Conditions: Psoriasis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 318
Healthy volunteers: no

Brief summary:
To evaluate the efficacy and to compare efficacy and safety of BI 695501 versus Humira in patients with moderate to severe chronic plaque psoriasis.

Detailed description:

Arms:
arm 1: None arm 2: None

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

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Clinical Trial Protocol
TITLE PAGE
Document Number:
c08917790-03
EudraCT No.:
EU Trial No:
2016-000613-79
BI Trial No.:
1297.12
BI Investigational 
Product(s):
BI 695501
Title:
Efficacy, Safety, and Immunogenicity of BI 695501 versus Humira® in 
Patients with Moderate to Severe Chronic Plaque Psoriasis: A 
Randomized, Double-Blind, Parallel-Arm, Multiple-Dose, Active 
Comparator Trial
Lay Title:
Efficacy, Safety, and Immunogenicity of BI 695501 versus Humira® in 
Patients with Moderate to Severe Chronic Plaque Psoriasis
Clinical Phase:
Phase III
Trial Clinical Monitor:
Tel.: 
Coordinating 
Investigator:
Tel.:
Fax.: 
Status:
Final Protocol
Version and Date:
Version: 1.0
Date:26 Apr 2016
Page 1 of 84
Proprietary confidential information.
2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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BI Trial No.: 1297.12
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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
26 Apr 2016
Trial number:
1297.12
Revision date:
Title of trial:
Efficacy, Safety, and Immunogenicity of BI 695501 versus Humira® in Patients 
with Moderate to Severe Chronic Plaque Psoriasis: A Randomized, Double-Blind, 
Parallel-Arm, Multiple-Dose, Active Comparator Trial
Coordinating
Investigator:
Trial site(s):
Multi-national, multi-center trial in approximately 50 clinical sites across 
approximately 10 countries
Clinical phase:
Phase III
Objective(s):
The primary objective of this trial is to evaluate equivalence in efficacy between BI 
695501 and US-licensed Humira® at Week 16 in patients with active moderate to 
severe chronic plaque psoriasis.
The secondary objectives of this trial are to compare the safety and efficacy
profiles of BI 695501 and US-licensed Humira. 
 
Methodology:
This is a randomized, double-blind, parallel-arm, multiple-dose, active comparator 
trial of BI 695501 and US-licensed Humira with a screening period of up to 
28 days, a 24-week treatment period and a 10-week safety follow-up period in 
patients with chronic plaque psoriasis and a primary endpoint assessment at 
Week 16.
Patients will be randomized 1:1 to either BI 695501 or Humira. Each patient will 
receive 80 mg of BI 695501 or US-licensed Humira at Baseline (Randomization) 
(Day 1, Week 0), followed by 40 mg of BI 695501 or Humira 1 week later
(Week 1), and then 40 mg of BI 695501 or Humira every other week. After 
Week 16, only patients who achieve a 50% reduction in Psoriasis Area and 
Severity Index (PASI 50) will continue the trial receiving their originally
randomized treatment. Those patients not achieving at least PASI 50 will not be 
treated further with the study drugs but only followed up for safety.
No. of patients: 
Total entered:
Approximately 300 patients will be randomized.
Each treatment:
Patients will be allocated to treatment in a 1:1 ratio to receive BI 695501 or 
US-licensed Humira.
Diagnosis:
Moderate to severe chronic plaque psoriasis.
Main criteria
for inclusion:
This study will include male or female participants at least 18 years of age who 
have a diagnosis of moderate to severe chronic plaque psoriasis of at least 
6 months duration. The patient’s chronic plaque psoriasis must have been stable for 
the last 2 months with no meaningful changes in morphology or significant flares.
At inclusion, patients must have a PASI score ≥ 12, Static Physician’s Global 
Assessment of psoriasis (sPGA) ≥ 3, and a body surface area (BSA) involvement ≥ 
10% at Screening and at baseline. Patients must be suitable for systemic treatment. 


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Trial Protocol
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Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
26 Apr 2016
Trial number:
1297.12
Revision date:
Patients with prior exposure to more than 1 biologic (must not be adalimumab) will 
be excluded from this trial.
Test product(s):
BI 695501, solution for subcutaneous (s.c.) injection in single-use prefilled syringe  
(40 mg)
dose:
Starting 1 week after a first administration of 80 mg BI 695501 after 
randomization, patients will receive 40 mg every other week.
mode of administration:
Subcutaneous injection
Comparator products:
US-licensed Humira, solution for s.c. injection in single-use prefilled syringe 
(40 mg)
dose:
Starting 1 week after a first administration of 80 mg Humira after randomization, 
patients will receive 40 mg every other week via a single prefilled glass syringe.
mode of 
administration:
Subcutaneous injection
Duration of treatment:
Patients are planned to be treated with trial medication for 24 weeks. 
Seven days after a first 80 mg administration of either BI 695501 or US-licensed
Humira, patients will receive 40 mg of either BI 695501 or US-licensed Humira 
every other week up to efficacy assessment at Week 16. Only patients achieving at 
least a PASI 50 response will continue the treatment after 16 weeks, ending at 
Week 24.
Endpoints
Efficacy endpoints will be measured at Week 16 (equivalence assessment) and 
Week 24.
Primary efficacy endpoint:

Proportion of patients with a 75% reduction in Psoriasis Area and Severity 
Index (PASI 75) response at Week 16
Secondary endpoints:
Efficacy

Proportion of patients with a PASI 75 response at Week 24

Mean percentage improvement in PASI at Week 16

Proportion of patients with a sPGA ≤ 1 (clear or almost clear) at Week 16

Proportion of patients achieving a Dermatology Life Quality Index 
(DLQI) of 0 or 1 at Week 16 
Safety

Proportion of patients with drug-related adverse events (AEs)
Safety criteria:
Physical examination, vital signs (blood pressure, pulse rate, body temperature), 
12-lead electrocardiogram (ECG), laboratory tests, continuous AE monitoring, and 
local tolerability.
Statistical methods:
Primary analysis
To conclude equivalence, the 95% confidence interval (CI) of the difference in 
PASI 75 response rate at Week 16 between BI 695501 and Humira must be fully 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 695501
Protocol date:
26 Apr 2016
Trial number:
1297.12
Revision date:
within the equivalence limits of ± 18%. 
Secondary analysis
For the secondary efficacy endpoints, point estimates (risk difference for binary 
endpoints) and CIs will be calculated, but will be interpreted in a descriptive 
manner. Safety endpoints and AESIs will be presented descriptively. Risk ratio 
together with 95% CI will be presented for the secondary safety endpoint.
 


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FLOW CHART
Visit1
1
2
3
4
5
6
7
8
9
10
Week
Screen
-4 to -1
Base
line
0
1
3
4
5
7
8
9
11
12
13
15
16
17
19
20
21
23
24
EoT
33
SFU2
Days
-28 
to -111
1
8
22
29
36
50
57
64
78
85
92
106
113
120
134
141
148
162
169
232
Permitted visit 
window (days)
-
-1/ +2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 3
± 3
± 3
± 3
± 3
± 3
± 3
+ 3
Informed consent
X
Assessment of 
eligibility 
X
X
Demographics
X
Medical history
X
LAB/SAFETY ASSESSMENTS3
Infection screen: 
TB, hepatitis B 
(HBsAg, anti-
HBc), hepatitis C 
(anti-HCV), HIV 
X
Chest X-ray
X4
TB testing (IGRA 
or PPD testing)5
X
X
Pregnancy test
X
X
X
X
X
X
Physical 
examination 
X
X
X
X
X
X
Vital signs6
X
X
X
X
X
X
Safety Laboratory 
tests
X
X
X
X
X
X
12-lead ECG 
X
X
X
X
X


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Visit1
1
2
3
4
5
6
7
8
9
10
Week
Screen
-4 to -1
Base
line
0
1
3
4
5
7
8
9
11
12
13
15
16
17
19
20
21
23
24
EoT
33
SFU2
Days
-28 
to -111
1
8
22
29
36
50
57
64
78
85
92
106
113
120
134
141
148
162
169
232
Permitted visit 
window (days)
-
-1/ +2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 3
± 3
± 3
± 3
± 3
± 3
± 3
+ 3
Previous and 
concomitant 
therapy
◄▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬X▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬►
Adverse events7
◄▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬X▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬▬►
EFFICACY ASSESSMENTS3
PASI
X
X
X
X
X
X
X
X
sPGA
X
X
X
X
X
X
X
X
DLQI
X
X
X
X
X
X
X
X
 
TRIAL MEDICATION
Contact IRT11
X
X
X
12
X
12
X
12
X
12
X
12
X
12
Trial medication9
X
X
X
X
X
X
X
X
X
X
X
X
X
Review patient 
diary13
X13
X13
X13
X13
X13
X13
X13
Randomization10
X


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Abbreviations: 
; AE=adverse event; anti-HBc=anti-hepatitis B core antibodies; anti-HCV=anti-hepatitis C antibodies; DLQI=Dermatology Life Quality Index; EoT=End 
of Treatment; IRT=Interactive Response Technology; HBsAg=hepatitis B surface antigen; HIV=human immunodeficiency virus; IGRA=interferon gamma-releasing assay; 
 
; PASI=Psoriasis Area and Severity Index; 
 PPD=purified protein derivative; SFU=Safety Follow-up; sPGA=Static 
Physician’s Global Assessment of psoriasis; TB=tuberculosis. 
1.
Patients will have to visit the site for efficacy assessments and to provide samples for 
/ safety. For other visits (Weeks 3, 5, 7, 9, 11, 
13, 15, 17, 19, 21 and 23), patients are be allowed to self-administer the drug at home (after training). 
2.
Patients who discontinue the trial early (also those not achieved PACI 50 at week 16) will, at discontinuation, have an End of Treatment (EoT) Visit 
equivalent to the Week 24 assessments (except trial medication administration). Every effort should be made for all patients to return for a Safety Follow-
up (SFU) Visit 10 weeks after last drug administration. 
3.
All efficacy (e.g., PASI,
and sPGA) and safety assessments will be performed by blinded personnel. 
4.
A chest X-ray is to be taken at Screening. Alternatively, results from a chest X-ray taken within 12 weeks of Screening can be used. 
5.
Patients must have a negative tuberculosis (TB) screening assessment, including a purified protein derivative (PPD) skin test or interferon 
gamma-releasing assay (IGRA) (e.g., QuantiFERON® TB Gold or T-SPOT®.TB). In addition, a TB test can be performed at any time during the trial if the 
investigator considers it clinically necessary. 
6.
Vital signs include measurement of body temperature, blood pressure, and pulse rate (all in the sitting position after a 5-minute rest). 
7.
Adverse events (AEs) will be collected from the time of informed consent. Adverse events continuing at the SFU Visit must be followed to resolution or 
followed up as agreed by the investigator and medical monitor. For patients who complete the trial or who discontinue the trial early, new AEs will be 
captured for up to 10 weeks after last drug administration (SFU Visit). 
8.
 
 
 
 
9.
Trial medication should be administered at Day 1, with the second injection 7 days later and subsequent injections every 2 weeks thereafter (± 2 days up to
Week 14 and ± 3 days from Week 16 onward). 
10. Randomization can occur through a randomization call or on Day 1 (-1 / +2) through a standard randomization visit call. The Day 1 randomization or call 
will depend on the trial site procedure. Patients will be randomized to each treatment in a 1:1 ratio (BI 695501:US-licensed Humira®). For some sites, the 
registration call might be made approximatelly10 days prior to the planned first administration of trial medication. Patients will be tentatively assigned to 
each treatment at random in a 1:1 ratio (BI 695501:US-licensed Humira®) and a position on the randomization scheme will be reserved. On Day 1 (or 
when the drug is at site), a randomization number will be assigned and patients will then be confirmed on the randomization scheme and will receive their 
first administration of trial medication according to their randomization. 
11. Interactive Response Technology (IRT) will be contacted on indicated Visits.
12. One or two syringes might be dispensed to the patient for the self-administration at home.
13. The patient will complete a diary, documenting the date and time of trial medication self-administration and any AEs experienced between study visits.  


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................15
MEDICAL BACKGROUND.............................................................................15
1.1
DRUG PROFILE................................................................................................16
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT-RISK ASSESSMENT .......19
RATIONALE FOR PERFORMING THE TRIAL.........................................19
2.1
TRIAL OBJECTIVES........................................................................................19
2.2
BENEFIT-RISK ASSESSMENT.......................................................................19
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................21
OVERALL TRIAL DESIGN AND PLAN .......................................................21
3.1
3.1.1
Administrative structure of the trial .................................................................22
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP...........................................................................................22
SELECTION OF TRIAL POPULATION .......................................................22
3.3
3.3.1
Main diagnosis for trial entry ............................................................................23
3.3.2
Inclusion criteria .................................................................................................23
3.3.3
Exclusion criteria ................................................................................................24
3.3.4
Removal of patients from therapy or assessments...........................................25
Removal of individual patients .............................................................................25
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................26
3.3.4.2
4.
TREATMENTS...................................................................................................27
INVESTIGATIONAL TREATMENTS ...........................................................27
4.1
4.1.1
Identity of the Investigational Medicinal Products..........................................27
4.1.2
Selection of doses in the trial..............................................................................28
4.1.3
Method of assigning patients to treatment groups...........................................28
4.1.4
Drug assignment and administration of doses for each patient......................29
4.1.5
Blinding and procedures for unblinding...........................................................30
Blinding.................................................................................................................30
4.1.5.1
Unblinding and breaking the code ........................................................................30
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................31
4.1.7
Storage conditions...............................................................................................31
4.1.8
Drug accountability.............................................................................................31
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ................................................................................................32
4.2.1
Other treatments and emergency procedures..................................................32


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4.2.2
Restrictions ..........................................................................................................32
Restrictions on diet and life style..........................................................................34
4.2.2.1
Restrictions regarding women of childbearing potential......................................34
4.2.2.2
Restrictions regarding male participants of reproductive potential ......................34
4.2.2.3
TREATMENT COMPLIANCE........................................................................35
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................36
TRIAL ENDPOINTS..........................................................................................36
5.1
5.1.1
Primary Endpoint ...............................................................................................36
5.1.2
Secondary Endpoints..........................................................................................36
ASSESSMENT OF EFFICACY........................................................................37
5.2
5.2.1
PASI......................................................................................................................37
5.2.2
Static Physician’s Global Assessment ...............................................................38
5.2.3
Dermatology Life Quality Index........................................................................39
ASSESSMENT OF SAFETY.............................................................................40
5.3
5.3.1
Physical examination ..........................................................................................40
5.3.2
Vital Signs............................................................................................................40
5.3.3
Safety laboratory parameters ............................................................................41
5.3.4
Electrocardiogram ..............................................................................................43
5.3.5
Other safety parameters.....................................................................................43
Local tolerability...................................................................................................43
5.3.5.1
5.3.6
Assessment of adverse events.............................................................................43
Definitions of AEs ................................................................................................43
5.3.6.1
Adverse event collection and reporting ................................................................46
5.3.6.2
 
APPROPRIATENESS OF MEASUREMENTS..............................................52
5.7
6.
INVESTIGATIONAL PLAN.............................................................................53
VISIT SCHEDULE.............................................................................................53
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................54
6.2
6.2.1
Screening and run-in period(s)..........................................................................54
6.2.2
Treatment period ................................................................................................55
6.2.3
Follow-up Period and Trial Completion...........................................................56


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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................58
STATISTICAL DESIGN - MODEL.................................................................58
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................58
7.2
PLANNED ANALYSES.....................................................................................58
7.3
7.3.1
Primary endpoint analyses.................................................................................59
7.3.2
Secondary endpoint analyses .............................................................................60
Secondary efficacy endpoints ...............................................................................60
7.3.2.1
Secondary Safety Endpoints .................................................................................60
7.3.2.2
7.3.4
Safety analyses.....................................................................................................61
INTERIM ANALYSES ......................................................................................63
7.4
7.4.1
Final analysis .......................................................................................................63
HANDLING OF MISSING DATA ...................................................................63
7.5
7.5.1
Efficacy endpoints...............................................................................................63
7.5.2
Safety and other endpoints.................................................................................63
RANDOMIZATION...........................................................................................64
7.6
DETERMINATION OF SAMPLE SIZE .........................................................64
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................66
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT ...........................................................................................................66
DATA QUALITY ASSURANCE ......................................................................67
8.2
RECORDS...........................................................................................................67
8.3
8.3.1
Source documents ...............................................................................................67
8.3.2
Direct access to source data and documents.....................................................68
8.3.3
Storage period of records ...................................................................................68
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................68
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........68
8.5
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................69
TRIAL MILESTONES.......................................................................................69
8.6
9.
REFERENCES....................................................................................................71
PUBLISHED REFERENCES............................................................................71
9.1
UNPUBLISHED REFERENCES......................................................................73
9.2
10.
APPENDICES.....................................................................................................74
CLINICAL EVALUATION OF LIVER INJURY ..........................................74
10.1


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10.1.1
Introduction.........................................................................................................74
10.1.2
Procedures ...........................................................................................................74
EFFICACY ASSESSMENTS ............................................................................76
10.2
MEDICATION BLINDING PROCEDURE FOR THIRD PARTY 
10.3
BLINDING ..........................................................................................................80
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................84


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ABBREVIATIONS
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
AST
aspartate aminotransferase
β-hCG
beta-human Chorionic Gonadotropin
BI
Boehringer Ingelheim
BSA
body surface area
CA
Competent Authority
CI
confidence interval
CK-MB
Creatine Kinase-MB
CRA
Clinical Research Associate
CRO
Contract Research Organization
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
drug-induced liver injury
DLQI
Dermatology Life Quality Index
ECG
electrocardiogram
eCRF
Electronic Case Report Form
ELISA
enzyme-linked immunosorbent assay
EoT
End of Treatment
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
FOXP3
forkhead box P3
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase 
GMP
Good Manufacturing Practice
GOT
Glutamic-Oxaloacetic Transaminase
GPT
Glutamic-Pyruvic Transaminase
Hb
hemoglobin
HbsAg
hepatitis B surface antigen
HBV
hepatitis B virus
Hct
Hematocrit 
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgG1
immunoglobulin G1


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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
k
kappa
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LOCF
last observation carried forward
LPDD
Last Patient Drug Discontinuation
MedDRA
Medical Dictionary for Drug Regulatory Activities
MI
multiple imputation
MTX
methotrexate
nAb
neutralizing antibody
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
PASI75
75% reduction in Psoriasis Area and Severity Index
PPD
purified protein derivative
PPS
per-protocol set
PUVA
psoralen with ultraviolet A light
RA
rheumatoid arthritis
RBC
red blood cell
REP
residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
SAE
serious adverse event
SAF
safety analysis set
s.c.
subcutaneous
SFU
Safety Follow-up
SOP
standard operating procedure (s)
SPC
summary of product characteristics
sPGA
static Physician’s Global Assessment
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
Th17
T helper 17 cells 
TNF
tumor necrosis factor
TSAP
Trial Statistical Analysis Plan
ULN
upper limit of normal
US-PI
United States Package Insert
UVA
Ultraviolet A light


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UVB
Ultraviolet B light
WHO
World Health Organization


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Psoriasis is the most prevalent immune-mediated skin disease that affects 1% to 3% of the 
population worldwide, with an equal sex distribution. The most common form of the disease, 
termed “plaque psoriasis”, is observed in more than 80% of psoriasis patients and is 
characterized by erythematous scaly plaques, typically on elbows, knees, scalp, and buttocks. 
Twenty-five percent of patients have moderate to severe disease, with considerable negative 
impact on their psychosocial and economic status (R11-1259). Psoriasis causes a high degree 
of morbidity and decreased quality of life, largely due to flares and disfiguring lesions in 
visible areas of the skin, systemic manifestations, and drug-related side effects.
Histological examination of psoriatic plaques reveals keratinocyte hyperproliferation, with 
parakeratosis and elongation of rete ridges, increased angiogenesis and dermal infiltration by
inflammatory cells, including T-cells, neutrophils, macrophages and dendritic cells. Psoriasis 
is probably a complex multifactorial disease in which various environmental triggers (e.g., 
trauma, stress, infections and drugs) promote, in genetically predisposed individuals, an 
exaggerated and poorly controlled immuno-inflammatory response in the skin which leads to 
excessive keratinocyte proliferation.
It is increasingly recognized that psoriasis is more than a skin disease, with up to 30% of 
patients having joint involvement and a high correlation between psoriasis and obesity, 
diabetes, depression, metabolic syndrome, and cardiovascular risk (R15-1393).
Current Treatment Options
Psoriasis treatment varies with the extent and severity of the disease. Current treatment 
options include topical treatments (topical corticosteroids, vitamin D analogues, anthralin, 
topical retinoids, calcineurin inhibitors, salicylic acid, coal tar, and moisturizers), 
phototherapy, and systemic treatments. Topical treatments are generally used for more 
localized and mild forms of psoriasis. Exposure of skin to artificial ultraviolet A or B light, 
either alone or in combination with medications such as psoralen, has also been shown to be 
quite effective for mild to moderate psoriasis. For more resistant or moderate to severe 
psoriasis, systemic oral or parenteral medications are used for better efficacy. Systemic oral 
medications such as methotrexate (MTX), cyclosporine and retinoids have traditionally been 
the most commonly prescribed drugs for moderate to severe psoriasis. Over the last few 
years, the introduction of biologic immunosuppressive drugs, such as anti-tumor necrosis 
factor agents (TNFs), anti-interleukin (IL)12/23 and anti-IL17, has significantly changed the 
treatment paradigm for moderate to severe psoriasis. These molecules have a much higher 
efficacy and better safety profile due to their specific targeting of immunopathologic 
pathways involved in psoriasis. Owing to the higher costs of biologic therapies, they are 
generally reserved for patients who have been unable to tolerate or are resistant to other 
systemic psoriasis therapies.


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DRUG PROFILE
1.2
The mechanisms of action of anti-TNF agents in psoriasis, including Humira, are not fully 
understood and may vary in different disease settings. 
TNF-α antagonists enhance T helper 17 cells (Th17) function, but suppress forkhead box P3
(FoxP3) + Tregs (regulatory T cells) in the skin in the murine psoriasis-like model 
(R16-0235).
Humira (adalimumab) has received regulatory approval for psoriasis in the US, the EU, and
many other countries (R15-5978 and R16-0358). BI 695501 is being developed as a proposed 
biosimilar to US-licensed Humira and EU-approved Humira.
Adalimumab (Humira) has a generally favorable clinical safety profile, and is not associated 
with AEs that would suggest a high risk to subjects participating in this trial. In patients 
treated with Humira, most common adverse reactions (incidence >10%) include infections 
(e.g., upper respiratory, sinusitis), injection site reactions, headache, 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.
BI 695501 is a monoclonal antibody being developed as a proposed biosimilar to the 
TNF-alpha blocker US-licensed and EU-approved Humira® (adalimumab). Adalimumab is a 
recombinant humanized monoclonal immunoglobulin (Ig) G1 antibody specific to human 
TNF-alpha. Humira binds specifically to TNF-alpha (not to TNF-beta) and blocks its 
interaction with the p55 and p75 cell surface TNF receptors. It has human-derived heavy and 
light chain variable regions and human immunoglobulin (Ig) G1:k (kappa) constant regions 
and is produced in a mammalian cell expression system (R15-5978 and R16-0358).
The preclinical studies that support the clinical program include: 

 
 
 


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To date, a total of 175 male healthy subjects were treated with 40 mg s.c. of BI 695501
administered via prefilled glass syringe in 2 trials with healthy subjects 1297.1 and 1297.8
(U13-1096-01 and c03070713). The PK similarity of BI 695501 to US-licensed Humira and 
EU-approved Humira was demonstrated in a healthy volunteers study using the final
commercial formulation (c03070713). Single s.c. doses of 40 mg BI 695501, US-licensed 
Humira and EU-approved Humira were generally well tolerated by healthy male subjects. 
There were no notable differences between the 3 treatment arms with respect to safety, 
tolerability, and immunogenicity.
Overall, the adverse events (AEs) seen in 2 healthy subject trials for BI 695501 and both 
EU-approved Humira and US-licensed Humira were in line with the known safety profile 
presented in the US prescribing information for Humira (R15-5978) and in the summary of 
product characteristics (SPC) for EU-approved Humira (R16-0358).
A phase III trial (1297.2) in patients with moderate to severe rheumatoid arthritis (RA) is 
ongoing. A total of 645 patients with moderate to severe RA were included in the study and 
are being treated with either BI 695501 or US-licensed Humira. The observed blinded AE
profile revealed no unexpected safety findings and showed no clinically relevant safety 
concerns.


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For further detailed description of the BI 695501 profile please refer to the current
‘Investigator’s Brochure’ (IB) (c01843589) and for the US-licensed Humira to the United 
States Package Insert (US-PI) (R15-5978).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT-RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
The current trial is being performed to establish an equivalence of efficacy between BI 
695501 and US-licensed Humira in patients with active moderate to severe chronic plaque 
psoriasis. It is expected that, based on the data from pivotal study in RA, BI 695501 will be 
granted extrapolation to all other indications of Humira. However, this additional study to 
generate comparative efficacy and safety data in psoriasis will be important to show scientific
evidence for biosimilar BI 695501.
TRIAL OBJECTIVES
2.2
The primary objective of this trial is to establish equivalence in efficacy between BI 695501 
and US-licensed Humira at Week 16 in patients with active moderate to severe chronic 
plaque psoriasis.
The secondary objectives of this trial are to compare the safety and efficacy profiles of BI 
695501 and US-licensed Humira. 
 
 
A description of the selected endpoints and the observations along with specific information 
on how to collect the data is provided in Section 5.
BENEFIT-RISK ASSESSMENT
2.3
Participation in this study may help to generate future benefit for larger groups of patients
with psoriasis.
Patient risk will be minimized in this trial by implementing conservative eligibility criteria.
Adverse events, body temperature, vital signs, electrocardiograms (ECGs) and safety 
laboratories as well as immunogenicity will be monitored at different time points during the 
trial and during the long term safety follow-up period up to 10 weeks after the last 
administration of trial medication.
Although rare, a potential for 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 patients’
safety, see also Section 5.3.6.1.
All safety aspects will be regularly monitored by both the Sponsor and a Contract Research 
Organization (CRO) during the Medical Quality Review Meetings.


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To avoid a risk of reactivating TB and other infections, TB tests (interferon-gamma release 
assay [IGRA] or purified protein derivative [PPD] skin test), Hepatitis B surface antigen
(HBsAg; qualitative), Hepatitis B antibody (anti-HBc; qualitative), Hepatitis C antibodies 
(Anti-HCV; qualitative), human immunodeficiency virus (HIV)-1 and HIV-2 antibody (at the 
discretion of the investigator where clinically indicated) will be performed to exclude 
subjects who test 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. Therefore, a possibly increased risk for the 
development of malignancies cannot be excluded.
TNF-antagonists including Humira have been associated, in rare instances, with new onset or
exacerbation of clinical symptoms and / or radiographic evidence of central nervous system 
demyelinating disease, including multiple sclerosis and optic neuritis, and peripheral 
demyelinating disease including Guillain-Barre syndrome. Prescribers should exercise 
caution in considering the use of Humira in patients with pre-existing or recent-onset central 
or peripheral nervous system demyelinating disorders.
To minimize the risks, patients with a significant disease other than psoriasis will be excluded 
from the trial participation.
The PK similarity of BI 695501 to US-licensed and EU-approved Humira was established in 
the phase I trial 1297.8 (c03070713). Additionally, there were no notable differences with 
respect to safety, tolerability, and immunogenicity between BI 695501 to US-licensed and 
EU-approved Humira in this phase I trial, and the dose of 40 mg BI 695501 was safe and well 
tolerated in male healthy volunteers. The observed blinded AE profile in the phase III trial 
1297.2 (c02158186) revealed no unexpected safety findings and showed no clinically 
relevant safety concerns. The review of safety data in 1297.2 trial by the Independent Data 
Monitoring Committee (IDMC) to date has not suggested any clinically relevant differences 
in safety profile between Humira and BI 695501.
There were no clinically relevant findings with respect to clinical laboratory evaluation, vital 
signs, ECGs, or injection site reactions. Based on extensive preclinical, analytical, functional,
and toxicological testing carried out prior to initiation of this trial, and the Phase I data 
described above, BI 695501, as a proposed biosimilar to Humira, is expected to show a
similar efficacy, safety, immunogenicity and PK profile in patients with psoriasis.
Patients not achieving at least PASI 50 (patients showing lack of efficacy), will not continue 
receiving their treatment up to Week 24 with the study drug, but only followed up for safety. 
These patients will receive an alternative treatment as deemed appropriate by the investigator.
The benefit-risk profile for the patients participating in this trial remains favorable and 
similar to the originator product. 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a multinational, randomized, double-blind, parallel-arm, multiple-dose, active 
comparator trial of BI 695501 and US-licensed Humira.
In total, approximately 300 patients with moderate to severe chronic plaque psoriasis are 
planned to be randomized in this trial.
Patients are included in the study once they have signed the informed consent. Patients
suitable after screening will be eligible to participate in the 24-week treatment period and will 
be randomized at a ratio of 1:1 in a blinded fashion to 1 of 2 treatment arms (BI 695501 or
US-licensed Humira) shown in Figure 3.1: 1.
After Week 16, only patients who achieve at least a 50% reduction in Psoriasis Area and 
Severity Index (PASI 50) response will continue the trial receiving their randomized 
treatment up to Week 24. Those patients not achieving at least PASI 50 (or who discontinue 
the trial early), will not be treated with the study drugs, but only followed up for safety. 
Patients will undergo visits and trial procedures as shown in the Flow Chart.
All patients who receive at least 1 injection of BI 695501 will have a Safety Follow-up visit 
10 weeks after the last dose of trial medication.
Every effort should be made for all patients who complete the 24-week treatment period or 
who discontinue the trial early (and do not withdraw their consent), to return for a safety 
follow-up visit 10 weeks after the last administration of trial medication.
Figure 3.1: 1 Trial design


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3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim International (BI).
CRO will perform Project Management, Clinical Field Monitoring, Medical Monitoring,
Data Management, and Statistical Evaluation according to CRO Standard Operating 
Procedures (SOPs). A list of responsible persons and relevant local information can be found 
in the Investigator Site File (ISF).
A Coordinating Investigator will be responsible to coordinate Investigators at different 
centers participating in this multicenter trial. Tasks and responsibilities will be defined in a 
contract. Relevant documentation on the participating (Principal) Investigators and other 
important participants, including their curricula vitae, will be filed in the electronic trial 
master file.
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all 
required activities, in order to 

manage the trial in accordance with applicable regulations and applicable Boehringer 
Ingelheim and CRO SOPs,

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate oversight of vendors.
A list of responsible persons and relevant local information can be found in the ISF.
A central laboratory service and an Interactive Response Technology (IRT) vendors will be 
used in this trial. Details will be provided in the IRT Manual and Central Laboratory Manual, 
available in the ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP
The current trial is being performed to establish an equivalence of efficacy between BI 
695501 and US-licensed Humira in patients with active moderate to severe chronic plaque 
psoriasis.
This is a randomized, double-blind, parallel arm, multiple dose, active comparator trial of BI 
695501 and US-licensed Humira with a planned 24-week treatment period followed by a 10-
week safety follow up, in patients with active moderate to severe chronic plaque psoriasis.
The treatment groups will be blinded throughout the whole trial, to minimize any bias that 
could be introduced by knowledge of the treatment by either the investigator or the patient.
SELECTION OF TRIAL POPULATION
3.3
A total of approximately 300 patients is planned to be randomized in the current trial. 


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A log of all patients enrolled into the trial (i.e., who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Patients must have moderate to severe chronic plaque psoriasis, stable for the last 2 months 
with no meaningful changes in morphology or significant flares, defined as ≥ 10% body
surface area (BSA) involvement, Psoriasis Area and Severity Index (PASI) score ≥ 12 and 
static Physician’s Global Assessment (sPGA) score ≥ 3.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
1. Males and females aged ≥18 to < 80 years who have a diagnosis of moderate to severe 
chronic plaque psoriasis (with or without psoriatic arthritis) for at least 6 months before 
the first administration of study drug (a self-reported diagnosis confirmed by the 
investigator is acceptable), and which has been stable for the last 2 months with no 
changes in morphology or significant flares at both Screening and Baseline 
(Randomization):
a.
involved BSA ≥ 10% and
b. PASI score ≥ 12 and
c.
sPGA score of ≥ 3.
2. Participants of reproductive potential (childbearing potential1) must be willing and able 
to use highly effective methods of birth control per International Council for
Harmonization (ICH) M3 (R2) that result in a low failure rate of less than 1% per year
when used consistently and correctly during the trial and for 6 months following 
completion or discontinuation from the trial medication. A list of contraception methods 
meeting these criteria is provided in the Section 4.2.2.2 and patient information.
3. Signed and dated written informed consent in accordance with Good Clinical Practice
(GCP) and local legislation prior to admission to the trial.
4. Patients who are candidates for systemic therapy.
                                                
1 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).


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3.3.3
Exclusion criteria
1. Active ongoing inflammatory diseases other than psoriasis that might confound trial 
evaluations according to investigator’s judgment.
2. Previous treatment with more than 1 biological agent, or adalimumab or adalimumab 
biosimilar. No prior biologic exposure within last 6 months of screening will be permitted
3. Patients with a significant disease other than psoriasis and/or a significant uncontrolled 
disease (such as, but not limited to, nervous system, renal, hepatic, endocrine, 
hematological, autoimmune or gastrointestinal disorders). A significant disease is defined 
as a disease which, in the opinion of the investigator, may (i) put the patient at risk 
because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause 
concern regarding the patient's ability to participate in the trial. 
4. Major surgery (major according to the investigator’s assessment) performed within 
12 weeks prior to randomization or planned within 6 months after screening, e.g., total 
hip replacement.
5. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ 
carcinoma of uterine cervix.
6. Patients who must or wish to continue the intake of restricted medications (see 
Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the 
trial.
7. Currently enrolled in another investigational device or drug study, or less than 30 days 
since ending another investigational device or drug study(s), or receiving other 
investigational treatment(s).
8. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
the patient an unreliable study subject or unlikely to complete the trial.
9. Women who are pregnant, nursing, or who plan to become pregnant during the course of 
this study or within the period at least 6 months following completion or discontinuation 
from the trial.
10. Forms of psoriasis (e.g., pustular, erythrodermic and guttate) other than chronic plaque 
psoriasis. Drug-induced psoriasis (i.e., new onset or current exacerbation from e.g., 
beta-blockers or lithium).
11. Primary or secondary immunodeficiency (history of, or currently active), including 
known history of HIV infection or a positive HIV test at screening (per the investigator 
discretion and where mandated by local authorities).
12. Known chronic or relevant acute tuberculosis,; IGRA TB test or PPD skin test will be 
performed according to the labelling for Humira. If the result is positive, patients may 
participate in the study if further work up (according to local practice/guidelines) 
establishes conclusively that the patient has no evidence of active tuberculosis. If latent 
tuberculosis is confirmed, then treatment must have been initiated before randomization 
and continued according to local country guidelines2.
                                                
2 For Germany: patients with positive IGRA TB test or PPD skin test will be excluded from the study 
participation.


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13. Known clinically significant coronary artery disease, significant cardiac arrhythmias, 
moderate to severe congestive heart failure (New York Heart Association Classes III or 
IV) or interstitial lung disease observed on chest X-ray. 
14. History of a severe allergic reaction, anaphylactic reaction, or hypersensitivity to a 
previously used biological drug or its excipients.
15. Positive serology for hepatitis B virus (HBV) or hepatitis C virus (HCV). 
16. Receipt of a live/attenuated vaccine within 12 weeks prior to the Screening Visit; patients 
who are expecting to receive any live/attenuated virus or bacterial vaccinations during the 
trial or up to 3 months after the last dose of trial drug.
17. Any treatment (including biologic therapies) that, in the opinion of the investigator, may 
place the patient at unacceptable risk during the trial.
18. Known active infection of any kind (excluding fungal infections of nail beds), any major 
episode of infection requiring hospitalization or treatment with intravenous (i.v.)
anti-infectives within 4 weeks of the Screening Visit or completion of oral anti-infectives 
within 2 weeks of the Screening Visit.
19. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times upper 
limit of normal (ULN) at Screening. 
20. Hemoglobin < 8.0 g/dL at Screening. 
21. Platelets < 100,000/µL at Screening.
22. Leukocyte count < 4000/µL at Screening.
23. Creatinine clearance < 60 mL/min/1.73 m2 at Screening.
24. Patients with a history of any clinically significant adverse reaction to murine or chimeric 
proteins, or natural rubber and latex, including serious allergic reactions.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
All patients have the right to withdraw from the study at any time without the need to justify 
their decision. The investigator has the right to remove patients from the study for 
non-compliance or other reasons. 
An individual patient is to be withdrawn from trial treatment if:

The patient decides to discontinue participation in the trial by withdrawal of consent. In 
this case, no more investigations will be performed.

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication.

Lack of efficacy defined as PASI 50 not reached at Week 16.

Development of a toxicity or adverse event which warrants BI 695501/Humira
discontinuation including but not limited to serious adverse events (SAEs) or suspected 
unexpected serious adverse reactions (SUSARs).

The patient has an AE that is categorized as a serious infection. A serious infection is
defined as an infection requiring i.v. antibiotics or meeting the regulatory definition of a 


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SAE (including, but not limited to, systemic fungal infections, HIV, HBV, HCV, TB, 
infected joint prosthesis).

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy).

If the trial treatment is not in the patient’s best interest at the investigator’s discretion. 
(e.g. severe worsening of psoriasis). The patient will be discontinued from the trial to 
receive treatment as deemed appropriate by the investigator.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
If a patient permanently discontinues trial medication for any reason (including lack of 
efficacy), every effort should be made to have the patient return for a safety follow-up visit 
10 weeks after the last dose of trial medication.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow-up as outlined in the Flow Chart (Safety Follow-up [SFU] visit)
and Section 6.2.3.
For all patients the reason for withdrawal (e.g., AEs) must be recorded in the electronic Case 
Report Form (eCRF). These data will be included in the trial database and reported.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for reasons including but not restricted to:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-risk 
assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract impairing the 
appropriate conduct of the trial.
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
INVESTIGATIONAL TREATMENTS 
4.1
The trial medication will be provided by BI.
4.1.1
Identity of the Investigational Medicinal Products
BI 695501 and US-licensed Humira will be used in this study. Details of the trial medication
are provided in Tables 4.1.1: 1, and 4.1.1: 2.
Table 4.1.1: 1
Test product
Substance:
BI 695501
Pharmaceutical formulation:
Solution for injection in prefilled syringe
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
40 mg / 0.8 mL
Posology
80 mg (loading dose) on Day 1 / Week 0,
40 mg every other week from Week 2 to Week 23
Route of administration:
Subcutaneous injection
Table 4.1.1: 2
Reference product
Substance:
US-licensed Humira (adalimumab)
Pharmaceutical formulation:
Solution for injection in prefilled syringe
Source:
AbbVie Inc.
Unit strength:
40 mg / 0.8 mL or 40 mg / 0.4 mL
Posology
80 mg (loading dose) on Day 1 / Week 0,
40 mg every other week from Week 1 to Week 23
Route of administration:
Subcutaneous injection
BI 695501 prefilled syringe will be provided as sterile, preservative-free, non-pyrogenic, 
single-use prefilled glass syringes containing 40 mg of BI 695501 per 0.8 mL. One syringe 
will be used per injection except for Week 0/Day 1, at which 2 syringes (80 mg) will be used. 
The needle cap of the syringe contains dry, natural rubber.
US-licensed Humira will be provided in sterile, preservative-free, non-pyrogenic, single-use, 
prefilled glass syringes containing 40 mg of adalimumab per 0.8 mL or 0.4 mL of solution. 
One syringe will be used per injection except for Week 0 / Day 1, at which 2 syringes 
(80 mg) will be used.
Any unused product or waste material will be disposed of in accordance with local 
requirements.


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4.1.2
Selection of doses in the trial
In the US and EU, adalimumab (Humira) has received health authority approval for the 
treatment of RA, Crohn’s disease, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis,
juvenile idiopathic arthritis and Hidradenitis suppurativa. The doses of BI 695501 and 
Humira selected for this trial are identical due to the similarity of both compounds (an initial 
dose of 80 mg s.c. injection followed 1 week later and subsequently every other week by 40 
mg) and are the doses that were used to assess the efficacy of the originator compound and 
are as per Humira label.
4.1.3
Method of assigning patients to treatment groups
Once patients have completed screening, have met all the inclusion criteria and none of the 
exclusion criteria, a pre-treatment call will be made using the IRT system. Screen failure 
patients may be rescreened once based on investigator judgment and prior permission from 
medical monitor of the study.
The registration call will depend on the trial site procedure. The process for treatment 
assignment might be different depending on the country and respective trial medication 
shipping timelines. In countries where trial medication needs to be sent to sites in advance 
due to long shipping timelines (e.g., cross border shipments), trial medication will be 
provided to the sites in advance and patients will be assigned treatment on Day 1. For 
countries where trial medication can be provided on short notice (short shipping times) a 
registration call will be made as described below and trial medication will be shipped. The 
registration call might be made within 10 days prior to the planned first administration of trial 
medication. Eligible patients will then be confirmed to the randomization scheme on Day 1 
(or when the drug is at site), according to their randomization.
Patients will be randomized to each treatment in a 1:1 ratio (BI 695501 or US-sourced 
Humira) at Visit 2.
Initial randomization will be stratified according to prior exposure to a biologic agent (yes / 
no).
Randomization will be performed in a blinded fashion via IRT. Patients will be randomized 
sequentially (the lowest sequentially available randomization number).
Each syringe of trial medication will be labeled with the trial code and a unique medication 
identification number. The IRT system will be used for the randomization, allocation, and 
supply of trial medication throughout the study. The IRT will assign each patient a unique 
medication number for each drug administration. Details of the IRT system will be provided 
in the ISF.
Access to the randomization code will be controlled and documented. All persons directly
involved in the conduct and analysis of the trial will have no access to the treatment 
allocation prior to final database lock.


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4.1.4
Drug assignment and administration of doses for each patient
Each patient will receive 80 mg of BI 695501 or US-licensed Humira at the Baseline Visit
(Day 1, Week 0) followed by 40 mg of BI 695501 or US-licensed Humira 1 week later, and 
then 40 mg of BI 695501 or US-licensed Humira every other week until Week 16 (primary 
endpoint). 
After Week 16 (Day 112), patients achieving at least a PASI 50 response will continue 
receiving their randomized treatment (40 mg BI 695501 or Humira every other week) until 
Week 24 in a blinded fashion.
Patients not achieving at least PASI 50 at Week 16 will not be further treated with the study 
drugs, but only followed up for safety.
The prefilled syringe must be removed from refrigeration 30 minutes before administration to 
permit the medication to warm. Injecting cold medication can cause discomfort. Once taken 
out of the refrigerator, the trial medication should be administered within 1 hour. A syringe 
must not be used if it is frozen or if it has been left in direct sunlight.
The patient will administer the injection in an area of the skin where post-administration 
assessments of any reaction would not be compromised by the presence of impairment to skin 
integrity. The location for the trial medication injection will be the lower abdomen (excluding 
a 2-inch [5-cm] area around the navel) and upper thigh. A different injection site should be 
selected for each injection (at least 1 inch [2.5 cm] away from the previous site).
For the duration of the trial, trial medication will be administered either at the trial site by 
dedicated trial personnel, or at home by the patients themselves. At all designated site visits 
(Weeks 0 and 1), the patient must administer BI 695501 while at the trial site. Between 
designated site visits (Weeks 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23), the patient may choose 
to come to the site to self-inject the trial medication with the support of suitably qualified, 
designated trial site personnel or the patient may self-inject the trial medication at home.
Patients will be instructed to accurately record the dates and times of dosing, problems 
encountered with dosing, the occurrence of any AEs, the use of concomitant therapies, and 
the prefilled syringe storage conditions on the provided diary cards between the trial site 
visits.
For self-administration, handling and administration of trial medication will be described in 
detail in the handling instructions. Cool bags and handling instructions will be provided to the 
patient (refer to the ISF).
In case of implementation of the third-party blinded procedure, for the duration of the trial, 
BI 695501 / US-sourced Humira will be administered by a dedicated trial personnel 
(designated unblinded person will administer the drug to patients but will not be involved in 
any assessment of safety or efficacy), either at the site or at the patient’s home. These trial 
personnel will be allowed to perform drug administrations and home visits only after suitable 
training has been received and they are considered to be qualified to perform the 
subcutaneous injections and the home visits.


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After the first injection (Visit 2), the patient will remain at the clinical site for at least 1 hour 
for observation of any AEs. 
Dose modification is not permitted during this trial. If a patient misses a dose of trial 
medication then the dose should be administered as soon as possible. 
The 2-week regimen for trial medication administration should resume from the time the last 
dose is administered. The last injection is planned to occur at Week 23 for all eligible 
patients. The treatment period will not be extended past this time point.
In the event of an anaphylactic or other serious hypersensitivity reaction, the administration 
of trial medication will be discontinued immediately, the patient will be discontinued from 
the trial and appropriate therapy will be initiated.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
This is a double-blind trial, therefore patients, Investigators and everyone involved in trial 
conduct (except the trial personnel administering the trial medication–third-party blinding) in
this double-blind trial will remain blinded with regard to the randomized treatment 
assignments until after the final database lock.
The randomization code will be kept secret by Clinical Trial Support up to database lock.
Bioanalytics will not disclose the randomization code or the results of their measurements 
until the trial is officially unblinded.
It is planned to conduct the study using 0.8 mL BI 695501 or a pre-filled Humira syringe as 
the reference product thoughout. 
However, if 0.8 mL Humira is not available, the study conduct may have to be continued
using the 0.4 mL pre-filled Humira syringe as the reference product. Taking into account that 
0.8 mL BI 695501 and 0.4 mL Humira might differ in their presentations, the blinding of 
treatments will be maintained by using a third-party blinding, where the study drug will be 
administered to the patients by persons who are independent of the other clinical trial 
procedures and not involved in other aspects of the study (see Appendix 10.3 for details on 
third party blinding procedure).
The secondary packaging (boxes containing syringes) will be identical for both BI 695501 
and Humira, allowing the blinding of the site pharmacy.
Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the Investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the Investigator
in order to provide appropriate medical treatment or otherwise assure safety of trial 
participants. If unblinding is required in the interest of the safety of a patient, and time 
allows, the investigator will discuss the matter with the Medical Advisor before unblinding 


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whenever possible. If the code is broken for a patient (via the IRT) the sponsor must be 
informed immediately. The reason for unblinding must be documented in the source 
documents and appropriate eCRF page along with the date and the initials of the person who 
broke the code.
Due to the requirements to report SUSARs, it may be necessary for a representative from the 
BI Pharmacovigilance group to access the randomization code for individual patients during 
trial conduct. The access to the code will only be given to authorised Pharmacovigilance
representatives and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational 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). Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
All trial medications must be kept in a secure place under appropriate storage conditions and 
handled according to GMP and GCP. The trial medication must be stored in a refrigerator at a 
controlled temperature (2°C to 8°C [36°F to 46°F]) and must not be frozen. A temperature 
log will be kept at the trial site and will be completed (with a minimum and maximum 
reading) on each business day. Syringes will be kept in their outer carton in order to protect 
from light. Detailed storage conditions will be described on the trial medication labels.
Patients self-injecting at home will be instructed on the correct storage of the trial medication
at home and will be required to document storage conditions in the patient diary. 
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The designated person at each site will receive the investigational drugs delivered by the 
sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the Institutional Review Board (IRB) / Independent 
Ethics Committee (IEC),

Availability of a signed and dated clinical trial contract between the sponsor and the 
Principal Investigator,

Approval/notification of the regulatory authority, e.g., competent authority (CA),

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated CTP,


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
Availability of the proof of a medical license for the Principal Investigator,

Availability of Form 1572
The designated person must maintain records of the product’s delivery to the trial site, the 
inventory at the site, the administration to each patient, and disposal of unused products. 
Unused trial medication will be destroyed in accordance with local requirements and the 
records will be maintained.
These records will include dates, quantities, batch / serial numbers, expiry (‘use by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
designated person will maintain records that document adequately that the patients were 
provided the doses specified by the CTP and reconcile all investigational products received 
from the sponsor. At the time of disposal of unused products, the designated unblinded 
person must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the Investigator’s possession.
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no specific rescue drugs foreseen for the treatment of AEs. There are no special 
emergency procedures to be followed.
In case of AEs in need of treatment, the investigator can authorize an appropriate therapy. In 
those cases, subjects will be treated as necessary and, if required, kept under supervision at 
the trial site or transferred to a hospital until all medical evaluation results have returned to an 
acceptable level.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study or must refer them for appropriate ongoing care according to local 
guidelines and daily practice, respectively.
4.2.2
Restrictions
Restrictions on prior and concomitant medications during the course of the trial are described 
in Table 4.2.2: 1.
Patients must be instructed not to take any new medications or to change the dose regimen of 
any existing medication (including over-the-counter products, herbal medications, and 
complementary therapies) without first consulting the investigator. All changes must be noted 
in the concomitant medication section of the eCRF.
Other medication that is considered necessary for the patient’s safety (e.g., as a result of an 
AE) may be given at the investigator’s discretion. Investigators are encouraged to adhere to 
the restrictions listed in Table 4.2.2: 1. 


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Any concomitant medications will be recorded in the appropriate sections of the eCRF.
Table 4.2.2: 1
Prior and concomitant treatments
Treatment
Restriction
Biologic agents (e.g., TNF 
antagonists, anti-IL12/23 and 
anti-IL17)
Prior treatment with more than 1 biologic agent is not permitted
Prior treatment with adalimumab or adalimumab biosimilar is not permitted.
No prior biologic exposure within last 6 months of screening will be permitted.
Cyclophosphamide
Cyclophosphamide will not be permitted within 6 months prior to Day 1 and 
for the duration of the study.
Topical steroids
Topical steroid treatment applied on psoriatic lesions/scalp/nails will not be 
permitted within 2 weeks prior to Day 1 and for the duration of the study. 
Topical corticosteroid under occlusion in any location will not be permitted 
within 2 weeks prior to Day 1 and for the duration of the study. Topical 
corticosteroids of low potency (WHO group VI/VII) are permitted during the 
study except within 24 hours before study visits.
Other topical treatments
Other topical treatment applied on psoriatic lesions/scalp/nails that is likely to 
impact signs and symptoms of psoriasis (e.g., vitamin D analogues, 
pimecrolimus, retinoids, salicyl vaseline, salicylic acid, lactic acid, tacrolimus, 
tar, urea, hydroxy or fruit acids will not be permitted within 2 weeks of Day 1 
and for the duration of the study. However, use of emollients (moisturizing 
treatments) will be permitted during the study duration except within the 24-
hour period immediately prior to each clinic visit.
UVB, UVA or PUVA 
treatment
(photo [chemo] therapy)
Treatment with UVB or UVA (without psoralen) will not be permitted within 2 
weeks prior to Day 1 and for the duration of the trial. PUVA treatment will not 
be permitted within 4 weeks prior to randomization. 
Traditional synthetic agents 
Systemic treatment with traditional synthetic agents (e.g., methotrexate, 
sulphasalazine, azathioprine, retinoids, fumarates) will not be permitted within 
4 weeks prior to Day 1 and for the duration of the study. 
Nutraceutical treatments
Nutraceuticals intended for the treatment of psoriasis will not be permitted 
within 4 weeks prior to Day 1 and for the duration of this study.
Other systemic or locally 
acting medications
Treatment with any other systemic or locally acting medications which might 
counter or influence the objective of the study (e.g., nonsteroidal 
anti-inflammatory drug [NSAID], antihistamine) is only permitted for 
occasional (single dose) use; medications known to potentially provoke or 
aggravate psoriasis (e.g., lithium, beta-blockers or antimalarial drugs), will 
only be permitted if the doses of such agents are stable within 4 weeks prior to 
Day 1 and are planned to remain so for the duration of this study.
Live/attenuated vaccine
Not permitted within 12 weeks prior to the Screening Visit, for the duration of 
the trial and up to 3 months after the last dose of trial drug.
Any drug/therapy that has not 
received regulatory approval 
for any indication
Not permitted within 12 weeks or a minimum of five half-lives, whichever is 
longer, prior to Day 1.
IV Gamma Globulin
Not permitted within 6 months of the Screening Visit.
Intravenous, intramuscular, 
intra-articular or parenteral
corticosteroids
Not permitted within 6 weeks prior to Day 1 and throughout the trial.
Oral corticosteroids
Not permitted within 4 weeks prior to Day 1 and throughout the trial.
Prosorba® Column
Not permitted within 6 months of the Screening Visit.


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Leflunomide 
Not permitted within at least 8 weeks prior to Day 1 and throughout the trial.
Abbreviations: IL=interleukin; NSAID=nonsteroidal anti-inflammatory drug; TNF=tumor necrosis factor; UVA=ultraviolet 
A light; UVB=ultraviolet B light. 
Restrictions on diet and life style
4.2.2.1
Moisturizers/emollients containing retinoids and the use of tanning beds are not allowed 
during the study.
Male subjects with female partner(s) of child-bearing potential must agree to use a medically
acceptable method of contraception during the trial and for 6 months after the last dose of 
trial drug.
Restrictions regarding women of childbearing potential 
4.2.2.2
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 treatment 
periods of the study requires immediate interruption of study treatment until serum β-hCG is 
performed and found to be negative. If the serum β-hCG test is positive, the patient must be 
discontinued from the trial.
Female patients of childbearing potential must use the contraception methods described in
Section 3.3.2 and the patient information. Acceptable methods of birth control include, for 
example, birth control pills, intrauterine devices (IUDs), surgical sterilization, vasectomized 
partner and double barrier method (for example male condom in combination with female 
diaphragm/cervical cap plus spermicidal foam/gel/film/cream/suppository).
*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).
Restrictions regarding male participants of reproductive potential
4.2.2.3
Male participants with female partner(s) of child-bearing potential must agree to use a 
medically acceptable method of contraception during the trial and for 6 months after the last 
dose of trial drug. Males should use a condom. Female partners must additionally use 1 of the
following methods if they are not pregnant: hormonal contraception, intrauterine device
(IUD), diaphragm, or cervical cap. If their partner is pregnant, males must agree to use a 
condom and no additional method of contraception is required for the pregnant partner. Male 
subjects must also agree to not donate sperm during the trial and for a period of 6 months
after the last dose of trial drug


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TREATMENT COMPLIANCE
4.3
Compliance on study visit days (Weeks 0 and 1) will be assured by the observation of trial 
medication administration by dedicated trial personnel considered qualified to perform or 
observe the subcutaneous injections. 
Between designated site visits (Weeks 3, 5, 7, 9, 11, 13, 15, 17, 19, 21 and 23), the patient 
may self-inject the trial medication at home. Patients will be instructed to notify the site if 
they miss a dose or receive a partial dose so the Investigator can determine any necessary 
follow-up. For all trial medication injections, patients will be asked to complete a patient 
diary documenting the date and time of the injections and problems encountered with dosing
(missed or incomplete injections should be recorded as well).
All used and unused syringes must be returned to the site at each visit.
Patients showing poor compliance as assessed by missing their allocated days for trial 
medication administration must be counseled on the importance of good compliance to the 
trial dosing regimen. 
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial by the investigator after consultation 
with the sponsor or sponsor’s representative, and the eCRF will be completed accordingly.


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5.
VARIABLES AND THEIR ASSESSMENT
Please refer to the Flow Chart for the Schedule of Assessments for the trial. 
The trial endpoints are listed in Section 5.1 below. Efficacy assessments are described in 
more detail in Section 5.2, safety assessments in Section 5.3, and PK sample collection in 
Section 5.4. 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint
The primary endpoint is:

Proportion of patients with a 75% reduction in Psoriasis Area and Severity Index (PASI
75) response at Week 16
5.1.2
Secondary Endpoints
Secondary endpoints are:
Efficacy

Proportion of patients with a PASI 75 response at Week 24

Mean percentage improvement in PASI at Week 16 

Proportion of patients with a sPGA ≤ 1 (clear or almost clear) at Week 16 

Proportion of patients achieving a Dermatology Life Quality Index (DLQI) of 0 or 1 at 
Week 16 
Safety

Proportion of patients with drug-related AEs


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Safety

Proportion of patients with AEs, SAEs and AEs of Special Interest (AESIs) (e.g., serious 
infections and hypersensitivity reactions);
 
 
 
ASSESSMENT OF EFFICACY
5.2
The following assessments will be made at the time points indicated in the Flow Chart for the 
purpose of calculating the PASI, sPGA, and DLQI scores.
5.2.1
PASI
The PASI is an established measure of clinical efficacy for psoriasis medications. (R96-3541)
The PASI is a tool which provides a numeric scoring for patients overall psoriasis disease 
state, ranging from 0 to 72. It is a linear combination of percent of surface area of skin that is 
affected and the severity of erythema, induration, and desquamation over four body regions. 
The endpoints used are based on the percent reduction from Baseline, generally summarized 
as a dichotomous outcome based on achieving over an X% reduction (or PASIX), where X is
50, 75, 90, and 100.
To calculate the PASI, the 4 main body areas are assessed: head (h), trunk (t), upper 
extremities (u) and lower extremities (l). These correspond to 10, 30, 20, and 40% of the 
total body area, respectively.
The area of psoriatic involvement of these four areas (Ah, At, Au, and Al) is given a 
numerical value: 0 = no involvement, 1 = < 10%, 2 = 10 to < 30%, 3 = 30 to < 50%, 4 = 50 to 
< 70%, 5 = 70 to < 90%, and 6 = 90 to 100% involvement.( Figure 10.2: 2)


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The signs of severity, erythema (E), induration (I) and desquamation (D) of lesions are 
assessed using a numeric scale 0-4 where 0 is a complete lack of cutaneous involvement and 
4 is the severest possible involvement; scores are made independently for each of the areas, h, 
t, u, and l and represents a composite score for each area. An illustration of judging erythema 
follows: 0 = no erythema, 1 = slight erythema, 2 = moderate erythema, 3 = severe erythema, 
and 4 = very severe erythema.
The PASI score is calculated according to the following formula:
PASI = 0.1(Eh+Ih+Dh)Ah + 0.3(Et+It+Dt)At + 0.2(Eu+Iu+Du)Au + 0.4(El+Il+Dl)Al
(Appendix 10.2, Figure 10.2: 4)
5.2.2
Static Physician’s Global Assessment
The sPGA is a 5-point score ranging from 0 to 4, based on the physician’s assessment of the 
average thickness, erythema, and scaling of all psoriatic lesions. The assessment is 
considered “static”, which refers to the subject’s disease state at the time of the assessments, 
without comparison to any of the subject’s previous disease states (dynamic), whether at 
Baseline or at a previous visit (Appendix 10.2, Figure 10.2: 1).
A lower score indicates less body coverage, with 0 being clear and 1 being almost clear. 
Erythema  
(0)   Normal (Post-inflammatory hyperpigmentation may be present
(1)   Pink coloration of lesions
(2)   Light red coloration of lesions
(3)   Dull to bright red coloration of lesions
(4)   Bright to deep red coloration of lesions
Induration
(0)   None
(1)   Just detectable 
(2)   Mild thickening
(3)   Clearly distinguishable to moderate thickening
(4)   Severe thickening with hard edges
Scaling
(0)   No scaling
(1)   Minimal focal scaling
(2)   Predominately fine scaling
(3)   Moderate scaling
(4)   Severe /coarse scaling covering almost all or all lesions
Scoring:
Clear 
0 = 0 for all 3
Almost clear 1 = mean > 0, < 1.5
Mild
2 = mean >= 1.5, < 2.5
Moderate 
3 = mean >= 2.5, < 3.5
Severe
4 = mean >= 3.5


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5.2.3
Dermatology Life Quality Index
The DLQI is a subject-administered, ten-question, quality of life questionnaire that covers 
6 domains including symptoms and feelings, daily activities, leisure, work and school, 
personal relationships and treatment (R05-2548). The DLQI has a one-week recall period. 
Item scores range from 0 (not relevant) and 1 (not at all) to 3 (very much). Question 7 is a 
“yes”/ “no” question where “yes” is scored as 3.
The DLQI will be self-administered by the patient at visits indicated in the Flow Chart.
The DLQI will be analyzed under 6 headings as follows (R05-2548):
Domain
Question Number
Score
Symptoms and feelings
Questions 1 and 2
Score maximum 6
Daily activities
Questions 3 and 4
Score maximum 6
Leisure
Questions 5 and 6
Score maximum 6
Work and school
Question 7
Score maximum 3
Personal relationships
Questions 8 and 9
Score maximum 6
Treatment
Question 10
Score maximum 3
DLQI total score is calculated by summing the scores of each question resulting in a range of 
0 to 30 where 0-1 = no effect on subject’s life, 2-5 = small effect, 6-10 = moderate effect, 
11-20 = very large effect, and 21-30 = extremely large effect on subject’s life. The higher the 
score, the more the quality of life is impaired. If the answer to 1 question in a domain is 
missing, that domain is treated as missing. If 2 or more questions are left unanswered 
(missing), DLQI total score is treated as missing. A 5-point change from Baseline is 
considered a clinically important difference (Figure 10.2: 3).
 
 
 
 
 
 
 
 


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ASSESSMENT OF SAFETY
5.3
At the Screening Visit, the medical examination will include documentation of subject 
information, informed consent, demographics including height and body weight, smoking 
and alcohol history, relevant medical history and concomitant therapy, review of inclusion 
and exclusion criteria, review of vital signs (blood pressure, pulse rate, temperature), 12-lead 
ECG, laboratory tests (including virus screening, IGRA/PPD test [where applicable], 
pregnancy test for females), and a physical examination. 
On all other visits, it will include review of vital signs, 12-lead ECG, laboratory tests 
(including IGRA at SFU), pregnancy test for females and a physical examination. 
Adverse events and concomitant therapies will be assessed throughout the trial.
Whenever possible, the same person should perform the physical examination throughout the 
trial (i.e., for all patients at each trial site).
5.3.1
Physical examination
A physical examination will be performed at the visits indicated in the Flow Chart.
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.
 
linically relevant abnormal findings will be reported as Baseline 
conditions or AEs.
5.3.2
Vital Signs
Vital signs will be assessed at the visits indicated in the Flow Chart.
Blood pressure and pulse rate measurements should be taken following at least 5 minutes rest 
while the patient is in a sitting position. The patient’s body temperature will also be recorded.
The method of measuring body temperature (oral/aural) should be consistent at a specific trial 
site.
The investigator must assess all vital signs findings and if the investigator finds any clinically 
relevant abnormalities, these must be reported as AEs / SAEs as appropriate.


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5.3.3
Safety laboratory parameters
The laboratory tests listed in Table 5.3.3: 1 will be analyzed by a central laboratory. The 
central laboratory provider will also provide the materials for blood sampling. Instructions for 
the labeling, storage, and shipment of the samples as well as details of all blood variable units 
and reference ranges can be found in the Laboratory Manual.
Pregnancy testing will be performed by a central laboratory using serum at Screening and
local laboratory using urine at all applicable visits thereafter. 
For time points of laboratory sampling, see the Flow Chart.
Laboratory results (i.e., all safety laboratory and clinical laboratory data relevant for current 
clinical practice) of the patients will be available to the respective investigator (via laboratory 
reports) and to the sponsor (via the central laboratory website) and selected abnormal 
laboratory alerts will be flagged to the site and sent to sponsor in real time.
The investigator must assess all laboratory results, evaluate any change in laboratory values, 
and review all clinical laboratory tests for potential clinical significance at all time points 
throughout the trial. The investigator should endeavor to provide a reason for all out-of-range 
results deemed not clinically significant. If the investigator determines a laboratory 
abnormality to be clinically significant, it will be considered an AE / SAE (see 
Section 5.3.6.1); however, if the laboratory value abnormality is consistent with a current 
diagnosis, it will be documented accordingly.


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Table 5.3.3: 1 
Laboratory tests
Category
Test name
Haematology
Hct
Hb
RBC count / erythrocytes
White blood cells / leukocytes
Platelet count / thrombocytes
Diff. Automatic
Neutrophils (relative count)
Lymphocytes (relative count)
Diff. Manual (if Diff Automatic is abnormal)
Neutrophils, bands (stabs)
Neutrophils, polymorphonuclear
Lymphocytes
Enzymes
AST (GOT)
ALT (GPT)
Creatine Kinase
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT)
Electrolytes
Calcium
Sodium
Potassium
Chloride
Substrates
Glucose
Creatinine
Bilirubin total
Bilirubin direct (if total is elevated)
Bilirubin indirect (if total is elevated)
Total protein
Albumin
Cholesterol, total
Urine Pregnancy test (only for female patients of 
childbearing potential) at randomization and 
continued as indicated in the Flow Chart (including 
EoT and End of Observational Period Visit)
Human Chorionic Gonadotropin in the urine
Serum Pregnancy test (only for female patients of 
childbearing potential) at screening and if urine 
pregnancy test is positive) 
Human Serum Chorionic Gonadotropin 
Urinalysis (dipstick)
Urine Protein
Urine Glucose
Urine RBC / erythrocytes
Screening for infections (only at screening)
HBsAg (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1, and HIV-2 antibody (qualitative, where 
mandated by local authorities at the discretion of the 
investigator where clinically indicated)
Screening for infections (only at screening and EoT 
Visit)
TB test (IGRA: QuantiFERON® Gold 
assay/T-SPOT®.TB)
(PPD skin test at the discretion of the investigator 
where clinically indicated)1
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CK-MB=Creatine Kinase-MB; EoT=End 
of Treatment; Gamma- GGT=Glutamyl Transferase; GOT=Glutamic-Oxaloacetic Transaminase; 
GPT=Glutamic-Pyruvic Transaminase; Hb=hemoglobin; Hct=hematocrit; HIV=human immunodeficiency virus; 
IGRA=interferon gamma-release assay; PPD=purified protein derivative; TB=tuberculosis. 
1
There is the trial site option to perform a PPD skin test, although this will not be provided or performed at Central Lab.


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5.3.4
Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the Flow Chart.
ECGs will be recorded after the patients have rested for at least 5 minutes in a supine position 
and will always precede blood sampling. 
ECGs may be repeated for quality reasons and the repeat used for analysis. Additional ECGs 
may be recorded for safety reasons. Clinically relevant, abnormal findings will be reported as 
AEs.
Information about the details of ECG collection and the parameters assessed will be provided 
in the ISF.
The original ECG traces and variables must be stored in the patients’ medical record as 
source data. A physician familiar with interpretation of ECG will evaluate the ECG from a 
clinical perspective and the result (whether the ECG result is normal, abnormal not clinically 
relevant or abnormal clinically relevant) will be recorded in the appropriate section of the 
eCRF.
5.3.5
Other safety parameters
Local tolerability
5.3.5.1
The assessment of injection site reactions will be done by the blinded investigator/designee
according to “swelling”, “hardening”, “heat”, “redness”, “pain”, “itching”, “bruising”, or 
“other symptoms”. If any injection site reactions are observed, these findings should also be 
reported on the AE eCRF page.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorization or from 


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occupational exposure. Conditions of use outside the marketing authorization include 
off-label use, overdose, misuse, abuse, and medication errors.
Serious adverse event
An SAE is defined as any AE which:

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 hospitalization or 

prolongation of existing hospitalization,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect,
or

is deemed serious for any other reason if it is an important medical event when based 
on 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.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI has set up a list of further AEs, which by their nature, can always be considered to be 
“serious” even though they may not have met the criteria of an SAE cited above.
A copy of the latest list of “Always Serious AEs” can be found in the ISF and eCRF. These 
events should always be reported as SAEs as described above.
Adverse events of special interest 
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g., the potential for AEs based on knowledge from other compounds in the same class. 


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AESI need to be reported to the sponsor’s/sponsor designee Pharmacovigilance Department 
within the same timeframe that applies to SAE, please see above.
The following are considered as AESIs:
1. Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood draw sample, and/or

marked peak aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analyzed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
2. Anaphylactic reactions
3. Serious infection (defined as infections requiring IV antibiotics or meeting the regulatory 
definition of a SAE)
4. Hypersensitivity reactions
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an AE. An adverse reaction, in 
contrast to an AE, is characterised by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 


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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 diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g., after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g.,
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Adverse event collection and reporting
5.3.6.2
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate eCRF(s) by the 
Investigator:

From signing the informed consent onwards through the Residual Effect Period (REP, 10
weeks after the last study drug administration), until individual patient’s end of trial: 
o
all AEs (serious and non-serious) and all AESIs.
However, if an individual patient discontinues trial medication prematurely but stays 
in the trial (i.e., if further visits including telephone visits or vital status assessments


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are planned) from then on and until the individual patient’s end of the trial the 
Investigator must report related SAEs and related AESIs.

After the individual patient’s end of trial:
o
the Investigator does not need to actively monitor the patient for AEs but 
should only report relevant SAEs and relevant AESIs of which the 
Investigator may become aware of.
The residual effect period (REP) is defined as 10 weeks after the last trial medication 
application. All AEs which occurred through the treatment phase and throughout the REP 
will be considered as on treatment. Events which occurred after the REP will be considered 
as post treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s / sponsor’s designee unique entry point (contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,
the Investigator could inform the sponsor / sponsor designee upfront via telephone. This does 
not replace the requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication and any possible interactions between the investigational drugs.
The following should also be recorded as an (S)AE in the eCRF and SAE form (if 
applicable):


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
Worsening of the underlying disease that cannot be explained with the natural fluctuation 
of disease severity or of other pre-existing conditions

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.

If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
Baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial, must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy to the sponsor’s / sponsor 
designee unique entry point (contact details will be provided in the ISF). The Pregnancy 
Monitoring Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s/sponsor’s designee unique entry point on the 
Pregnancy Monitoring Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
 
 


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APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements performed during this trial are standard measurements in psoriasis 
treatment trials and will be performed in order to monitor safety aspects or assess treatment 
response in an appropriate way.
 
Therefore, the appropriateness of all measurements applied in this trial is assured.
Information about race should be obtained from all study participants as allowed by local 
regulations. This is because the prevalence and characteristics of psoriasis differ widely 
between patients of different racial origin. It will thus be worthwhile to assess if patients of 
different race will respond differently to the study treatment.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
A schedule of assessments is provided in the Flow Chart.
Each visit date (with its window) is to be counted from Day 1 (randomization). If any visit 
has to be rescheduled, the 2-week regimen for trial medication administration should resume 
from the time the last dose was administered. Additional visits for the purpose of re-testing of 
laboratory parameters or AE monitoring may be included as deemed necessary by the 
investigator.

A visit window of -1 / + 2 days is permitted for Visit 2 (Day 1)

A visit window of ± 2 days is permitted from Visit 3 up to Visit 7

A visit window of ± 3 days is permitted for Visit 8 to Visit 10
All assessments should be performed prior to administration trial medication, unless 
otherwise specified. Laboratory samples must be drawn prior to trial medication injection.
The questionnaire will be completed at the site by the patient (DLQI) before any 
investigations or discussions about their disease with the clinic staff and may only be 
recorded by a trial nurse/investigator on behalf of the patient if the patient has difficulty 
writing during the visit or is unable to read. This must be documented clearly in the patient 
notes.
Also the scales are to be completed by study site personnel (PASI sPGA, 
All questionnaires and scales are detailed in Appendix 10.
The total estimated volume of blood that will be drawn from each patient during the course of 
the trial is shown in Table 6.1: 1.
Table 6.1: 1
Estimated blood sample volumes per patient
Parameter
Sample volume (mL)
Number of samples
Total volume (mL)
Laboratory tests (including serum 
chemistry, serum pregnancy test)
3
6
18
Hematology
3
6
18
Infection screen
4
1
4
TB test
3
2
6
Approximate total
82
Abbreviations: ADA=anti-drug antibodies; nAb=neutralizing ADA; TB=tuberculosis.
Additional samples may be required if medically indicated, e.g., at unscheduled visits to follow safety findings.


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DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
Study procedures to be performed at each visit are listed in the Flow Chart and the respective 
protocol sections. Refer to Section 5 for explanations of procedures. Additional details on 
procedures at selected visits are provided below. 
6.2.1
Screening and run-in period(s)
Screening Period
Once the patient has provided informed consent (before any trial-specific procedures or 
assessments are performed), meets the inclusion criteria and does not meet the exclusion 
criteria (see Section 3.3), the following will be performed/collected:

Demographic information (including gender, date of birth, ethnicity, and race), and 
medical and surgical history (including psoriasis history and history of opportunistic 
infection)

Infection screen (TB, HBsAg, anti-hepatitis B core antibodies [anti-HBc], anti-HCV, and 
HIV test, per the investigator’s discretion)

Chest X-ray, unless taken within the previous 12 weeks 

TB test 

Serum pregnancy test for women of child-bearing potential

Physical examination, including height (cm) and weight (kg) 

Vital signs (blood pressure, pulse rate, and body temperature)

Laboratory testing (serum chemistry, hematology, and urinalysis)

12-lead ECG 

Previous and concomitant therapy 

Assessment of AEs 

Efficacy assessments: PASI, sPGA, DLQI, 
Once patients have completed screening, have met all the inclusion criteria and none of the
exclusion criteria, randomization can occur through a registration call through a standard 
randomization visit call, using the IRT system. The Day 1 randomization or registration call 
will depend on the trial site procedure. Patients will be randomized to each treatment in a 1:1 
ratio (BI 695501: US-licensed Humira) according to the stratification factors. The 
registrationcall can be made within 10 days prior to the planned first administration of trial 
medication. Eligible patients will then be confirmed to the randomization scheme on Day 1 
(or when the drug is at site), according to their randomization. Eligible patients will be 
randomized in blocks to double-blind treatment at Day 1 according to the randomization. 
Patients will be randomly assigned in a blinded fashion to BI 695501 or US-licensed Humira.


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6.2.2
Treatment period
Baseline, Visit 2 (Day 1)
For the duration of the trial, BI 695501 / US-licensed Humira will be administered by a
suitably qualified, designated trial personnel, either at the site or at the patient’s home. 
Eligible patients will be randomized  and will receive their first administration of trial 
medication on Day 1.
The following will also be performed/collected:

Urine pregnancy test for women of child-bearing potential

Physical examination (see Section 5.3.1)

Vital signs 

Laboratory testing (serum chemistry, hematology and urinalysis)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs (see Section 5.3.6)

Previous and concomitant therapy 

Efficacy assessments: PASI, sPGA, DLQI, 
(see Section 5.2)


Contact IRT

The first injection of trial medication
Visit 3
The following will be performed/collected:

Assessment of AEs and concomitant therapy

Contact IRT, training and administer trial medication
Visits 4 to 9
On study days with self-administration of BI 695501 or Humira, patients must complete a 
patient diary. This occurs on Weeks 3, 5, 7, 9, 11, 13, 15, 17, 19, 21 and 23. Trial site 
personnel will instruct the patient on how to complete the patient diary. The purpose of the 
diary is to record events occurring between site visits. Patients will be instructed to accurately 
record the dates and times of trial medication dosing; problems encountered with dosing; the 
occurrence of any AEs; the use of concomitant therapies; and the prefilled syringe storage 
conditions on the provided diary cards between the site visits. The patient will be instructed 
to contact the site if they are experiencing any AEs between designated site visits.
The following will be performed/collected:

Urine pregnancy test for women of child-bearing potential (Visits 5, 7, 9)


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
Physical examination (Visits 5, 7, 9)

Vital signs (blood pressure, pulse rate, and body temperature; see Section 5.3.2) (Visits 5,
7, 9)

Laboratory testing (serum chemistry, hematology and urinalysis; see Section 5.3.3) 
(Visits 5, 7, 9)

12-lead ECG (Visits 5, 7, 9) (

Assessment of AEs and concomitant therapy

Review of the patient diary card entries

Efficacy assessments: PASI, sPGA, DLQI; (see Section 5.2)


Contact IRT and administer trial medication (see Section 4.1.4)
The patient will return all used and unused trial medication at each visit after Week 4 and will 
bring his / her patient diary for review. Prefilled syringes will be collected by the trial site 
personnel and destroyed in accordance with local requirements, as instructed in the ISF.
6.2.3
Follow-up Period and Trial Completion
Patients who discontinue the trial prematurely at any time after Day 1 including patients with 
discontinued treatment at week 16 due to lack of efficacy (but do not withdraw their consent) 
will, at discontinuation, have an End of Treatment (EoT) Visit equivalent to the Week 24 
assessments (except trial medication administration). Patients who discontinue the trial will 
also be required to have all of the evaluations planned for Visit 10 (Week 34) 10 weeks after 
their last administered dose of trial medication. These patients should be registered as 
prematurely discontinued in IRT.
The following will be performed/collected:

Urine pregnancy test for women of child-bearing potential

Physical examination, including weight (kg) (see Section 5.3.1)

Vital signs 

Laboratory testing (serum chemistry, hematology, and urinalysis)

Previous and concomitant therapy (see Section 4.2)

Assessment of AEs and concomitant therapy 

Review patient diary

TB test 
Unscheduled visit assessments
Patients may attend the trial site for unscheduled visits at any time for additional safety 
monitoring at the discretion of the investigator. 
All abnormal values that are judged clinically relevant by the investigator will be monitored 
using the appropriate tests until a return to a medically acceptable level is achieved. Adverse 


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events persisting after trial completion must be monitored until they have normalized or have 
been sufficiently characterized.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is a randomized, double-blind, parallel-arm, multiple-dose, active comparator, 
multi-center, multi-national trial.
The primary objective of this trial is to establish equivalence between BI 695501 and 
US-licensed Humira in terms of efficacy at Week 16 in patients with active moderate to 
severe chronic plaque psoriasis.
Equivalence in efficacy between BI 695501 and US-sourced Humira will be based on a 
comparison of:

Proportion of patients with a PASI 75 response at Week 16 with a margin of ± 18%.
Based upon these design considerations, the trial will be analyzed using logistic regression, 
which will include term for baseline PASI as covariate. Details of the models are presented 
below.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The test for equivalence will be performed with respect to BI 695501 versus US-sourced 
Humira.
The hypotheses for the equivalence test can be written as follows:
H0:
Difference in PASI 75 response rates at Week 16 (BI 695501 versus US-sourced 
Humira) is less than -18% or more than 18%
H1:
Difference in PASI 75 response rates at Week 16 (BI 695501 versus US-sourced 
Humira) is within [-18%, 18%]
To conclude equivalence, the two-sided 95% CI of the difference in PASI 75 response rate 
(BI 695501 – Humira) has to be fully within the equivalence limits of ± 18%.
PLANNED ANALYSES
7.3
The primary analysis set will be the Full Analysis Set (FAS) according to the intention to 
treat principle. For all efficacy analyses, the FAS consists of all randomized patients who 
received at least 1 dose of trial medication, and have all efficacy measures relevant for the 
PASI75, measured at baseline and at least once post-baseline.
A Per-Protocol Set (PPS) of patients who have followed the CTP in all essential criteria will 
be created for sensitivity analyses. Patients included in the FAS who have important protocol 


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violations relevant for efficacy will be excluded from the PPS. A protocol violation will be 
considered important if it can be expected to have a distorting influence on the assessment of 
the primary endpoint. Such important protocol violations will be defined further in the TSAP 
and include:

Incorrect trial medication taken

Severe violation of treatment compliance

Severe violation of inclusion/exclusion criteria
All patients treated with at least 1 dose of trial medication will be included in the safety 
evaluation (Safety Analysis Set [SAF]).
Further details on the definition of the different analysis sets will be provided in the Trial 
Statistical Analysis Plan (TSAP).
7.3.1
Primary endpoint analyses
The primary analyses will be performed on the FAS. Patients will be assigned to the 
treatment they were randomized to.
The primary analysis of the observed difference in PASI 75 response rates at Week 16 will be 
based on logistic regression with subsequent transformation of the estimated parameters to 
the difference in proportions. Multiple imputation (MI) method will be used to deal with 
missing data (see Section 7.5).
The estimates from the logistic regression are on the logit scale, and the difference in 
proportions will be calculated as the difference between the predicted probabilities in the 
treatment groups on the original scale, with the variance calculated using the cumulative 
distribution function method of Reeve (Statistical Methods in Medical Research, forthcoming 
2016); details will be provided in the TSAP.
The statistical model can be described as follows:
(M1)
Logit(response to treatment at Week 16) = treatment + Baseline PASI + random error
This model includes fixed, categorical effects of:

Treatment (BI 695501 versus US-sourced Humira)
and continuous effect of:

Baseline PASI 
The random error is assumed to be binomially distributed.
As sensitivity analysis the primary endpoint will also be analyzed on the PPS with non-
responder imputation (NRI) using M1 as for the primary analysis. 


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7.3.2
Secondary endpoint analyses
Secondary efficacy endpoints
7.3.2.1
Secondary efficacy endpoints: 

Proportion of patients with a PASI 75 response at Week 24

Mean percentage improvement in PASI at Week 16

Proportion of patients with sPGA ≤ 1 at Weeks 16

Proportion of patients achieving a DLQI of 0 or 1 at Week 16
All secondary analyses will be based on FAS with NRI.
For the proportions, the risk difference will be computed and presented together with its 95% 
CI.
For the percentage improvement from baseline in PASI, analysis of covariance (ANCOVA) 
will be used, comparing the mean percentage improvement from Baseline of PASI between 
BI 695501 versus US-licensed Humira at Week 16. The estimate of the difference will be 
computed with its 95% CI.
ANCOVA will be performed based on the following model:
(M2)
PASI percentage improvement from baseline at Week 16 = treatment + Baseline PASI 
+ random error
The covariates will be handled in a similar way to those described in model M1.
Secondary Safety Endpoints
7.3.2.2
The secondary endpoint is:

Proportion of patients with drug-related AEs.
 
 


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). The analysis of AEs will be based on the concept of treatment-emergent AEs.
That means that all AEs with an onset between start of treatment and end of the REP, a 
period of 10 weeks after the last dose of trial medication, will be assigned to the treatment 


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period for evaluation. AEs that start before first drug intake and deteriorate under treatment 
will also be considered as ‘treatment-emergent’. Other AEs will be assigned to the 
appropriate trial phases, i.e., screening or post-treatment.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’. The residual effect 
period is defined as 10 weeks after last dose of trial medication. Adverse events that start 
before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
Safety analyses will be descriptive in nature. No formal inferential analyses are planned for 
safety comparison. The analyses will be on the SAF. Frequency of adverse events will be 
tabulated overall and by system organ class and preferred term after coding according to the 
current version of MedDRA. In addition, risk ratio together with 95% CIs will be presented
for the overall proportion.
 
 
 
 
 
 
 
 


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INTERIM ANALYSES
7.4
For this trial a “Fast track” analysis is planned for analyses of the primary efficacy endpoint. 
After all primary efficacy endpoint data are available and cleaned (i.e. approximately 16 
weeks after the last patient has been randomized) a snapshot of the database will be taken.
This snapshot will be used for performing the Fast track analysis. 
Only cumulated results will be presented, i.e. patient level data will be excluded. Details 
regarding statistical analysis will be outlined in the TSAP. 
Only a selected team, not involved into the trial activities, will have access to the unblinded 
snapshot data and need to sign a confidentiality agreement. To ensure that the data integrity 
of the continuing trial will not be violated, a charter will be prepared beforehand, outlining 
the procedures to be followed. This document will describe the measures to be implemented 
by the Sponsor to protect the integrity of the trial until the final database. Team members 
involved in the conduct of the trial as well as the site personnel and patients will remain 
blinded until the final database lock.
7.4.1
Final analysis
A final analysis (including all endpoints) will be performed when all trial data are available, 
i.e., approx. 34 weeks after the last patient has been randomized. In this analysis, all analyses 
performed for the fast track analysis will be repeated with the (partially) updated data, in 
particular with respect to safety collected at Week 34 and efficacy endpoints collected at 
Week 34. The results of the final analysis will be summarized in a CTR.
HANDLING OF MISSING DATA
7.5
7.5.1
Efficacy endpoints
For the primary endpoint, missing PASI 75 data will be imputed using MI as the imputation 
method. However, all patients who discontinue treatment, are lost-to-follow-up, or have any 
major protocol deviation related to any therapy that may significantly impact efficacy 
assessment (Table 4.2.2.1: 1) prior to the primary endpoint assessment will be considered as a 
non-responder. This is referred to as ‘NRI’. 
For other endpoints, rules for handling of missing data will be specified in the TSAP, if 
necessary.
7.5.2
Safety and other endpoints
In case of missing AE relationship status, the AE will be considered as related. For other 
safety endpoints, rules for handling of missing data will be specified in the TSAP, if 
necessary.


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RANDOMIZATION
7.6
Patients who meet all the inclusion criteria and none of the exclusion criteria will be 
randomized 1:1 to either BI 695501 or Humira over the 24-week treatment period after the 
screening period. Randomization will be stratified according to prior exposure to a biologic 
agent (yes / no). Patients will be randomized sequentially (the lowest sequentially available 
randomization number)
Randomization can occur through a registrationcall or on Day 1 (-1 / +2) through a standard 
randomization visit call. The Day 1 randomization call will depend on the trial site procedure. 
Patients will be randomized to each treatment in a 1:1 ratio (BI 695501: US-sourced Humira) 
using an IRT system. The registration call might be made 10 days prior to the planned first 
administration of trial medication. Eligible patients will then be confirmed on to the 
randomization scheme on Day 1 (or when the drug is at site) and will receive their first 
administration of trial medication, according to their randomization.
Randomization will be performed in a blinded fashion by IRT. Boehringer Ingelheim Pharma 
GmbH & Co. KG, Clinical Trial Supply Unit or a third party appointed by the sponsor will 
provide the randomization list using a validated randomization number generating system. 
Access to the randomization code will be controlled and documented. All persons directly 
involved in the conduct of the trial have no access to the treatment allocation prior to final 
database lock. The block sizes of the randomization will be documented in the CTR.
DETERMINATION OF SAMPLE SIZE
7.7
To perform the equivalence test BI 695501 versus US-licensed Humira with ≥ 85% power, 
approximately 300 patients are needed for this comparison (FAS).
For the calculation of the sample size a meta-analysis on Week 16 data of the REVEAL and 
CHAMPION trials (R14-4849, R14-4898) was performed. This meta-analysis revealed a risk 
difference of 64.2% and a 95% CI (60.4% to 67.9%). Table 7.7: 1 shows the information 
used in the meta-analysis.
The classical 95-50-95 approach would give a non-conservative acceptance margin of 30.2% 
for the risk difference preserving 50% of the Humira effect. 
Calculation of a conservative equivalence margin
Preserve 70% of the lower confidence limit (lcl) 60.4% (obtained from the meta-analysis) of 
the historical effect over placebo. Equivalence margin = (1 – preserved proportion)*lcl, 
(1-0.7)*60.4% = 18%. 


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Table 7.7: 1
CHAMPION and REVEAL results
Humira versus 
Placebo
Treatment
Placebo
Events
Total
%
Events
Total
%
CHAMPION
86
108
79.6%
10
53
18.9%
REVEAL
578
814
71%
26
398
7%
The weighted mean response rate is assumed to be the true response rate of 72%.
This sample size is based on an assumed treatment difference in proportions of patients with 
PASI 75 at Week 16 of 0%, a standard proportion of 72% and an equivalence margin of 18%.
At a power of 85% the sample size would be 288. 
Table 7.7: 2 presents the sample size at different margins and different power.
Table 7.7: 2
Sample size according to different scenarios
Assumed true response rate 
(RR)
Margin
Confidence level 
(two-sided)
Power
Sample Size#
Equivalence
72%
15%
95%
75%
340
72%
15%
95%
80%
366
72%
15%
95%
85%
414
72%
15%
95%
90%
572
72%
18%
95%
75%
234
72%
18%
95%
80%
256
72%
18%
95%
85%
288
72%
18%
95%
90%
330
72%
20%
95%
75%
188
72%
20%
95%
80%
200
72%
20%
95%
85%
228
72%
20%
95%
90%
262
# Allocation ratio 1:1


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for GCP, relevant BI SOPs, the EU regulation 536/2014) and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP*.
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor with regard 
to publication of the results of this trial are described in the Investigator contract. 
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF.
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB / IEC and CA according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional 
patient-information form retained by the Investigator as part of the trial records. A signed 
copy of the informed consent and any additional patient information must be given to each 
patient or the patient’s legally accepted representative.”
The Investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. The patient must be given sufficient time to consider 
participation in the trial. The Investigator obtains written consent of the patient’s own free 
will with the informed consent form after confirming that the patient understands the contents. 
The Investigator must sign (or place a seal on) and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
RECORDS
8.3
Electronic Case Report Forms for individual patients will be provided by the sponsor. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the eCRF must be consistent with the source data, or the discrepancies must 
be explained. The investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For the eCRF, all data must be derived from source documents:
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of patients’ source documents to the sponsor, the investigator 
must ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, 
social security number) have properly been removed or redacted to ensure patient 
confidentiality.
If the patient is not compliant with the protocol, any corrective action, e.g., re-training must 
be documented in the patient file.


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8.3.2
Direct access to source data and documents
An adaptive approach to clinical trial monitoring will be utilised. The sponsor will perform a 
risk assessment of the trial to determine the extent and nature of monitoring required in order 
to ensure the reliability and robustness of the results. Regular review of risk reports will 
provide sponsor oversight during trial conduct and direct monitoring activities to the areas of 
greatest risk which have the most potential impact to subject safety and data quality.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results. 
The Clinical Research Associate (CRA) and auditor may review all CRFs and informed 
consents. The accuracy of the data will be verified by direct comparison with the source 
documents described in Section 8.3.1. The sponsor will also monitor compliance with the 
protocol and ICH GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
the national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
8.5
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the World Health 
Organization (WHO) GCP handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.


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8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with the 
Principles of GCP as outlined in 'Note For Guidance On Good Clinical Practice' 
(CPMP/ICH/13 5/95).

The BI-internal facilities storing and analyzing biological samples and data from clinical 
trial participants as well as the laboratories’ activities for clinical trials sponsored by BI 
are regularly audited. The analytical groups and the banking facilityare therefore assessed 
to be qualified for the storage and use of biological samples and data collected in clinical 
trials.

Samples and data are used only if an appropriate informed consent is available.
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrollment of the first patient in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of SUSARs occurring with the trial 
medication until 10 weeks after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / CA in each participating EU member state will be notified about the trial 
milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.


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The sponsor will submit to the EU database a summary of the final trial results within 1 year 
from the end of a clinical trial as a whole, regardless of the country of the last patient (EU or 
non-EU).


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
R05-2548
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple
practical measure for routine clinical use. Joint Ann Mtg of the British 
Association of Dermatologists and the Canadian Dermatology Association, 
Oxford, 6 - 10 Jul 1993 Clin Exp Dermatol 1994. 19:210-216.
R08-1089
Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis.
Nature 2007; 445(7130):866-873.
R11-1257
Nestle FO, Kaplan DH, Barker J. Mechanisms of disease: psoriasis. N Engl J 
Med 2009; 361(5):496-509.
R11-1259
Menter A, Griffiths CEM. Psoriasis 2: current and future management of 
psoriasis. Lancet 2007; 370:272-284.
R11-1501
Adalimumab (LU 200134), anti-tumor necrosis factor alpha (TNF-alpha IgG1 
monoclonal antibody) (Abbott Laboratories): Clinical pharmacology and 
biopharmaceutics review(s), application number:125057/0. 
Webpage:fda.gov/downloads/Drugs/DevelopmentApprovalProcess/ 
HowDrugsareDevelopedandApproved/ApprovalApplications/ 
TherapeuticBiologicApplications/ucm092770.pdf (access date: 
27 October 2011); Center for Drug Evaluation and Research, Center for 
Biologics Evaluation and Research (2002).
R11-1547
Smith RLI, Warren RB, Eyre S, Ho P, Ke X, Young HS, Griffiths CEM, 
Worthington J. Polymorphisms in the IL-12beta and IL-23R genes are 
associated with psoriasis of early onset in a UK cohort. J Invest Dermatol 
2008. 128:1325-1327.
R13-3515
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, Tsuji W, 
Stevens R, Fries J, Witter J, Johnson K, Lassere M, Brooks P. Standardizing 
assessment and reporting of adverse effects in rheumatology clinical trials II: 
the Rheumatology Common Toxicity Criteria v.2.0. J Rheumatol 2007. 
34(6):1401-1414.
R14-3562
Bushnell DM, Martin ML, McCarrier K, Gordon K, Chiou CF, Huang X, 
Ortmeier B, Kricorian G. Validation of the Psoriasis Symptom Inventory 
(PSI), a patient-reported outcome measure to assess psoriasis symptom 
severity. J Dermatol Treat 2013. 24(5):356-360.


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Revicki DA, Jin Y, Wilson HD, Chau D, Viswanathan HN. Reliability and 
validity of the psoriasis symptom inventory in patients with 
moderate-to-severe psoriasis. J Dermatol Treat 2014. 25(1):8-14.
R14-4849
Gordon K, Papp K, Poulin Y, Gu Y, Rozzo S, Sasso EH. Long-term efficacy 
and safety of adalimumab in patients with moderate to severe psoriasis treated 
continuously over 3 years: results from an open-label extension study for 
patients from REVEAL. J Am Acad Dermatol 2012. 66(2):241-251.
R14-4898
Saurat JH, Stingl G, Dubertret L, Papp K, Langley RG, Ortonne JP, Unnebrink 
K, Kaul M, Camez A, CHAMPION Study Investigators. Efficacy and safety 
results from the randomized controlled comparative study of adalimumab vs. 
methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J 
Dermatol 2008. 158(3):558-566.
R14-5159
Reich K, Puig L, Paul C, Kragballe K, Luger T, Lambert J, Chimenti S, 
Girolomoni G, Nicolas JF, Rizova E, Brunori M, Mistry S, Bergmans P, 
Barker J, TRANSIT Investigators. One-year safety and efficacy of 
ustekinumab and results of dose adjustment after switching from inadequate 
methotrexate treatment: the TRANSIT randomized trial in moderate-to-severe 
plaque psoriasis. Br J Dermatol 2014. 170(2):435-444.
R15-1219
Martin ML, McCarrier KP, Chiou CF, Gordon K, Kimball AB, Voorhees AS 
van, Gottlieb AB, Huang X, Globe D, Chau D, Viswanathan HN, Kricorian G. 
Early development and qualitative evidence of content validity for the 
Psoriasis Symptom Inventory (PSI), a patient-reported outcome measure of 
psoriasis symptom severity. J Dermatol Treat 2013. 24(4):255-260.
R15-1393
Davidovici BB, Sattar N, Joerg PC, Puig L, Emery P, Barker JN, Kerkhof P 
van de, Stahle M, Nestle FO, Girolomoni G, Krueger JG, Psoriasis Education 
and Learning Syllabus (PEARLS). Psoriasis and systemic inflammatory 
diseases: potential mechanistic links between skin disease and co-morbid 
conditions. J Invest Dermatol 2010. 130(7):1785-1796.
R15-3846
Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: a review of 
its history, issues, progress, and documentation. J Rheumatol 2003. 
30(1):167-178.
R15-3849
The Health Assessment Questionnaire (HAQ) and the improved HAQ 
(formerly called the PROMIS HAQ) (revised June 2009). 
Webpage:aramis.stanford.edu/downloads/HAQ%20Instructions%20(ARAMIS
)%206-30-09.pdf (access date: 15 July 2015) ; Stanford: Stanford University 
School of Medicine, Division of Immunology & Rheumatology 2009
 
 


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R15-5978
Humira® (adalimumab) injection, for subcutaneous use (AbbVie) (U.S. 
prescribing information, revised: 11/2015 website 
rxabbvie.com/pdf/humira.pdf.
R16-0235
Ma HL, Liang S, Li J, Napierata L, Brown T, Benoit S, Senices M, Gill D, 
Dunussi-Joannopoulos K, Collins M, Nickerson-Nutter C, Fouser LA, Young 
DA. IL-22 is required for Th17 cell-mediated pathology in a mouse model of 
psoriasis-like skin inflammation. J Clin Invest 2008; 118 (2):597-607.
R16-0358
Humira 40 mg/0.8 ml solution for injection for paediatric use, Humira 
40 mg/0.8 ml solution for injection in pre-filled syringe, Humira 40 mg/0.8 ml 
solution for injection in pre-filled syringe with needleguard, Humira 
40 mg/0.8 ml solution for injection in pre-filled pen, Humira 40 mg/0.4 ml 
solution for injection in pre-filled syringe, Humira 40 mg/0.4 ml solution for 
injection in pre-filled pen (AbbVie) (summary of product characteristics, 
manufacturer(s) of the biological active substance(s) and manufacturers 
responsible for batch release, conditions or restrictions regarding supply and 
use, other conditions and requirements of the marketing authorisation, 
conditions or restrictions with regard to the safe and effective use of the 
medicinal product, labelling and package leaflet, last updated: 28/01/2016).
webpage:ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/ human/000481/WC500050870.pdf (access date: 29 
January 2016) (2016)
R96-3541
Fredriksson T, Pettersson U. Severe psoriasis - oral therapy with a new 
retinoid. Dermatologica 1978; 157:238-244.
UNPUBLISHED REFERENCES
9.2
U13-1096-01
. Pharmacokinetics 
and safety of BI 695501 in healthy subjects: a randomized, open-label, 
single-dose, parallel arm, active-comparator clinical Phase I study. 1297.1, 24 
Jan 2013.
c01843589
ib-bi-695501-1297-p1
c02158186
Efficacy, safety and immunogenicity of BI 695501 versus adalimumab in 
patients with active rheumatoid arthritis: a randomized, double-blind, parallel 
arm, multiple dose, active comparator trial. 1297.2, 16 Aug 2013.
c03070713
. Pharmacokinetics 
and safety of BI 695501 in healthy subjects: a randomized, open-label, 
single-dose, parallel arm, active-comparator clinical Phase I study. 1297.1, 24 
Jan 2013.


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10.
APPENDICES
CLINICAL EVALUATION OF LIVER INJURY
10.1
10.1.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.3.6 (Protocol-specified 
AESIs), are to be further evaluated using the following procedures.
10.1.2
Procedures
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) - within 48 
to 72 hours. If it is confirmed that ALT and/or AST values ≥3 times ULN occur in 
conjunction with an elevation of total bilirubin of ≥2 times ULN, the laboratory parameters 
listed below (clinical chemistry, serology, hormones, haematology) must be determined and 
made available to the investigator and to BI as soon as possible.
In addition,

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the ‘DILI checklist’ provided in the ISF

obtain history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets according to the ‘DILI checklist’ provided in the ISF;

obtain a history of exposure to environmental chemical agents (consider home and 
work place exposure) according to the ‘DILI checklist’ provided in the ISF;
and report these via the CRF.
Clinical chemistry
Alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C 
(Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E 
(Anti-HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody 
(titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, 
Anti-mitochondrial antibody
Hormones, tumor marker
TSH


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Hematology
Thrombocytes, eosinophils

Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic 
pathology, e.g. bile duct stones or neoplasm.

Initiate close observation of subjects by repeat testing of ALT, AST, and total 
bilirubin (total and direct) at least weekly until the laboratory ALT and/or AST 
abnormalities stabilize or return to normal, then monitor further as specified in the 
CTP. Depending on further laboratory changes, additional parameters identified, e.g.,
by reflex testing will be followed up based on medical judgement and GCP.


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EFFICACY ASSESSMENTS
10.2
Score
Short description
Detailed description
0
clear
No signs of psoriasis 
Post-inflammatory hyperpigmentation may be present
1
almost clear
Normal to pink coloration
No thickening
No to minimal focal scaling
2
mild
Pink to light red coloration
Just detectable to mild thickening
Predominantly fine scaling
3
moderate
Dull to bright red coloration
Clearly distinguishable to moderate thickening 
Moderate scaling
4
severe
Bright to deep dark red coloration 
Severe thickening with hard edges 
Severe coarse scaling covering almost all or all lesions
Figure 10.2: 1 sPGA Rating Scale for Overall Psoriatic Disease
Figure 10.2: 2 Body Surface Area Involved in Psoriasis


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Figure 10.2: 3 Dermatology Life Quality Index


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Figure 10.2: 4 PASI


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MEDICATION BLINDING PROCEDURE FOR THIRD PARTY 
10.3
BLINDING
This is a double-blind trial, therefore patients, investigators, and trial personnel (except the 
trial personnel administering the trial medication at site) will remain blinded with regard to 
the randomized treatment assignments until after database lock. 
To prevent unblinding, a designated, person will receive the trial medication at site. In 
addition, a qualified unblinded designee will administer the trial medication, maintain records 
of the product’s delivery to the trial site, the inventory at the site, as well as will be 
responsible for preparation of unused 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 personal. 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. 
The unblinded trial personnel administering the trial medication will not be involved in any 
other trial assessments or procedures.
A description of the trial medication is provided in Table 4.1.1:1.
Patient blinding procedure
Trial medication will be administered by unblinded trial personnel and no self-administration 
will be allowed. 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 each site, a 
form with the name(s) of the staff members, blinded and unblinded, with their respective 
responsibilities will be filled in.


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(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
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

Contacts IXRS® to enter screen failures, screened 
patients, randomizations and obtain subsequent 
medication assignments 
Independent Joint Assessor:
CANNOT ADMINISTER THE MEDICATION

Remains blinded to the medication assignment 
during the whole trial

Joint assessment
Blinded Sub-Investigator or Study Coordinator/Study 
Nurse:
CANNOT ADMINISTER THE MEDICATION

Remains blinded to the medication assignment 
during the whole trial

Contacts IXRS to enter screen failures, screened 
patients, randomizations and obtain subsequent 
medication assignments 

Monitors patient status

Provides direct patient care if applicable

Works and communicates with blinded monitor
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

Reviews ELPRO Libero temperature monitoring 
device for shipment temperature excursions

Acknowledges trial medication receipt in IXRS

Registers the trial medication in IXRS

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 IXRS 
confirmation

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:
(Sub-Investigator or study nurse)
Back-up 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
Training
All professional personnel taking part in the clinical trial are trained and aware of the need to 
respect study blinding principles as foreseen by the protocol. Blinded and unblinded study 


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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 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.”
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08917790
3.0
clinical-trial-protocol
Efficacy, Safety, and Immunogenicity of BI 695501 versus Humira in Patients with
Moderate to Severe Chronic Plaque Psoriasis: A Randomized, Double-Blind,
Parallel-Arm, Multiple-Dose, Active Comparator Trial
Author-Clinical Monitor
26 Apr 2016 13:33 CEST
Author-Clinical Program 
26 Apr 2016 13:39 CEST
Approval-Therapeutic Area 
26 Apr 2016 14:18 CEST
Author-Clinical Pharmacokineticist
27 Apr 2016 14:54 CEST
Author-Trial Statistician
28 Apr 2016 07:47 CEST
Verification-Paper Signature
Completion
02 May 2016 11:08 CEST


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Document Number: 
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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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3.0

SAP_001.pdf: 
Statistical Analysis Plan 
PROTOCOL 1297.12 
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STATISTICAL ANALYSIS PLAN 
1297.12 
EFFICACY, SAFETY, AND IMMUNOGENICITY OF BI 695501 VERSUS HUMIRA® IN 
PATIENTS WITH MODERATE TO SEVERE CHRONIC PLAQUE PSORIASIS: A 
RANDOMIZED, DOUBLE-BLIND, PARALLEL-ARM, MULTIPLE-DOSE, ACTIVE 
COMPARATOR TRIAL 
AUTHOR: 
 
VERSION NUMBER AND DATE: V2.0, 31JAN2018 


Statistical Analysis Plan 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V2.0 (Dated 31JAN2018) for Protocol 1297.12. 
Name 
Signature 
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Position: 
Statistical Team lead 
Company: 
Boehrif!ger 
\Jdlhv Ingelhe1m 
PROTOCOL 1297.12 
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Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this trial. 
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Position: 
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Company: 
Approved By: 
Position: 
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Position: 
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ffi Boehringer 
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PROTOCOL 1297.12 
Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN REVIEWED BY 
Boehringer Ingelheim 
Team Role 
 
Trial Statistician 
 
Project Statistician 
 
Project Programmer 
 
Clinical Program Leader 
 
Clinical Program Leader 
 
Clinical Project Manager 
 
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ADA/nAb specialist 
 
Regulatory 
 
Regulatory 
 
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Pharmacovigilance, Risk Management Physician 
 
Team Role 
 
Senior Reviewer 
 
Biostatistician 
 
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OUTPUT TEMPLATES SIGNATURE PAGE 
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MODIFICATION HISTORY 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
0.9 
16DEC2016 
 
Not Applicable – First Version 
1.0 
06FEB2017 
 
Apply comments from client 
1.1 
28MAR2017 
 
Updated SDTM cut off document 
1.2 
07APR2017 
 
Updated 14.1 per client email 
1.3 
23AUG2017 
 and 
 
 
-Updated 
 per client comments 
-Updated windowing for EOT visits 
1.4 
26JAN2018 
 
Updated to match final dry run comments 
2.0 
31JAN2018 
 
Set to final version 2.0 for signatures 


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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ............................................................................................................ 1 
TABLE OF CONTENTS ............................................................................................................................. 6 
1.
Introduction .............................................................................................................................................. 11
2.
Trial Objectives .......................................................................................................................................... 11
2.1. 
Primary Objective ...................................................................................................................................... 11 
2.2. 
Secondary Objectives ................................................................................................................................ 11 
 
 
3.
Trial Design ................................................................................................................................................ 11
3.1. 
General Description ................................................................................................................................... 11 
3.2. 
Schedule of Events..................................................................................................................................... 12 
3.3. 
Changes to Analysis from Protocol ............................................................................................................ 13 
4.
Planned Analyses ....................................................................................................................................... 13
4.1. 
Primary Analysis ........................................................................................................................................ 14 
4.2. 
Final Analysis ............................................................................................................................................. 14 
5.
Analysis Sets .............................................................................................................................................. 14
5.1. 
All Subjects Enrolled Set [ENR] .................................................................................................................. 14 
5.2. 
All Subjects Randomized Set [RND] ........................................................................................................... 14 
5.3. 
Full Analysis Set [FAS] ................................................................................................................................ 15 
5.4. 
Per Protocol Analysis Set [PPS] .................................................................................................................. 15 
5.5. 
Safety Analysis Set [SAF] ........................................................................................................................... 16 


 
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6. 
General Considerations ............................................................................................................................. 17 
6.1. 
Reference Start Date and Study Day .......................................................................................................... 17 
6.2. 
Baseline ..................................................................................................................................................... 17 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 17 
6.4. 
Windowing Conventions ............................................................................................................................ 18 
6.5. 
Statistical Tests .......................................................................................................................................... 18 
6.6. 
Common Calculations ................................................................................................................................ 18 
6.7. 
Software Version ....................................................................................................................................... 18 
7. 
Statistical Considerations .......................................................................................................................... 19 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 19 
7.2. 
Multicenter Trial ........................................................................................................................................ 19 
7.3. 
Missing data .............................................................................................................................................. 19 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 19 
7.5. 
Examination of Subgroups ......................................................................................................................... 19 
7.5.1. Region ....................................................................................................................................................... 20 
7.5.2. Prior Use of Biological Agent ..................................................................................................................... 20 
8. 
Output Presentations ................................................................................................................................ 20 
9. 
Disposition and Withdrawals ..................................................................................................................... 20 
9.1. 
Important Protocol Deviations .................................................................................................................. 22 
10. 
Demographic and other Baseline Characteristics ....................................................................................... 22 
10.1. Derivations ................................................................................................................................................ 24 


 
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11. 
Surgical and Medical History ..................................................................................................................... 25 
12. 
Medications ............................................................................................................................................... 26 
13. 
Trial Medication Exposure ......................................................................................................................... 26 
13.1. Derivations ................................................................................................................................................ 27 
14. 
Trial Medication Compliance ..................................................................................................................... 27 
14.1. Derivations ................................................................................................................................................ 27 
15. 
Efficacy Outcomes ..................................................................................................................................... 28 
15.1. Primary Efficacy ......................................................................................................................................... 28 
15.1.1. Primary Efficacy Variable & Derivation ...................................................................................................... 28 
15.1.2. Missing Data Methods for Primary Efficacy Variable ................................................................................. 29 
15.1.3. Primary Analysis of Primary Efficacy Variable ............................................................................................ 32 
15.1.4. Sensitivity Analysis of Primary Efficacy Variable ........................................................................................ 35 
15.2. Secondary Efficacy ..................................................................................................................................... 35 
15.2.1. Secondary Efficacy Variables & Derivations ............................................................................................... 35 
15.2.2. Missing Data Methods for Secondary Efficacy Variable(s) ......................................................................... 35 
15.2.3. Analysis of Secondary Efficacy Variables .................................................................................................... 36 
 
 
 
 
 
16. 
Safety Outcomes ....................................................................................................................................... 38 
16.1. Adverse Events .......................................................................................................................................... 38 


 
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16.1.1. Adverse Event Specific Derivation ............................................................................................................. 38 
16.1.2. All TEAEs .................................................................................................................................................... 39 
16.1.3. TEAEs Leading to Discontinuation of Trial Medication ............................................................................... 40 
16.1.4. Serious Adverse Events .............................................................................................................................. 40 
16.1.5. Adverse Events Leading to Death .............................................................................................................. 40 
16.1.6. Other Safety Endpoints and Adverse Events Of Special Interest ................................................................ 40 
16.1.7. Aes Occuring After the Last Injection For Subjects Discontinued Due to Lack of Efficacy ........................... 43 
16.2. Deaths ....................................................................................................................................................... 43 
16.3. Laboratory Evaluations .............................................................................................................................. 43 
16.3.1. Laboratory Specific Derivations ................................................................................................................. 44 
16.3.2. Laboratory Reference Ranges and Abnormal Criteria ................................................................................ 45 
16.3.3. Other safety laboratory evaluations .......................................................................................................... 45 
16.4. ECG Evaluations ......................................................................................................................................... 45 
16.5. Vital Signs .................................................................................................................................................. 46 
16.6. Physical Examination ................................................................................................................................. 46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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19. 
References ................................................................................................................................................. 51 
APPENDIX 1. 
Programming Conventions for Outputs ...................................................................................... 52 
APPENDIX 2. 
Partial Date Conventions ............................................................................................................ 58 
APPENDIX 3. 
EMA SOC order for presentation of the AE in the tables. ............................................................ 62 
APPENDIX 4. 
Files Attached to SAP .................................................................................................................. 63 
APPENDIX 5. 
Laboratory Assessments ............................................................................................................. 64 
APPENDIX 6. 
SAS code for Difference in proportion CIs ................................................................................... 65 
 
 


 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy, safety, 
immunogenicity, and pharmacokinetics data for Protocol 1297.12. It describes the data to be summarized and 
analyzed, including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version 1.0, dated 26th of April 2016. 
2. TRIAL OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of this trial is to establish equivalence in efficacy between BI 695501 and US-licensed 
Humira at Week 16 in patients with active moderate to severe chronic plaque psoriasis. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of this trial are to compare the safety and efficacy profiles of BI 695501 and US-licensed 
Humira. Secondary efficacy endpoints are detailed in section 15.2 and safety endpoints are described in section 
16. 
 
 
 
 
 
3. TRIAL DESIGN 
3.1. 
GENERAL DESCRIPTION 
This is a multinational, randomized, double-blind, parallel-arm, multiple-dose, active comparator trial of BI 
695501 and US-licensed Humira. 
In total, approximately 300 patients with moderate to severe chronic plaque psoriasis are planned to be 
randomized in this trial. 


 
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Patients are included in the trial once they have signed the informed consent. Patients suitable after screening 
will be eligible to participate in the 24-week treatment period and will be randomized at a ratio of 1:1 in a 
blinded fashion to 1 of 2 treatment arms (BI 695501 or US-licensed Humira). 
After Week 16, only patients who achieve at least a 50% reduction in Psoriasis Area and Severity Index (PASI 50) 
response will continue the trial receiving their randomized treatment up to Week 24. Those patients not 
achieving at least PASI 50 (or who discontinue the trial early), will not be treated with the trial drugs, but only 
followed up for safety. 
All patients who receive at least 1 injection of BI 695501 will have a Safety Follow-up visit 10 weeks after the last 
dose of trial medication. 
Diagram of trial design 
 
3.2. 
SCHEDULE OF EVENTS 
Schedule of events can be found in Section “FLOW CHART” of the protocol. 


 
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3.3. 
CHANGES TO ANALYSIS FROM PROTOCOL 
• 
Full Analysis Set (FAS) definition was updated in this SAP to include subjects with one component 
variable post-baseline (and not systematically the full score available) 
• 
The randomization strata was not considered as a covariate in the primary endpoint analysis in the 
protocol. This has been updated in section 7.1 of this SAP. The reason for this change is that 
randomization strata should be included in the model to follow the ICH E9 guidelines. The same was 
done for the secondary efficacy endpoint analysis. 
• 
The item score of DLQI was defined as ranging “from 0 (not relevant) and 1 (not at all) to 3 (very 
much)”. This has been updated in section 10.1 of this SAP as “Every item score ranges from 0 (Not 
relevant/Not at all) to 3 (Very much)” to be consistent with DLQI scoring. 
• 
 
• 
The definition of drug induced liver injury was not correctly stated in the protocol. This has been 
updated in section 16.3.1 of this SAP. 
• 
The primary endpoint has been rephrased as: “The proportion of subjects with at least 75% 
reduction in Psoriasis Area and Severity Index (PASI 75) response at Week 16” instead of “The 
proportion of subjects with a 75% reduction in Psoriasis Area and Severity Index (PASI 75) response 
at Week 16” 
• 
 
4. PLANNED ANALYSES 
The following analyses will be performed for this trial: 
• 
Primary Analysis (after primary endpoint is available) 
• 
Final Analysis (after Database lock, based on all available data) 
This document will provide details for Primary Analysis and Final Analysis. 
The analyses described in this SAP will be performed by
Biostatistics following Sponsor Authorization of 
this Statistical Analysis Plan, Sponsor Authorization of Analysis Sets and Data Snapshot/Database Lock. 


 
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4.1. 
PRIMARY ANALYSIS  
The primary analysis will take place when the primary endpoint is available, i.e., after the last patient has 
completed the Week 16 visit. The corresponding calendar date will be referred to as the cut-off date (please 
refer to APPENDIX 4). 
At the time of primary analysis, all available data up to and including the cut-off date will be considered. The 
Week 16 visit date of the last patient will be used as cut-off date for this analysis (please refer to APPENDIX 4). Only 
cumulated results will be presented, i.e., patient level data will be excluded meaning that N, mean and SD will be 
displayed instead of usual summary statistics. Indeed, there may be a risk for unblinding when presenting individual 
data such as minimum or maximum values, quartiles together with the treatment groups. 
The 
 study team, including those responsible for creating the programs to produce the outputs for the 
Primary Analysis, will remain blinded. Once the programs have been produced by the 
 study team, these 
programs will be sent to an independent statistician from 
 
 who will apply the 
randomization schedule and remove those tables that contain unblinding information due to sparse data 
(remove from delivery those tables where for any treatment groups only one subject is displayed). After this 
step, the independent statistician 
 
 will provide Boehringer-Ingelheim with a set of outputs without 
patient level information. 
4.2. 
FINAL ANALYSIS  
A final analysis (including all endpoints) will be performed when all trial data are available, i.e., approx. 33 weeks 
after the last patient has been randomized. In this analysis, all analyses performed for the primary analysis will be 
repeated with the (partially) updated data, in particular with respect to safety data collected at Week 33 and 
efficacy endpoints collected at Week 33. The results of the final analysis will be summarized in a CTR. 
5. ANALYSIS SETS 
Agreement and authorization of subjects included/ excluded from each analysis set will be conducted prior to 
the unblinding for primary analysis (Week 16). 
5.1. 
ALL SUBJECTS ENROLLED SET [ENR] 
The all subjects enrolled (ENR) set will contain all subjects who provide signed informed consent for this trial. 
5.2. 
ALL SUBJECTS RANDOMIZED SET [RND] 
The all subjects randomized (RND) set will contain all subjects in the ENR set who were randomized to trial 


 
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medication. 
For analyses and displays based on RND, subjects will be classified according to randomized treatment.  
5.3. 
FULL ANALYSIS SET [FAS] 
The full analysis set (FAS) will contain all randomized patients who received at least 1 dose of trial medication, 
and have all efficacy measures relevant for the PASI 75, measured at baseline and at least once post-baseline 
(prior to or on Week 16). Post-baseline, at least one component variable should be available (not systematically 
the whole PASI score). 
For analyses and displays based on FAS, subjects will be classified according to randomized treatment.  
5.4. 
PER PROTOCOL ANALYSIS SET [PPS] 
The per-protocol analysis set (PPS) will contain all subjects in the FAS who did not experience any important 
protocol violations relevant for efficacy. Important protocol violations will be reviewed and approved prior to the 
Data Snapshot/Database Lock. However, additional unexpected protocol deviations may be added afterwards. 
The important protocol violations relevant for efficacy until week 16 inclusive may include but are not limited to: 
• 
Incorrect trial medication taken. Kit numbers which were actually used for the preparation of the 
trial drug will be recorded on the eCRF. If, on the patient level, at least one kit number used before 
Week 16 does not correspond to the initial randomized treatment group then this will be an 
important protocol violation. 
• 
Severe violation of treatment compliance prior to Week 16: medical team will review subjects with 
treatment compliance outside 80% and 120% (refer to section 14.1) and decide if the violation is 
severe. 
• 
Severe violation of inclusion/exclusion criteria 
o 
Exclusion criterion 2: Previous treatment with more than 1 biological agent, or adalimumab or 
adalimumab biosimilar. No prior biologic exposure within last 6 months of screening will be 
permitted 
o 
Exclusion criterion 6: Patients who must or wish to continue the intake of restricted medications 
(see CTP Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the 
trial. 
o 
Exclusion criterion 7: Currently enrolled in another investigational device or drug study, or less 
than 30 days since ending another investigational device or drug study(s), or receiving other 
investigational treatment(s). 


 
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o 
Exclusion criterion 10: Forms of psoriasis (e.g., pustular, erythrodermic and guttate) other than 
chronic plaque psoriasis. Drug-induced psoriasis (i.e., new onset or current exacerbation from 
e.g., beta-blockers or lithium). 
Severe violations related to inclusion/exclusion criteria will be defined considering the eCRF page displaying the 
inclusion and exclusion criteria as well as available data in the database at baseline. 
Subjects to be excluded from the PPS will be identified prior to the Data Snapshot/Database Lock. For criteria not 
assessable before unbinding (such as incorrect trial medication taken), the subjects will be identified after the 
Data Snapshot/Database Lock. 
For analyses and displays based on PPS, subjects will be classified according to randomized treatment.  
5.5. 
SAFETY ANALYSIS SET [SAF]  
The safety analysis set (SAF) will contain all subjects in the RND set who receive at least one dose of trial 
medication.  
If there is any doubt whether a subject was treated or not, they will be assumed treated for the purposes of 
analysis. 
For analyses and displays based on SAF: 
In case the subject was fully incorrectly treated, the subject will be classified according to treatment received 
In case the subject was partially incorrectly treated, the subject will be classified according to treatment 
randomized. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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6. GENERAL CONSIDERATIONS 
6.1. 
REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/ stop day of 
assessments and events. It will appear in every listing where an assessment date or event date appears. 
Reference start date is defined as the day of the first dose of trial medication, (Day 1 is the day of the first dose 
of trial medication), or for subjects randomized but not treated it is the day of randomization.  
• 
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1. 
 
• 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, Study Day, and any corresponding durations will 
appear partial or missing in the listings. 
6.2. 
BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to reference 
start date (including unscheduled assessments) except for the primary efficacy endpoint (refer to section 
15.1.2.2). In the case where the last non-missing measurement and the first dose of trial medication date 
coincide, that measurement will be considered as baseline. 
6.3. 
RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. In the case of a retest, an 
unscheduled assessment will be created. For laboratory assessments as described in APPENDIX 5, the latest 
available measurement within 2 days after the planned assessment will be used for by-visit summaries. Unless 
assigned to a planned visit number, unscheduled measurements will not be included in by-visit summaries 
except for DILIs (refer to section 16.3). 
Subjects who are terminated from the study early will have their End of Treatment (EoT) visit on a date which 
may or may not coincide with the window designated for one of the 8 regular planned visits.   
Remapping of EOT visit assessment data to a regular scheduled visit will be performed only if the EOT visit 


 
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assessment was performed during the window for a regular scheduled visit and if the assessment value is non-
missing for each regular planned visit between the last regular planned visit for which it was non-missing and the 
date of the EOT visit. Otherwise, the data will be classified as Early Termination and identified as such in the 
relevant listings. 
If a subject’s EOT visit for an assessment was performed in the window designated for a regular planned visit X and 
the last time point prior to visit X at which the assessment was to have been performed, according to the study 
flow chart, is the last regular planned visit for which it was non-missing then the assessment’s value will be mapped 
to visit X, if it is an assessment that is scheduled to be performed at visit X.   
If a subject’s EOT visit for an assessment was performed  at some time point after the window designated for a 
regular planned visit X and before the window designated for a regular planned visit X + 1 and the last time point 
prior to visit X + 1 at which the assessment was to have been performed, according to the study flow chart is the 
last regular planned visit for which it was non-missing then the assessment’s value will be mapped to visit X + 1, if it 
is an assessment that is scheduled to be performed at visit X + 1.  
Listings will include scheduled, unscheduled, and retest data as collected in the eCRF database. 
6.4. 
WINDOWING CONVENTIONS  
Unless otherwise specified, visit data as recorded in the database will be used for the analysis. No visit 
windowing recalculation will be performed for this trial. 
6.5. 
STATISTICAL TESTS 
The default significance level will be (5%); confidence intervals will be 95% and all tests will be two-sided, unless 
otherwise specified in the description of the analyses. 
6.6. 
COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
• 
Test Value at Visit X – Baseline Value 
6.7. 
SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher.  


 
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7. STATISTICAL CONSIDERATIONS 
7.1. 
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN 
ANALYSES 
The following covariates and factors are used in the primary and secondary efficacy analyses. For details of their 
inclusion in the models, see the specific analysis section. 
• 
Treatment (BI 695501 or US-sourced Humira) 
• 
Baseline PASI 
• 
Prior exposure to a biologic agent (Yes / No). 
7.2. 
MULTICENTER TRIAL 
This trial will be conducted by multiple investigators at multiple centers internationally, approximately 50 clinical 
sites across approximately 10 countries. Randomization to treatment arms is stratified by prior exposure to 
biological agent. No stratification by site was planned because of the small number of subjects to be randomized 
per site. 
7.3. 
MISSING DATA 
Missing safety data will not be imputed, unless otherwise specified in section 16. 
Missing efficacy data will be handled as described in section 15. 
Calculation for a partial date is described in APPENDIX 2. 
7.4. 
MULTIPLE COMPARISONS/ MULTIPLICITY 
No multiplicity consideration is required in this trial. 
7.5. 
EXAMINATION OF SUBGROUPS 
Subgroup analyses will be performed if the smallest group includes at least 10% of the randomized subjects. 


 
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7.5.1. REGION 
A further subgroup analysis will be performed to evaluate the impact of the region on the primary efficacy 
endpoint. For this purpose, region will be defined as: 
USA 
Non-USA (Other countries) 
7.5.2. PRIOR USE OF BIOLOGICAL AGENT 
A further subgroup analysis will be performed to evaluate the impact of the stratification factor on the primary 
efficacy endpoint. For this purpose, the following stratification factor will be considered: prior use of biological 
agent Yes/No. 
8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this trial and therefore the format and 
content of the summary tables, figures, and listings to be provided by 
 Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this trial. 
The counts of the analysis sets will be presented: 
• 
All Subject Enrolled Set (ENR) 
• 
All Subjects Randomized Set (RND) 
• 
Full Analysis set (FAS) 
• 
Per Protocol Analysis Set (PPS) 
• 
Safety Analysis Set (SAF) 
• 
 
The reasons for exclusion from the analysis sets will be listed. 
The following subject disposition and withdrawals will be presented for the ENR set: 


 
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• 
Screened 
• 
Rescreened 
• 
Screen failure (defined as withdrawn from trial prior to randomization). The information will be 
displayed only once for subjects being rescreened and will correspond to the last information 
available in the eCRF. 
• 
Primary reason for non-inclusion. The information will be displayed only once for subjects being 
rescreened and will correspond to the last information available in the eCRF. 
• 
Randomized 
• 
Randomized but not treated 
• 
Treated 
• 
Subjects with PASI 50 at Day 113 (Week 16) 
• 
Subjects treated after Day 113 (Week 16) 
• 
Completed treatment at Day 169 (Week 24) 
• 
Completed the trial 
• 
Discontinued from treatment strictly before Day 113 (Week 16), primary reason for premature 
discontinuation from treatment before Day 113 (Week 16) 
• 
Discontinued from treatment, primary reason for premature discontinuation from treatment 
• 
Discontinued from trial, primary reason for premature discontinuation from trial 
The following subject disposition and withdrawals will be presented for the ENR set per site: 
• 
Screened 
• 
Rescreened 
• 
Screen failure (defined as withdrawn from trial prior to randomization). The information will be 
displayed only once for subjects being rescreened and will correspond to the last information 
available in the eCRF. 
• 
Randomized 


 
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• 
Randomized but not treated 
• 
Treated 
• 
Subjects with PASI 50 at Day 113 (Week 16) 
• 
Subjects treated after Day 113 (Week 16) 
• 
Completed treatment at Day 169 (Week 24) 
• 
Completed the trial 
9.1. 
IMPORTANT PROTOCOL DEVIATIONS 
Protocol violations (as defined in section 5.4), as well as inclusion and exclusion criteria violators will be 
tabulated and listed for the FAS. 
Separately, important protocol violations (not systematically excluding from PPS) are defined as: 
• 
entering the study even though the subject did not satisfy the entry criteria;  
• 
developing withdrawal criteria during the study but the subject did not withdraw;  
• 
receiving the wrong treatment or incorrect dose;  
• 
receiving a prohibited concomitant treatment. 
Important protocol violations confirmed by a clinical and medical review as recorded in the protocol deviations 
log will be tabulated and listed for the FAS. These violations are not necessarily excluding subjects from the PPS 
(for exclusions from PPS refer to section 5.4). 
The full protocol deviations log will be attached to the clinical study report. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic characteristics will be reported at Primary Analysis for the FAS, PPS, SAF, and at Final 
Analysis for RND, FAS, PPS, and SAF: 
• 
Age (years) at Informed Consent 
• 
Category of age groups at Informed Consent  


 
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o 
Adolescent (12-17 years): 12 <= AGE < 18 – no patient expected 
o 
Adults (18-64 years): 18<= AGE < 65 
o 
Adults (65-84 years): 65<= AGE < 85 
o 
Adults (Over 85 years): 85<= AGE – no patient expected 
• 
First age category at Informed Consent 
o 
AGE < 65 years 
o 
AGE >= 65 years 
• 
Second age category at Informed Consent 
o 
AGE < 65 years 
o 
65 <= AGE < 76 
o 
76 <= AGE <85 
o 
AGE >= 85 
• 
Gender (Male/Female) 
• 
Childbearing potential (Post-Menopausal / Surgically Sterile / Childbearing Potential (includes tubal 
ligation)) 
• 
Race (American Indian or Alaska Native / Asian / Black or African American / Native Hawaiian or 
Other Pacific Islander / White / Other) 
• 
Ethnicity (Hispanic or Latino / Not Hispanic or Latino / Not reported/ Unknown) 
• 
Country 
• 
Weight at baseline (kg) 
• 
Height at baseline (cm) 
• 
BMI at baseline (kg/m2) 
The randomization stratification categories (Prior exposure to a biological agent Yes/No) based on eCRF data, will 
be presented at Primary and Final Analyses for the FAS. 
The following baseline disease characteristics will be presented at Primary Analysis for the FAS, SAF, and at Final  
Analysis for FAS, PPS, and SAF: 
• 
PASI score at baseline as collected in the eCRF 
• 
Static Physician’s Global Assessment of psoriasis (sPGA) score at baseline 


 
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• 
Dermatology Life Quality Index (DLQI) score at baseline 
• 
 
Other baseline characteristics will be presented on FAS, and SAF: 
• 
Infection screen (for HBsAg, HCV and HIV test) 
• 
Chest X-Ray result 
• 
Tuberculosis (TB) test 
• 
 
 
 
Accountability for missing data will be displayed in case of any missing entries. 
10.1. 
DERIVATIONS 
• 
Conversion factors: 
o 
1 lbs=0.453592 kg 
o 
1 in=2.54 cm 
• 
BMI (kg/ m2) = weight (kg)/ height (m2) 
• 
DLQI 
The questionnaire will be analysed under 6 headings as follows: 
Domain 
Question Number 
Score 
Symptoms and feelings 
Questions 1 and 2 
Score maximum 6 
Daily activities 
Questions 3 and 4 
Score maximum 6 
Leisure 
Questions 5 and 6 
Score maximum 6 
Work and school 
Question 7 
Score maximum 3 
Personal relationships 
Questions 8 and 9 
Score maximum 6 


 
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Treatment 
Question 10 
Score maximum 3 
Every item score ranges from 0 (Not relevant/Not at all) to 3 (Very much). The domain score is obtained by 
summing the score of the corresponding items. 
DLQI total score is calculated by summing the scores of each question resulting in a range of 0 to 30 where 0-1 = 
no effect on subject’s life, 2-5 = small effect, 6-10 = moderate effect, 11-20 = very large effect, and 21-30 = 
extremely large effect on subject’s life. The higher the score, the more the quality of life is impaired. If the 
answer to 1 question in a domain is missing, that domain is treated as missing and the score calculated by 
summing the score of the 5 non-missing domains. If 2 or more questions are left unanswered (missing), DLQI 
total score is treated as missing. 
• 
 
 
 
 
 
11. SURGICAL AND MEDICAL HISTORY 
Surgical and Medical History information will be presented at Primary Analysis for the SAF, at Final Analysis fo  
the FAS, PPS and SAF. 
Surgical and Medical History will be coded using MedDRA version 19.1 or higher. 
The system organ classes will be sorted by internationally agreed EMA SOC order (refer to APPENDIX 3), 
preferred terms will be sorted by decreasing frequencies (within system organ class). 
Data captured on the “Medical History and Previous surgical procedures” page of the eCRF will be assigned to prior 
or concomitant. 
See APPENDIX 2 for handling of partial dates for medical history, surgeries and procedures; if it is not possible to 
define a history, surgery or procedure as prior, concomitant, or post-treatment, it will be classified by the worst 
case; i.e., concomitant. 
• 
Prior medical history, surgeries, and procedures are defined as those conditions or procedures 
which stop prior to or at Screening.  
• 
Concomitant medical history, surgeries, and procedures  are defined as those conditions or 
procedure which: 
• 
started prior to or at Screening and are ongoing or active at the date of Screening 
or 
• 
started after Screening during the treatment period. 


 
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For rescreened patient the latest Screening information will be considered. 
Prior and concomitant surgical and medical history will be presented by SOC (System Organ Class) and PT 
(Preferred Term) in two separate tables. 
12. MEDICATIONS 
Medications will be presented at Primary and Final Analyses for the FAS, PPS, and SAF. They will be coded using 
the WHO Drug Dictionary version SEP2016 or higher. 
No ATC class coding will be performed. The medical terms will be summarized by WHO-DD Preferred Name. The 
WHO-DD Preferred Name will be sorted by decreasing frequencies. 
See APPENDIX 2 for handling of partial dates for medications, in the case where it is not possible to define a 
medication as prior, concomitant, or post treatment, the medication will be classified by the worst case; i.e., 
concomitant.  
• 
‘Prior’ medications are medications which started and stopped prior to the first dose of trial 
medication.  
• 
‘Concomitant’ medications are medications which:  
• 
started prior to, on, or after the first dose of trial medication and started no later than end of trial medication,  
• 
AND ended on or after the date of first dose of trial medication or were ongoing at the end of the trial. 
• 
‘Post’ medications are medications which started after the last dose of trial medication. 
In addition, concomitant medications will be allocated to Period 1 as follows: 
• 
Period 1: Concomitant medication with start date prior to Week 16 visit date, and [end date after 
randomization or ongoing at the end of the trial]. 
13. TRIAL MEDICATION EXPOSURE 
Exposure to trial medication will be presented at Primary Analysis for the SAF, at Final Analysis for the FAS, PPS 
and SAF. 
The proportion of subjects treated at each planned visit (administration on Day 1, Day 8, and every other week 
until Day 162) and per treatment group will be presented.  
Descriptive statistics for the number of injections from Day 1 up to Week 16 (included), from Week 16 (excluded) 
up to Week 24 and overall per subjects will be presented. 
Number of subjects per duration of exposure categories, patient time (years) per duration of exposure 
categories, and descriptive statistics for duration of exposure will be presented. 


 
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Exposure categories will be the following cumulative categories: >= 1 day, >= 2 weeks, >= 4 weeks, >=12 weeks, 
>=16 weeks, and >=24 weeks. 
13.1. 
DERIVATIONS 
The date of first and last trial medication administration will be taken from the eCRF page “Trial Medication 
Injection”. 
Duration of exposure (days) = (date of last injection - date of first injection + 1). 
Duration of exposure (weeks) = Duration of exposure (days) / 7. 
Patient Year Exposure (year) = cumulative duration of exposure in days per subjects / 365.25. 
14. TRIAL MEDICATION COMPLIANCE  
Compliance to trial medication will be presented at Primary Analysis for the SAF, at Final Analysis for the FAS, PPS 
and SAF. 
14.1. 
DERIVATIONS 
Compliance with trial medication will be based on the eCRF page “Trial Medication Injection”. An administered 
injection is considered when the question “Was full dose given” is answered “Yes”. 
Compliance will be based on the comparison of actual administered injections and the planned usage. 
Compliance will include visits until treatment discontinuation. 
• 
“Per visit” compliance will be calculated as follows and will correspond to the observed compliance 
between visit N and N-1: 
Compliance (%) = (Number of administered injections at visit X)*100/Planned number of injections at visit 
X 
Planned usage is detailed below. 
• 
“Overall” compliance will be calculated as follows: 
Compliance (%) = (Number of administered injections)*100/Planned number of injections 
Where 
Planned usage 
Visit N 
1 
2 
3 
4 
5 
6 
7 
8 
9 


 
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Number of 
injections 
between visit N 
and N-1 
- 
2 
1 
1 
2 
2 
2 
2 
2 
Planned 
cumulative 
number of 
injections 
0 
2 
3 
4 
6 
8 
10 
12 
14 
 
• 
“Week 16” compliance will be calculated considering the injections until Week 16 (visit 7) (included). 
15. EFFICACY OUTCOMES  
15.1. 
PRIMARY EFFICACY 
15.1.1. 
PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy endpoint is: 
• 
The proportion of subjects with at least 75% reduction in Psoriasis Area and Severity Index (PASI 75) 
response at Week 16 
PASI reduction at Week 16 is assessed as the decrease relative to baseline measurement and expressed as a 
percentage: 
• 
Reduction (%) = [100*(PASI at Baseline - PASI at Week 16)/PASI at Baseline] 
In case of baseline value equal to 0 and non-missing post-baseline value recorded, then the change is set to 0% 
for the corresponding visit (no reduction). 
Subjects with a reduction greater or equal to 75% are responders. Other subjects are considered as non-
responders. 


 
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15.1.2. 
MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE 
15.1.2.1. Missing Data Methods for Primary Analysis: Non-Responder Imputation and Multiple 
Imputation 
For the primary analysis, missing PASI 75 data will be imputed using a combination of non-responder imputation 
(NRI) and multiple imputation (MI) methods. 
Unscheduled visits are in general not included in the analysis in this approach. However if an unscheduled visit 
was performed within a visit window. The visit closest to the planned visit date will be used for the analysis. 
The following table details exactly where the NRI / MI imputation method will be applied for the primary 
analysis. 
 
Table 1: Application of NRI / MI for the primary analysis on the FAS  
 
prior to/on Week 16 
Primary analysis (FAS) 
Discontinued treatment#  
Did NOT discontinue treatment 
PASI 75 computable using observed data at Week  16 
NRI 
Observed 
PASI 75 NOT computable using observed data at 
Week  16 
NRI applied 
MI applied 
 
# lost to follow-up (according to eCRF record for “End of Treatment” or “Trial Completion”) is also included here, or patients who took a therapy 
that may significantly impact efficacy assessment prior to this time-point. 
 
The following steps will be followed: 
15.1.2.2. Multiple Imputation 
STEP 1: 
1. Creation of monotone missing data structure: 
Intermediate (non-monotone) missing data will be multiple imputed using the Markov Chain Monte Carlo 
(MCMC) method and assuming MAR and multivariate Normality. The SAS procedure PROC MI with the MCMC 
option will be used. 
The number of burn-in iterations has been identified based on approximately 90% of subject data up to Week 16 
and fixed to 200. 
This step will be performed on the longitudinal continuous PASI score (between Week 0 and Week 16), and SAS 
output for missing data pattern will be provided. 
Baseline value will be imputed only if both Screening and Day 1 values are missing. Otherwise, the last available 
value will be considered as baseline value. 
2. The datasets, now with monotone missing data, will be imputed further using sequential regression, with the 
following model for each visit: 


 
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PASI = Treatment + Prior exposure to a biological agent + <Previous baseline and Post-baseline 
data for the score>. 
That is, if the screening visit is Visit 1 and PASI score S at Visit v is denoted Sv, then for example the model 
to impute PASI score S for Visit 4 will include observed S1 and S2; the model for Visit 5 will include 
observed S1, S2 and S4.  
This model includes fixed, categorical effects of: 
o 
Treatment (BI 695501 versus US-sourced Humira) 
o 
Prior exposure to a biologic agent (Yes versus No) 
Note for 1 and 2: The seed 1000 will be used throughout. If a second seed is required, 1001 will be used, and so on 
as necessary. 
The PASI 75 will then be calculated for each of the multiple imputed data sets. 
15.1.2.3. Non Responder Imputation 
STEP 2: 
The imputed PASI 75 will be set to non-responder at Week 16 if the subject: 
• 
discontinue treatment prior to Week 16 
or 
• 
is lost-to-follow-up (according to eCRF record for “End of Treatment” or “Trial Completion”)  prior to 
Week 16 
or 
• 
has any severe violation related to any therapy that may significantly impact efficacy assessment 
prior to Week 16  
Severe violation related to any therapy (according to CTP Table 4.2.2.1: 1) that may significantly impact efficacy 
assessment will be assessed by: 
• 
providing to the trial medical advisor 
• 
a list of medication codes (WHO Drug Dictionary version September 2016 or higher) presented in CTP Table 
4.2.2.1: 1 and taken by at least one subject during trial conduct. 
• 
full individual concomitant medication information including dose, frequency and Study day at start of 
medication.  


 
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• 
Trial medical advisor will then identify the medications and start date of severe violation which may 
impact efficacy assessment 
15.1.2.4. Missing Data Methods for Sensitivity Analysis: Non Responder Imputation and Last 
Observed Carried Forward  
For the sensitivity analysis, missing PASI 75 data will be imputed using a combination of non-responder 
imputation and Last Observed Carried Forward (LOCF). 
Only the data up to Week 16, inclusive, will be considered. 
The following table details exactly where the NRI / LOCF imputation method will be applied for the sensitivity 
analysis. 
Table 1: Application of LOCF / NRI for the primary analysis on the FAS  
 
prior to/on Week 16 
Primary analysis (FAS) 
Discontinued treatment#  
Did NOT discontinue treatment 
PASI 75 computable using observed data at Week 16 
NRI 
Observed 
PASI 75 NOT computable using observed data at Week 
16 
NRI applied 
LOCF applied 
 
# lost to follow-up (according to eCRF record for “End of Treatment” or “Trial Completion”) is also included here, or patients who took a therapy 
that may significantly impact efficacy assessment prior to this time-point.  
 
The following steps will be followed: 
a. 
Last Observed Carried Forward 
STEP 1: 
Missing PASI score will be imputed using LOCF method and PASI 75 will be calculated based on the imputed scores. 
Last observation will be carried forward as many times as needed. 
b. 
Non Responder Imputation 
STEP 2: 
The imputed PASI 75 will be set to non-responder at Week 16 if the subject: 
• 
discontinues treatment prior to Week 16 
• 
are lost-to-follow-up (according to eCRF record for “End of Treatment” or “Trial Completion”)  prior 
to Week 16 
• 
have any severe violation related to any therapy that may significantly impact efficacy assessment 
prior to Week 16  
Severe violation related to any therapy (according to CTP Table 4.2.2.1: 1) that may significantly impact efficacy 


 
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assessment will be assessed by: 
• 
providing to the trial medical advisor 
• 
a list of medication codes (WHO Drug Dictionary version September 2016 or higher) presented in CTP Table 
4.2.2.1: 1 and taken by at least one subject during trial conduct. 
• 
full individual concomitant medication information including dose, frequency, and Study day at start of 
medication.  
• 
Trial medical advisor will then identify the medications and start date of severe violation which may 
impact efficacy assessment 
15.1.3. 
 PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The primary efficacy analysis will be performed for the FAS. 
The primary objective of this trial is to test the hypothesis that BI 695501 and US-sourced Humira are equivalent. 
The test for equivalence will be performed with respect to BI 695501 versus US-sourced Humira. 
The hypotheses for the equivalence test can be written as follows: 
• 
H0: Difference in PASI 75 response rates at Week 16 (BI 695501 minus US-sourced Humira) is less 
than -18.0% or more than 18.0%  
• 
H1: Difference in PASI 75 response rates at Week 16 (BI 695501 minus US-sourced Humira) is within 
[-18.0%, 18.0%] 
To conclude equivalence, the two-sided 95% CI of the difference in PASI 75 response rate (BI 695501 – Humira) 
rounded to 1 decimal place has to be fully within the equivalence limits of ± 18.0%. 
The primary analysis of the difference in PASI 75 response rates at Week 16 will be based on logistic regression 
with subsequent transformation of the estimated parameters to the difference in proportions. 
The estimates from the logistic regression are on the logit scale, and the difference in proportions will be 
calculated as the difference between the predicted probabilities in the treatment groups on the original scale, 
with the variance calculated using the cumulative distribution function method of Reeve (Reeve 2016). 
The statistical model can be described as follows: 
(M1)  
Logit (response to treatment at Week 16) = Treatment + Baseline PASI + Prior exposure to a biologic agent  
                                                                               + random error 
This model includes fixed, categorical effects of: 
• 
Treatment (BI 695501 versus US-sourced Humira) 


 
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• 
Prior exposure to a biologic agent (Yes versus No) 
and continuous effect of: 
• 
Baseline PASI 
The random error is assumed to be binomially distributed. 
The analysis will consist of the following four steps:  
STEP 1: Starting from the incomplete dataset, data imputation method are applied (described in section 15.1.2) 
to generate 1000 completed datasets. 
STEP 2: Calculation of difference in proportion based on adjusted PASI 75 responders 
The adjusted proportions of subjects with PASI 75 response in each groups at Week 16 are estimated from the 
logistics regressions on the logit scale, on each of the 1000 completed datasets. 
The difference in proportions is calculated as the difference between the probabilities predicted by the model for 
both treatment groups on the original scale at Week 16. 
STEP 3: Calculation of confidence intervals based on cumulative distribution function method of Reeve 
The risk-difference confidence intervals are calculated on each completed datasets using the risk differences 
calculated in STEP 2) and the cumulative distribution function method of Reeve (Reeve 2016) with 1,000,000 
simulations. 
STEP 4: Computation of the final confidence interval 
The estimated risk differences from STEP 2, and estimated standard errors back calculated using STEP 3 
confidence intervals are combined using Rubin’s Rules into the final confidence interval. 
15.1.3.1. Calculation of difference in proportion (STEP 2 details) 
The Week 16 endpoint will be analyzed using (M1) model. 
The following SAS code will be used: 
proc genmod data=data_PASI75_week_16 descend; 
class PASI75(ref="N") TRTP(ref="HUMIRA") EXPOS_BIO(ref=”N”) / 
param=GLM; 
model PASI75=TRTP BASELINE_PASI EXPOS_BIO/ dist=binomial  link=logit; 
 
lsmeans TRT / ilink OBSMARGINS diff=all; 
run; 
 
The population adjusted natural scaled proportion at Week 16 are the estimates produced by the LSMEANS 
statement. 


 
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15.1.3.2. Calculation of confidence interval (STEP 3 details) 
The difference in proportion at Week 16 is produced in STEP 1. 
The Week 16 confidence interval for the estimated difference in proportion are produced using the cumulative 
distribution function method of Reeve (Reeve 2016).  
The SAS code to implement the method is provided in APPENDIX 6 and required as input: 
1. Variance (g) is directly provided by SAS PROC GENMOD Empirical Standard Error Estimates. 
2. 𝐶𝐶𝐶𝐶𝐶𝐶൫𝑏𝑏𝑖𝑖, 𝑏𝑏𝑗𝑗൯ 𝑎𝑎𝑎𝑎𝑎𝑎 𝐶𝐶𝐶𝐶𝐶𝐶(γ, 𝑏𝑏𝑖𝑖)  ∀𝑖𝑖, 𝑗𝑗∈[0; 𝑘𝑘]  are directly provided by SAS PROC GENMOD Covariance Matrix 
(Empirical). 
3. Variance (z) will be calculated using the formula: 
𝑉𝑉𝑉𝑉𝑉𝑉(𝑧𝑧) = 𝑉𝑉𝑉𝑉𝑉𝑉ቆ
*
*
1
1
0
k
kx
b
x
b
b
+
+
+

ቇ= ෍𝑥𝑥𝑖𝑖
∗
𝑘𝑘
𝑖𝑖,𝑗𝑗=0
𝑥𝑥𝑗𝑗
∗𝐶𝐶𝐶𝐶𝐶𝐶൫𝑏𝑏𝑖𝑖, 𝑏𝑏𝑗𝑗൯  𝑤𝑤ℎ𝑒𝑒𝑒𝑒𝑒𝑒 𝑥𝑥0
∗= 1 
4. Covariance (g,z) will be calculated using the formula: 
Cov(g, z) = Cov ቆγ,
*
*
1
1
0
k
kx
b
x
b
b
+
+
+

ቇ= ෍𝑥𝑥𝑖𝑖
∗𝐶𝐶𝐶𝐶𝐶𝐶(γ, 𝑏𝑏𝑖𝑖)
𝑘𝑘
𝑖𝑖=0
 
Then VarTheta is equal to ൬𝑉𝑉𝑉𝑉𝑉𝑉(𝑔𝑔)
𝐶𝐶𝐶𝐶𝐶𝐶(𝑔𝑔, 𝑧𝑧)
𝐶𝐶𝐶𝐶𝐶𝐶(𝑔𝑔, 𝑧𝑧)
𝑉𝑉𝑉𝑉𝑉𝑉(𝑧𝑧) ൰ 
15.1.3.3. Computation of the final confidence interval with missing data method (NRI+MI) (STEP 4 
details) 
STEPS 1 and 2 are repeated on each imputed dataset produced by the multiple imputation method (fixed to 
1000 datasets). 
Estimated risk difference (RDestimated) per imputed datasets is calculated using STEP 1. 
Using Lower and Upper bounds calculated with Reeve’s method per imputed datasets in STEP 2, and assuming 
that risk difference is normally distributed, the estimated standard error (SEestimated) is calculated as: 
SElow= (RDestimated – Lower Bound) / (zα/2) 
SEup= (Upper bound - RDestimated) / (zα/2) 
Where zα/2=1.96 for 95% CI bounds 
SEestimated = mean (SEup, SElow). 
The couple (RDestimated, SEestimated) per imputed dataset is then combine using Rubin’s Rules to produce the final 
confidence interval. 
The following SAS code will be used to combine the results: 


 
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proc mianalyze data=data_RD_SE_per_MI_dataset; 
 
modeleffects RD_ESTIMATE; 
 
stderr RD_SE; 
run; 
 
15.1.4. 
SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
As sensitivity analysis, the primary endpoint will also be analyzed on the PPS with the combination of NRI and MI 
methods as the missing data method (described in section 15.1.2.4) using M1 as for the primary analysis.  
15.2. 
SECONDARY EFFICACY 
15.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
15.2.1.1. PASI 75 
The proportion of patients with a PASI 75 response will be assessed at Week 24. 
The derivation of PASI 75 is detailed in section 15.1.1. 
15.2.1.2. Improvement in PASI 
The mean percentage improvement in PASI at Week 16 will be assessed. 
15.2.1.3. sPGA 
The proportion of patients with a sPGA ≤ 1 (clear or almost clear) at Week 16 will be assessed. 
15.2.1.4. DLQI 
The proportion of patients achieving a DLQI of 0 or 1 at Week 16 will be assessed. 
15.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
Missing PASI 75 at Week 24 as well as missing sPGA and DLQI at Week 16 will be imputed using the combination 
of NRI and LOCF methods as missing data method considering NRI at Week 24 or Week 16 according to the 
variable considered (see Section 15.1.2.4). 


 
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15.2.3. 
ANALYSIS OF SECONDARY EFFICACY VARIABLES 
All secondary analyses will be based on FAS. 
15.2.3.1. PASI 75, sPGA and DLQI analysis 
The risk difference will be estimated using the method of Reeve with a 95% significance level (see Section 
15.1.3). 
15.2.3.2. Improvement in PASI 
For the percentage improvement from baseline in PASI, analysis of covariance (ANCOVA) will be used, comparing 
the mean percentage improvement from Baseline of PASI between BI 695501 versus US-licensed Humira at 
Week  16. The estimate of the difference will be computed with its 95% CI. 
ANCOVA will be performed based on the following model: 
(M2)  
PASI percentage improvement from baseline at Week 16 = Treatment + Baseline PASI + Prior exposure 
to a biologic agent + random error 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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16. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF for overall and Period 1 outputs.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise 
specified with the relevant section. 
Safety will be assessed as a secondary objective in this trial. 
The safety endpoint is defined as the proportion of subjects with drug-related AEs. This safety endpoint is 
considered a secondary endpoint in this trial. 
Other safety endpoints are: 
• 
Proportion of patients with AEs, SAEs, and AESIs 
16.1. 
ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA central coding dictionary, Version 19.1 or higher. The system 
organ classes will be sorted by internationally agreed EMA SOC order (refer to APPENDIX 3); preferred terms will 
be sorted by decreasing frequencies (within system organ class). 
A summary of the number of subjects and percentages within each of the categories described in the sub-section 
below will be provided.  
In case of worsening in severity, a new entry is created with start date equal to start of worsening. 
Listings will include Treatment-Emergent Adverse Events (TEAEs) and Non-TEAEs. 
16.1.1. 
ADVERSE EVENT SPECIFIC DERIVATION 
16.1.1.1. Treatment Emergent Adverse Event 
Treatment-Emergent Adverse Events (TEAEs) are defined as AEs that started or worsened on or after the first 
dose of trial medication and prior to the last date of trial medication + 10 weeks (70 days) inclusive. 
There is one specific period of interest: 
• 
Period 1 starts on the first administration day (Day 1 visit) and finishes prior to the visit date of Day 
113 visit. 
Period 1 Treatment-Emergent Adverse Events (P1 TEAEs) are defined as AEs that started or worsened on or 
after the first dose of trial medication during period 1 and prior to or at the last date of trial medication during 
period 1 + 10 weeks (70 days) inclusive. 
Non-TEAEs will be classified as “Screening” if AE start date is strictly prior the first injection date. Non-TEAEs will 


 
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be classified as “Post treatment” if AE start date is strictly after the last injection date + 70 days. 
See APPENDIX 2 for handling of partial dates for AEs. In the case where it is not possible to define an AE as 
treatment-emergent or not, the AE will be classified by the worst case, i.e., treatment-emergent in the period of 
the last injection of trial medication. 
16.1.1.2. Risk ratio 
Risk ratios and associated 95% exact confidence interval will be presented for adverse events of special interest. 
Risk ratio will be defined as: [a/(a+b)]/[c/(c+d)] 
where: 
1. a is the number of subjects with AESI within treatment group BI 695501 
2. a+b is the total number of subjects in treatment group BI 695501 
3. c is the number of subjects with AESI within treatment Humira 
4. c+d is the total number of subjects in treatment group Humira 
 
PROC FREQ with option RELRISK will be used for programming purpose. 
proc freq data=data_AESI; 
tables AESI_WITH_CRITERION*TRT; 
exact relrisk(method=score); 
weight count; 
run; 
16.1.2. 
ALL TEAES  
Number of subjects, percentages, and number of events overall and for period 1 will be presented by System 
Organ Class (SOC) and Preferred Term (PT) and also broken down further by maximum intensity and relationship 
to trial medication.  
16.1.2.1. Intensity 
Intensity is classed as mild/ moderate/ severe (increasing intensity). TEAEs starting after the first dose of trial 
medication with a missing severity will be classified as severe. If a subject reports a TEAE more than once within 
that SOC/ PT, the AE with the worst case intensity will be used in the corresponding severity summaries. 
16.1.2.2. Relationship to Trial Medication 
A related AE is defined as a TEAE with the item “Causal Relationship between the event and the trial drug” ticked 
“Related” on the AE form of the eCRF according to the investigator. 
TEAEs with a missing relationship to trial medication will be regarded as related to trial medication. If a subject 
reports the same TEAE more than once for the given period within that SOC/ PT, the TEAE with the worst case 


 
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relationship to trial medication within that period will be used in the corresponding relationship summaries. 
All drug related AEs will be listed. 
16.1.3. 
TEAES LEADING TO DISCONTINUATION OF TRIAL MEDICATION 
TEAEs leading to permanent discontinuation of trial medication will be identified by using the “Action taken with 
trial drug due to AE” equal to “Drug Withdrawn” from AEs eCRF pages. 
The number and percentages of subjects with TEAEs leading to permanent discontinuation of trial medication 
will be prepared overall and for period 1 by SOC and PT. 
The AEs causing treatment modification or drug withdrawal will be listed. 
16.1.4. 
SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as ”Serious” on the Adverse Events page of the eCRF. A 
summary of serious TEAEs by SOC and PT will be prepared overall and for period 1 including the number of 
subjects, percentages and number of events. 
Non-Serious TEAEs with incidence in preferred terms strictly greater than 5% in at least one of treatment groups 
by SOC and PT will also be displayed overall and for period 1. 
A summary of related SAEs by SOC and PT will also be prepared overall and for period 1. 
The SAEs and Non-SAEs will be listed. 
16.1.5. 
ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as ”Fatal” on the Adverse Events page of the eCRF. A 
summary of TEAEs leading to death by SOC and PT will be prepared overall including the number of subjects, 
percentages and number of events. 
16.1.6. 
OTHER SAFETY ENDPOINTS AND ADVERSE EVENTS OF SPECIAL INTEREST 
A summary of the number of subjects, percentages, and number of events within each of the categories 
described in the sub-section below will be provided by SOC and PT. 
The below table describes the allocation of adverse events to AESI group and Other safety endpoints group: 
 
Adverse Event : 
AESI 
Other safety 
endpoint 


 
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     Serious infections 
√ 
√ 
     Hypersensitivity reactions 
√ 
√ 
     Drug induced liver injury 
√ 
√ 
     Injection site reactions 
 
√ 
     Anaphylactic reactions 
√ 
√ 
16.1.6.1. Reported by Investigator 
AESI reported by Investigators are those events recorded as “Adverse Event of Special Interest” equal to “Yes” on 
the Adverse Events page of the eCRF. 
AESI reported by investigators and CTP specified are detailed in the following sections. 
16.1.6.2. Serious Infections 
Infections are those events with a SOC equal to “Infections and infestations". 
Serious infections are: 
• 
AEs which are both infections and SAEs as reported on the Adverse Events page of the eCRF. 
• 
AEs which are both infections and identified by the medical advisor as requiring class IV 
(intravenous) antibiotics. 
Serious infection events of special interest (Serious infection AESI) are those events both identified as serious 
infection adverse events and recorded as “Adverse Event of Special Interest” equal to “Yes” on the Adverse 
Events page of the eCRF. 
Infections and Serious Infections will be summarized. Infections / Serious Infections will also be listed. The listing 
will include the “Adverse Event of Special Interest” equal to “Yes” information from the Adverse Events page of 
the eCRF as a flag. 
16.1.6.3. Hypersensitivity Reactions 
Hypersensitivity reactions are those events recorded as MedDRA code in the pre-defined Standardized MedDRA 
Queries (SMQ) “Hypersensitivity” (narrow). 
Hypersensitivity reaction adverse events of special interest (Hypersensitivity reactions AESI) are those events 
both identified as Hypersensitivity reaction adverse events and recorded as “Adverse Event of Special Interest” 
equal to “Yes” on the Adverse Events page of the eCRF. 
Hypersensitivity reactions will also be listed. The listing will include the “Adverse Event of Special Interest” equal 


 
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to “Yes” information from the Adverse Events page of the eCRF as a flag. 
16.1.6.4. Drug Induced Liver Injury (DILI) 
Drug Induced Liver Injury (DILI) are those events identified by medical advisor on the subset of AEs for subjects 
presenting laboratory potential DILI findings (refer to section 16.3.1) 
DILI events of special interest (DILI AESI) are those events both identified as DILI adverse events and recorded as 
“Adverse Event of Special Interest” equal to “Yes” on the Adverse Events page of the eCRF. 
Drug Induced Liver Injury (DILI) will be listed. The listing will include the “Adverse Event of Special Interest” equal 
to “Yes” information from the Adverse Events page of the eCRF as a flag. 
16.1.6.5. Injection-site reactions 
Injection-site reactions are those events recorded with MedDRA high level terms (as listed in BIcMQs 
Administration site reaction subsearches 1,2,4 and 5, with a version consistent with the MedDRA version, refer to 
APPENDIX 4): 
• 
Administration site reactions NEC  
• 
Application and instillation site reactions  
• 
Infusion site reactions  
• 
Injection site reactions 
Moreover, the number and percentage of subjects with injection site reactions will be summarized for each 
injection site reaction (Swelling / Hardening / Heat / Redness / Pain / Itching / Bruising / Other). 
Injection-site reactions will be listed. 
16.1.6.6. Anaphylactic reactions 
Anaphylactic reactions are those events recorded as MedDRA code in the pre-defined Standardized MedDRA 
Queries (SMQ) = “Anaphylactic reactions” (narrow) 
Anaphylactic reaction adverse events of special interest (Anaphylactic reaction AESI) are those events both 
identified as Anaphylactic reactions and recorded as “Adverse Event of Special Interest” equal to “Yes” on the 
Adverse Events page of the eCRF. 
Anaphylactic reactions will also be listed. The listing will include the “Adverse Event of Special Interest” equal to 
“Yes” information from the Adverse Events page of the eCRF as a flag. 


 
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16.1.7. AES OCCURING AFTER THE LAST INJECTION FOR SUBJECTS DISCONTINUED DUE TO LACK OF 
EFFICACY 
Subjects who discontinued treatment due to lack of efficacy will be identified from “End of treatment visit” eCRF 
page, where “Reason for End of Treatment” is “Lack of Efficacy”. 
Number of subjects, percentages, and number of events occurring after the last injection and prior to the last 
injection + 10 weeks for subjects discontinued due to lack of efficacy by SOC and PT will be prepared. 
AEs occurring after the last injection and prior to the last injection + 10 weeks for subjects discontinued due to 
lack of efficacy will be listed. 
16.2. 
DEATHS 
If any subjects die during the trial as recorded on the “End of Treatment” page or the “Trial Completion” page or 
the ”Safety Follow-Up” page or the AE page (SAE which “Results in death” or AE with “Fatal” outcome) or the 
“Death” form, the information will be presented in a summary table and a data listing. 
16.3. 
LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this trial for Serum Chemistry, Hematology 
and Urinalysis. A list of laboratory assessments to be included in the outputs is included in APPENDIX 5. 
Presentations will use SI and US Units.  
Quantitative laboratory measurements reported as “< X”, i.e., below the lower limit of quantification (BLQ), or 
“> X”, i.e., above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, i.e., as “< X” or “> X” in the listings. 
Qualitative laboratory urinalysis results measured by central laboratory will be classified to the categories 
“Positive” and “Negative” based on the central laboratory normal reference. 
The handling of retests, unscheduled, and end of trial measurements is described in Section 6.3. However, 
laboratory values taken after the first dose of trial medication up to the end of a period (i.e. up to 10 weeks after 
the last dose of the trial medication) will be assigned to the treatment phase for evaluation. Moreover, tables 
about DILI will include unscheduled visits. 
All available data will be listed. 
The following summaries will be provided for laboratory data: 
• 
Actual and change from baseline by visit (for quantitative measurements) 
• 
Shifts from baseline category (Low/ Normal/ High) by visit (except for urinalysis) 


 
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• 
Shift from baseline category (Negative/ Positive) by visit (for urinalysis) 
• 
Listing of subjects meeting abnormal criteria 
• 
Proportion of possible Hy’s law subjects 
• 
Proportion of possible Drug Induced Liver Injuries (DILIs) 
• 
The time course of ALT, AST and total bilirubin (TBL) for all possible Hy’s law subjects, all parameters 
shown on a logarithm to base 10 scale of the multiple of the upper limit of normal (ULN) (Y axis) 
versus days since treatment start (X axis). 
• 
Scatter plots for Evaluation of Potentially Drug-Induced Liver Injury: 
o 
log ALT on the X axis and log TBL on the Y axis, both shown on a logarithm to base 10 scale of the 
multiple of the ULN 
o 
log AST on the X axis and log TBL on the Y axis, both shown on a logarithm to base 10 scale of the 
multiple of the ULN. 
Baseline is described in section 6.2. 
16.3.1. 
LABORATORY SPECIFIC DERIVATIONS 
• 
Log ALT = logarithm to base 10 scale of the multiple of the ULN of ALT 
• 
Log AST = logarithm to base 10 scale of the multiple of the ULN of AST 
• 
Log TBL = logarithm to base 10 scale of the multiple of the ULN of TBL. Note: Bilirubin value instead 
of TBL will be used. 
• 
Potential Hy’s law categories: 
o 
Category 1: ALT or AST >=3xULN and TBL >=2xULN within the same sample 
o 
Category 2: TBL >=2xULN within 30 days after transaminase peak (ALT or AST >=3 ULN) 
• 
Potential Hy’s Law subjects are defined as subjects with laboratory data in at least one Potential 
Hy’s law categories at any time point of the trial. 
• 
Drug induced liver injury (DILI): 
1. 
Normal liver function at Baseline is defined as AST and ALT and Total Bilirubin values measured 


 
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at baseline are each <= respective ULN. 
2. 
Impaired liver function tests at Baseline is defined as AST or ALT or Total Bilirubin values 
measured at baseline is > respective ULN. 
3. 
For post baseline visits: 
1. 
Category 1: Subject with normal liver function at Baseline and (AST and/or ALT ≥3 
times ULN and TBL ≥2 times ULN within the same sample). 
2. 
Category 2: Subject with impaired liver function at Baseline and (AST and/or ALT 
≥3 times the Baseline value and TBL ≥2 times the Baseline value within the same 
sample.). 
3. 
Category 3: marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN 
16.3.2. 
LABORATORY REFERENCE RANGES AND ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in SI units 
and categorized as: 
• 
Low: Strictly below the lower limit of the laboratory reference range.  
• 
Normal: Within the laboratory reference range (upper and lower limit included). 
• 
High: Strictly above the upper limit of the laboratory reference range. 
16.3.3. 
OTHER SAFETY LABORATORY EVALUATIONS 
16.3.3.1. Pregnancy test 
Descriptive table will present pregnancy results for females by visit on SAF. 
The pregnancy results will be listed as well. 
16.3.3.2. Tuberculosis test 
Descriptive table will present Tuberculosis (TB) test results by visit on SAF. 
The TB test results will be listed as well. 
16.4. 
ECG EVALUATIONS 
Results from ECGs will be summarized by visit to the categories as recorded in the eCRF page “12-Lead-ECG” 
(“Normal”, “Abnormal, not clinically significant” and “Abnormal, clinically significant”). 


 
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ECG evaluations will also be listed. 
16.5. 
VITAL SIGNS 
The following Vital Signs measurements will be reported: 
• 
Sitting Systolic Blood Pressure (mmHg) 
• 
Sitting Diastolic Blood Pressure (mmHg) 
• 
Sitting Pulse Rate (bpm) 
• 
Temperature (⁰C). Conversion: Temperature(°C)=[Temperature (F)-32]/1.8  
Weight will be presented along with vital signs. 
• 
Weight (kg) 
The handling of retests, unscheduled, and end of trial measurements is described in Section 6.3. 
The summary of actual and change from baseline by visit will be provided for vital sign data. In case of multiple 
measurement timepoints at one visit, the pre-injection data will be used for summary tables. 
Vital signs data will be listed. 
16.6. 
PHYSICAL EXAMINATION 
Incidence of evaluation categories (Normal, Abnormal) at baseline and post-baseline visits will be provided for 
physical examination data. 
The handling of retests, unscheduled, and end of trial measurements is described in Section 6.3. 
Baseline is described in Section 6.2. 
 
 
 
 
 
 
 


 
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19. REFERENCES  
ICH E9 – Statistical Principles for Clinical Trials (Issued 1998) 
Reeve Russel (2016) Confidence interval of difference of proportions in logistic regression in presence of 
covariates. Statistical Methods in Medical Research. DOI : 10.1177/0962280216631583 
 
 
 
 
 
 


 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
 Output Conventions 
File names should only consist of lowercase letters, digits (0 to 9) and hyphens. A period should only be used to 
indicate a separator between the file name and the extension. No spaces, other special characters or 
punctuation marks are permitted.  
The program, program log and output file name should reflect the type of the statistical output. The output files 
will contain the output number in addition. If this is not possible, then the output name should be at least as 
descriptive as possible. A prefix can be used to distinguish between a Table, Listing and Figure document (‘t’ for 
table, ‘l’ for listing and ‘f’ for figure). If there is only 1 digit in the number of the table, listing or figure in the place 
where 2 digits are possible, a leading zero should be added in the file name to make sorting consistent with the 
sequence (eg t-14-3-01-1.RTF) 
As far as possible, output files should be in RTF format. 
The outputs will be provided in pdf format. 
 
Paper Size, Orientation and Margins 
The size of paper will be Letter. 
The page orientation should preferably be landscape, but portrait is also permitted. 
Margins should provide at least 1 inch (2.54 centimeters) of white space all around the page, regardless of the 
paper size. 
The number of columns per page (linesize) should 134 for Letter. 
The number of rows per page (pagesize) should be 40 for Letter. 
FONTS 
The font type ‘Courier New’ should be used as a default for tables and listings, with a font size of 8. The font 
color should be black. No bolding, underlining italics or subscripting should be permitted. Try to avoid using 
superscripts, unless absolutely necessary. Single spacing should be used for all text. 
Figures should have a default font of “Times Roman”, “Helvetica”, or “Courier New”. 
This can be achieved by using the following options in SAS: 
goptions 
gunit = pct 
cback = white 
colors = (black) 
hby = 2.4 


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


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


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


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


 
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Dates & Times 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
Spelling Format 
English US. 
Presentation of Treatment Groups 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment Group 
For Tables and Graphs 
BI 695501 
BI 695501 
US-licensed Humira® 
Humira 
Presentation of Visits 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Visits as per protocol 
Day -28 to -1 
D-28 to -1 
 
Day 1 
D1 
Baseline 
Day 8 
D8 
Day 8 (Week 1) 
… 
… 
… 
Day 232 
D232 
…. 
 
Listings 
All listings will be ordered by the following (unless otherwise indicated in the template): 
• 
randomized treatment group (or treatment received if it’s a safety output) 
• 
center-subject ID 
• 
date including Study Day (where applicable), 
• 
For listings where non-randomized subjects are included, these will appear in a category after the 
randomized treatment groups labeled ‘Not Randomized’. 
The visit as recorded in the eCRF will be displayed in the listings (and not the remapped visit). 


 
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APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR PRIOR / ACTIVE MEDICAL HISTORY, SURGERIES AND PROCEDURES 
Partial date to be imputed as: 
Start date 
Earliest possible date  
first day of month if day unknown or 
1st January if day and month are 
unknown 
 
Stop date 
Latest possible date  
last day of month if day unknown or 
31st December if day and month are 
unknown, if not resulting in a date 
later than the date of subject's 
death. In the later case the date of 
death will be used for imputation.  
General rules: 
 
If stop date < trial med start date, assign as prior  
If stop date >= trial med start date and start date <= end of treatment, assign as concomitant 
If stop date >= trial med start date and start date > end of treatment, assign as post Treatment 
If Missing stop date: (Rules 2) 
If stop date is missing could never be assumed as prior  
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
If Missing Start date: (Rules 3) 
If stop date < trial med start date, assign as prior 
If stop date >= trial med start date, assign as active 
Cannot be assigned as ‘post treatment’ 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
General rules 
 
Partial 
General rules 
 
Missing 
Rules 2 
 
 
 
Partial 
Known 
General rules 
 
Partial 
General rules 
 
Missing 
Rules 2 


 
Statistical Analysis Plan 
 
PROTOCOL 1297.12 
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Author: 
 
Version Number: 
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Version Date: 
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Template No:  CS_TP_BS016  Revision 4 
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Effective Date: 01Apr2016 
 
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reproduction is strictly prohibited. 
START DATE 
STOP DATE 
ACTION 
 
 
 
Missing 
Known 
Rules 3 
 
Partial 
Rules 3 
 
Missing 
Assign as concomitant 
 
Algorithm for Treatment Emergence of Adverse Events: 
START DATE 
STOP DATE 
ACTION 
Known 
Known  
Partial  
Missing 
If start date < trial med start date or start date> trial med stop 
date +70 days, then not TEAE 
If start date >= trial med start date and start date <= trial 
med stop date +70 days, then TEAE 
 
 
 
Partial, but known 
components show that it 
cannot be on or after trial 
med start date 
Known  
Partial  
Missing 
Not TEAE 
 
 
 
Partial, could be on or after 
trial med start date 
Known 
Impute start date as earliest possible date, (i.e., first day of 
month if day unknown or 1st January if day and month are 
unknown), except if only day is missing and month and year of 
start date are the same as for trial med start date or if day and 
month are missing and year of start date is the same as for trial 
med start date. In the later cases, the trial med start date will 
be used for the imputation. 
 
If start date <= stop date, then: 
If stop date < trial med start date, then not TEAE 
If start date > trial med end date +70 days, then not TEAE 
If stop date >= trial med start date and start date <= trial 
med end date +70 days, then TEAE 
If start date > stop date, then: 
Consider the start date as Missing and apply the algorithms 
for missing start date 
 
Partial 
Impute start date as above. 
Impute stop date as latest possible date (i.e., last day of month 


 
Statistical Analysis Plan 
 
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Author: 
 
Version Number: 
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Version Date: 
31JAN2018 
Template No:  CS_TP_BS016  Revision 4 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
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The contents of this document are confidential and proprietary to 
 Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
START DATE 
STOP DATE 
ACTION 
if day unknown or 31st December if day and month are 
unknown), if not resulting in a date later than the date of 
subject's death. In the later case the date of death will be used 
for imputation.  
 
If start date <= stop date, then: 
If stop date < trial med start date, then not TEAE 
If start date > trial med end date +70 days, then not TEAE 
If stop date >= trial med start date and start date <= trial 
med end date +70 days, then TEAE 
If start date > stop date, then: 
Consider the start and stop dates as Missing and apply the 
algorithms for missing start date 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < trial med start date, then not TEAE 
If stop date >= trial med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If stop date < trial med start date, then not TEAE 
If stop date >= trial med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
Algorithm for Prior / Concomitant Medications:  
Partial date to be imputed as: 
Start date 
Earliest possible date  
first day of month if day unknown or 
1st January if day and month are 
unknown 
 
Stop date 
Latest possible date  
last day of month if day unknown or 
31st December if day and month are 
unknown, if not resulting in a date 
later than the date of subject's 
death. In the later case the date of 


 
Statistical Analysis Plan 
 
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Author: 
 
Version Number: 
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Version Date: 
31JAN2018 
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Reference:  CS_WI_BS005 
Effective Date: 01Apr2016 
 
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The contents of this document are confidential and proprietary to 
 Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
death will be used for imputation. 
 
 
General rules: 
 
If stop date < trial med start date, assign as prior  
If stop date >= trial med start date and start date <= end of treatment, assign as concomitant  
If stop date >= trial med start date and start date > end of treatment, assign as post Treatment 
 
If Missing stop date: (Rules 2) 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
If Missing Start date: (Rules 3) 
If stop date < trial med start date, assign as prior 
If stop date >= trial med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
General rules 
 
Partial 
General rules 
 
Missing 
Rules 2 
 
 
 
Partial 
Known 
General rules 
 
Partial 
General rules 
 
Missing 
Rules 2 
 
 
 
Missing 
Known 
Rules 3 
 
Partial 
Rules 3 
 
Missing 
Assign as concomitant 


 
Statistical Analysis Plan 
 
PROTOCOL 1297.12 
Page 62 of 65 
 
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Version Number: 
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Version Date: 
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Effective Date: 01Apr2016 
 
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 Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
APPENDIX 3. EMA SOC ORDER FOR PRESENTATION OF THE AE IN THE TABLES. 
Order System Organ Class                                                                    
0 Uncoded                   
1 Infections and infestations                                            
2 Neoplasms benign, malignant and unspecified (incl cysts and polyps)    
3 Blood and lymphatic system disorders                                   
4 Immune system disorders                                                
5 Endocrine disorders                                                    
6 Metabolism and nutrition disorders                                     
7 Psychiatric disorders                                                  
8 Nervous system disorders                                                
9 Eye disorders                                                          
10 Ear and labyrinth disorders                                            
11 Cardiac disorders                                                      
12 Vascular disorders                                                     
13 Respiratory, thoracic and mediastinal disorders                        
14 Gastrointestinal disorders                                             
15 Hepatobiliary disorders                                                
16 Skin and subcutaneous tissue disorders                                 
17 Musculoskeletal and connective tissue disorders                        
18 Renal and urinary disorders                                            
19 Pregnancy, puerperium and perinatal conditions                         
20 Reproductive system and breast disorders                               
21 Congenital, familial and genetic disorders                             
22 General disorders and administration site conditions                   
23 Investigations                                                         
24 Injury, poisoning and procedural complications                         
25 Surgical and medical procedures                                        
26 Social circumstances                                                   
27 Product issues 
 


 
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Version Date: 
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 Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
APPENDIX 4. FILES ATTACHED TO SAP 
 
Current BIcMQs Administration site reaction 
Cut-off implementation document: BI1297_12_cut_off_v1.3_19SEP2017 
 
 


 
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Author: 
 
Version Number: 
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Version Date: 
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Effective Date: 01Apr2016 
 
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 Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
APPENDIX 5. LABORATORY ASSESSMENTS 
Laboratory parameter 
SI unit 
US unit 
Serum chemistry 
 
 
Creatinine 
umol/L 
mg/dL 
Alkaline phosphatase 
IU/L 
IU/L 
Aspartate aminotransferase (AST) 
IU/L 
IU/L 
Alanine aminotransferase (ALT) 
IU/L 
IU/L 
Gamma glutamyl transpeptidase (GGT) 
IU/L 
IU/L 
Total bilirubin 
umol/L 
mg/dL 
Direct bilirubin 
umol/L 
mg/dL 
Glucose 
mmol/L 
mg/dL 
Total cholesterol 
mmol/L 
mg/dL 
Total protein 
g/L 
g/dL 
Sodium  
mmol/L 
mEq/L 
Potassium  
mmol/L 
mEq/L 
Chloride 
mmol/L 
mEq/L 
Calcium  
mmol/L 
mg/dL 
Albumin 
g/L 
g/dL 
Hematology 
 
 
Hemoglobin 
g/L 
g/dL 
Hematocrit 
V/V 
% 
Erythrocyte 
10^12/L 
10^6/uL 
Platelets 
10^9/L 
10^3/uL 
White blood cells 
10^9/L 
10^3/uL 
Lymphocytes 
10^9/L 
10^3/uL 
Neutrophils 
10^9/L 
10^3/uL 
Urinalysis 
 
 
Protein 
g/L 
g/dL 
Glucose 
mmol/L 
mg/dL 
Blood 
N/A 
N/A 
 
 
 


 
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Version Date: 
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reproduction is strictly prohibited. 
APPENDIX 6. SAS CODE FOR DIFFERENCE IN PROPORTION CIS 
 
%let K=1000000;/*number of simulation*/ 
%let alpha=0.05;/*confidence level*/ 
 
proc IML; 
 
/*create theta and vartheta*/ 
 
theta={&G. &Z.}; print theta; /*create theta vector*/ 
 
vartheta={&VARG. &COVGZ. , &COVGZ. &VARZ.}; print vartheta; /*create 
vartheta vector*/ 
 
 
/*Create Xc the cholesky decomposition of Vartheta*/ 
 
Xc = t(root(Vartheta)); 
 
 
 
/*create X random normal vector*/ 
 
call randseed(456); /* set random number seed */ 
 
X = j(&K.,2);  /* allocate the X vector */ 
 
call randgen(X,"Normal"); 
 
 
/*Write X matrix in a sas dataset called X*/ 
 
X1=X[,1]; 
 
X2=X[,2]; 
 
create X var{X1 X2};  
 
append; 
 
close X; 
 
 
/*Calculate Y = X %% Xc*/ 
 
Y=X*Xc;  
 
 
/*G,Z*/ 
 
G=Y[,1]+Theta[1,1];  
 
Z=Y[,2]+Theta[1,2];  
 
DELTA=(1/(1+exp(-(G+Z))))-(1/(1+exp(-Z))); 
 
call sort(DELTA); 
 
 
LOW=DELTA[round(&k.*(&alpha./2))]; print low; 
 
UP=DELTA[&K.-round(&k.*(&alpha./2))]; print up; 
 
quit;