on an as-needed basis during the trial.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the labelled storage conditions. The medication must be stored in a 
refrigerator at a controlled temperature (2 to 8°C [36 to 46oF]) and must not be frozen. A
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temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
Clinical Research Associate (CRA) (as provided in the list of contacts) is to be immediately 
contacted.
4.1.8
Drug accountability
The Investigator < and/or > Pharmacist < and/or > investigational drug storage manager will 
receive the investigational drugs delivered by the sponsor when the following requirements 
are fulfilled:

Approval of the trial protocol by the IRB / ethics committee Institutional Review Board
(IRB) / Independent Ethics Committee (IEC)

Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the principal Investigator

Availability of Form 1572, if applicable
Only authorized personnel as documented in the form ‘Trial Staff List’ (site delegation log)
may dispense medication to trial subjects. The identification of drug kits for retention 
sampling must be completed by the designated site personnel.
The trial medication must be administered in the manner specified in the CTP. All unused 
medication will be disposed locally by the trial site upon written authorization by the clinical 
monitor. Receipt, usage and disposal must be documented on the respective forms. Account 
must be given for any discrepancies. 
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each subject, and the disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
investigator will maintain records that document adequately that the subjects were provided 
the doses specified by the CTP, and that reconcile all investigational products received from 
the sponsor. At the time of disposal, the investigator must verify that all unused or partially 
used drug supplies have been returned and that no remaining supplies are in the investigator’s 
possession.
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OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no specific rescue drugs foreseen for the treatment of AEs. No special emergency 
procedures are to be followed. No additional treatment is planned. However, in case of AEs
in need of treatment, the investigator can authorize symptomatic therapy. In those cases, 
subjects will be treated as necessary and, if required, kept under supervision at the trial site or 
transferred to a hospital until all medical evaluation results have returned to an acceptable 
level.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
In principle, no concomitant therapy is expected in this healthy volunteers trail. All 
concomitant or rescue therapies will be recorded (including time of intake on trial days) on 
the appropriate pages of the eCRF. Hormonal contraceptives are allowed for women of child-
bearing potential; limited amounts of paracetamol (or ibuprofen) are allowed to treat aches 
and pains.
Supplements and herbal preparations are discouraged from use during the course of the trial. 
Vitamins may be used during the trial based on the discretion of the investigator.
Any live or attenuated vaccines are strictly prohibited during the course of the trial.
Use of any prescribed or over-the counter drugs should be reported and discussed with the 
investigator.
The subjects are instructed not to undergo any medical treatment or any surgical 
procedure 14 days prior to, during and until the end of the trial without having 
informed the investigator or his deputy unless necessary to treat medical emergencies. 
Restrictions on diet and life style
4.2.2.2
While admitted to the trial site the subjects are restricted from smoking, consuming any food 
or drink other than those provided by the site staff.
On all days when laboratory sampling is planned, subjects must have fasted for 4 hours prior 
to blood samples being collected.
Excessive exercise should be avoided from 4 days prior to and up to 14 days after trial 
medication administration. Contact sport must be avoided for the duration of the trial.
Female subjects and Male subjects with female partner(s) of child-bearing potential must 
agree to use a medically acceptable method of contraception during the trial and for 6 months 
after the dose of trial drug. Males and male partners of female subjects should use a condom. 
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Female subjects and female partners of male subjects must additionally use one of the
following methods if they are not pregnant: implants, injectables, combined oral or vaginal 
contraceptives, intrauterine device.
Male subjects must also agree to not donate sperm during the trial and for a period of 6 
months after the last dose of trial drug.
Subjects should abstain from alcoholic beverages for 24 hours prior to each trial visit.
Alcoholic beverages are not permitted from 48 hours prior to the first trial medication
administration on Day 1 and until Day 14 and then no more than three units of alcohol per 
day are allowed until e.o.t.
One unit of alcohol is 10 mL (1 cL) by volume, or 8 g by weight, of pure alcohol. For 
example:
One unit of alcohol is about equal to:

Half a pint (290 mL) of ordinary strength beer, lager, or cider (3% to 4% alcohol by 
volume); or

A small pub measure (25 mL) of spirits (40% alcohol by volume): or

A standard pub measure (50 mL) of fortified wine such as sherry or port (20% alcohol 
by volume).
There are one and a half units of alcohol in:

A small glass (125 mL) of ordinary strength wine (12% alcohol by volume); or

A standard pub measure (35 mL) of spirits (40% alcohol by volume).
Restrictions regarding women of childbearing potential
4.2.2.3
A serum beta-human Chorionic Gonadotropin (β-hCG) test will be performed at Screening in 
women of childbearing potential. A local urine pregnancy test will be then performed as 
indicated in the Flow Chart. Any woman with a confirmed positive pregnancy test during 
screening is not eligible for the trial. A positive urine pregnancy test during the study duration 
should be reported and followed up. Female subjects of childbearing potential must use the 
contraception methods described in Section 4.2.2.2 and the subject information.
Acceptable methods of birth control include, for example, birth control pills, intrauterine 
devices (IUDs), surgical sterilization, vasectomized partner and for example male condom in 
combination with female implants, injectables, combined oral or vaginal contraceptives, 
intrauterine device).
TREATMENT COMPLIANCE
4.3
Compliance will be assured by administration of all trial medication at the trial center by the 
investigator or an authorised designee. The measured plasma concentrations will provide 
additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the eCRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).
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5.
VARIABLES AND THEIR ASSESSMENT
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint(s)
The following primary endpoints for PK will be determined for BI 695501 administered via 
PFS and AI:

AUC0-1368 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 1368 hours after dose)

Cmax (maximum measured concentration of the analyte in plasma)

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
5.1.2
Secondary Endpoints
For safety:
Number (proportion) of subjects with drug-related TEAEs occurring from Day 1 through Day 
70.
For PK/immunogenicity:
No secondary endpoints for PK and immunogenicity are defined.
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ASSESSMENT OF EFFICACY
5.2
No efficacy will be evaluated.
ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
A physical examination will be performed at the visits indicated in the Flow Chart.
At the screening visit, the medical examination will include documentation of subject 
information, informed consent, demographics including height and body weight, smoking 
and alcohol history, relevant medical history and concomitant therapy, review of inclusion 
and exclusion criteria, review of vital signs (BP, PR, temperature), 12-lead ECG, laboratory 
tests (including drug and virus screening, IGRA-T), and a physical examination. At the e.o.t.
examination, the medical examination will include review of vital signs, 12-lead ECG, 
laboratory tests (including IGRA-T), and a physical examination with determination of 
weight. Adverse events and concomitant therapies will be assessed throughout the trial.
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.
5.3.2
Vital Signs
Systolic and diastolic BP as well as PR or heart rate (heart rate is considered to be equal to 
PR) will be measured by means of a validated BP device at the times indicated in the 
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Flow Chart, after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of BP recording instrument on the same arm if possible.
The method of measuring body temperature (oral/aural) should be consistent at a specific trial 
site.
5.3.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 hours (or 4 hours before admission on Day -1). Overnight fasting is not required at 
the discretion of the investigator or designate for retests.
Required sample volumes for safety/serology laboratory assessments may vary between local 
laboratories. Sample amount may be exceeded if unscheduled (additional) monitoring of 
laboratory results is warranted.
The parameters that will be determined are listed in Table 5.3.3: 1 and Table 5.2.3: 2. 
Reference ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is a relevant abnormality in the automatic blood cell count or in the 
urinalysis, respectively.
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Table 5.3.3: 1
Routine laboratory tests
Functional lab group
Test name 
Hematology
Hematocrit 
Hemoglobin 
Red blood cell count (RBC) 
White blood cell count (WBC)
Platelet count  
Automatic WBC differential 
(relative)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (at the 
investigator’s discretion)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes 
Coagulation1
Activated partial thromboplastin time (Aptt)
Prothrombin time (Quick’s test and international normalized ratio 
[INR])
Fibrinogen
Enzymes
Aspartate aminotransferase (AST/GOT)
Alanine aminotransferase (ALT/GPT)
Gamma glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Substrates
Plasma glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Bilirubin indirect 
Total protein
Albumin
C-Reactive Protein (CRP) 
Total cholesterol 
Electrolytes
Sodium
Potassium
Calcium
Serum Pregnancy test (only for female 
subjects of childbearing potential) at 
screening and if urine pregnancy test is 
positive
Human Serum Chorionic Gonadotropin
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine erythrocytes
Urine Pregnancy test (only for female 
subjects of childbearing potential) at 
randomization and continued as 
indicated in the Flow Chart (including 
EoT
Human Chorionic Gonadotropin in the urine
1 at screening only
The tests listed in Table 5.3.3: 1 will be performed at screening, and as part of the end of trial 
examination.
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The tests listed in Table 5.3.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the eCRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and prior to treatment period on Day -1.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine
Barbiturates
Benzodiazepine
THC
Cocaine
Methadone
Methamphetamines
Opiates
PCP
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Tuberculosis
IGRA-T (e.g. QuantiFERON®-TB Gold IT Test)
The following laboratory parameters will be analyzed at all other visits indicated in 
Flow Chart:

Serum chemistry: creatinine, alkaline phosphatase, AST, ALT, GGT, CK, bilirubin 
(total and direct), glucose, total cholesterol, total protein, albumin, sodium, potassium, 
calcium

Hematology: hemoglobin, hematocrit, platelets, red blood cells, white blood cells, 
lymphocytes, neutrophils

Urinalysis: protein, glucose, erythrocytes
To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed 
prior to the treatment period, and may be repeated at any time during the trial at the discretion 
of the investigator or designee. Alternately, alcohol screening may be done as part of urine 
drug screening. The results will not be included in the CTR.
The laboratory tests listed in Table 5.3.3: 1 and Table 5.3.3: 2 will be performed at the local 
site laboratory with the exception of the drug screening tests. These tests will be performed at 
the trial sites.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.3.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, Avr, Avl, Avf, V1 – V6) will be recorded using a computerized 
electrocardiograph as scheduled in the Flow Chart.
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ECGs will be recorded after the subjects have rested for at least 5 minutes in a supine 
position and will always precede blood sampling. 
All locally printed ECGs will be evaluated by the investigator or a designee. ECGs may be 
repeated for quality reasons (like alternating current artefacts, muscle movements, electrode 
dislocation) and the only valid ECG will be used for analysis and reported in CRF. 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 subject will be removed 
from the trial and will receive the appropriate medical treatment. A physician familiar with 
interpretation of ECG will evaluate the ECG from a clinical perspective and the result 
(whether the ECG result is normal, abnormal not clinically relevant or abnormal clinically 
relevant) will be recorded in the appropriate section of the eCRF. The digitally recorded 
ECGs will be electronically stored.
5.3.5
Other safety parameters
Local tolerability
Injection site reaction assessment will be performed by investigator or site staff according to 
“swelling”, “induration”, “heat”, “redness”, “pain”, or “other findings”. Tolerability will be 
assessed at Day 1 from the time of the injection until Day 2. If any injection site reactions are 
observed, these findings should also be reported on the AE eCRF page.
5.3.6
Immunogenicity evaluation
The following further parameters of interest will be evaluated:

The proportion of subjects with antidrug antibodies (ADAs) at baseline (pre-dose),
Day 22, and Day 57.

ADA titers of ADA positive subjects at baseline (pre-dose), Day 22, and Day 57

The proportion of subjects with neutralizing antidrug antibodies (nAbs) at baseline 
(pre-dose), Day 22, and Day 57
5.3.7
Assessment of adverse events
Definitions of AEs 
5.3.7.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a subject 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 unfavourable 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.
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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 adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalisation or 

prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the subject 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 hospitalisation but might jeopardise 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 hospitalisation 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” can be found in the ISF. A copy of the latest list of 
“Always Serious AEs” will be provided to you upon request. 
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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. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs:
1. 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 lab findings constitute a hepatic injury alert and the subjects showing these lab 
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 lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, 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.
2. Anaphylactic reactions
3. Serious infection (defined as infections requiring IV antibiotics or meeting the 
regulatory definition of a SAE)
4. Hypersensitivity reactions
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 adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
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 
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•
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 aetiologies 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 study drug treatment continues or remains 
unchanged.
Adverse event collection and reporting
5.3.7.2
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their subject files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
•
From signing the informed consent onwards through the Residual Effect Period (REP), 
until individual subject’s end of trial: 
-all AEs (serious and non-serious) and all AESIs.
However, if an individual subject discontinues trial assessments 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 subject’s end of the trial the Investigator must report related SAEs 
and related AESIs.
•
After the individual subject’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 of.
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
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, please 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 designee’s unique entry point (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 upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
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 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 
of AE to the trial medication.
The following should also be recorded as an (S)AE in the CRF 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 subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a subject has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately 
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(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the 
sponsor’s/sponsor designee’sunique entry point (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 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.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
Date and clock time of drug administration and PK sampling will be recorded in the eCRFs.
The actual sampling times will be used for determination of PK parameters.
The PK endpoints to be evaluated are outlined in Section 5.1.
5.4.2
Methods of sample collection
Plasma sampling for pharmacokinetic analysis
Samples of whole blood (approximately 3 mL) will be taken (in tubes containing dipotassium 
ethylenediaminetetraacetic acid [K2EDTA] anticoagulant) at the time points shown in the 
Flow chart for the determination of concentrations of BI 695501.
Method to process the sample after collection will be described in the laboratory manual. 
After completion of the trial, selected PK samples may be retained and used for further 
methodological investigations, e.g., stability testing. The PK samples will be discarded after 
completion of the additional investigations, but not later than 5 years after the final Clinical 
Trial Report (CTR) has been signed.
Wherever possible, blood samples for other analyses will be taken at the same time as blood 
is drawn for PK analyses to limit repeated venipuncture.
In the event of early withdrawal from the trial, every effort should be made to take a PK 
sample as part of the early withdrawal procedures, if possible, with date and time of sample 
recorded.
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5.4.3
Analytical determinations
Plasma concentrations of BI 695501 will be measured using a validated method.
After completion of the trial, selected PK samples may be retained and may be analyzed for 
the presence of species (e.g., soluble proteins or small molecule entities) potentially
interfering with the analysis method or for generation of ADA positive control material and 
stability testing for use in future assays. Retained samples may also be used to further 
characterize the immune response (e.g., isotyping of ADA) if required and as additional assay 
methods are developed. The results of any additional ADA analyses of the retained samples 
(i.e., analyses not already specified in this protocol) will be reported separately from the 
CTR. 
All remaining trial samples will be discarded after completion of the additional investigations
upon written authorization by the sponsor, but not later than 5 years after the final CTR has 
been signed.
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
Not applicable.
ASSESSMENT OF BIOMARKER(S) 
5.5
Not applicable.
OTHER ASSESSMENTS
5.6
5.6.1
Assessment of immunogenicity
Plasma sampling for Anti-Drug-antibodies characterization
5.6.1.1
For characterization of human anti-BI 695501 antibodies (ADA), approximately 3 mL of 
blood will be collected from a forearm vein in a K2EDTA anticoagulant blood drawing tube 
at time points indicated in Flow Chart.
Method to process the sample after collection will be described in the laboratory manual. 
Anti-drug antibody will be detected in human plasma samples using validated methods.
After completion of the trial, selected immunogenicity samples (ADA and nAb) may be 
retained and may be analyzed for the presence of species (e.g., soluble proteins or small 
molecule entities) potentially interfering with the analysis method or for generation of ADA 
positive control material and stability testing for use in future assays. Retained samples may 
also be used to further characterize the immune response (e.g., isotyping of ADA) if required 
and as additional assay methods are developed. The results of any additional ADA analyses 
of the retained samples (i.e., analyses not already specified in this protocol) will be reported 
separately from the CTR. 
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All remaining trial samples will be discarded after completion of the additional investigations
upon written authorization by the sponsor, but not later than 5 years after the final CTR has 
been signed.
Plasma sampling for neutralizing antibody characterization
5.6.1.2
For characterization of human neutralizing anti-BI 695501 antibodies (nAb), approximately
6 mL of blood will be collected from a forearm vein in a K2EDTA anticoagulant blood 
drawing tube at the same time points as ADA samples are collected. Method to process the 
sample after collection will be described in the laboratory manual.
Neutralizing antibodies will be detected in human plasma samples using validated methods.
APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine PK parameters in an 
appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of a subcutaneously administered drug, and are widely 
used in clinical trials. The PK parameters and measurements outlined in Section 5.1 are 
generally used assessments of drug exposure. Therefore, the appropriateness of all 
measurements applied in this trial is confirmed.
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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for all visits are given in Flow Chart.

General medical examination: at screening (2 to 28 days prior to the first trial day);

Trial measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 hour period prior 
to the trial drug administration. 

The acceptable deviation from the scheduled time for vital signs, ECG and laboratory 
tests PK, ADA, nAb sampling) will be:
-
±15 minutes for Day 1
-
±2 hours from Day 2 to Day 10;
-
±1 day from Day 15 to Day 57
-
The e.o.t. IGRA may be performed up to 72 hours prior to the other e.o.t. assessments.
If scheduled in the Flow Chart at the same time as a meal, vital signs, 12-lead ECG 
recordings and blood sampling have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned individual plasma concentration sampling times refer to Flow Chart. While these 
nominal times should be adhered to as closely as possible, the actual sampling times will be 
recorded and used for determination of PK parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening Period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.3.1 to 5.3.5.
If possible, spare subjects will be provided for each group to guarantee the start of a complete 
group. The spare subjects will participate in all trial activities up to Day 1, i.e. on Day -1 they 
will be admitted to the clinic and all examinations, which have been scheduled up to drug 
administration on Day 1 will be performed. The spare subjects from one group will be given 
the option to participate in the next planned group.
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6.2.2
Treatment period(s)
Subjects will be randomly allocated to the treatment (autoinjector or prefilled syringe).
On Day -1 trial participants will be admitted to the trial site and kept for 8 days following 
drug administration. The subjects will be allowed to leave the trial site from Day 8 after 
formal assessment and confirmation of their fitness. On all other trial days, the trial
assessments will be performed in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK, ADA and 
nAb analysis, refer to Flow Chart and Section 5.5. 
The safety measurements performed during the treatment period are specified in Section 5.3. 
of this CTP and in Flow Chart. For details on time points for all other trial procedures, refer 
to Flow Chart. Adverse events and concomitant therapy will be assessed continuously from 
screening until the end of trial.
6.2.3
Follow Up Period and Trial Completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of treatment (e.o.t.) visit (day 57), see Sections 5.3.1 to 5.3.5.
Subjects who discontinue trial participation before the end of the planned observational
period but not withdraw consent - should undergo the e.o.t. visit and Safety Follow-up (end 
of trial) visit 10 weeks after administration of the trial medication.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. Adverse events persisting after trial completion must be 
monitored until they have normalized or have been sufficiently characterized. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.
Long-term safety follow-up observational period will continue for 10 weeks after BI 695501 
administration to collect AEs (SAEs). 
The subjects are to be instructed to contact the investigator or his/her designee in case of 
occurrence of any AEs, any additional concomitant drug or if they undergo any medical 
treatment or any surgical procedure during the observational period until the safety follow-up 
visit call. Subjects will be contacted by the investigator or designee 10 weeks after 
administration of the trial medication to collect the information on subject’s wellbeing and 
document all AEs (SAEs) and concomitant medication. 
All AEs, serious and non-serious, will be followed up until they have normalized or been 
sufficiently characterized and documented in the safety database.
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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
This is a randomized, open-label, parallel-group, single-dose, Phase I trial. 
STATISTICAL DESIGN - MODEL
7.1
For the purposes of the exploratory analysis, the primary PK endpoints for BI 695501 will be 
estimated using an analysis of variance (ANOVA) model on the logarithmic scale with fixed 
effects for treatment, and baseline body weight (continuous).
The ANOVA model is described by the following equation:
yij = + i + β*weightij + eij, where 
yij = logarithm of PK parameter measured on subject j receiving treatment i,
= the overall mean,
i = the i-th treatment effect, i = 1, 2 (1=Test, 2=Reference),
β = the slope parameter for the baseline body weight covariate,
weightij = baseline body weight of subject j receiving treatment i,
eij = the random error associated with the j-th subject, receiving treatment i,
where eij ~ N(0, i2) are independent random variables.
The randomisation will be stratified by site, but this is considered to be a logistical 
stratification and will therefore be not included in the primary model.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The relative bioavailability of BI 695501 using autoinjector (A) compared to BI 695501 
using prefilled syringe (B) will be estimated, in an exploratory manner, by the ratios of the 
geometric means (A/B) for the primary endpoints using the ANOVA described in 
Section 7.1. All PK further parameters of interest will be analysed descriptively.
PLANNED ANALYSES
7.3
Primarily, all endpoints will be presented descriptively. The PK parameters (see
Section 5.1.1) will be calculated according to the BI SOP ‘Standards and processes for 
analyses performed within Clinical Pharmacokinetics/ Pharmacodynamics’ (001-MCS-36-
472).
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The logarithmic transformed primary PK endpoints will be evaluated using scatterplots and 
boxplots for prefilled syringe versus autoinjector administration of BI 695501, by baseline 
body weight and overall.
7.3.1
Primary endpoint analyses
In an exploratory manner, the relative bioavailability of BI 695501 using autoinjector (A) 
compared to BI 695501 using prefilled syringe (B) will be estimated by the ratios of the 
geometric means (A/B) for the primary PK endpoints. Point estimates of relative 
bioavailability, the ratios (A/B) of the geometric means for the primary PK endpoints (see 
Section 5.1.1), and their two-sided 90% CIs will be provided for the overall comparison A 
versus B.
The PK endpoints will be log-transformed (natural logarithm) prior to fitting the ANOVA 
model (see Section 7.1). For each PK endpoint, the difference between the means for log(A)-
log(B) will be estimated by the difference in the corresponding adjusted means (least-squares 
means), and a two-sided 90% CI based on the t-distribution will be computed. These 
quantities will then be back-transformed to the original scale to provide the point estimate 
and 90% CIs for the corresponding ratio of geometric means (A/B) for each PK endpoint.
The ANOVA will be conducted on the PK Analysis Set (PKS). The PKS will consist of all 
randomized subjects who receive the single dose of trial medication (BI 695501 using 
autoinjector or BI 695501 using prefilled syringe), and have at least one evaluable primary 
PK parameter, and are without important protocol deviations or violations thought to 
significantly affect the PK of BI 695501.
Pharmacokinetic parameters of a subject will be included in the analysis unless the subject 
has an important protocol violation relevant for the evaluation. Whether a protocol violation 
is important will be decided no later than in the Report Planning Meeting.
Reasons for exclusion of single pharmacokinetic parameters can for example be:

Time deviations

Use of restricted medications

Dosing errors 
It will also be decided in the Report Planning Meeting which subjects are to be included in 
the PKS.
Details of the presentation and analysis of PK data will be provided in the Trial Statistical 
Analysis Plan (TSAP).
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7.3.4
Analysis of Safety endpoints
Safety will be assessed for the secondary and further endpoints listed in Section 5.1.2 and 
Section 5.1.3 using the Safety Analysis Set. All treated subjects (that is, all subjects who 
received one dose of trial drug), will be included in the Safety Analysis Set. Safety analyses 
will be descriptive in nature.
The safety summaries will be presented by treatment according to treatment received.
Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). All events 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 (i.e., end of the REP) will be assigned to 
the treatment phase for evaluation, and will be referred to as treatment emergent adverse 
events (TEAEs). Frequency, intensity and causal relationship of AEs will be tabulated by 
treatment, primary system organ class and preferred term. SAEs and other significant AEs 
(according to ICH E3), and protocol-specified AESIs will be listed separately (see Section 
5.3.7.1).
The number and percentage of subjects with injection site reactions (assessed at Day 1 from 
the time of the injection until Day 2, prior to discharge from the trial site) will be summarized 
by treatment for each injection site reaction.
Laboratory values taken after the first dose of trial medication up to a period of 10 weeks
after the last dose of the trial medication will be assigned to the treatment phase for 
evaluation. Descriptive statistics of laboratory values over time and for the change from 
baseline will be provided for each treatment group. Laboratory parameters will be compared 
to their reference ranges and frequency tables will be provided for the number of subjects 
within and outside the reference range.
Observed values and changes from baseline in BP (systolic and diastolic), PR, and body 
temperature will be summarized by treatment group.
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Details of the presentation and analysis of safety data will be provided in the TSAP.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
The PK parameters listed in Section 5.1.1 and Section 5.1.3 for drug BI 695501 will be 
calculated according to the relevant SOP of the Sponsor (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3.1) will be reported with their 
individual plasma concentrations and individual PK parameters; however, they will not be 
included in descriptive statistics for plasma concentrations, PK parameters or other statistical 
assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of PK parameters. Concentrations used in the PK calculations 
will be in the same format provided in the bioanalytical report (that is, to the same number of 
decimal places provided in the bioanalytical report).
If a pre-dose concentration value is greater than 5% of Cmax, the subject’s PK data will not 
be included in any statistical evaluations, in accordance with international guidance. The 
individual PK parameters of such a subject will be calculated and listed separately. If a pre-
dose concentration is above below the limit of quantification (BLQ), but less than or equal to 
5% of the subject’s Cmax value, the subject’s data without any adjustments will be included 
in all PK measurements and calculations.
INTERIM ANALYSES
7.4
No interim analysis is planned in this study.
HANDLING OF MISSING DATA
7.5
7.5.1
Safety
With respect to AE analysis, missing relationship will be imputed to “yes”. For other safety 
evaluation, no imputation of missing data is planned.
7.5.2
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure of the Sponsor (001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ, or NOP (no peak detectable) will be displayed as such and not 
replaced by zero at any time point except the lag phase. 
7.5.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
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For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit. 
Descriptive statistics of parameters are calculated only when a parameter value is available
for certain for at least 2/3 of the treated individuals. If the actual sampling time is not 
recorded or is missing for a certain time point, the planned time will generally be used for this 
time point instead. PK parameters that cannot be determined will be identified as “not 
calculated”.
RANDOMISATION
7.6
Subjects will be randomized to one of the two treatments in a 1:1 ratio. The block size will be 
documented in the CTR.
The sponsor will arrange for the randomization as well as packaging and labelling of trial 
medication. The randomization list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable. Randomization will be stratified by:

site (2 levels and for logistical reasons only)

baseline body weight category with ranges:
•
low: ≤ 60.0 kg
•
medium: > 60.0 to ≤ 90.0 kg
•
high: ≥90.0 kg
and will be randomized sequentially (the lowest sequentially available randomization 
number).
The randomization list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
DETERMINATION OF SAMPLE SIZE
7.7
It is planned to enter a total of 160 subjects for the primary analysis of this trial, because this 
sample size is considered sufficient to assess the primary objective of this exploratory trial. 
With this sample size, the precisions of the ratio of the geometric means (test/reference) to be 
expected with 95% probability, are presented in Table 7.7: 1. That is to say, we expect with 
95% probability, that the precision is no greater than the value specified, where precision is 
defined as the ratio of upper CI limit to the point estimate of the geometric mean ratio. 
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The observed ratio of the geometric means (and geometric coefficient of variation (gCV)) in 
previous trials (1297.8, c03070713; 1297.6, CTR in reporting stage) were:

108% (45%) for AUC(0-∞) in 1297.8 

104% (54%) for AUC(0-∞) in 1297.6

112% (32%) for Cmax in 1297.6
The values from 1297.6 are estimated from the models adjusted for BMI (continuous). 
Although the main analysis for this study will be adjusted for baseline body weight 
(continuous), these model estimates serve as a good approximation, given the high correlation 
expected between BMI and body weight. The values coming from 1297.8 are unadjusted.
Table 7.7: 1 Precision and illustrative two-sided 90% confidence intervals around the ratios 
of geometric means (T/R) for different gCVs in a parallel  trial (N=160).
gCV [%]
Precision 
upper CL / 
relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
32
1.09
112
102.44
122.45
45
1.13
108
95.53
122.09
54
1.16
104
90.01
120.17
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The calculation was performed as described by Julious (R12-0972) using R Version 3.2.2.
Regarding the assessment of the primary PK parameters, albeit in an exploratory manner, the 
following table (Table 7.7: 2) provides an overview of the probability of success (power) 
given some assumed effect sizes and assumptions on the gCV, as described above. The 
calculations are based upon the overall treatment effect, adjusting for BMI continuous (as a 
good substitute for body weight), where data is available.
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Table 7.7: 2
Power (%) for concluding bioequivalence (acceptance range 80-
125%) based on a geometric coefficient of variation around 50% and 
for different expected ratios of geometric means (test/reference) in a 
parallel trial (N=160).
Ratio [%]*
gCV [%]
100
104
108
112
32
>99%
98%
90%
71%
45
89%
83%
68%
55%
50
81%
75%
61%
-
54
74%
68%
55%
-
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The calculations were performed using nQuery Version 2.0.1.0.
Therefore, with the expectation that there is less variability in this planned trial, there should 
be more than 70% power to have the resulting 90% confidence interval of the ratio of the 
gMeans lying within the range of 80-125%. The reason for less expected variability is that the 
the drug is now to be administered in the thigh, and there is also expected to be slightly less 
variability when adjusting for baseline body weight.
Thus a total sample size of up to 160 subjects is planned for this trial and with no planned 
adjustment for drop-outs.
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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) 
and the harmonised standards for Medical Devices (ISO 14155, current version).
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 Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (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 subject.
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. 
The certificate of insurance cover is made available to the Investigator and the subjects, and 
is stored in the ISF (Investigator Site File).
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to subject participation in the trial, written informed consent must be obtained from 
each subject 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 subject -information form retained by the Investigator as 
part of the trial records. A signed copy of the informed consent and any additional subject
information must be given to each subject.
The Investigator must give a full explanation to trial subjects based on the subjects
information form. A language understandable to the subjects should be chosen, technical 
terms and expressions avoided, if possible. The subjects must be given sufficient time to 
consider participation in the trial. The Investigator obtains written consent of the subject’s 
own free will with the informed consent form after confirming that the subject understands 
the contents. The Investigator must sign (or place a seal on) and date the informed consent 
form. 
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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 (CRF) for individual subjects will be provided by the sponsor. 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.
For the CRF, all data must be derived from source documents.
The LabPas and Oracle Clinical (TD Synergy) systems is an electronic data capturing and 
information management system that will also serve as an e-source system for this trial. The 
system combines all aspects of source data capturing with process control and clinical trial 
management. Clinical and laboratory data, except those which are paper based, will be
collected in there.
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 
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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 site(s) must retain the source and essential documents (including ISF) according to 
the national or local requirements (whatever 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.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
STATEMENT OF CONFIDENTIALITY
8.5
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Subject privacy will 
be ensured by using subject identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’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 Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/13 5/95)

The facilities storing and analysing 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 
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facilityare 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 subject in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(“Last Patient Out”). 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 subjects 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 subject
(EU or non-EU).
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9.
REFERENCES
PUBLISHED REFERENCES
9.1
R05-2311
ICH E14: the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs (ICH harmonised tripartite 
guideline, recommended for adoption at step 4 of the ICH process on 12 May 
2005 by the ICH Steering Committee). 
webpage.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/20
09/09/WC500002879.pdf
R07-0637
Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. 
Arthritis Res 4 (Suppl 3), S265 - S272 (2002).
R12-0972
Kupper LL, Hafner KB How appropriate are popular sample size formulas?  Am 
Stat 43 (2), 101 - 105 (1989).
R13-3614
Singh JA, et al. 2012 update of the 2008 American College of Rheumatology 
recommendations for the use of disease-modifying antirheumatic drugs and 
biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 
(Hoboken) 2012. 64(5):625-639.
R13-4095
ICH guideline E14 - questions and answers: EMA/CHMP/ICH/310133/2008 
Committee for medicinal products for human use (CHMP), May 2012. 
website.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/200
9/09/WC500002878.pdf
R13-5230
Guidance for industry: rheumatoid arthritis: developing drug products for 
treatment (draft guidance) (this guidance document is being distributed for 
comment purposes only) (May 2013, clinical/medical, revision1).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformat
ion/Guida nces/UCM354468.pdf (access date: 2 December 2013); U.S. 
Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER), Center for Biologics 
Evaluation and Research (CBER), Center for Devices and Radiological Health 
(CDRH) (2013)
R14-3385
Smolen JS, et al. EULAR recommendations for the management of rheumatoid 
arthritis with synthetic and biological disease-modifying antirheumatic drugs: 
2013 update. Ann Rheum Dis 2014. 73:492-509.
R15-0739
Humira® (adalimumab) injection, for subcutaneous use (AbbVie) (U.S. 
prescribing information, revised: 12/2014webpage.rxabbvie.com/pdf/humira.pdf
R15-3225
Humira® 40 mg/0.8 mL solution for injection for paediatric use, 40 mg solution 
for injection in pre-filled syringe, 40 mg solution for injection in pre-filled 
syringe with needleguard, 40 mg solution for injection in pre-filled pen 
Boehringer Ingelheim 
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(AbbVie) (summary of product characteristics, manufacturer(s) of the biological 
active substance and manufacturer(s) responsible for batch release, conditions or 
restrictions regarding supply and use, other conditions and requirements of the 
marketing authorisation, conditions or restrictions with regard to the safe and 
effective use of the medicinal product, labelling and package leaflet, last 
updated:12/05/2015).webpage.ema.europa.eu/docs/en_GB/document_library/EP
AR_-_Product_Information/human/000481/WC500050870.pdf (access date: 26 
June 2015) (2015)
R16-2901
Humira® (adalimumab) injection, for subcutaneous use (AbbVie) (U.S. 
prescribing information, revised: 11/2015 website rxabbvie.com/pdf/humira.pdf.
R16-2926
Humira (adalimumab) injection, for subcutaneous use (AbbVie) (U.S. 
prescribing information, revised: 6/2016).
http://www.rxabbvie.com/pdf/humira.pdf (access date: 5 July 2016) (2016)
UNPUBLISHED REFERENCES
9.2
U13-1096-01
. Pharmacokinetics 
and safety of BI 695501 in healthy subjects: a randomized, open-label, 
single-dose, parallel arm, active-comparator clinical Phase I study. 1297.1, 24 
Jan 2013.
c01843589
, Investigator's Brochure BI 695501: Rheumatoid Arthritis, Psoriasis, 
Crohn´s Disease et al. 1297.P1, 28 Sep 2015.
c02158186
Efficacy, safety and immunogenicity of BI 695501 versus adalimumab in 
patients with active rheumatoid arthritis: a randomized, double-blind, parallel 
arm, multiple dose, active comparator trial. 1297.2, 16 Aug 2013.
c02715841
 Randomized, single-dose, parallel-arm, open-label Phase I trial 
to investigate and compare the pharmacokinetics, safety and tolerability of BI 
695501 administered subcutaneously via prefilled syringe or autoinjector. 
1297.6. Version 3.0. 21 Jan 2016.
c03070713
. Pharmacokinetics and safety of BI 
695501 in healthy subjects: a randomized, open-label, single-dose, parallel 
arm, active-comparator clinical Phase I study. 1297.8. Version 2.0. 23 May 
2016.
001-MCS-36-472
. Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics.Version 2.0. 15 May 2016.
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10.
APPENDICES
Not available
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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
“This is the original protocol.”
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
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
Description of change
Rationale for change
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Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11534380
1.0
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16.1.9 Documentation of Statistical Methods
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Statistical Analysis Plan 
PROTOCOL 1297.13 
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reproduction is strictly prohibited. 
 
STATISTICAL ANALYSIS PLAN 
 
1297.13 
Randomized, single-dose, parallel-arm, open-label Phase I trial to compare the pharmacokinetics, 
safety and tolerability of BI 695501 administered subcutaneously via prefilled syringe or autoinjector 
AUTHOR: 
 
VERSION NUMBER AND DATE: V1.0, 09JAN2017 
 
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Statistical Analysis Plan 
PROTOCOL 1297.13 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V1.0 (Dated 09JAN2017) for Protocol 1297.13. 
Name 
Signature 
Date 
Author 
(except 
PK): 
 
 
DDMMMYYYY 
 
Position: 
Statistical Team Lead 
 
Company: 
Author 
(PK 
analysis): 
DDMMMYYYY 
 
Position: 
Trial Clinical Pharmacokineticist 
 
Company: 
Boehringer-Ingelheim 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, 
authorizing that the content is acceptable for the reporting of this study. 
Name 
Signature 
Date 
Approved By: 
 
 
DDMMMYYYY 
 
Position: 
Senior Reviewer 
 
Company: 
Approved By: 
DDMMMYYYY 
 
Position: 
Trial Statistician 
 
Company: 
Boehringer-Ingelheim 
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Statistical Analysis Plan 
PROTOCOL 1297.13 
Page 3 of 49 
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reproduction is strictly prohibited. 
Approved By: 
 
 
DDMMMYYYY 
 
Position: 
Clinical Program Lead 
 
Company: 
Boehringer-Ingelheim 
Approved By: 
 
 
DDMMMYYYY 
 
Position: 
ADA/nADA specialist 
 
Company: 
Boehringer-Ingelheim 
Approved By: 
 
 
DDMMMYYYY 
 
Position: 
Clinical Program Manager 
 
Company: 
Boehringer-Ingelheim 
 
 
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Statistical Analysis Plan 
PROTOCOL 1297.13 
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Statistical Analysis Plan Reviewed By 
Boehringer Ingelheim 
Team Role 
Trial Statistician  
Project Statistician 
Project Programmer  
Project Medical Writer 
Clinical Program Lead 
Clinical Project Manager  
ADA/nAbs specialist 
Global Pharmacovigilance 
Global DRA 
  
Team Role 
Senior Reviewer 
Lead Programmer 
Global Project Manager 
Global Medical Monitor  
Medical Writer 
OUTPUT TEMPLATES SIGNATURE PAGE 
Please refer to Output Templates V1.0 (Dated 09JAN2017) for Protocol 1297.13. 
 
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Statistical Analysis Plan 
PROTOCOL 1297.13 
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reproduction is strictly prohibited. 
MODIFICATION HISTORY 
Unique 
Identifier 
for 
this 
Version 
Date of the 
Document 
Version 
Author 
Significant 
Changes 
from  
Previous Authorized Version 
1.0 
09JAN2017 
 
Not Applicable – First Version 
 
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Statistical Analysis Plan 
PROTOCOL 1297.13 
Page 6 of 49 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...................................................... 10 
1. 
INTRODUCTION .................................................................................................................... 12 
2. 
TRIAL OBJECTIVES ............................................................................................................... 12 
2.1. 
Primary Objective ...................................................................................................................................... 12 
2.2. 
Secondary Objectives ................................................................................................................................ 12 
.......................................................................................................................... 12 
3. 
TRIAL DESIGN ........................................................................................................................ 13 
3.1. 
General Description ................................................................................................................................... 13 
3.2. 
Schedule of Events ..................................................................................................................................... 13 
3.3. 
Changes to Analysis from Protocol ............................................................................................................ 13 
4. 
PLANNED ANALYSES ............................................................................................................ 14 
4.1. 
Final Analysis ............................................................................................................................................. 14 
5. 
ANALYSIS SETS ...................................................................................................................... 14 
5.1. 
All Subjects Enrolled Set [ENR] .................................................................................................................. 14 
5.2. 
All Subjects Randomized Set [RND] ........................................................................................................... 14 
5.3. 
Full Analysis Set [FAS] ................................................................................................................................ 15 
5.4. 
Per Protocol Analysis Set [PPAS] ................................................................................................................ 15 
5.5. 
Safety Analysis Set [SAF]............................................................................................................................ 15 
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PROTOCOL 1297.13 
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5.6. 
Pharmacokinetic Analysis Set [PKS] ........................................................................................................... 15 
6. 
GENERAL CONSIDERATIONS ............................................................................................. 16 
6.1. 
Reference Start Date and Study Day .......................................................................................................... 16 
6.2. 
Baseline ..................................................................................................................................................... 16 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 16 
6.4. 
Windowing Conventions ............................................................................................................................ 17 
6.5. 
Statistical Tests .......................................................................................................................................... 17 
6.6. 
Common Calculations ................................................................................................................................ 17 
6.7. 
Software Version ....................................................................................................................................... 17 
7. 
STATISTICAL CONSIDERATIONS ...................................................................................... 18 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 18 
7.2. 
Missing data .............................................................................................................................................. 18 
7.3. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 19 
7.4. 
Examination of Subgroups ......................................................................................................................... 19 
7.4.1. 
Randomization Stratification Factors ................................................................................................... 19 
8. 
OUTPUT PRESENTATIONS ................................................................................................. 19 
9. 
DISPOSITION AND WITHDRAWALS................................................................................. 19 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ..................................... 20 
10.1. 
Derivations ............................................................................................................................................ 22 
11. 
SURGICAL AND MEDICAL HISTORY ................................................................................. 22 
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12. 
MEDICATIONS........................................................................................................................ 22 
13. 
TRIAL MEDICATION EXPOSURE ....................................................................................... 23 
14. 
EFFICACY OUTCOMES .......................................................................................................... 23 
15. 
SAFETY OUTCOMES.............................................................................................................. 23 
15.1. 
Adverse Events ...................................................................................................................................... 24 
15.1.1. 
All TEAEs ............................................................................................................................................. 24 
15.1.1.1. 
Intensity...................................................................................................................................... 24 
15.1.1.2. 
Relationship to Trial Medication .................................................................................................. 24 
15.1.2. 
Serious Adverse Events ....................................................................................................................... 24 
15.1.3. 
Adverse Events Leading to Death ........................................................................................................ 25 
15.1.4. 
Adverse Events Of Special Interest (AESI) ............................................................................................ 25 
15.1.4.1. 
Reported by Investigator ............................................................................................................. 25 
15.1.4.2. 
Serious Infections ........................................................................................................................ 26 
15.1.4.3. 
Hypersensitivity Reactions........................................................................................................... 26 
15.1.4.4. 
Drug Induced Liver Injury (DILI) ................................................................................................... 26 
15.1.4.5. 
Injection-site Reactions ............................................................................................................... 27 
15.1.4.6. 
Anaphylactic Reactions ............................................................................................................... 27 
15.1.5. 
Non-Serious Treatment Emergent AEs ................................................................................................ 27 
15.1.6. 
Other Significant AEs .......................................................................................................................... 28 
15.2. 
Deaths ................................................................................................................................................... 28 
15.3. 
Laboratory Evaluations .......................................................................................................................... 28 
15.3.1. 
Laboratory Specific Derivations ........................................................................................................... 29 
15.3.2. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ........................................................... 29 
15.3.3. 
Other Safety Laboratory Evaluations ................................................................................................... 30 
15.3.3.1. 
Pregnancy test ............................................................................................................................ 30 
15.4. 
ECG Evaluations ..................................................................................................................................... 30 
15.5. 
Vital Signs .............................................................................................................................................. 30 
15.6. 
Physical Examination ............................................................................................................................. 31 
15.7. 
Other Safety Assessments...................................................................................................................... 31 
15.7.1. 
Immunogenicity Evaluation ................................................................................................................. 31 
15.7.2. 
Local Tolerability ................................................................................................................................. 32 
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PROTOCOL 1297.13 
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16. 
PHARMACOKINETIC DATA ................................................................................................ 32 
16.1. 
Primary Pharmacokinetic ....................................................................................................................... 32 
16.1.1. 
Pharmacokinetic Variables & Derivations ............................................................................................ 32 
16.1.2. 
Missing Data Methods for Primary Pharmacokinetic Variables ............................................................ 33 
16.1.3. 
Analysis of Pharmacokinetic Variables................................................................................................. 33 
........................................................................ 34 
17. 
REFERENCES .......................................................................................................................... 35 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AI 
Autoinjector 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
AUC 
Area Under the Curve 
BI 
Boehringer-Ingelheim 
BLQ 
Below the lower limit of quantification 
BMI 
Body Mass Index 
CI 
Confidence Interval 
DBL 
Database Lock 
DILI 
Drug Induced Liver Injury 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Agency 
ENR 
Enrolled Set 
EOI 
End of Infusion 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
IGRA 
Interferon-Gamma Release Assay 
MedDRA 
Medical Dictionary for Regulatory Activities 
nAb 
Neutralizing Anti-Drug Antibody 
NOA 
Not analyzed 
NOS 
No available sample 
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NOR 
No valid result 
PFS 
Prefilled syringe 
PK 
Pharmacokinetic 
PKS 
Pharmacokinetic Set 
PPAS 
Per Protocol Analysis Set 
PT 
Preferred Term 
RND 
Randomized Set 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SFU 
Safety Follow-up 
SI 
Système International 
SMQ 
Standardized MedDRA Queries 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TBL 
Total Bilirubin 
TEAE 
Treatment-Emergent Adverse Event 
TLF 
Tables Listings Figures 
ULN 
Upper Limit of Normal 
ULQ 
Above the upper limit of quantification 
WHO DD 
World Health Organization Drug Dictionary 
 
 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of 
pharmacokinetics (PK), tolerability, safety and immunogenicity data for Protocol 1297.13. It describes 
the data to be summarized and analyzed, including specifics of the statistical analyses to be performed. 
The derivation and analyses description related to PK, except the statistical model, are provided by the 
sponsor PK specialist. The description of the safety analyses and statistical model for PK parameter are 
provided by 
  
This statistical analysis plan (SAP) is based on protocol version 1.0, dated 23 August 2016. 
2. TRIAL OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective of this trial is to compare the PK of 40 mg of BI 695501 administered using an 
autoinjector and 40 mg of BI 695501 administered using a prefilled syringe following a single 
subcutaneous (s.c.) injection in the thigh. In particular: Cmax, AUC0-1368 and AUC0-∞. 
2.2. SECONDARY OBJECTIVES 
The secondary objective is to assess safety. 
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3. TRIAL DESIGN 
3.1. GENERAL DESCRIPTION 
Trial 1297.13 is a 14-week, randomized, single-dose, open-label trial in healthy volunteers. 
Each subject will receive one subcutaneous injection with either 40 mg BI 695501 autoinjector (AI) or 
40 mg BI 695501 prefilled syringe (PFS) followed by an observation period of approximately 57 days and 
an additional safety follow-up period up to 70 days after the trial drug administration. Subjects who meet 
all the inclusion criteria and none of the exclusion criteria will be randomly assigned to one of the two 
groups with a 1:1 allocation ratio. Randomization will be stratified by site (2 levels and for logistical 
reasons only) and body weight category (low: ≤ 60.0 kg, medium: > 60.0 to < 90.0 kg, high: ≥ 90.0 kg). 
It is planned to include 160 healthy male and female subjects (at least 30% of each gender will be 
included in the trial) with a broad range of weight for the primary analysis report describing the PK profiles 
of BI 695501 given in a PFS and an AI as well as the assessments of safety and immunogenicity. All 
efforts will be made to enroll subjects in all subgroups, in order to ensure a wide distribution of weight in 
the study. 
This trial will have a screening period of up to 28 days. The subject will check in to the trial center on 
Day-1, will be randomized and dosed on Day 1, and will be resident until the Day 8 discharge procedures 
are complete. All subjects will remain in the clinic until Day 8 after dosing. The subject will then return to 
the clinic for 7 ambulatory visits on Days 10, 15, 22, 29, 36, 43 and 57 (End-of-Trial [EOT] visit). 
Additionally, all adverse events (AEs), regardless of relatedness, will be collected until up to 10 weeks 
after the administration of trial medication. Adverse events not fully resolved at the safety follow-up (SFU) 
visit (Day 70 visit) will be followed until recovery or in case of persistency, sufficient characterization has 
been achieved and the investigator and medical monitor agree to not pursue them further. 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Section “FLOW CHART” of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
Per the protocol, hepatic injuries, anaphylactic reactions, serious infections and hypersensitivity 
reactions are defined as Adverse Events of Special Interest (AESIs). In addition, all treatment-emergent 
infections will be analyzed, for consistency with the analysis performed on 1297.6 trial. 
No PK sensitivity analysis is planned per the protocol. However, if PK profiles suggest biologically 
implausible results for s.c. administration or suggest extreme values (high or low), then a sensitivity 
analysis may be conducted post-hoc to repeat the analyses described in section 16.1 without the 
patients with implausible or extreme results. The decision of a sensitivity analysis addition will be taken 
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Statistical Analysis Plan 
PROTOCOL 1297.13 
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by Boehringer-Ingelheim (BI). 
Per the protocol, one of the primary PK endpoint is the AUC00-∞ based on observed concentration at 
time of last measurable concentration. In addition, the AUC00-∞ based on predicted concentration at time 
of last measurable concentration will be analyzed as a further PK endpoint. 
4. .PLANNED ANALYSES 
According to protocol section 7.4, no formal interim analysis will be performed for this trial.  
The following analyses will be performed for this trial: 
 
Final Analysis  
The planned analysis identified in this SAP will be performed by 
 Biostatistics (excluding 
PK descriptive analyses) and by BI (responsible for PK descriptive analyses and PK Tables, Listings, 
and Figures (TLFs) related to descriptive analysis) following Sponsor Authorization of this Statistical 
Analysis Plan, Database Lock, and Sponsor Authorization of Analysis. 
4.1. FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by 
 Biostatistics 
(excluding PK descriptive analyses) and by BI (responsible for PK descriptive analyses and PK Tables, 
Listings, and Figures (TLFs) related to descriptive analysis) following Sponsor Authorization of this 
Statistical Analysis Plan, Database Lock (DBL), and Sponsor Authorization of Analysis Sets. 
5. ANALYSIS SETS 
Agreement and authorization of subjects included/ excluded from each analysis set will be conducted by 
BI during the report planning meeting prior to the database lock of the trial. 
5.1. ALL SUBJECTS ENROLLED SET [ENR] 
The ’All Subjects Enrolled’ (ENR) set will contain all subjects who provide informed consent for this trial. 
5.2. ALL SUBJECTS RANDOMIZED SET [RND] 
The ’All Subjects Randomized’ (RND) set will contain all subjects in the ENR set who were randomized 
to trial medication. 
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Statistical Analysis Plan 
PROTOCOL 1297.13 
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reproduction is strictly prohibited. 
For analyses and displays based on RND, subjects will be classified according to randomized 
treatment.  
5.3. FULL ANALYSIS SET [FAS] 
No FAS is defined in this trial. 
5.4. PER PROTOCOL ANALYSIS SET [PPAS] 
No PPAS is defined in this trial. 
5.5. SAFETY ANALYSIS SET [SAF] 
The Safety Analysis Set (SAF) will contain all subjects in the ENR set who receive at least one dose of 
trial medication and subjects will be classified according to treatment received.  
If there is any doubt whether a subject was treated or not, they will be assumed treated for the purposes 
of analysis.  
5.6. PHARMACOKINETIC ANALYSIS SET [PKS] 
The Pharmacokinetic Set (PKS) will consist of all randomized subjects who receive the single dose of 
trial medication (BI°695501 using AI or BI°695501 using PFS), and have at least one evaluable primary 
PK parameter, and are without important protocol deviations or violations thought to have a relevant 
impact on the PK of BI 695501. 
Pharmacokinetic parameters for a subject will be included in the analysis unless the subject has an 
important protocol violation relevant for the evaluation. Whether a protocol violation is relevant will be 
decided no later than in the report planning meeting. 
Reasons for exclusion of single pharmacokinetic parameters may include (but are not limited to): 
 
Relevant time deviations 
 
Use of restricted medications 
 
Dosing errors 
 
Missing samples relevant for correct estimation of PK parameters Cmax or AUC 
It will also be decided in the report planning meeting which subjects are to be excluded from the PKS. 
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Statistical Analysis Plan 
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reproduction is strictly prohibited. 
Important protocol violations will be defined before the final database lock. 
In case of PK profiles suggesting biologically implausible results for s.c. administration or suggesting 
extreme values (high or low), then the patients with implausible or extreme results may be excluded 
from the PKS for a sensitivity analysis. 
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/ stop day of 
assessments and events.  
Reference start date is defined as the day of the first and single injection of trial 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 (Day 1). 
Reference start date will appear in every listing where an assessment date or event date appears.  
 
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1. 
 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, Study Day, and any corresponding durations, 
will appear partial or missing in the listings. 
6.2. BASELINE 
Baseline is defined as the last non-missing measurement taken prior to drug administration (including 
unscheduled assessments). In the case where the last non-missing measurement and the reference 
start date coincide, that measurement will be considered 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. 
Unscheduled measurements (unless assigned to a planned visit number, as stated above) will not be 
included in by-visit summaries. 
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Statistical Analysis Plan 
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Early treatment termination data will not be included in by-visit table summaries and by-visit graphs. 
Listings will include scheduled, unscheduled, retest and early discontinuation data collected in the 
electronic Case Report Form (e-CRF) database. 
6.4. WINDOWING CONVENTIONS  
The acceptable deviations from the scheduled time for PK assessments are: 
- ±15 minutes for Day 1; 
- ±2 hours from Day 2 to Day 10; 
- ±1 day from Day 15 to Day 57. 
The relevance of measurements outside the permitted time windows for their inclusion in the PK 
analysis will be assessed no later than at the Report Planning Meeting. 
6.5. STATISTICAL TESTS 
The default significance level will be 10%; confidence intervals will be 90% 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 
Logarithmic transformation of PK parameters will be performed as follows: 

Ln (PK parameter) = natural logarithm of the PK parameter 
6.7. SOFTWARE VERSION 
Analyses provided by 
 will be conducted using SAS version 9.4 or higher. Analysis 
provided by BI will be using Phoenix WinNonlin Version 6.3 or higher and/or SAS Version 9.4 or higher. 
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Statistical Analysis Plan 
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 Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN ANALYSES 
The following covariates and factors are used in the analyses. For details of their inclusion in the 
models, see the specific analysis section. 
 
Treatment group (BI 695501 using AI or BI 695501 using PFS) 
 
Baseline body weight (continuous variable) 
7.2. MISSING DATA 
Missing PK data will be handled as described in section 16 of this analysis plan. 
Missing safety data will not be imputed unless otherwise specified in section 15. 
 
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Statistical Analysis Plan 
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reproduction is strictly prohibited. 
7.3. MULTIPLE COMPARISONS/ MULTIPLICITY 
The relative bioavailability will be evaluated in an exploratory manner. No formal alpha adjustment is 
required. 
7.4. EXAMINATION OF SUBGROUPS 
7.4.1.
RANDOMIZATION STRATIFICATION FACTORS 
Disposition will be displayed for each randomization strata: 
 
Baseline body weight (≤60.0 kg, >60.0 - <90.0 kg, ≥90.0 kg), 
 
Site 
8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows conventions for presentation of data in outputs provided by 
  
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 following analysis sets will be presented: 
 
All Subject Randomized Set (RND) 
 
Safety Analysis Set (SAF) 
 
Pharmacokinetic Analysis Set (PKS) 
The following subject disposition and withdrawals will be presented for the ENR set overall and by body 
weight group: 
 
Screened 
 
Screen failure (defined as withdrawn from trial prior to randomization) 
 
Randomized 
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Statistical Analysis Plan 
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 
Randomized but not treated 
 
Completed treatment (assessed at Day 1) 
 
Completed trial (observational period, assessed at Day 57)  
 
Discontinued from trial, reason for premature discontinuation from trial 
 
Completed safety follow-up 
 
Discontinued from safety follow-up, reason for premature discontinuation from safety follow-
up 
Protocol violations relevant for primary PK analysis (as defined in section 5.6) will be presented for the 
RND set. 
In addition, subject disposition by country and by age groups will be reported overall and will be 
displayed for ENR population for disclosure purpose. 
The following age groups will be reported: 
 
18 - 64 years 
 
65 - 84 years 
10.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the RND, SAF and PKS. 
In this trial, there is a high probability that RND is equivalent to SAF. In order to avoid duplicate tables 
regarding demographic characteristics, it will be checked before the final DBL whether: 
 
Subjects were treated but not randomized 
 
Subjects were randomized but not treated 
 
Subjects did not receive the allocated treatment  
If RND is equivalent to SAF, tables will be displayed for RND only. Otherwise, both populations will be 
considered. 
In the same manner, tables will be repeated for PKS only if PKS is not equivalent to RND. 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic and other baseline characteristics will be reported for this trial: 
 
Age (years) 
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Statistical Analysis Plan 
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 
Age groups 1: 
o 
<65 years 
o
Ӌ65 - <75 years 
o
Ӌ75 years 
 
Age groups 2: 
o 
<65 years 
o
≥65 years
 
Gender (Male / Female) 
 
Childbearing potential (Post-menopausal / Surgically sterile / Childbearing potential 
(includes tubal ligation)) 
 
Race (American Indian or Alaska Native / Asian / Black or African American / Native 
Hawaiian or Other Pacific Islander / White / Other) 
 
Ethnicity (Hispanic or Latino / Not Hispanic or Latino / Not reported) 
 
Weight (kg) 
 
Weight groups (equivalent to the stratification factor): 
o
≤60.0 kg,
o 
>60.0 - <90.0 kg, 
o
Ӌ90.0 kg. 
 
Height (cm) 
 
Body mass index (BMI) (kg/m2) 
 
Smoking status (never smoked / is an ex smoker / currently smokes) 
 
Alcohol consumption (does not drink any alcohol / drinks alcohol but should not interfere 
with participation in trial / drinks alcohol and could interfere with participation in trial) 
Any discrepancies between randomized strata and derived body weight group based on eCRF data will 
be reported in a subject level footnote. 
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reproduction is strictly prohibited. 
10.1.DERIVATIONS 
 
Age (years) = (date of consent – date of birth)/365.25 
11.
SURGICAL AND MEDICAL HISTORY 
Surgical and Medical History information will be presented for the SAF. Surgical and Medical History 
conditions are defined as those conditions which stop prior to or at Screening. 
Surgical and Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 19.1 or higher. 
Data captured on the “Medical and surgical history” page of the eCRF will be assigned to prior or 
concomitant phase. 
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 
procedures which: 
o 
started prior to or at Screening and are ongoing or active at the date of Screening 
 or 
o 
started after Screening during the treatment period.  
Only prior surgical and medical history will be presented by SOC (System Organ Class) and PT (Preferred 
Terms). They will be sorted by decreasing frequencies. All reported surgical and medical history will be 
listed. 
12.
MEDICATIONS 
Medications will be presented for the SAF and coded using World Health Organization Drug Dictionary 
version (WHO DD) SEP2016 or higher. 
No Anatomical Therapeutic Chemical (ATC) class coding will be performed. 
The medical terms will be summarized by generic medication name. 
The generic medication name will be sorted by decreasing frequencies. 
See APPENDIX 2 for handling of partial dates for medications, in the case where it is not possible to 
define a medication as prior or concomitant, the medication will be classified by the worst case; i.e. 
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concomitant.  
 
‘Prior’ medications are medications which started and stopped prior to the first dose of trial 
medication.  
 
‘Concomitant’ medications are medications which were ongoing at the time of administration 
or started during the trial (until end of trial date on Day 70).
All prior and concomitant prohibited/restricted medications outlined in protocol section 4.2.2.1 as 
determined by the trial medical advisor will be listed. 
13.
TRIAL MEDICATION EXPOSURE 
The number of subjects receiving trial medication will be reported for the SAF. 
Information about injection difficulty will be displayed according to the answers on page “Administration of 
Trial Medication” of the eCRF. 
A listing will be created with the randomisation number, medication kit number, as well as injection site 
selected. 
14.
EFFICACY OUTCOMES  
No efficacy outcomes will be analyzed in this trial. 
15.
SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise 
specified with the relevant section.  
The secondary safety endpoint is defined as the number (proportion) of subjects with drug-related 
treatment emergent adverse events (TEAEs) occurring from Day 1 through Day 70. 
Safety and tolerability of the investigational products will be assessed based on: 
 
TEAEs (including clinically relevant findings from the physical examination and AESIs) 
 
Safety laboratory tests 
 
12-lead ECG 
 
Vital signs (Blood pressure, pulse rate, temperature) 
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 
Local tolerability 
15.1.ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA central coding dictionary, Version 19.1 or higher. 
SOCs will be sorted by internationally agreed European Medicines Agency (EMA) SOC order (refer to 
APPENDIX 4), PTs will be sorted by decreasing frequencies (within system organ class). 
In case of worsening in severity, a new entry is created with start date equal to start of worsening. 
TEAEs are defined as AEs that started or worsened in severity on or after the first and single dose of 
trial medication up to 10 weeks (70 days) post dose. 
See APPENDIX 2 for handling of partial dates for AEs. In case 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. 
An overall summary of number of subjects within each of the categories described in the sub-section 
below, will be provided as specified in the templates.  
Listings will include TEAEs and Non-TEAEs. 
15.1.1.
ALL TEAES  
Incidence of TEAEs will be presented by SOC and PT within each SOC and also broken down further 
by maximum severity and relationship to trial medication. 
15.1.1.1. 
Intensity 
Intensity is classed as mild/ moderate/ severe (increasing severity). 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. 
15.1.1.2. 
Relationship to Trial Medication 
A related TEAE is defined as a TEAE with a relationship to trial medication ticked “yes” according to the 
investigator. TEAEs with a missing relationship to study medication will be regarded as related to trial 
medication. If a subject reports the same AE more than once within that SOC/ PT, the AE with the worst 
case relationship (TEAE with a relationship to trial medication ticked “yes”) to trial medication will be 
used in the corresponding relationship summaries.  
15.1.2.
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. All SAEs as recorded in the 
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Template No:  CS_TP_BS016  Revision 4 
 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
Copyright © 2009, 2010, 2012, 2016 
Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to
 Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
eCRF will be listed. 
15.1.3.
ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as “Results in death” on the Adverse 
Events page of the eCRF. A summary of subjects with TEAEs leading to death will be presented in 
overview summary. All AEs leading to Death as recorded in the eCRF will be listed. 
15.1.4.
ADVERSE EVENTS OF SPECIAL INTEREST (AESI) 
An overall summary of the number of subjects and percentages within each of the categories described in 
the sub-sections below will be provided. 
The risk difference between both treatment groups will be displayed together with its 95% confidence 
interval (CI). 
The SAS code below will be used to produce exact unconditional CI for risk difference: 
PROC FREQ data= Data; 
  TABLES trt*aesi_overall; 
  EXACT riskdiff(method=score); 
  WEIGHT count; 
RUN; 
In addition, risk ratio will be displayed together with associated 95% exact confidence interval. 
Risk ratio will be defined as: (a/(a+b))/(c/(c+d)). 
Where a is the number of subjects with AESI within treatment group, a+b is the total number of subjects in 
treatment group, c is the number of subjects with AESI within treatment, c+d is the total number of 
subjects in treatment group. 
PROC FREQ with option RELRISK will be used for programming purpose.  
PROC FREQ data=data_AESI;  
TABLES trt*aesi_overall;  
EXACT relrisk(method=score);  
WEIGHT count;  
RUN; 
15.1.4.1. 
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. 
Number of subjects, percentages and number of events of Treatment Emergent AESI reported by 
investigators by SOC and PT table will be prepared. 
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Statistical Analysis Plan 
PROTOCOL 1297.13 
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 Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
15.1.4.2. 
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 medical advisor as requiring class IV (intravenous) 
antibiotics. 
Serious infections events of special interest are those events both identified as serious infections adverse 
events and recorded as “Adverse Event of Special Interest” equal to “Yes” on the Adverse Events page of 
the eCRF. 
Number of subjects, percentages and number of events of Treatment Emergent Infections by SOC and 
PT tables will be prepared. 
Number of subjects, percentages and number of events of Treatment Emergent Serious Infections by 
SOC and PT tables overall will be prepared. 
Serious Infections will be listed. The listing will include the “Adverse Event of Special Interest” equal to 
“Yes” and the “Is the AE an infection?” equal to “Yes” information from the Adverse Events page of the 
eCRF as flags.
15.1.4.3. 
Hypersensitivity Reactions 
Hypersensitivity reactions adverse events are those events recorded as MedDRA code in the pre-defined 
Standardized MedDRA Queries (SMQ) “Hypersensitivity” (narrow). 
Hypersensitivity reactions adverse events of special interest are those events both identified as 
Hypersensitivity reactions adverse events and recorded as “Adverse Event of Special Interest” equal to 
“Yes” on the Adverse Events page of the eCRF. 
Number of subjects, percentages and number of events of Treatment Emergent Hypersensitivity reactions 
by SOC and PT tables will be prepared. 
Hypersensitivity reactions 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. 
15.1.4.4. 
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 15.3.2). 
DILI events of special interest are those events both identified as DILI adverse events and recorded as 
“Adverse Event of Special Interest” equal to “Yes” on the Adverse Events page of the eCRF. 
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Statistical Analysis Plan 
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 Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
Number of subjects, percentages and number of events of Treatment Emergent DILI by SOC and PT 
tables will be prepared. 
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. 
15.1.4.5. 
Injection-site Reactions 
Injection-site reactions are those events recorded within the following subsearches of the BIcMQ 
“Administration site reactions” (narrow):  
 
Administration site reactions NEC (subsearch 1) 
 
Application and instillation site reactions (subsearch 2) 
 
Infusion site reactions (subsearch 4) 
 
Injection site reactions (subsearch 5) 
Number of subjects, percentages and number of events of Treatment Emergent Injection-site reactions by 
SOC and PT tables will be prepared. 
Injection-site reactions will be listed. 
15.1.4.6. 
Anaphylactic Reactions 
Anaphylactic reactions are those events recorded as MedDRA code in the pre-defined SMQ = 
“Anaphylactic reactions” (narrow). 
Anaphylactic reactions adverse events of special interest are those events both identified as Anaphylactic 
reactions and recorded as “Adverse Event of Special Interest” equal to “Yes” on the Adverse Events page 
of the eCRF. 
Number of subjects, percentages and number of events of Treatment Emergent Anaphylactic reactions by 
SOC and PT tables will be prepared. 
Anaphylactic reactions 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. 
15.1.5.
NON-SERIOUS TREATMENT EMERGENT AES 
Non-serious TEAEs are those events for which the investigator ticked “No” to the item “Is this a serious 
adverse event?” on the Adverse Events page of the eCRF. 
Frequency of subjects, number of events and incidence of subject with non-serious TEAEs will be 
presented by SOC and PT, if preferred term total incidence >5%. 
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Statistical Analysis Plan 
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Document: 
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 Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
15.1.6.
OTHER SIGNIFICANT AES 
Other significant AEs are not applicable in this single-dose trial as discontinuation, withdrawal or dose 
reduction cannot happen. 
15.2.DEATHS 
If any subjects die during the trial as recorded on the “End of trial visit” page of the eCRF, the 
information will be presented in a summary table and a data listing based on the RND set. 
15.3.LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this trial for Serum chemistry, 
Hematology, Coagulation, and Urinalysis. A list of laboratory assessments performed at screening, 
admission (Day -1), Day 8, Day 22 and Day 57 is included in APPENDIX 3. 
Presentations will use SI 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 and single dose of trial medication up to a period of 10 
weeks after the last dose of the trial medication will be assigned to the treatment phase for evaluation. 
All available data (including IGRA results) will be listed. 
In case the results of a laboratory parameter are reported in different units, depending on the site who 
performed the measurement, and no conversion factor between the two units is available, the laboratory 
parameter will be analyzed by site. 
The following summaries will be provided for laboratory data: 
 
Actual and change from baseline by visit (for quantitative measurements) 
 
Shift from baseline category (Low / Normal / High) by visit (all parameters except urinalysis 
parameters) 
 
Shift from baseline category (Negative / Positive) by visit (for urinalysis parameters)  
 
Incidence of possible Hy’s law subjects 
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Statistical Analysis Plan 
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 Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
 
Incidence of possible DILI 
 
The time course of ALT, AST and total bilirubin (TBL) for all possible Hy’s law subjects, all 
parameters shown on a logarithm to base 10 scale of the multiple of the upper limit of 
normal (ULN) (Y axis) versus days since treatment start (X axis) 
 
Scatter plots for Evaluation of Potentially Drug-Induced Liver Injury: 
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 
15.3.1.
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 
 
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 
>=3xULN ) 
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 
Category 1 : AST and/or ALT ≥3 times ULN and TBL ≥2 times ULN within the same 
sample 
o 
Category 2 : marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold 
ULN 
15.3.2.
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: Below the lower limit of the laboratory reference range.  
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Statistical Analysis Plan 
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 
Normal: Within the laboratory reference range (upper and lower limit included). 
 
High: Above the upper limit of the laboratory reference range. 
15.3.3.
OTHER SAFETY LABORATORY EVALUATIONS 
15.3.3.1. 
Pregnancy test 
Descriptive table will present pregnancy results for females overall on SAF. 
The pregnancy results will be listed as well on ENR. 
15.4.ECG EVALUATIONS 
Results from the central ECG (Electrocardiogram) 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”). 
In case of multiple assessments at the same date, the evaluation with the worst result is taken into 
account. 
15.5.VITAL SIGNS 
The following Vital Signs measurements will be reported for this trial: 
 
Systolic Blood Pressure (mmHg) 
 
Diastolic Blood Pressure (mmHg) 
 
Pulse Rate (bpm) 
 
Temperature (⁰C) 
 
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 time points at one visit, the pre-administration data will be considered or the last 
available measurement at a specific visit (if pre-administration data is not applicable) will be used for 
summary tables.  
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Statistical Analysis Plan 
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 Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
15.6.PHYSICAL EXAMINATION  
Physical examination findings are required to be reported as relevant medical history/baseline condition 
or as adverse event. No separate listing or analysis of physical examination findings will be prepared. 
15.7.OTHER SAFETY ASSESSMENTS 
15.7.1.
IMMUNOGENICITY EVALUATION 
All outputs for Immunogenicity will be based on the SAF. There will be no inferential statistical 
comparisons between the treatment groups for immunogenicity data. 
The following summary tables will be provided for immunogenicity data: 
 
Number and frequency of subjects with the following anti-drug antibody (ADA) / neutralizing anti-drug 
antibodies (nAbs) sampling results, by visit (baseline, Day 22, Day 57 and overall): 
o 
Negative  
o 
Positive  
o 
Total reportable (= sum of Negative and Positive)  
o 
Not Reportable (=no sample available or invalid sample)  
o 
Total (= sum of Total Reportable and Not Reportable)  
 
Descriptive statistics of ADA titers will be provided by visit (baseline, Day 22, Day 57 and overall), 
when available 
The ADA and nAb results will be listed as well. 
Following figures will be generated: 
 
Time course of ADA development (percent positive subjects) over time for all treatments 
 
Box plot (with whiskers) of titer within ADA positive subjects over time: at baseline, Day 22, 
and Day 57. 
 
Box plot (with whiskers) of titer within ADA positive subjects at each ADA timepoint (multiple 
graphs; baseline, Day 22, and Day 57)  
 
Time course of nAb development (percent positive subjects) over time (by planned visit day) 
for all treatments 
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Statistical Analysis Plan 
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reproduction is strictly prohibited. 
15.7.2.
LOCAL TOLERABILITY 
Outputs for local tolerability will be based on the SAF.  
The number and percentage of subjects with injection site reactions (assessed at Day 1 from the time of 
the injection until Day 2) will be summarized by treatment for each injection site reaction. 
The number of patients with at least one injection site reaction post-administration will also be reported. 
All injections site reactions will be listed. 
16.
PHARMACOKINETIC DATA 
All outputs for pharmacokinetic outcomes will be based on the PKS. 
PK analysis constitutes the primary objective of this trial to compare BI 695501 administration via PFS 
vs AI.  
16.1.
PRIMARY PHARMACOKINETIC 
16.1.1. PHARMACOKINETIC VARIABLES & DERIVATIONS 
The primary endpoints are: 
 
AUC0-1368 (area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 to 1368 hours after dose) 
 
Cmax (maximum measured concentration of the analyte in plasma) 
 
AUC00-∞ (area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 extrapolated to infinity) based on observed concentration at time of last 
measurable concentration 
No secondary endpoints for PK are defined. 
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Statistical Analysis Plan 
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reproduction is strictly prohibited. 
The PK parameters will be calculated according to the BI SOP ‘Standards and processes for analyses 
performed within Clinical Pharmacokinetics/ Pharmacodynamics’ [001-MCS-36-472]. 
Only concentration values within the validated concentration range and actual sampling times will be 
used for the calculation of PK parameters. Concentrations used in the PK calculations will be in the 
same format as provided in the bioanalytical report (that is, to the same number of decimal places 
provided in the bioanalytical report). 
If a pre-dose concentration value is greater than 5% of Cmax, the subject’s PK data will not be included in 
any statistical evaluations, in accordance with international guidance. The individual PK parameters of 
such a subject will be calculated and listed separately. These PK parameters and observed 
concentrations will not be included in descriptive statistics. If a pre-dose concentration is above the limit 
of quantification (BLQ), but less than or equal to 5% of the subject’s Cmax value, the subject’s data, 
without any adjustments, will be included in all PK measurements and calculations. 
16.1.2. MISSING DATA METHODS FOR PRIMARY PHARMACOKINETIC VARIABLES 
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor.  
For the non-compartmental analysis, concentration data identified with NOS (no available sample), 
NOR (no valid result) or NOA (not analyzed) will generally not be considered. Concentration values in 
the lag phase identified as BLQ will be set to zero. All other BLQ values of the profile will be ignored. 
The lag phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit. 
Descriptive statistics of parameters and concentrations are calculated only when a parameter value is 
available for at least 2/3 of the treated individuals. If the actual sampling time is not recorded or is 
missing for a certain time point, the planned time will generally be used for this time point instead. PK 
parameters that cannot be determined will be identified as “not calculated”. 
16.1.3. ANALYSIS OF PHARMACOKINETIC VARIABLES 
The primary PK endpoints will be evaluated using boxplots (linear and log-scale) for prefilled syringe 
versus autoinjector administration of BI 695501. In addition, scatterplots will be produced to examine the 
primary PK endpoints using baseline body weight as a continuous variable. 
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Statistical Analysis Plan 
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 Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
Descriptive statistics of plasma concentrations and PK endpoints, as well as the tables and graphs for 
the pharmacokinetic noncompartmental analyses, will follow specific definitions of this SAP or, 
otherwise, the BI standard procedure “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics” [001-MCS-36-472]. 
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Statistical Analysis Plan 
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 Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
17.
REFERENCES  
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON. 
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