Clinical trial NCT05203289
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2022-02-18; Completion date: 2022-08-29
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this trial is to compare the pharmacokinetics (PK) of 40 mg BI 695501 100 mg/mL with 40 mg BI 695501 50 mg/mL following single subcutaneous administration.

Detailed description:

Arms: arm 1: Participants were subcutaneously injected 40 milligram (mg)/0.4 milliliter (mL) of BI 695501 solution for injection in prefilled syringe (PFS) (Test Treatment (T)). arm 2: Participants were subcutaneously injected 40 milligrams (mg)/0.8 milliliter (mL) of BI 695501 solution for injection in prefilled syringe (PFS) (Reference Treatment (R)).
Interventions: intervention 1: BI 695501 - higher concentration intervention 2: BI 695501 - lower concentration
Intervention descriptions: intervention 1: BI 695501 - higher concentration intervention 2: BI 695501 - lower concentration

Protocol documents:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
26 November 2021
Revision date
Not applicable
BI trial number
1297-0015
Title of trial
Relative bioavailability of 40 mg/0.4 mL of BI 695501 compared to 40 mg/0.8 
mL of BI 695501 formulation following single subcutaneous administration in 
healthy male and female subjects (a double blind, randomised, single-dose, 
parallel-arm study).
Coordinating
Investigator
Trial site(s)
Multicenter trial to be conducted in two sites:
Clinical phase
I
Trial rationale
Relative bioavailability of a test product (40 mg BI 695501 100 mg/ml, 0.4 ml) 
compared to the reference product (40 mg BI 695501 50 mg/ml, 0.8 ml) is to be 
investigated
Trial objective
The main objective of this trial is to compare the pharmacokinetics (PK) of 40 
mg BI 695501 100 mg/mL with 40 mg BI 695501 50 mg/mL following single 
subcutaneous administration.
Trial endpoints
Primary endpoints: AUC0-∞, AUC0-1344 and Cmax of BI 695501
Secondary endpoints: No secondary endpoints defined
Trial design
Double blind, randomised, single-dose, parallel-arm study
Number of subjects 
total entered
200
on each treatment
100
Diagnosis
Not applicable
Main inclusion criteria
Healthy male/female subjects, age of 18 to 55 years (inclusive), body mass index 
(BMI) of 18.5 to 29.9 kg/m2 (inclusive)
Test product
BI 695501 Solution for injection in prefilled syringe (T)


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dose
40 mg / 0.4 mL / 100 mg/mL
mode of 
administration
Subcutaneous injection
Reference product
BI 695501 Solution for injection in prefilled syringe (R)
dose
40 mg / 0.8 mL / 50 mg/mL
mode of admin.
Subcutaneous injection
Duration of treatment
Single dose administration trial followed by a 57-day observation period and up
to 70 days safety follow up period
Statistical methods
Relative bioavailability of 40 mg/ 0.4 ml BI 695501 formulation (Test, T) 
compared to 40 mg/ 0.8 ml of BI 695501 formulation (Reference, R) will be 
estimated by the ratios of the geometric means (T/R) for the primary endpoints. 
Additionally, their two-sided 90% confidence intervals (CIs) will be provided. 
This method corresponds to the two one-sided t-test procedure, each at a 5% 
significance level. Since the main focus is on estimation and not testing, a formal 
hypothesis test and associated acceptance range is not specified. The statistical 
model will be an analysis of covariance (ANCOVA) on the logarithmic scale 
including effects for ‘treatment’, ‘location of trial medication injection’ and 
‘baseline body weight’. CIs will be calculated based on the residual error from 
the ANCOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Visit
Day
Planned time
[h:min]
Approx. time (actual 
time) [h:min]6
Event and comment
Laboratory/
Urinalysis4
Injection site / Local 
tolerability Assessment
PKblood
Physical Exam
12-lead ECG
Vital signs 
(BP, PR and Temp3)
AE/Concomitant 
Mediation
1
-28 
to 
-2
Screening
A7
X
X
X
▲
▼
-1
Admission to 
trial center
B7,8
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
4:00
12:00
X
X
X
X
12:00
20:00
X
X
2
24:00
8:00
Discharge 
from trial site
X
X
X
X
X
X
3
48:00
8:00
Ambulatory 
visit
X
X
▲
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
│
▼
X
4
72:00
8:00
Ambulatory 
visit
X
5
96:00
8:00
Ambulatory 
visit
X
6
120:00
8:00
Ambulatory 
visit
X
7
144:00
8:00
Ambulatory 
visit
X
8
168:00
8:00
Ambulatory 
visit
X
10
216:00
8:00
Ambulatory 
visit
B
X
X
X
X
15
336:00
8:00
Ambulatory 
visit
X
X
X
22
504:00
8:00
Ambulatory 
visit
B
X
X
X
X
29
672:00
8:00
Ambulatory 
visit
X
X
X
36
840:00
8:00
Ambulatory 
visit
X
43
1008
8:00
Ambulatory 
visit 
X
3
57
1344
8:00
Ambulatory 
e.o.t. 
D8
X
X
X
X
X
X
70
Safety Follow-
up (e.o.s.)5


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Note: Please refer to table 1 for specific planned time points.
1.
Days -1 to 2 will be inpatient visits. Days 3 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 inclusive IGRA-T will be performed at screening and e.o.t.; Abbreviated laboratory testing 
will be performed on Day -1, 10, 22, 57 according to the Table 5.2.3:1, and at the investigator’s discretion.
5.
Day 70 (e.o.s.): 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.
7.
SARS-CoV-2 PCR test will be performed at screening shortly (within 72 hours) before admission to the site
8.
Including Urine β-hCG


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS AND DEFINITIONS..................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................13
1.2.1
Residual Effect Period..........................................................................14
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................15
1.4
BENEFIT - RISK ASSESSMENT ...................................................................15
1.4.1
Benefits...................................................................................................15
1.4.2
Risks .......................................................................................................15
1.4.3
Discussion...............................................................................................17
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 18
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......18
2.1.1
Main objectives......................................................................................18
2.1.2
Primary endpoint(s)..............................................................................18
2.1.3
Secondary endpoint ..............................................................................18
2.2.2.2
Safety and tolerability..............................................................19
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 20
3.1
OVERALL TRIAL DESIGN............................................................................20
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................20
3.3
SELECTION OF TRIAL POPULATION ......................................................20
3.3.1
Main diagnosis for trial entry..............................................................21
3.3.2
Inclusion criteria...................................................................................21
3.3.3
Exclusion criteria ..................................................................................21
3.3.4
Withdrawal of subjects from treatment or assessments ...................23
3.3.4.1
Withdrawal from trial treatment ..............................................23
3.3.4.2
Withdrawal of consent to trial participation ............................24
3.3.4.3
Discontinuation of the trial by the sponsor..............................24
3.3.5
Replacement of subjects .......................................................................24
4.
TREATMENTS........................................................................................ 25


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4.1
INVESTIGATIONAL TREATMENTS ..........................................................25
4.1.1
Identity of the Investigational Medicinal Products ...........................25
4.1.2
Selection of doses in the trial................................................................26
4.1.3
Method of assigning subjects to treatment groups ............................26
4.1.4
Drug assignment and administration of doses for each subject .......26
4.1.5
Blinding and procedures for unblinding ............................................27
4.1.6
Packaging, labelling, and re-supply ....................................................27
4.1.7
Storage conditions.................................................................................27
4.1.8
Drug accountability ..............................................................................28
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................28
4.2.1
Other treatments and emergency procedures....................................28
4.2.2
Restrictions............................................................................................29
4.2.2.1
Restrictions regarding concomitant treatment .........................29
4.2.2.2
Restrictions on diet and life style.............................................29
4.2.2.3
Contraception requirements.....................................................30
4.3
TREATMENT COMPLIANCE.......................................................................30
5.
ASSESSMENTS....................................................................................... 31
5.1
ASSESSMENT OF EFFICACY.......................................................................31
5.2
ASSESSMENT OF SAFETY............................................................................31
5.2.1
Physical examination ............................................................................31
5.2.2
Vital signs...............................................................................................31
5.2.3
Safety laboratory parameters..............................................................31
5.2.4
Electrocardiogram................................................................................34
5.2.5
Other safety parameters.......................................................................35
5.2.5.1
Local tolerability......................................................................35
5.2.6
Assessment of adverse events...............................................................35
5.2.6.1
Definitions of adverse events...................................................35
5.2.6.1.1 Adverse event ............................................................35
5.2.6.1.2 Serious adverse event ................................................36
5.2.6.1.3 AEs considered ‘Always Serious’.............................36
5.2.6.1.4 Adverse events of special interest .............................36
5.2.6.1.5 Intensity (severity) of AEs.........................................37
5.2.6.1.6 Causal relationship of AEs ........................................37
5.2.6.2
Adverse event collection and reporting ...................................38
5.2.6.2.1 AE collection.............................................................38
5.2.6.2.2 AE reporting to the sponsor and timelines ................39
5.2.6.2.3 Pregnancy ..................................................................39
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................39
5.3.1
Assessment of pharmacokinetics .........................................................39
5.3.2
Methods of sample collection...............................................................40
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................40




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8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................51
8.2
DATA QUALITY ASSURANCE .....................................................................52
8.3
RECORDS..........................................................................................................52
8.3.1
Source documents .................................................................................52
8.3.2
Direct access to source data and documents.......................................53
8.3.3
Storage period of records.....................................................................53
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................53
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......54
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................54
8.6
TRIAL MILESTONES .....................................................................................54
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................55
9.
REFERENCES......................................................................................... 56
9.1
PUBLISHED REFERENCES...........................................................................56
9.2
UNPUBLISHED REFERENCES.....................................................................56
10. APPENDICES .......................................................................................... 57
10.1
INSTRUCTIONS FOR USE.............................................................................57
10.2
MEDICATION BLINDING PROCEDURE FOR THIRD PARTY 
BLINDING .........................................................................................................58
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 63


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ABBREVIATIONS AND DEFINITIONS
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
anti-HBc
anti-hepatitis B core antibodies
anti-HCV
hepatitis C antibodies
AST
aspartate aminotransferase
AUC
area under the curve
β-hCG
beta-human chorionic gonadotropin
BI
Boehringer Ingelheim
BLQ
below the limit of quantitation
BSA
body surface area
CA
competent authority
CI
confidence interval
Cmax
maximum concentration of the analyte in plasma
Cmin
minimum concentration of the analyte in plasma
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
coefficient of variation
DILI
drug-induced liver injury
DLQI
Dermatology Life Quality Index
DRM
Data Review Meeting
ECG
electrocardiogram
eCRF
electronic Case Report Form
EoT
End-of-Treatment
EU
European Union


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EudraCT
European Clinical Trials Database
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
immunoglobulin
IGRA
interferon gamma-release assay
IL
interleukin
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
intrauterine device
i.v.
intravenous
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LPDD
Last Patient Drug Discontinuation
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
MTX
methotrexate
NOA
not analysed
NOR
no valide result
NOS
no sample
NRI
non-responder imputation
NSAID
non-steroidal anti-inflammatory drug
PASI
Psoriasis Area and Severity Index
PASI50
50% reduction in Psoriasis Area and Severity Index


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PASI75
75% reduction in Psoriasis Area and Severity Index
PK
pharmacokinetic(s)
PKS
Pharmacokinetic Set
PPD
purified protein derivative
PPS
Per-Protocol Set
PUVA
psoralen with ultraviolet light
RA
rheumatoid arthritis
REP
residual effect period
RTS
Run-in Treated Set
SAE
serious adverse event
s.c.
subcutaneous
SFU
Safety Follow-up
SOP
standard operating procedure
SPC
summary of product characteristics
sPGA
Static Physician’s Global Assessment
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
tmax
time to reach maximum concentration
tmin
time to reach minimum concentration
TNF
Tumor necrosis factor
TNFR1
tumor necrosis factor 1
TNFR2
tumor necrosis factor 2
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
upper limit of normal
US
United States
US-PI
United States Prescribing Information
WHO
World Health Organisation
ADME
Absorption, distribution, metabolism, and excretion


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
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. 
Humira® (adalimumab) was first launched in 2002 for the treatment of active moderately to
severely active rheumatoid arthritis. As of February 2019, Humira® is approved for 
many indications (R18-2637, R19-0075) in the US and EU
1.2
DRUG PROFILE
BI 695501 is a monoclonal antibody, developed and approved as a biosimilar to the TNF-
alpha blocker Humira® under the trade name Cyltezo®. The marketing authorisation 
application and aBLA seeking registration of Cyltezo® as a biosimilar to Humira®
(adalimumab) were submitted to US FDA in October 2016, and the FDA approved it on 25 
Aug 2017 (R17-4157).
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 (R18-2637, R19-0075).
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 Humira. There was no difference in systemic 
exposure between BI 695501 and Humira with repeated dosing. This trial 
demonstrated the similarity of the toxicology profile for BI 695501 and Humira.
!
A single dose pharmacokinetic (PK), subcutaneous (s.c.) trial in cynomolgus monkeys 
comparing BI 695501 to Humira. There were no differences in the exposure or 
antidrug antibody (ADA) response in cynomolgus monkeys to BI 695501 and 
Humira.
!
A comparative human tissue cross-reactivity trial of BI 695501 and Humira. This trial 
showed that the patterns of staining of BI 695501 and Humira were similar with 
minor differences 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 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
and Humira. 


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!
The potential for BI 695501 to induce in vitro cytokine release or directly activate 
complement compared to Humira. The results from this trial demonstrated that 
BI 695501 and 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.
Clinical studies
A total of 408 healthy subjects have been treated with BI 695501 in 4 phase I studies 
investigating single administrations of BI 695501 (408) or Humira (342) (U13-1096-01, 
c03070713, c08933656, c15874906). There were no notable differences between BI 695501 
and Humira and between PFS and AI with respect to safety, tolerability, and immunogenicity.
Overall, the adverse events (AEs) seen in healthy subject trials were in line with the known 
safety profile of Humira (R18-2637, R19-0075).
A total of 1060 patients have been treated with BI 695501 including patients with RA, 
Crohn´s disease and plaque psoriasis.
Overall, the safety profile of BI 695501 observed in the clinical trials is considered similar to
and consistent with the known safety profile of Humira®. The trials showed that BI 695501 
and Humira are highly similar in terms of efficacy over a treatment duration up to 48 weeks.
The results of the immunogenicity assessment across trials demonstrated a comparable 
immunogenicity profiles.
Cyltezo® is approved for the following indications in the US:
!
Rheumatoid arthritis
!
Juvenile idiopathic arthritis
!
Axial spondyloarthritis
!
Psoriatic arthritis
!
Crohn’s disease
!
Paediatric Crohn's disease
!
Psoriasis
!
Paediatric plaque psoriasis
!
Ulcerative colitis
!
Uveitis
For a more detailed description of the BI 695501 (Cyltezo®) profile, please refer to the 
current Investigator’s Brochure (IB) [c01835608]
1.2.1
Residual Effect Period
The Residual Effect Period (REP) of BI 695501 is 70 days. This is the period after the last 
dose during which measurable drug levels and/or pharmacodynamic effects are still likely to 
be present.


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1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 695501 is being developed in two different formulations, 50 mg/mL per 0.8 mL solution 
for injection (current formulation) and 100 mg/mL per 0.4 mL solution for injection (HCLF), 
both containing the same amount of the drug product - 40 mg BI 695501. Pursuant to the 
Guidance for industry, the relative bioavailability of a test product (40 mg BI 695501, 100 
mg/ml, 0.4 ml) compared to the reference product (40 mg BI 695501, 50 mg/ml, 0.8 ml) is to 
be investigated.
Additionally, clinical data to support the safety, including 
 and local 
tolerability will be evaluated. 
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
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 lower volume formulation to be used for patient’s treatment. The subjects are 
exposed to the risks of the trial procedures and the risks related to the exposure to the trial 
medication.
1.4.2
Risks
Subjects are exposed to risks of trial procedures and risks related to the exposure to the trial 
medication.
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 (BI 695501 (Cyltezo®), 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 


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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. 
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 (R18-2637, R19-0075). 
The PK similarity of BI 695501 to US-licensed and EU-approved Humira was established 
(c03070713). Additionally, there were no notable differences with respect to safety, 
tolerability and immunogenicity between groups 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 24 hours after trial medication administration 
for 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 1-8, 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 


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 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.
In addition, hypersensitivity reactions, anaphylaxis, and serious infections are considered as 
adverse events of special interest (AESI), see Section 5.2.6.1.4.
Based upon preclinical and clinical information available to date, healthy subjects in this trial 
will not be exposed to undue safety risks.
1.4.3
Discussion
The nature of the target and the mechanism of action of BI 695501 is well understood.
In the context of the unmet medical need and anticipated benefit of BI 695501, the benefit 
risk evaluation of the compound, based upon the available preclinical and clinical 
information, is favourable.
Considering the medical need for the development of a better tolerated and more effective 
treatment for patients with BI 695501, the expected benefit outweighs the potential risks.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the relative bioavailability of 40 mg BI 
695501 100 mg/mL (test) versus 40 mg BI 695501 50 mg/mL (reference) following single 
subcutaneous administration.
2.1.2
Primary endpoint(s)
The following pharmacokinetic parameters will be determined for 40 mg BI 695501
100 mg/mL and 40 mg BI 695501 50 mg/mL:
!
AUC0-1344 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 1344 hours after dose administration)
!
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
!
Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
Not applicable.


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2.2.2.2
Safety and tolerability
Safety and tolerability of 40 mg BI 695501 100 mg/mL and 40 mg BI 695501 50 mg/mL will 
be assessed based on:
!
Adverse events (including clinically relevant findings from the physical examination
or 12-lead ECG)
!
Safety laboratory tests
!
Local tolerability 
!
Vital signs (BP, PR)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
The trial will be performed as a randomized, single-dose, double blind, parallel arm trial in 
healthy male and female subjects aged ∀18 to #55 years.
It is planned to include 200 healthy male and female subjects into the trial to ensure at least 
190 subjects for the primary analysis. Subjects will be randomly assigned to receive one dose 
of either BI 695501 40 mg/0.4 mL (T) or BI 695501 40 mg/0.8 mL (R). All study drugs will 
be administered by subcutaneous injection.
The trial will consist of a Screening period of up to a maximum of 28 days. The subject will 
check-in to the trial center on Day -1, will be dosed on Day 1. All subjects will remain in the 
clinic until day 2 after dosing. The subject will then return to the clinic for 13 ambulatory 
visits on Days 3, 4, 5, 6, 7, 8, 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.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
This is a 14-week, double blind, randomized, single dose, parallel arm trial to investigate and 
compare the PK, safety, tolerability and immunogenicity of two formulations of BI 695501 
administered subcutaneously via prefilled syringe.
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.
The trial endpoints are derived from measurement of plasma concentrations of the analyte 
provided by a bioanalytical laboratory which is blinded to treatment allocation.
The group size of up to 100 subjects per treatment group is considered adequate for an 
evaluation of the PK, safety, tolerability, 
.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 200 healthy male and female subjects will enter the trial. They will be 
recruited from the volunteers' pool of the trial sites.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF, irrespective of whether they have been treated with investigational 
drug or not.


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3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy 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
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male or female subjects according to the assessment of the investigator, as based 
on a complete medical history including a physical examination, vital signs, 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
5. Participants of reproductive potential (childbearing potential1) must be willing and able 
to use highly effective methods of birth control per International Council for 
Harmonisation (ICH) M3 (R2) that result in a low failure rate of less than 1% per year 
from at least 30 days before administration of the trial medication until 30 days after trial 
completion. A list of contraception methods meeting these criteria is provided in the 
Section 4.2.2.3 and ICF.
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
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.
                                                          
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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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 30 days 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 4 days 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).
17. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because
 
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, or 
planned to be vaccinated with any vaccine during the study
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
25. During COVID-19 pandemic*: laboratory test indicative of an ongoing SARS-CoV-2 
infection
*Participants enrolled to the study should be either fully vaccinated or recovered at least 2 
weeks prior to the study start. 


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For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may withdraw or may be removed from trial treatment or may withdraw consent to 
trial participation as a whole (‘withdrawal of consent’) with very different implications; 
please see Sections 3.3.4.1 and 3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR).
If a subject is removed from or withdraws from the trial after the first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, trial data will be included in the CRF and will be reported in the CTR. 
Following removal or withdrawal, a complete end-of-trial examination should be performed.
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.1, the
discontinued subject should, if possible, be questioned for AEs and concomitant therapies at 
or after the end of the REP, in order to ensure collection of AEs and concomitant therapies 
throughout the REP, if not contrary to any consent withdrawal of the subject.
3.3.4.1
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:
1. The subject wants to withdraw from trial treatment. The subject will be asked to explain 
the reasons but has the right to refuse to answer
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, the safety of the 
subject cannot be guaranteed as he / she is not willing or able to adhere to the trial 
requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as pregnancy,
surgery, adverse events (AEs), or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
If new efficacy or safety information becomes available, Boehringer Ingelheim will review 
the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
subjects or take any other appropriate action to guarantee the safety of the trial subjects.


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3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons (if reasons 4 and/or 5 are met, the trial should 
be discontinued immediately):
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. The sponsor decides to discontinue the further development of the investigational 
products
3. Deviation from GCP, or the CTP impairing the appropriate conduct of the trial
4. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment (see Section 3.3.4.1)
5. More than 50% of the subjects show drug-related and clinically relevant adverse events of 
moderate or severe intensity
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than 10 subjects do not complete the trial (including subjects non- evaluable for 
PK), additional subjects may be recruited and treated with the respective treatment if 
considered necessary to reach the objective of the trial. Subjects who withdraw or are
withdrawn from treatment or assessments because of a drug-related adverse event will not be 
replaced and no additional subject will be recruited in such a case. The Clinical Trial Leader
together with the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how 
many subjects will be replaced, i.e. recruited in addition. The total number of replacements 
may not exceed 1/4 of the total number of evaluable subjects anticipated to complete the trial. 
A replacement subject will be assigned a unique trial subject number, and will be assigned to 
the same treatment as the subject he or she replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Test product:
Substance:
BI 695501 
Pharmaceutical formulation: Solution for injection in prefilled syringe
Source:
Boehringer Ingelheim
Unit strength:
40 mg / 0.4 mL / 100 mg/mL
Posology:
1-0-0*
Route of administration:
s.c.
Duration of use:
single dose
Reference product:
Substance:
BI 695501 
Pharmaceutical formulation: Solution for injection in prefilled syringe
Source:
Boehringer Ingelheim
Unit strength:
40 mg / 0.8 mL / 50 mg/mL
Posology:
1-0-0*
Route of administration:
s.c.
Duration of use:
single dose
*administered in the morning
BI 695501 will be provided as sterile, preservative-free, non-pyrogenic, single-use prefilled 
glass syringes containing 40 mg of BI 695501 per 0.4 or 0.8 mL. One syringe will be used 
per injection. The needle cap of the syringe contains dry, natural rubber.


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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. The design and handling of the BI 695501 prefilled syringes are 
standard, and intended to be marketed.
4.1.3
Method of assigning subjects to treatment groups
The randomisation scheme will be provided to the trial sites in advance.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
Several subjects may be treated in one cohort, i.e. all subjects may receive treatment on the 
same calendar day. In case this is not feasible (e.g., due to logistical or recruitment reasons), 
the group may be split into several cohorts as required.
The randomisation procedure is described in Section 7.4.
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 summarised in Table 4.1.4: 1 below.
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T (Test)
BI 695501
Solution for 
injection in 
PFS
100 mg/mL
0.4 mL
40 mg
R (Reference)
BI 695501
Solution for 
injection in 
PFS
50 mg/mL
0.8 mL
40 mg
The prefilled syringes should be taken out of the fridge and wait approximately 30 minutes 
before administration, to permit the medication to warm to room temperature. Injecting cold 
medication can cause discomfort. Once taken out of the refrigerator, the trial medication 
should be administered within approx. 1 hour. A syringe must not be used if it is frozen or if 
it has been left in direct sunlight.
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 trial medication injection will be the lower abdomen (excluding a 2-inch 
[5-cm] area around the navel) or upper thigh. Each injection site should be used for at least 
60 subjects (~30%), preferably 100 subjects (i.e. 50%) of the study population. Detailed 
“Instructions for use” are provided in the Appendix 10.1 and 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.


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4.1.5
Blinding and procedures for unblinding
This is a double-blind trial, therefore patients, investigators, and everyone involved in clinical 
conduct (except the trial personnel administering the trial medication – third party blinding) 
will remain blinded with regard to the randomized treatment assignments until after database 
lock.
The unblinded site personnel administering the trial medication will not be involved in any 
other trial assessments or procedures.
Details of blinding procedures are described in Appendix 10.2 Medication Blinding 
Procedures.
The secondary packaging (boxes containing PFS) will be identical for both BI 695501 40 mg 
per 0.4 or 0.8 mL, allowing the blinding of the site pharmacy.
The data will be unblinded at the time point of the primary analysis (see Section 7.4), only for 
individuals involved in the primary analysis and reporting.
Access to the randomization code will be controlled and documented. All persons directly 
involved in the conduct of the trial will have no access to the treatment allocation prior to 
final database lock.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
Emergency envelopes will not be provided, since all subjects will receive the same dose of 
the same drug.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP).
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
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 


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Clinical Research Associate (as provided in the list of contacts) is to be contacted
immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:
!
Approval of the clinical trial protocol by the IRB / ethics committee
!
Availability of a signed and dated clinical trial contract between the sponsor or 
delegate and 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 FDA Form 1572
Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
The investigator or designee 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 medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
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 results of medical 
evaluations are acceptable.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed except for hormonal contraceptives or ovary 
hormone replacement; 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 
 deputy unless necessary to treat medical emergencies. 
All concomitant or rescue therapies will be recorded (including time of intake on trial days) 
on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff and are restricted from smoking. Standardised 
meals will be served at the standard times.
On all days when safety laboratory sampling is planned, subjects must have fasted for at least 
6 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.
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


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!
A standard pub measure (35 mL) of spirits (40% alcohol by volume).
4.2.2.3
Contraception requirements
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 and Male subjects with female partner(s) of child-bearing potential must 
agree to use a medically acceptable method of contraception from at least 30 days before the 
first administration of trial medication, during the trial and until 30 days after trial 
completion. Males and male partners of female subjects should use a condom.
If female subjects of child-bearing potential are included in the trial, adequate contraception 
is to be maintained throughout the course of the trial. Acceptable methods of birth control 
include, for example: combined (estrogen and progestogen containing) hormonal 
contraception that prevents ovulation (oral, intravaginal or transdermal); progestogen-only 
hormonal contraception that inhibits ovulation (only injectables or implants); intrauterine 
devices (IUDs) or intrauterine hormone-releasing system (IUS); surgical sterilization;
vasectomized partner or be Sexually abstinent.
Women of childbearing potential are defined as:
!
Having experienced menarche and
!
Not postmenopausal (12 months with no menses without an alternative medical 
cause) and 
!
Not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy).
Women must not breast-feed for at least six months after the adalimumab treatment.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication 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 CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
BMI, smoking and alcohol history (smoking/alcohol history not mandatory to be entered into
CRF or to be reported), relevant medical history and concomitant therapy, review of 
inclusion and exclusion criteria, review of vital signs (BP, PR, T), 12-lead ECG, laboratory 
tests, and a physical examination. The physical examination will include assessment of 
general appearance, skin, head, neck, throat, lymph nodes, cardiovascular and neurological 
systems, thyroid gland, musculoskeletal system/limbs, respiratory tract and abdomen. 
Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
At the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, and a physical examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor (e.g. 
Welch Allyn Spot Vital Signs LXi) at the times indicated in the 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 blood pressure recording instrument on the same arm, if possible. Body 
temperature (T) will also be recorded. The method of measuring body temperature 
(oral/aural) should be consistent at a specific trial site.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 6 h. 
For retests, at the discretion of the investigator or designee, overnight fasting is not required.
The parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will 
be provided in the ISF. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
D
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes;
Eosinophils/Leukocytes;
Basophils/ Leukocytes; 
Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Enzymes
AST [Aspartate aminotransferase] /GOT, SGOT 
ALT [Alanine aminotransferase] /GPT, SGPT
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated]
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
X
--
--


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct (if total elevated)
Albumin (Protein Electrophoresis)
Alpha-1-Globulin (Protein Electrophoresis)  
Alpha-2-Globulin (Protein Electrophoresis)
Beta-Globulin (Protein Electrophoresis) 
Gamma-Globulin (Protein Electrophoresis)
C-Reactive Protein (Quant)  
Uric Acid 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy test 
(only for female 
subjects of 
childbearing potential) 
at screening and if 
urine pregnancy test is 
positive
Human Serum Chorionic Gonadotropin
X
Electrolytes
Sodium
Potassium
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Ketone (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
Urine Pregnancy test 
(only for female 
subjects of 
childbearing potential) 
at randomization as 
indicated in the Flow 
Chart (including EoT)
Human Chorionic Gonadotropin in the urine
X
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 2 on Day -1, 10, 22 (for time points refer to Flow Chart)
D: parameters to be determined at Visit 3 (end of trial examination)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, prior to 
randomisation, and as part of the end of trial examination. Drug screening will be performed 
at screening and prior to randomisation.


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines
Opiates 
Phencyclidine
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)
COVID 19 infection
SARS-CoV-2 virus PCR test
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. AlcoTrue® M, 
) will be performed at screening and prior to 
randomisation, and may be repeated at any time during the trial at the discretion of an 
investigator or designee. The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at
 
 with the exception of 
urine pregnancy tests. These tests will be performed at the trial site using Consult 
diagnostics® hCG Urine tests, or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
It is the responsibility of the Investigator to evaluate the laboratory reports. Clinically 
relevant abnormal findings as judged by the Investigator are to be reported as adverse events 
(please refer to Section 5.2.6). 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4). 
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (i.e. Burdick ELI 150C) at the times provided in the Flow 
Chart. 
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.


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All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other trial procedures scheduled
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically. Electrode placement will be performed according to 
the method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). Precise electrode placement will be marked with an 
indelible mark on the skin to allow reproducible placement throughout the trial.
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (if identified at the 
screening visit) if assessed to be clinically relevant by the investigator. Any ECG 
abnormalities will be carefully monitored and, if necessary, the subject will be removed from 
the trial and will receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Local tolerability
Local tolerability will be assessed by the investigator or qualified designee on the basis of 
swelling, induration, heat, redness, pain, and other findings. Tolerability will be assessed at 
Day 1 from the time of the injection until Day 2. Local findings assessed as clinically 
relevant by the investigator or qualified designee must be recorded as AE.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
!
Worsening of the underlying disease or of other pre-existing conditions 
!
Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.


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5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
!
Results in death 
!
Is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 
!
Requires inpatient hospitalisation, or prolongation of existing hospitalisation
!
Results in persistent or significant disability or incapacity 
!
Is a congenital anomaly/birth defect
!
Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. 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
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
1.
Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters: 


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o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
o
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 via
the eDC. 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 that 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
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
!
The event is consistent with the known pharmacology of the drug 
!
The event is known to be caused by or attributed to the drug class
!
A plausible time to onset of the event relative to the time of drug exposure
!
Evidence that the event is reproducible when the drug is re-introduced
!
No medically sound alternative 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 reduced)


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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
!
There is an alternative explanation (e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned
!
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs. In addition, each subject will be 
regularly assessed by the medical staff throughout the clinical trial and whenever the 
investigator deems necessary. As a minimum, subjects will be questioned for AEs (and 
concomitant therapies) at the time points indicated in the Flow Chart. Assessment will be 
made using non-specific questions such as ‘How do you feel?’. Specific questions will be 
asked wherever necessary in order to more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
!
From signing the informed consent onwards until an individual subject’s end of trial
(the End of Study (EoS) visit): 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF and will not be reported in the CTR.
!
After the individual subject’s end of trial: 


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o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and trial treatment related SAEs
and trial treatment related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should be 
reported on the BI SAE form (see Section 5.2.6.2.2), but not on the CRF.
5.2.6.2.2
AE reporting to the 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 to the sponsor’s unique entry point within 
24 hours of becoming aware of the event, the country specific reporting process will be 
provided in the ISF. The same timeline applies if follow-up information becomes available. 
On specific occasions, the Investigator could inform the sponsor upfront via telephone. This 
does not replace the requirement to complete and send 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. All (S)AEs, including those persisting after the individual subject’s end of trial, 
must be followed up until they have resolved, have been sufficiently characterized (e.g. as 
‘chronic’ or ‘stable’), or no further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Studies (Part A and Part 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 Studies 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.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time indicated 
in the Flow Chart. The actual sampling times will be recorded and used for determination of 
pharmacokinetic parameters. 


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5.3.2
Methods of sample collection
5.3.2.1
Blood 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.
Full instructions for collection, labelling, storage and shipment of samples are provided 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.
5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
5.4
ASSESSMENT OF BIOMARKERS 
Not applicable.




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5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic and 
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 pharmacokinetic parameters and 
measurements outlined in Section 5.3 are generally used assessments of drug exposure.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration.
!
The acceptable deviation from the scheduled time for vital signs, ECG, laboratory tests 
PK, 
 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, blood sampling has to be done 
first. 
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic 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.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide 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 5.2.1 to 5.2.5.
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.
6.2.2
Treatment period
On Day -1 trial participants will be admitted to the trial site and kept for 24 h following drug 
administration. The subjects will be allowed to leave the trial site on Day 2 after formal 


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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, 
 and 
 analysis, refer to Flow Chart and in the Laboratory Manual.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining subject’s written informed consent until the end of trial
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
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 follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoT Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoT
Visit for continued safety monitoring.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved.
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
(EoS) 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
7.1
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of 40 mg BI 695501 100 mg/mL formulation (T) versus 40 mg BI 
695501 50 mg/mL formulation (R) will be estimated by the ratios of the geometric means 
(T/R) for each primary endpoint, and their corresponding 2-sided 90% confidence intervals 
(CIs) will be provided. This method corresponds to the two one-sided t-test procedure, each 
at the 5% significance level. Since the main focus is on estimation and not testing, a formal 
hypothesis test and associated acceptance range is not specified and no significance level 
adjustment for multiple testing will be applied.
7.2
PLANNED ANALYSES
7.2.1
Analysis sets
Statistical analyses will be based on the following analysis sets:
!
Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The TS will be used for safety analyses.
!
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary and 
was without important protocol deviations or violations thought to significantly affect 
the PK of BI 695501 (as specified in 7.2.1.2). Descriptive and model based analyses 
of PK parameters will be based on the PKS.
Descriptions of additional analysis sets may be provided in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be suggested in the iPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the iPD categories will be updated as needed.
7.2.1.1
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1
for drug BI 695501 will be 
calculated according to the relevant procedures of the Sponsor. 
Pharmacokinetic parameters of a subject will be included in the analysis unless the subject 
has an important protocol violation relevant for the evaluation. Reasons for exclusion of 
single pharmacokinetic parameters can for example be:
!
Time deviations
!
Use of restricted medications
!
Dosing errors 
Whether a protocol violation is important will be decided no later than in the Report Planning 
Meeting. It will also be decided in the Report Planning Meeting which subjects are to be 
excluded from the PKS. Subjects who are not included in the PKS (refer to Section 7.2.1) 
will be reported with their individual plasma concentrations and individual PK parameters;


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however, they will not be included in descriptive statistics for plasma concentrations, PK 
parameters or other statistical assessments.
In case 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 
predose concentration is above the limit of quantification, 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.
Details of the analysis and presentation of PK data will be provided in the Trial Statistical 
Analysis Plan (TSAP).
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic 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). 
7.2.2
Primary endpoint analyses
Primary analyses
The primary analysis is based on  the PKS (see Section 7.2.1.1). The statistical model used 
for the analysis of the primary endpoints will be an analysis of covariance (ANCOVA) model 
on the logarithmic scale. That is, the PK endpoints will be log-transformed (natural 
logarithm) prior to fitting the ANCOVA model. This model will include effects accounting 
for the following sources of variation: ‘treatment’, ‘location of trial medication injection’ and 
‘baseline body weight’. The model is described by the following equation:
ykjm = ∃+ %k + φj + &·weightkm + ekjm, where
ykjm = logarithm of response on subject m receiving treatment k at location j,
∃= the overall mean,
%k = the kth treatment effect, k = 1, 2,
φj = the jth effect of location (thigh, abdomen), j= 1, 2,
& = the slope parameter for the baseline body weight covariable,
weightkm = baseline body weight of subject m receiving treatment k
ekjm = the random error associated with the mth subject who received
in location j treatment k
where  ~ 	(0, 
) are independent random variables.
Point estimates for the ratios of the geometric means (T/R) for the primary endpoints (see 
Section 2.1) and their two-sided 90% confidence intervals (CIs) will be provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 


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Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANCOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.2.3
Secondary endpoint analyses
Not applicable as no secondary endpoints specified.
7.2.5
Safety analyses 
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed at the Report 
Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate 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 (see Section 5.2.6.1), will be listed 
separately.


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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.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
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.
Details of the presentation and analysis of safety data will be provided in the TSAP.
Relevant ECG findings will be reported as AEs.
7.2.6
Interim analyses
No interim analysis is planned.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
With respect to AE analysis, missing relationship will be imputed to “yes”. For other safety 
evaluation, no imputation of missing data is planned.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant procedures of the 
Sponsor. 
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed)will not be considered for the non-compartmental analysis and the 
creation of graphs, except for concentration values in the lag phase identified as BLQ which 
will be set to zero. 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 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”.


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7.4
RANDOMISATION
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 randomization will be stratified by trial site for logistical 
reasons.
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.
The randomization list will contain additional blocks to allow for subject replacement (refer
to Section 3.3.5).
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of N=200 subjects in the trial including up to 10 subjects, that 
may be considered as non-PK evaluable (refer to Section 7.2), because this sample size is 
considered sufficient to assess the primary objective of this exploratory trial. With this 
sample size, the following precision in estimating the ratio of geometric means (T/R) can be 
expected with 95% probability. Precision is defined as the ratio of upper 90% confidence 
interval limit (CL) to the relative BA estimate. Note that the precision is independent of the 
actual ratio of geometric means.
In previous trials (1297.6 and 1297.13) the observed total geometric coefficient of variation 
(gCV) for the primary endpoints AUC and Cmax were in the range of 25% - 54%. The 
observed gCVs tended to be higher in trial 1297.6, in which the study drug was injected in 
lower abdomen only. 
For various assumptions of the gCV, Table 7.5: 1 provides an overview of the achievable 
precision for estimating the ratio of geometric means (T/R). For illustrative purposes, the 
expected 90% confidence intervals are displayed for different values of the ratio T/R of 
geometric means.


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Table 7.5: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a parallel trial (N=190) assessing 
formulation differences
N
gCV 
[%]
Precision 
upper CL* / 
relative BA 
estimate
90% CI [%] of respective ratio**
100
105
110
190
25
1.066
(93.80; 106.61)
(98.49; 111.94)
(103.18; 117.27)
40
1.105
(90.47, 110.54)
(94.99, 116.06)
(99.51, 121.59)
50
1.131
(88.44, 113.07)
(92.86, 118.72)
(97.28, 124.38)
*CL = confidence interval limit
**Ratio of geometric means (T/R) for a PK endpoint is defined by exp(∃T)/exp(∃∋).
The expected 90% confidence interval limits in the table were derived by
CI limit, = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230, Chapter 8] using R 
Version 4.02.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
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 Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), and other 
relevant regulations. Investigators and site staff must adhere to these principles. Deviation 
from the protocol, the principles of ICH GCP or applicable regulations will be treated as 
‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract.
As a general rule, no trial results should be published prior to finalisation of the CTR.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 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 a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional 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 or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate 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 or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
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.


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8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
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.
8.3
RECORDS
eCRFs for individual subjects will be provided by the sponsor. See Section 4.1.5 for rules 
about emergency. 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 for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the subject, documented 
in their medical records, would be acceptable.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:
!
Subject identification: gender, year of birth (in accordance with local laws and 
regulations)


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!
Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)
!
Dates of subject’s visits, including administration of trial medication
!
Medical history (including trial indication and concomitant diseases, if applicable)
!
Medication history
!
AEs and outcome events (onset date [mandatory], and end date [if available])
!
SAEs (onset date [mandatory], and end date [if available])
!
Concomitant therapy (start date, changes)
!
Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)
!
ECG results (original or copies of printouts)
!
Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)
!
Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator/institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They 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 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.


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8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised 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 at the site 
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 and clinical data, in particular
!
Sample and data usage have to be in accordance with the informed consent
!
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.
!
An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place
!
A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage
!
A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
!
Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(‘Last Subject Completed’).
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.




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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R17-4157
Cyltezo (adalimumab-adbm) injection, for subcutaneous use (U.S. 
prescribing information, revised: 8/2017). 2017.
R18-2637
Humira (adalimumab) injection, for subcutaneous use (AbbVie) 
(U.S.prescribing information, revised: 8/2018). 2018
R19-0075
Humira 20 mg solution for injection in pre-filled syringe, 40 mg/0.8 ml 
solution for injection, 40 mg solution for injection in pre-filled syringe, 40 
mg solution for injection in pre-filled pen, 80 mg solution for injection in 
prefilled syringe, 80 mg solution for injection in pre-filled pen 
(AbbVie)(summary of product characteristics, last updated: 12/12/2018). 
2018.
9.2
UNPUBLISHED REFERENCES
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.
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.
c08933656
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, 
(BI Trial 1297.6). Follow-up Clinical Trial Report. 28 Sep 2017.
c15874906
Randomized, single-dose, parallel-arm, open-label Phase I trial to 
investigate and compare the pharmacokinetics, safety and tolerability of BI 
695501 administered subcutaneously to thigh via pre-filled syringe or 
autoinjector (BI Trial 1297.13). 30 May 2017.
c01835608
ib-bi-695501-1297-p1


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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
BI456906 or placebo Pre-Filled Syringe Instructions For Use
Important Safety Information 
!
DO NOT use the pre-filled syringe unless you have been trained to do so. 
!
DO NOT remove the protective cap until right before injection. 
!
DO NOT shake the pre-filled syringe. 
!
DO NOT use the pre-filled syringe if it is dropped or crushed. 
Storage instructions 
!
Store the pre-filled syringe in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC). Do not 
store the pre-filled syringe at the back of your refrigerator, where the pre-filed syringe’s 
medication might freeze. 
!
Keep your pre-filled syringe in a dry and clean environment when warming up prior to 
use. 
!
Never subject your pre-filled syringe to extreme temperatures or direct sunlight (e.g., do 
not store your pre-filled syringe in a car or freezer). 
!
Keep the pre-filled syringe in the original carton until you are ready to use them.
Drug Administration:
Step 1
•
Gather supplies (Pre-filled syringe, Alcohol wipe, Sharps Container) onto clean, flat 
surface in a quiet and well lift area. 
•
Take out of the fridge and wait 15–30 minutes for medication to warm to room 
temperature. 
•
Wash your hands with soap and water, then dry them completely. 
Inspect the pre-filled syringe’s medication, expiration date (on box), and body closely. 
Step 2 
Inspect pre-filled syringe closely:
Using the white tab at the top of the label unwrap the label carefully from around the syringe 
so you can see the medication. 
It is normal to see one or more bubbles in the medication. 
DO NOT use pre-filled syringe if: 
•
Pre-filled syringe has been left outside of the refrigerator or is stored at room-
temperature 15- 25°C (59-77°F) for more than 2 hours. 
•
Medication is cloudy, is or was frozen, or contains flakes or particles. 
•
Pre-filled syringe appears cracked, damaged, or leaking. 
•
Pre-filled syringe has been used. 
•
Pre-filled syringe has been left in direct sunlight for an extended period of time.
Rewrap the label around the syringe. 
Step 3 
Select an injection site on the upper thighs or on the belly (at least 2ins/5cm away from 
navel). 


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•
DO NOT inject an area near your waistline or navel. 
•
DO NOT inject into a tender, bruised or scarred area. 
•
DO NOT inject through clothes. 
Step 4 
Clean the injection site
Use an alcohol wipe to clean the injection site. 
Let cleaned site air dry to avoid stinging. 
•
DO NOT fan or blow on clean site. 
•
DO NOT touch clean site before injecting.
Step 5 
Remove needle cap
Gently pull cap straight off pre-filled syringe. 
Dispose of the cap in general waste.
•
DO NOT twist cap. 
•
DO NOT touch needle or let needle touch anything. 
•
DO NOT re-attach needle cap.
Step 6 
Pinch and hold skin
Raise the skin of the injection site by loosely bringing your finger and thumb together on the 
sides of the injection site. Hold skin around cleaned injection site between finger and thumb. 
You will inject into this raised area of skin.
Step 10 
Dispose of the device
•
DO NOT re-attach needle cap. 
Please dispose of the device in the sharps container.
10.2
MEDICATION BLINDING PROCEDURE FOR THIRD PARTY 
BLINDING
This is a double-blind trial, therefore subjects, Investigators, and trial personnel involved 
clinical conduct (except the trial personnel administering, receiving and handling the trial 
medication at site) will remain blinded with regard to the randomized treatment assignments 
until after database lock. 
To prevent unblinding, a designated person will receive the trial medication and maintain 
records of the product’s delivery to the trial site. In addition, a qualified unblinded designee 
will administer the trial medication, maintain the inventory at the site, as well as will be 
responsible for preparation of used trial medication for return to the sponsor or destruction in 
a blinded fashion and in accordance with local requirements.
Records of the product’s delivery to the trial site will include dates, quantities, batch/serial 
numbers, expiry (‘use by’) dates and the unique code numbers assigned to the investigational 
products and trial patients. The designated unblinded person will maintain records that 
document doses administration to patients and reconcile all investigational product received 
at site. These records should be kept separate from the patients file and not be accessible for 
the blinded personnel. At the time of return to the sponsor or local destruction, the designated 
unblinded person must verify that no supplies remained at the trial site. 


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The unblinded trial personnel administering the trial medication will not be involved in any 
other trial assessments or procedures.
Patient blinding procedure
Trial medication will be administered by unblinded trial personnel on day 1. 
To ensure patient’s blinding during the administration process, the following procedures are 
to be applied:
•
Syringes unpacked and prepared for injection are to be covered by a surgical drape at 
the time of patient preparation for dosing. The same procedure is to be applied to used 
syringes after injection.
•
During the dose administration, patients are to be separated from the unblinded 
designee who will administer the trial medication, by surgical drape, screen or pillow.
•
If a patient’s dosing is required in a supine position, the screen or curtain (the way it is 
used during surgery) or towel are to be put at chest level.
Site staff blinding procedure
Responsibilities for blinded and unblinded study site staff are defined below. At the site, a 
form with the name(s) of the staff members, blinded and unblinded, with their respective 
responsibilities will be filled in.
(NOTE: all personnel noted below will have signed the Site Personnel Signature Log, clearly 
outlining each individual’s responsibility).
In case of non-availability of blinded or unblinded study staff, the Clinical Research 
Organization and sponsor should be informed immediately.
Blinded Personnel
Main Responsibilities
Coordinating/principal Investigator:
CANNOT ADMINISTER THE MEDICATION
!
Remains blinded to the medication assignment 
during the whole trial
!
Monitors patient status
!
Responsible for the delegation of tasks to 
appropriate staff and to ensure correctness of all 
assessments
!
Provides direct patient care
!
Works and communicates with blinded CRA
!
Ensures adequate unblinded pharmacy staff and 
medication administrator and facilities
Blinded Sub-Investigator or Study 
Coordinator/Study Nurse:
CANNOT ADMINISTER THE MEDICATION
!
Remains blinded to the medication assignment 
during the whole trial
!
Monitors patient status
!
Provides direct patient care if applicable
!
Works and communicates with blinded monitor


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Blinded CRA:
CANNOT MAKE SAFETY OR EFFICACY 
EVALUATIONS
CANNOT ADMINISTER THE MEDICATION 
!
Remains blinded to the medication assignment 
during the whole trial
!
Acts as the primary point of contact for the 
blinded site team
!
Provides ongoing site support in all areas of trial 
conduct, except accountability and reconciliation 
of trial medication
!
Conducts blinded site monitoring visits and 
performs source document verification


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Unblinded Personnel 
Main Responsibilities 
Unblinded Pharmacist/Back-up Unblinded 
Pharmacist: 
CANNOT MAKE SAFETY OR EFFICACY 
EVALUATIONS
!
Receives trial medication; unpacks, inventories 
and stores trial medication in a secure, limited 
access refrigerator
!
Responsible for the retention samples handling 
and documentation
!
Reviews temperature monitoring device for 
shipment temperature excursions
!
Acknowledges trial medication receipt 
!
Completes the Master Drug Accountability Log 
and Subject Drug Dispensing Log
!
Monitors temperature using min/max. 
thermometer and completes refrigerator 
temperature storage log
!
Reports temperature excursions to unblinded 
monitor
!
Receives the kit numbers for injection from the 
sponsor 
!
Dispenses trial medication to the unblinded 
medication administrator
!
Trains back-up pharmacist(s), if applicable
!
Implements blinding plan
!
Monitors and maintains drug inventory at site
!
Reports all protocol deviations regarding dosing 
errors to the unblinded CRA
!
Ensures all accountability logs are kept separate 
from the medication blinded staff
!
Works and communicates with unblinded 
monitor
!
Retains used kits for reconciliation by unblinded 
monitor prior to destruction. Destroys used 
medication per SOPs.
Set Unblinded Trial Medication Administrator:
CANNOT MAKE SAFETY OR EFFICACY 
EVALUATIONS
!
Cooperates with the unblinded pharmacist 
!
Performs the trial medication administration and 
ensures patient is blinded during IP 
administration
!
Works and communicates with unblinded CRA
Unblinded CRA:
CANNOT MAKE SAFETY OR EFFICACY 
EVALUATIONS
CANNOT ADMINISTER THE MEDICATION
!
Acts as the primary point of contact for the 
unblinded site team
!
Provides ongoing site support in the management 
of trial medication
!
Conducts unblinded site monitoring visits and 
monitors accountability of trial medication
CRA = clinical research associate


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Training
All professional personnel taking part in the clinical trial are to be trained and aware of the 
need to respect study blinding principles as foreseen by the protocol. Blinded and unblinded 
study site staff as well as blinded and unblinded CRAs will be trained on study blinding 
procedures before the start of any study activities at site. Unblinded study site staff is 
restricted to persons handling trial medications including the injection of study drug. Training 
in study blinding procedures for blinded and unblinded study CRAs will be provided during a 
CRA Meeting. Training in study blinding procedures for blinded and unblinded site staff will 
be provided at the Investigators’ Meeting; during workshop or WebEx sessions, separately 
designed for blinded and unblinded study personnel in which CRAs will participate, as well. 
Part of both workshops will review the Medication Blinding Procedures, with blinding 
procedures described. For the rest of site staff, who did not participate in an Investigators’ 
Meeting, applicable training in study blinding procedures will be provided by a blinded CRA 
during the Site Initiation Visit, based on information in Study Protocol, Medication Blinding 
Procedures and Pharmacy Manual. Such training is a part of study specific agenda for Site 
Initiation Visit, as well as slide presentation prepared for the visit. All training will be 
documented.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
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Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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