Clinical trial NCT03210259
Conditions: Psoriasis
Sponsor: Boehringer Ingelheim
Start date: 2017-07-10; Completion date: 2019-04-16
Enrollment: 259 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the trial is to assess the PK similarity between patients receiving Humira® continuously vs those who alternate between BI 695501 and Humira®, in patients with moderate-to-severe chronic plaque psoriasis.

The secondary objectives of this trial are to descriptively compare the safety, immunogenicity and efficacy profiles between patients receiving Humira® continuously vs those who alternate between BI 695501 and Humira®.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Humira® intervention 2: BI 695501
Intervention descriptions: intervention 1: Duration - 58 weeks intervention 2: Duration - 58 weeks

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 October 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c16011431-03
EudraCT No.:
EU Trial No:
2016-002254-20
BI Trial No.:
1297.9
BI Investigational 
Product(s):
BI 695501
Title:
VOLTAIRE-X: Pharmacokinetics, safety, immunogenicity and 
efficacy 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:
The VOLTAIRE-X trial looks at the effect of switching 
between Humira® and BI 695501 in patients with plaque 
psoriasis. 
Clinical Phase:
Phase III
Trial Clinical 
Monitor:
Tel.: 
Coordinating 
Investigator:
Tel.: 
Status:
Final Protocol (Revised Protocol [based on Global 
Amendment 2])
Version and Date:
Version: 3.0
Date: 25 Jul 2019
Page 1 of 105
Proprietary confidential information.
2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Finished product name
NA
Active ingredient name:
BI 695501
Protocol date
Revision date 25 Jul 2019
Trial number
1297.9
Title of trial:
Pharmacokinetics, safety, immunogenicity and efficacy 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. The 
VOLTAIRE-X Trial.
Coordinating 
Investigator:
Trial site(s):
Multi-national, multi-center trial in approximately 80 clinical sites across 
approximately 12 countries
Clinical phase:
Phase III
Objective(s):
The primary objective of the trial is to assess the pharmacokinetic (PK) similarity 
between patients receiving United States (US)-licensed Humira® continuously vs 
those who switch between BI 695501 and US-licensed Humira®, in patients with 
moderate to severe chronic plaque psoriasis.
The secondary objectives of this trial are to descriptively compare the safety, 
immunogenicity and efficacy profiles between patients receiving US-licensed 
Humira® continuously vs those who switch between BI 695501 and US-licensed 
Humira®.
Methodology:
This is a 58-week, multiple-dose, active comparator trial with a single-arm run-in 
period of 14 weeks duration for all entered patients, followed by a randomized, 
double-blind, two-arm period of 34 weeks. The total treatment period will be 
48 weeks followed by 10 weeks of safety follow-up. 
All entered patients will have a planned run-in period of 14 weeks during which 
they will be treated with US-licensed Humira® (last dose at Week 12/Visit 8). Each 
patient will receive 80 mg of US-licensed Humira® at the start of the run-in period 
(Day 1, Week 1) followed by 40 mg of Humira® 1 week later, and then 40 mg of 
Humira® every other week. At the beginning of Week 14 (Visit 9), patients 
achieving at least a 50% reduction in Psoriasis Area and Severity Index (PASI50) 
response will be randomized in a 1:1 ratio to either continue receiving US-licensed 
Humira® (continuous US-licensed Humira® arm) until Week 48 or receive BI 
695501/US-licensed Humira®/BI 695501 alternately for three periods (switching 
arm) in a blinded fashion (BI 695501 at Week 14/Visit 9 and Week 16/Visit 10, 
US-licensed Humira® at Week 18/Visit 11 and Week 20/Visit 12, and BI 695501 
every other week from Week 22/Visit 13 to Week 48/Visit 26). At Week 14, the 
randomization will be stratified by the level of their Week 14 PASI response 
(≥PASI50 to < PASI75 and ≥PASI75). In the switching arm, the first two 
treatment periods will be of 4 weeks (2 injections) duration, and the third treatment 
period will be of 10 weeks (5 injections) duration, with an extension period of 16 
weeks beyond the primary endpoint assessed at Week 32. 
Those patients not achieving at least PASI50 at Week 14 will be discontinued from 
any further treatment in the trial, and will only be followed up for safety. 


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Company name
Boehringer Ingelheim
Finished product name
NA
Active ingredient name:
BI 695501
Protocol date
Revision date 25 Jul 2019
Trial number
1297.9
Starting at Week 14, the treatment regimen of the two arms will be:

Continuous Humira® arm: US-licensed Humira® (34 weeks)

Switching arm: BI 695501 (4 weeks, 2 injections)/US-licensed Humira®
(4 weeks, 2 injections)/BI 695501 (10 weeks, 5 injections for primary 
endpoint + 16 weeks, 9 injections extension period; 26 weeks total)
Patients will undergo intensive PK sampling between Weeks 12-14 (Visit 8, Visits 
8a-d, and Visit 9) and 30-32 (Visit 17, Visits 17a-d, and Visit 18) to assess PK 
similarity between the two arms. 
After approximately 86 patients have had their Week 32 endpoint assessments and 
are PK evaluable, a blinded interim analysis with sample size re-assessment will be 
performed. Recruitment (for stage 2) will however not be stopped.
The interim analysis will be performed in a blinded manner.
Number of patients 
entered: 
Initial enrollment into the run-in US-licensed Humira® arm: Approximately 
240 patients will be entered.
Number of patients on 
each treatment:
Patients will be randomized 1:1 into continuous US-licensed Humira® and 
switching arms at Week 14, leading to approximately 96 patients per arm, 
considering approximately 80% achieve PASI50 and a PK non-evaluable drop-out 
rate of approximately 10%-15%, to obtain approximately 86 PK evaluable patients 
per arm for the primary endpoint analysis.
Diagnosis :
Moderate to severe chronic plaque psoriasis.
Main in- and exclusion 
criteria
This trial will include male and 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 prior to randomization, and which has been stable for the last 2 months 
with no changes in morphology or significant flares. Patients must be suitable for
systemic treatment or phototherapy. Patients must have a PASI score ≥12, Static 
Physician’s Global Assessment of psoriasis (sPGA) ≥3 at screening and at baseline, 
and a body surface area (BSA) involvement ≥ 10%. Patients with prior exposure to 
any biologic therapy will be excluded from this trial.
Test product(s):
BI 695501 solution in a pre-filled syringe
dose:
40 mg every other week, starting at Week 14
mode of 
administration:
Subcutaneous (s.c.) injection
Comparator products:
US-licensed Humira® solution in a pre-filled syringe
dose:
80 mg initial dose, followed by 40 mg every other week starting 1 week after initial 
dose
mode of 
administration:
s.c. injection
Duration of treatment:
Patients will be treated with trial medication for 48 weeks.


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Company name
Boehringer Ingelheim
Finished product name
NA
Active ingredient name:
BI 695501
Protocol date
Revision date 25 Jul 2019
Trial number
1297.9
Endpoints
The following will be the endpoints of the trial: 
Primary endpoints:
Pharmacokinetics

AUCτ, 30-32
(Area under the adalimumab plasma concentration-time curve [AUC] 
over the dosing interval of Week 30-32) 

Cmax, 30-32
(Maximum observed adalimumab plasma concentration during the 
dosing interval Week 30-32)
Secondary endpoints:
Pharmacokinetics

Cmin, 30-32
(Minimum observed adalimumab plasma concentration during the 
dosing interval Week 30-32)

tmax, 30-32
(Time to maximum observed adalimumab plasma concentration 
during the dosing interval Week 30-32)
Efficacy

Proportion of patients with a 75% reduction in PASI (PASI75) 
response at Week 32

Proportion of patients with an sPGA ≤ 1 (clear or almost clear) at 
Week 32
Safety

Proportion of patients with drug-related adverse events (AEs) during 
the treatment phase and the safety follow-up period
Immunogenicity

Proportion of patients with anti-drug antibodies (ADAs) and ADA 
titer at Week 32, 

Proportion of patients with neutralizing ADAs (nAbs) frequency and 
titer at Week 32
Safety criteria:
Physical examination, vital signs (blood pressure, pulse rate, and body 
temperature), 12-lead electrocardiogram (ECG), laboratory tests, continuous AE 
monitoring and local tolerability.
Statistical methods:
The assessment of PK similarity will be based upon two-sided 90.2% confidence 
intervals (CIs) for the ratios of the means (test/reference, where the test treatment 
corresponds to the switching arm and the reference to the Humira®-only arm) for 
the primary endpoints using an acceptance range of 80.00% to 125.00%. This 
method is equivalent to the two one-sided t-tests procedure, each at the 4.9 % 
significance level The statistical model will be an analysis of covariance 
(ANCOVA) on the original scale including effects for “treatment”, “log(rPASI)”, 
“weight”, and “AUCτ, 12-14” or “Cmax, 12-14”, where rPASI=ratio of PASI at Week 14 
and PASI at Week 1. 
The randomization will be stratified by the level of their Week 14 response 
(≥PASI50 to < PASI75 and ≥PASI75)


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Company name
Boehringer Ingelheim
Finished product name
NA
Active ingredient name:
BI 695501
Protocol date
Revision date 25 Jul 2019
Trial number
1297.9
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Trial Periods
Screening
Run-in Period
Double-blind Period
Visit1
1
2
3
4
5
6
7
8
92
10
11
12
13
14
Week
Screening
-5 to -2
Baseline
1
2
4
6
8
10
12
14
16
18
20
22
24
Days
-38 to -15
1
8
22
36
50
64
78
92
106
120
134
148
162
Permitted visit window (days)
-
0
± 2
± 2
± 2
± 2
± 2
± 2
02
± 3
± 3
± 3
± 3
± 3
Informed consent
X
Assessment of eligibility 
X
X
Run-in Phase/Randomization3
X
X
Demographics
X
Medical and surgical history, incl. 
history of opportunistic inf.
X
LABS/SAFETY ASSESSMENTS4
Infection screen: Hepatitis B 
(HBsAg, anti-HBc), hepatitis C 
(anti-HCV), HIV 
X
Chest X-ray
X5
TB testing (IGRA or PPD 
testing)6
X
X
Pregnancy test for women of 
childbearing potential
X
X
X
X
X
Physical examination7
X
X
X
X
X
Vital signs7
X
X
X
X
X
Laboratory tests (serum 
chemistry, hematology, 
urinalysis)
X
X
X
X
X
12-lead electrocardiogram8
X
X
X
Previous and concomitant therapy
◄--------------------------------------------------------------------------X----------------------------------------------------------------------►
Adverse events9
◄--------------------------------------------------------------------------X----------------------------------------------------------------------►


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FLOW CHART – SCREENING TO WEEK 24 (CONT’D)
Trial Periods
Screening
Run-in Period
Double-blind Period
Visit1
1
2
3
4
5
6
7
8
92
10
11
12
13
14
Week
Screening
-5 to -2
Baseline
1
2
4
6
8
10
12
14
16
18
20
22
24
Days
-38 to -15
1
8
22
36
50
64
78
92
106
120
134
148
162
Permitted visit window (days)
-
0
± 2
± 2
± 2
± 2
± 2
± 2
02
± 3
± 3
± 3
± 3
± 3
EFFICACY ASSESSMENTS4
PASI
X
X
X
X
X
X
X
sPGA
X
X
X
X
X
X
X
OTHER ASSESSMENTS
Pharmacokinetics10
X
X
X
X
X
X
X
Anti-drug antibodies11
X
X
X
X
X
X
X
Neutralizing anti-drug 
antibodies11
X
X
X
X
X
X
X
TRIAL MEDICATION
Pre-treatment call
X
Contact IRT12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Trial Medication2
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: ADA=anti-drug antibody; AE=adverse event; anti-HBc=anti-hepatitis B core antibodies; anti-HCV=anti-hepatitis C antibodies; 
; 
EoT=End-of-Treatment; HBsAg=hepatitis B surface antigen; HIV=human immunodeficiency virus; IGRA=interferon gamma-release assay; IRT=Interactive Response Technology; 
nAb=neutralizing antibody; PASI=Psoriasis Area and Severity Index; PK=pharmacokinetics; PPD=purified protein; SFU=Safety Follow-up; sPGA=Static Physician’s Global Assessment of 
psoriasis; TB=tuberculosis. 


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FLOW CHART – WEEK 26 TO END OF TRIAL
Double-blind Period
Extension Period
Follow-up
Visit1
15
16
17
182
19
20
21
22
23
24
25
26
27
28
Week
26
28
30
32
34
36
38
40
42
44
46
4813
5013
EoT
58
SFU13
Days
176
190
204
218
232
246
260
274
288
302
316
330
344
400
Permitted visit window (days)
± 3
± 3
± 3
02
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
TB testing (IGRA or PPD 
testing)6
X
Pregnancy test for women of 
childbearing potential
X
X
X
Physical examination7
X
X
X
Vital signs7
X
X
X
Laboratory tests (serum 
chemistry, hematology, 
urinalysis)
X
X
X
12-lead electrocardiogram8
X
X
Previous and concomitant 
therapy
◄--------------------------------------------------------------------------X----------------------------------------------------------------------►
Adverse events9
◄--------------------------------------------------------------------------X----------------------------------------------------------------------►
EFFICACY ASSESSMENTS4
PASI
X
X
X
X
sPGA
X
X
X
X
OTHER ASSESSMENTS
Pharmacokinetics10
X
X
X
X
X
Anti-drug antibodies11
X
X
X
X
X
Neutralizing anti-drug 
antibodies11
X
X
X
X
X
TRIAL MEDICATION
Contact IRT12
X
X
X
X
X
X
X
X
X
X
X
X
X
Trial Medication2
X
X
X
X
X
X
X
X
X
X
X
X


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Abbreviations: ADA=anti-drug antibody; AE=adverse event; anti-HBc=anti-hepatitis B core antibodies; anti-HCV=anti-hepatitis C antibodies; 
 
EoT=End-of-Treatment; HBsAg=hepatitis B surface antigen; HIV=human immunodeficiency virus; IGRA=interferon gamma-release assay; IRT=Interactive Response Technology; 
nAb=neutralizing antibody; PASI=Psoriasis Area and Severity Index; PK=pharmacokinetic; PPD=purified protein derivative; SFU=Safety Follow-up; sPGA=Static Physician’s Global 
Assessment; TB=tuberculosis. 
1.
Patients will have to visit the site for the visits where safety samples and efficacy assessments need to be conducted. Medication will be administered at the site by a 
qualified site staff member. 
2.
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 14 onward). All assessments and procedures should be performed prior to trial medication administration.
Note: The below trial medication administration time points will need to be strictly followed as shown. 
Trial medication at Week 14 (Visit 9) should be administered exactly 14 days after the Week 12 Visit (Visit 8).
Trial medication at Week 32 (Visit 18) should be administered exactly 14 days after the Week 30 Visit (Visit 17).
3.
Entry into the run-in phase can occur through a pre-treatment call. The pre-treatment call will be done by the site 15 days prior to Day 1, and will depend on the trial site 
procedure. Patients will be randomized to each treatment in a 1:1 ratio (US-licensed Humira®:Switching Arm) at Week 14. 
4.
All efficacy (e.g., Psoriasis Area and Severity Index [PASI] and Static Physician’s Global Assessment of psoriasis [sPGA]) and safety assessments will be performed by 
blinded personnel. 
5.
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. 
6.
Patients must have a negative tuberculosis (TB) assessment at screening, including a purified protein derivative (PPD) skin test or an interferon gamma-release 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. If the result is positive, patients may participate in the trial if further work up (according to local practice/guidelines) establishes conclusively that the patient 
has no evidence of active TB. If latent TB is confirmed, then treatment must have been initiated before treatment in the study and continued according to local country 
guidelines.1 Post-screening, if the patient is positive for TB tests, additional work up would be needed to conclude either latent or active TB and appropriate measures 
need to be taken as per the local country guidelines.
7.
The physical examination will include assessment of general appearance, body weight, skin, head, neck, throat, lymph nodes, cardiovascular and neurological systems, 
thyroid gland, musculoskeletal system/limbs, respiratory tract and abdomen. Clinically relevant abnormal findings will be reported as baseline conditions or AEs. Vital 
signs include measurement of body temperature, blood pressure, and pulse rate (all in the sitting position after a 5-minute rest). 
8.
Patients should rest for at least 5 minutes in a supine position before electrocardiogram (ECG) evaluations. 
9.
Adverse events (AEs) will be collected from the time of informed consent. Adverse events continuing at the End-of-Treatment (EoT) 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 the EoT Visit. 
10. Pharmacokinetics (PK) samples will be taken pre-dose at baseline visit, Week 2, Week 8, Week 12; and additionally at 72 h, 120 h, 168 h, and 240 h at sub-visits 8a, 8b, 
8c, and 8d for PK sampling after the Week 12 dosing; pre-dose Week 14, Week 18, Week 22, Week 30 and 72 h, 120 h, 168 h, and 240 h at sub-visits 17a, 17b, 17c, and 
17d for PK sampling after the Week 30 dosing; pre-dose Week 32 and Week 40, during follow-up at Week 50 and Week 58 (see Table 5.3.1: 1). The PK samples at sub-
                                                
1 For Germany: patients with positive IGRA TB test or PPD skin test will be excluded from the trial participation.


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visits 8a, 8b, 8c, 8d, 17a, 17b, 17c, and 17d may be drawn by a qualified home healthcare professional (nurse) at the patient’s home or at an alternative location specified 
by the patient and agreed by the study team (see Section 5.3.1). 
11. Anti-drug antibody (ADA) samples (including neutralizing ADA samples [nAbs]) should be taken at each visit designated with an “X” prior to dosing of trial 
medication. 
12. Interactive Response Technology (IRT) will be contacted prior to every trial medication administration visit.
13. Patients who pre-maturely discontinue the trial at any time after Day 1 (but do not withdraw their consent) will be required to have all of the evaluations for the EoT Visit 
(equivalent to the Week 50 assessments) as soon after trial discontinuation as possible. Patients will then be followed for efficacy assessments until Week 50, wherever 
possible. Every effort should be made for all patients who complete the total 50-week treatment period, or who discontinue the trial early, to return for an SFU Visit at 
Week 58 or 10 weeks after the last treatment administration.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ......................................................................................................11
ABBREVIATIONS................................................................................................................15
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................18
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................19
1.4
BENEFIT - RISK ASSESSMENT.....................................................................20
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........22
2.1.1
Main objectives....................................................................................................22
2.1.2
Primary endpoint(s)............................................................................................22
2.1.3
Secondary endpoint(s) ........................................................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................25
3.3
SELECTION OF TRIAL POPULATION .......................................................26
3.3.1
Main diagnosis for trial entry ............................................................................26
3.3.2
Inclusion criteria .................................................................................................26
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Withdrawal of patients from therapy or assessments .....................................28
3.3.4.1
Withdrawal from trial treatment ...........................................................................29
3.3.4.2
Withdrawal of consent for trial participation........................................................29
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................30
3.3.5
Replacement of subjects .....................................................................................30
4.
TREATMENTS...................................................................................................31
4.1
INVESTIGATIONAL TREATMENTS ...........................................................31
4.1.1
Identity of the Investigational Medicinal Products..........................................31
4.1.2
Selection of doses in the trial..............................................................................32
4.1.3
Method of assigning patients to treatment groups...........................................32
4.1.4
Drug assignment and administration of doses for each patient......................33
4.1.5
Blinding and procedures for unblinding...........................................................33
4.1.5.1
Blinding.................................................................................................................33
4.1.5.2
Unblinding and breaking the code ........................................................................34
4.1.6
Packaging, labelling, and re-supply...................................................................34
4.1.7
Storage conditions...............................................................................................34


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4.1.8
Drug accountability.............................................................................................34
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................35
4.2.1
Other treatments and emergency procedures..................................................35
4.2.2
Restrictions ..........................................................................................................35
4.2.2.1
Restrictions regarding concomitant treatment ......................................................35
4.2.2.2
Restrictions on diet and life style..........................................................................37
4.2.2.3
Restrictions regarding women of childbearing potential......................................37
4.2.2.4
Restrictions regarding male participants of reproductive potential ......................37
4.3
TREATMENT COMPLIANCE........................................................................38
5.
ASSESSMENTS..................................................................................................39
5.1
ASSESSMENT OF EFFICACY........................................................................39
5.1.1
PASI......................................................................................................................39
5.1.2
Static Physician’s Global Assessment ...............................................................39
5.2
ASSESSMENT OF SAFETY.............................................................................41
5.2.1
Physical examination ..........................................................................................41
5.2.2
Vital signs.............................................................................................................41
5.2.3
Safety laboratory parameters ............................................................................42
5.2.4
Electrocardiogram ..............................................................................................43
5.2.5
Other safety parameters.....................................................................................44
5.2.5.1
Local tolerability...................................................................................................44
5.2.6
Assessment of adverse events.............................................................................44
5.2.6.1
Definitions of AEs ................................................................................................44
5.2.6.2
Adverse event collection and reporting ................................................................46
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................48
5.3.1
Assessment of pharmacokinetics .......................................................................48
5.3.2
Methods of sample collection .............................................................................50
5.3.3
Analytical determinations ..................................................................................50
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................50
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................50
5.5
OTHER ASSESSMENTS...................................................................................51
5.5.1
Assessment of immunogenicity ..........................................................................51
5.5.1.1
Plasma sampling for anti-drug-antibodies characterisation..................................51
5.5.1.2
Plasma sampling for neutralizing antibody characterisation ................................51
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................51
6.
INVESTIGATIONAL PLAN.............................................................................53
6.1
VISIT SCHEDULE.............................................................................................53
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................54
6.2.1
Screening and run-in period(s)..........................................................................54
6.2.2
Treatment period(s)............................................................................................54
6.2.3
Follow-up period and trial completion..............................................................55
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................56


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7.1
STATISTICAL DESIGN - MODEL.................................................................56
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................56
7.3
PLANNED ANALYSES.....................................................................................56
7.3.1
Primary endpoint analyses.................................................................................57
7.3.2
Secondary endpoint analyses .............................................................................59
7.3.2.1
Secondary PK endpoint analyses ..........................................................................59
7.3.2.2
Secondary efficacy endpoint analyses ..................................................................59
7.3.2.3
Secondary immunogenicity endpoint analyses.....................................................59
7.3.4
Safety analyses.....................................................................................................60
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................60
7.4
INTERIM ANALYSES ......................................................................................61
7.4.1
Blinded review of sample size ............................................................................61
7.5
FINAL ANALYSIS.............................................................................................62
7.6
HANDLING OF MISSING DATA ...................................................................62
7.6.1
Pharmacokinetic data.........................................................................................62
7.6.2
Efficacy data........................................................................................................62
7.6.3
Safety data ...........................................................................................................62
7.7
RANDOMISATION ...........................................................................................63
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........64
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................64
8.2
DATA QUALITY ASSURANCE ......................................................................65
8.3
RECORDS...........................................................................................................65
8.3.1
Source documents ...............................................................................................65
8.3.2
Direct access to source data and documents.....................................................66
8.3.3
Storage period of records ...................................................................................66
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................66
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........66
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................67
8.6
TRIAL MILESTONES.......................................................................................67
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................68
9.
REFERENCES....................................................................................................69
9.1
PUBLISHED REFERENCES............................................................................69
9.2
UNPUBLISHED REFERENCES......................................................................70
10.
APPENDICES.....................................................................................................71
10.1
CLINICAL EVALUATIONS OF LIVER INJURY........................................71
10.1.1
Introduction.........................................................................................................71
10.1.2
Procedures ...........................................................................................................71


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10.2
EFFICACY ASSESSMENTS ............................................................................73
10.3
MEDICATION BLINDING PROCEDURE FOR THIRD PARTY 
BLINDING ..........................................................................................................76
10.4
POTENTIAL DRUG-INDUCED LIVER INJURY (DILI) CHECKLIST ...80
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................98
11.1
GLOBAL AMENDMENT 1 ..............................................................................98
11.2
GLOBAL AMENDMENT 2 ............................................................................101


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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
anti-HCV
hepatitis C antibodies
AST
aspartate aminotransferase
AUC
area under the curve
β-hCG
beta-human chorionic gonadotropin
BI
Boehringer Ingelheim
BLQ
below the limit of quantitation
BSA
body surface area
CA
competent authority
CI
confidence interval
Cmax
maximum concentration of the analyte in plasma
Cmin
minimum concentration of the analyte in plasma
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
coefficient of variation
DILI
drug-induced liver injury
DRM
Data Review Meeting
ECG
electrocardiogram
eCRF
electronic Case Report Form
EoT
End-of-Treatment
EU
European Union
EudraCT
European Clinical Trials Database
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
immunoglobulin
IGRA
interferon gamma-release assay
IL
interleukin


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IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
intrauterine device
i.v.
intravenous
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LPDD
Last Patient Drug Discontinuation
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
MTX
methotrexate
nAb
neutralizing antibody
NOA
not analysed
NOR
no valide result
NOS
no sample
NRI
non-responder imputation
NSAID
non-steroidal anti-inflammatory drug
PASI
Psoriasis Area and Severity Index
PASI50
50% reduction in Psoriasis Area and Severity Index
PASI75
75% reduction in Psoriasis Area and Severity Index
PK
pharmacokinetic(s)
PKS
Pharmacokinetic Set
PPD
purified protein derivative
PPS
Per-Protocol Set
PUVA
psoralen with ultraviolet light
RA
rheumatoid arthritis
REP
residual effect period
RTS
Run-in Treated Set
SAE
serious adverse event
s.c.
subcutaneous
SFU
Safety Follow-up
SOP
standard operating procedure
SPC
summary of product characteristics
sPGA
Static Physician’s Global Assessment
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
tmax
time to reach maximum concentration
tmin
time to reach minimum concentration
TNF
Tumor necrosis factor
TNFR1
tumor necrosis factor 1
TNFR2
tumor necrosis factor 2
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
upper limit of normal
US
United States
US-PI
United States Prescribing Information
WHO
World Health Organisation


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
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 
characterised 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 (TNF) agents, 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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1.2
DRUG PROFILE
Humira® (adalimumab) is a recombinant humanized monoclonal immunoglobulin (Ig)G1 
antibody specific to TNF alpha and has received regulatory approval for psoriasis in the 
United States (US), the European Union (EU), and many other countries (R16-5078 and R16-
0358). Humira® binds specifically to TNF-alpha (not to TNF-beta) and blocks its interaction 
with the TNF receptors 1 (TNFR1) and 2 (TNFR2). It has human-derived heavy and light 
chain variable regions and human IgG1:k (kappa) constant regions and is produced in a 
mammalian cell expression system (R16-5078 and R16-0358). Humira® is administered as a 
monotherapy. 
Humira® has a generally favourable clinical safety profile, and is not associated with adverse 
events (AEs) that would suggest a high risk to patients participating in this trial. In patients 
treated with Humira®, the most commonly reported adverse reactions are infections (such as 
upper respiratory tract infection and sinusitis), nausea, headache, rash, accidental injuries and 
injection site reactions (erythema, itching, haemorrhage, pain or swelling).
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.
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.
The drug being studied in this trial, BI 695501, is a monoclonal antibody being developed as 
a proposed biosimilar to US-licensed and EU-approved Humira® (adalimumab). 
The preclinical studies that support the clinical program of BI 695501 include:
•
A comparative 5-week toxicology trial with an 8-week recovery in cynomolgus 
monkeys comparing BI 695501 and EU-approved Humira®. There was no 
difference in systemic exposure between BI 695501 and EU-approved Humira®
with repeated dosing. This trial demonstrated the similarity of the toxicology 
profile for BI 695501 and EU-approved Humira®.
•
A single-dose pharmacokinetic (PK), subcutaneous (s.c.) trial in cynomolgus 
monkeys comparing BI 695501 to EU-approved Humira®. There were no 


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differences in the exposure or anti-drug antibody (ADA) response in cynomolgus 
monkeys to BI 695501 and EU approved Humira®.
•
A comparative human tissue cross-reactivity trial of BI 695501, US-licensed, and 
EU-approved Humira®. This trial showed that the patterns of staining of 
BI 695501, US-licensed, and EU-approved Humira® were similar, with minor 
differences attributable to section-to-section variation, rather than any true staining 
differences. All of the tissue cross-reactivity staining was consistent with reported 
sites of TNF expression and/or previously reported sites of reference product 
cross-reactivity.
•
A determination of other potential cytokines that may bind to BI 695501 or inhibit 
binding of BI 695501 to TNF compared to US-licensed and EU-approved 
Humira®. None of the 3 antibodies bound to any of the 8 other cytokines that were 
tested. Additionally, there was no difference in the effect of these cytokines on the 
binding of TNF between BI 695501, US-licensed, and EU-approved Humira®. 
•
The potential for BI 695501 to induce in vitro cytokine release or directly activate 
complement compared to EU-approved Humira®. The results from this trial 
demonstrated that BI 695501 and EU-approved Humira® are not anticipated to 
induce cytokine release in humans and do not directly activate complement.
•
A tissue irritation potential trial in rabbits with BI 695501 demonstrated that 
BI 695501 did not cause irritation.
To date, a total of 241 male healthy subjects were treated with 40 mg s.c. of BI 695501 in 
3 phase I trials with healthy subjects: 1297.1 (U13-1096-01), 1297.6 (c09477818-01) and 
1297.8 (c03070713). The PK similarity of BI 695501 to US-licensed Humira® and 
EU-approved Humira® was demonstrated in the healthy volunteer trial 1297.8 (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.
A phase III trial (1297.2) in patients with moderate to severe rheumatoid arthritis (RA) has 
recently completed. A total of 645 patients with moderate to severe RA were included in the 
trial and treated with either BI 695501 or US-licensed Humira®. The observed AE profile 
revealed no unexpected safety findings and showed no clinically relevant safety or 
immunogenicity differences between BI 695501 and US-licensed Humira®.
For a more detailed description of the BI 695501 profile please refer to the current 
Investigator’s Brochure (IB) (c01843589) and for US-licensed Humira® to the United States 
Prescribing Information (US-PI) (R16-5078).
1.3
RATIONALE FOR PERFORMING THE TRIAL
The current trial is being performed to assess whether multiple switches between Humira®
and BI 695501 lead to the same PK, safety and immunogenicity profile compared to 
continuous Humira® treatment, as this may happen in clinical practice.


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1.4
BENEFIT - RISK ASSESSMENT
Participation in this trial may help to improve access to and availability of the respective drug 
treatment for other patients in the future. 
Patient risk will be minimized in this trial by implementing conservative eligibility criteria, 
e.g., patients with pre-existing diseases are excluded from trial participation, although in real 
time clinical practice, such patients might be treated. 
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 5.2.6.1.
All safety aspects will be regularly monitored by both the sponsor and a Contract Research 
Organization (CRO) during the Medical Quality Review Meetings.
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 core 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 patients 
who test positive. Investigators are also expected to carefully consider the risks and benefits 
of treatment with adalimumab in patients who have been exposed to TB and patients who 
have travelled in areas of high risk of TB or endemic mycoses, such as histoplasmosis, 
coccidioidomycosis, or blastomycosis.
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. 
Tumor necrosis factor-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. 
To minimize the risks, patients with a significant disease other than psoriasis will be excluded 
from the trial participation.
The AEs seen in 3 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 


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prescribing information (USPI) for Humira® (R16-5078) and in the summary of product 
characteristics (SPC) for EU-approved Humira® (R16-0358).
The AE profile in the phase III trial 1297.2 (c02158186) revealed no unexpected safety 
findings and showed no clinically relevant safety differences between US-licensed Humira®
and BI 695501. The review of safety data in 1297.2 trial by the Independent Data Monitoring 
Committee (IDMC) also did not suggest any clinically relevant differences in safety profile 
between Humira® and BI 695501.
There were no clinically relevant differences with respect to clinical laboratory evaluation, 
vital signs, ECGs, or injection site reactions in previous studies comparing BI 695501 with 
either US-licensed or EU-approved Humira®. Based on extensive preclinical, analytical, 
functional, and toxicological testing carried out prior to initiation of this trial, and the phase I 
and III 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 a 50% reduction in Psoriasis Area and Severity Index (PASI50) 
(patients showing lack of efficacy), will be discontinued from treatment after Week 14 with 
the trial drug, but only followed up for safety. 
There are certain risks that arise when patients switch between different products. Multiple 
switches could theoretically lead to higher immunogenicity in patients, resulting in a higher 
number of hypersensitivity reactions and lower efficacy. This risk will be mitigated by 
closely monitoring the patient for hypersensitivity reactions, collection and follow-up of 
reported AEs.
The benefit-risk profile for the patients participating in this trial remains favourable and 
similar to the originator product Humira®. BI 695501, as a proposed biosimilar product, is 
expected to provide comparable efficacy, safety, tolerability and immunogenicity in patients 
with moderate-to-severe chronic plaque psoriasis and therefore is expected to provide a 
similar benefit-risk profile as US-licensed Humira®.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary objective of the trial is to assess the PK similarity between patients receiving 
US-licensed Humira® continuously vs those who switch between BI 695501 and US-licensed 
Humira®, in patients with moderate-to-severe chronic plaque psoriasis.
The secondary objectives of this trial are to descriptively compare the safety, immunogenicity 
and efficacy profiles between patients receiving US-licensed Humira® continuously vs those 
who switch between BI 695501 and US-licensed Humira®.
2.1.2
Primary endpoint(s)
The primary endpoints are: 
•
AUCτ, 30-32
(Area under the adalimumab plasma concentration-time curve [AUC] over the 
dosing interval of Week 30-32) 
•
Cmax, 30-32
(Maximum observed adalimumab plasma concentration during the dosing interval 
Week 30-32) 
2.1.3
Secondary endpoint(s)
The secondary endpoints are: 
Pharmacokinetic
•
Cmin, 30-32
(Minimum observed adalimumab plasma concentration during the dosing interval 
Week 30-32)
•
tmax, 30-32
(Time to maximum observed adalimumab plasma concentration during the dosing 
interval Week 30-32)
Efficacy
•
Proportion of patients with a PASI75 response at Week 32
•
Proportion of patients with an Static Physician’s Global Assessment (sPGA) ≤1 
(clear or almost clear) at Week 32
Immunogenicity
•
Proportion of patients with ADAs at Week 32 
•
ADA titer of patients with ADAs at Week 32
•
Proportion of patients with neutralizing antibody (nAb) frequency and titer at 
Week 32
Safety
•
Proportion of patients with drug-related AEs during the treatment phase and the 
safety follow-up period


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a 58-week, multiple-dose, active comparator trial with a single-arm run-in period of 
14 weeks duration for all entered patients, followed by a randomized, double-blind, two-arm 
period of 34 weeks. The total treatment period will be 48 weeks followed by 10 weeks of 
safety follow-up. 
All entered patients will have a planned run-in period of 14 weeks during which they will be 
treated with US-licensed Humira® (last dose at Week 12/Visit 8) (see Section 4.1 for dosage). 
At the beginning of Week 14 (Visit 9), patients achieving at least a PASI50 response will be 
randomized in a 1:1 ratio to either continue receiving US-licensed Humira® (continuous US-
licensed Humira® arm) until Week 48 or receive BI 695501/US-licensed Humira®/BI 695501 
alternately for three periods (switching arm) in a blinded fashion (BI 695501 at Week 
14/Visit 9 and Week 16/Visit 10, US-licensed Humira at Week 18/Visit 11 and Week 
20/Visit 12, and BI 695501 every other week from Week 22/Visit 13 to Week 48/Visit 26). 
At Week 14, the randomization will be stratified by the level of their Week 14 PASI response 
(≥PASI50 to < PASI75 and ≥ PASI75). All patients will continue to receive 40 mg 
US-licensed Humira® or BI 695501 every other week until Week 48.
Those patients not achieving at least PASI50 at Week 14 will be discontinued from any 
further treatment in the trial, but will undergo the End-of-Treatment (EoT) and Safety 
Follow-up (SFU) for safety. 
Patients will undergo intensive PK sampling between Weeks 12-14 (Visit 8, Visits 8a-d, and 
Visit 9), and Weeks 30-32 (Visit 17, Visits 17a-d, and Visit 18) to assess PK similarity 
between the two arms. 
The co-primary PK endpoints of the trial are AUCτ, 30-32 and Cmax, 30-32 (see Section 2.1.2). 
After approximately 86 patients have had the Week 32 endpoint assessment and are PK 
evaluable, a statistician will perform a blinded evaluation of the variability to assess whether 
the initially planned sample size will be increased or not.
Figure 3.1: 1 summarizes the trial design.


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Note: Trial medications are administered at the beginning of the specified week. 
Figure 3.1: 1 Trial Design
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Chronic plaque psoriasis is considered a sensitive indication to assess PK similarity in this 
trial as BI 695501/Humira® are administered as a monotherapy in this indication. It will be 
also assessed whether patients receiving Humira® and BI 695501 in an alternating fashion 
generate a clinically relevant different immunogenic response as compared to patients 
receiving Humira® continuously.
Clinical efficacy endpoints are not considered to be sufficiently sensitive to assess any impact 
of immunogenicity on efficacy, since patients discontinuing Humira® therapy after achieving 
a 75% PASI (PASI75) response may take up to 5 months to deteriorate. “Diminished 
efficacy”, if it occurs in the context of switching, is expected to result from the increased 
development of ADAs. Increased ADA formation may lead to increased drug clearance and 
decreased exposure which in turn would result in diminished efficacy. Therefore, the 
assessment of PK after switching is considered as a sensitive surrogate marker for changes in 
efficacy.
A total of three switches will be performed for patients randomized to the switching group. 
The final switching duration provides a sufficient washout period for US-licensed Humira® in 
switching arm to reach low plasma levels, which may potentially maximize the generation of 
immunogenic response. Pharmacokinetic equivalence at the end of this switching period 


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would suggest similar immunogenicity in switching vs non-switching arms. In the context of 
switching, similar PK and immunogenicity may be extrapolated to similar long-term efficacy 
and safety between BI 695501 and US-licensed Humira®.
3.3
SELECTION OF TRIAL POPULATION
Approximately 240 patients will be randomized in approximately 80 clinical sites across 
approximately 12 countries.
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
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Males and females aged ≥ 18 to < 80 years at screening 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 trial drug (a self-reported diagnosis 
confirmed by the Investigator is acceptable), and which has been stable per Investigator 
opinion for the last 2 months with no changes in morphology or significant flares at both 
screening and baseline:
a.
involved body surface area (BSA) ≥ 10% and
b. PASI score ≥ 12 and
c.
sPGA score of ≥ 3.
2. Participants of reproductive potential (childbearing potential2) must be willing and able to 
use highly effective methods of birth control per International Council for Harmonisation 
(ICH) M3 (R2) that result in a low failure rate of less than 1% per year 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 4.2.2.3 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 or phototherapy according to 
Investigator judgement.
                                                
2 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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3.3.3
Exclusion criteria
1. Active ongoing inflammatory diseases other than psoriasis that might confound trial 
evaluations according to Investigator's judgment.
2. Prior exposure to any biologic therapies for any auto-immune diseases (eg: RA, Psoriasis, 
Crohns Disease, etc). 
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 before enrollment 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 (in the opinion of the Investigator) 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 trial, or less than 30 days (or 
less than 5 half-lives, whichever is longer) since ending another investigational device or 
drug trial(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 trial subject or unlikely to complete the trial.
9. Women who are pregnant, nursing, or who plan to become pregnant during the course of 
this trial or within the period at least 6 months following completion or discontinuation 
from the trial medication.
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 TB; 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 trial if further work up (according to local practice/guidelines) establishes 
conclusively that the patient has no evidence of active TB. If latent TB is confirmed, then 
treatment must have been initiated before treatment in the study and continued according 
to local country guidelines.3
13. Known clinically significant (per Investigator opinion) 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. 
                                                
3 For Germany: patients with positive IGRA TB test or PPD skin test will be excluded from the trial 
participation.


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14. Patients with a history of any clinically significant adverse reaction (including serious 
allergic reactions, or anaphylactic reaction, or hypersensitivity) to murine or chimeric 
proteins, previously used biological drug or its excipients, or natural rubber and latex.
15. Positive serology for HBV or 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 hospitalisation 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. Calculated creatinine clearance < 60 mL/min at screening.
3.3.4
Withdrawal of patients from therapy or assessments
Patients who do not meet all of the inclusion criteria or who meet one or more of the 
exclusion criteria will not be randomized, and will be considered screen failures. Screen 
failure patients may be rescreened once based on Investigator judgment and prior permission 
from medical monitor of the trial. The primary reason for the screen failure will be recorded 
on the electronic Case Report Form (eCRF).
All patients have the right to withdraw from the trial at any time without the need to justify 
their decision. The Investigator has the right to remove patients from the trial for non-
compliance or other reasons.
Patients may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”) with very different implications, please see Sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the randomised patients in the trial: if possible on
tretament, or at least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to randomization, as well as the
explanation of the consequences of withdrawal. 
If a patient discontinues (drops out or withdraws after randomization) from this trial, the 
patient will not be replaced.


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The decision to withdraw from trial treatment or from the whole trial as well as the reason
must be documented in the patient files and eCRF.
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication.

Lack of efficacy defined as PASI50 not reached at Week 14.

Development of a toxicity or AE which warrants BI 695501/ Humira® discontinuation 
including but not limited to 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 an 
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 stick 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 (SFU Visit) and Section 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g., AEs) must be recorded in 
the eCRF. These data will be included in the trial database and reported.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow-up on safety cannot opccur.


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If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment, please see Section 3.3.4.1
above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the trial protocol, 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).
3.3.5
Replacement of subjects
In case more than 30% of the patients are not eligible for the primary endpoint analysis, the 
trial clinical monitor together with the trial pharmacokineticist and the trial statistician are to 
decide if and how many subjects will be replaced. However the total number of patients 
recruited will not exceed 350. A replacement patient will be assigned a unique study patient 
number, and will be assigned to the same treatment as the patient he or she replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
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 trial. 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 1
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:
40 mg at Week 14 and Week 16 (2 injections), and every other 
week from Week 22 to Week 48 in the switching arm 
(14 injections)
Route of administration:
s.c. injection
Site of administration:
Front of the thighs or abdomen/belly, at least 2 inches (about 
5 centimeters) away from the navel
Table 4.1.1: 2
Reference product
Substance:
US-licensed Humira® (adalimumab)
Pharmaceutical formulation:
Solution for injection in prefilled syringe
Source:
.
Unit strength:
40 mg / 0.8 mL or 40 mg / 0.4 mL
Posology:
80 mg (loading dose) on Day 1, Week 1
40 mg every other week from Week 2 to Week 12
Continuous US-licensed Humira® arm: 40 mg every other week 
from Week 14 to Week 48
Switching arm: 40 mg at Week 18 and Week 20 (2 injections)
Route of administration:
s.c. injection
Site of administration:
Front of the thighs or abdomen/belly, at least 2 inches (about 
5 centimeters) away from the navel
BI 695501 will be provided as sterile, preservative-free, non-pyrogenic, single-use prefilled 
glass syringes containing 40 mg of BI 695501 per 0.8 mL. One syringe will be used per 
injection. The needle cap of the syringe contains dry, natural rubber. 


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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 (40 mg) will be used, except for Week 1 / 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.
4.1.2
Selection of doses in the trial
In the US and EU, Humira® has received health authority approval for the treatment of RA, 
Crohn’s disease, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile 
idiopathic arthritis, Uveitis and Hidradenitis suppurativa. The doses of BI 695501 and 
Humira® selected for this trial are reflective of the approved treatment regimen for plaque 
psoriasis of Humira® (initial dose of 80 mg, followed by 40 mg given every other week 
starting one week after the initial dose) (R16-0358).
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. 
The Day 1 pre-treatment call will depend on the trial site procedure. The process for 
treatment assignment will 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 pre-
treatment call will be made as described below and trial medication will be shipped. The pre-
treatment call might be made 15 days prior to the planned first administration of trial 
medication. 
At the beginning of Week 14, patients with at least a PASI50 response will be randomized to 
one of two sequences (1:1) to either switching or non-switching arm. At Week 14, the 
randomization will be stratified by the level of their Week 14 response (≥ PASI50 to 
< PASI75 or ≥ PASI75). Access to the randomization code will be controlled and 
documented. The block sizes of the randomization will be documented in the clinical trial 
report (CTR).
Randomization will be performed by the IRT. Patients will be randomized sequentially (the 
lowest sequentially available randomization number).
Each syringe of trial medication will be labelled with the trial code and a unique medication 
identification number. The IRT system will be used for the randomization, allocation and 
supply of trial medication throughout the trial. The IRT will assign each patient a unique 
medication number. Details on the IRT system will be provided in the ISF.


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4.1.4
Drug assignment and administration of doses for each patient
The trial design is described in Section 3.1. 
Prefilled syringes will be used for the injections (see Section 4.1.1). Injections will be 
administered subcutaneously to the front of the thighs or abdomen/belly, at least 2 inches 
(about 5 centimeters) away from the navel. Rotate injection sites and do not give injections 
into areas where the skin is tender, bruised, red or hard.
After the first injection (Visit 2) and at randomization (Visit 9), 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 dose is administered. As 
soon as possible, the dosing should return to the original schedule and refer back to baseline. 
A minimum interval of 1 week between 2 successive injections should be adhered to. 
In the event of an anaphylactic or other serious allergic 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
4.1.5.1
Blinding
The trial is carried out in a double-blind fashion. Third-party blinding will be used to 
administer trial medication. 
Access to the randomization code will be controlled and documented. All persons directly 
involved in the conduct of the trial will have no access to the treatment allocation prior to 
final database lock (see Section 4.1.5.2).
The randomization code will be kept secret by IRT up to database lock.
It is planned to conduct the trial using pre-filled syringes of 0.8 mL Humira® (40 mg) as the 
reference product throughout.
However, if this 0.8 mL pre-filled Humira® syringe is not available for complete trial supply, 
the trial conduct may have to be continued using the 0.4 mL pre-filled Humira® syringe as the 
reference product. Taking into account that the 0.8 mL BI 695501 and the 0.4 mL Humira®
presentations might differ, the blinding of treatments will be maintained by using a third-
party blinding procedure. This means that the trial 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 trial (see Appendix 10.3 for details on third party blinding procedure).
The secondary packaging (carton containing syringes) will be the same design for both 
BI 695501 and Humira®. The label text on secondary packaging (carton containing syringes) 
will be identical for both the products. However, the use-by date (expiry date) will be open.


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4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator / pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and/or appropriate eCRF page along with the date and 
the initials of the person who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’ s Pharmacovigilance group to 
access the randomisation 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. Detailed storage conditions will be described on the 
trial medication labels.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (CRA) (as provided in the list of contacts in the ISF) 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 head 
of the investigational site;

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;

Availability of the proof of a medical license for the principal Investigator; and

Availability of Form 1572 (for US). 


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The designated person must maintain records of the investigational 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.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
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 authorise an appropriate therapy. In 
those cases, patients 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 trial or must refer them for appropriate ongoing care according to local 
guidelines and daily practice, respectively.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Restrictions on prior and concomitant medications during the course of the trial are described 
in Table 4.2.2.1: 1.
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 with 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 discuss the 
introduction of any of the medications listed in Table 4.2.2.1: 1 with the CRO Medical 
Monitor. 
Any concomitant medications will be recorded in the appropriate sections of the eCRF.


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Table 4.2.2.1: 1
Prior and concomitant treatments
Treatment
Restriction
Biologic agents (e.g., TNF 
antagonists, anti-IL12/23 and 
anti-IL17)
Previous or concomitant treatment with any biologic therapy for auto-
immune diseases is not permitted. 
Concomitant medication with either anakinra or abatacept is not 
recommended.
Cyclophosphamide
Cyclophosphamide will not be permitted within 6 months prior to 
Visit 2/Day 1 and for the duration of the trial.
Topical steroids
Topical steroid treatment applied on psoriatic lesions/scalp/nails will not be 
permitted within 2 weeks prior to Visit 2/Day 1 and for the duration of the 
trial. Occlusive topical corticosteroids in any location will not be permitted 
within 2 weeks prior to Visit 2/Day 1 and for the duration of the trial. 
Topical corticosteroids of low potency (WHO group VI/VII) are permitted 
during the trial except within 24 hours before trial 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 Visit 2/Day 1 and for the duration of the trial. However, use of 
emollients (moisturizing treatments) will be permitted during the trial 
duration except within the 24-hour period immediately prior to each clinic 
visit.
UVB or UVA or PUVA 
treatment
Treatment with UVB or UVA (without psoralen) will not be permitted 
within 2 weeks prior to Visit 2/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 Visit 2/Day 1 and for the duration of the trial. 
Nutraceutical treatments
Nutraceuticals intended for the treatment of psoriasis will not be permitted 
within 4 weeks prior to Visit 2/Day 1 and for the duration of this trial.
Other systemic or locally acting 
medications
Treatment with any other systemic or locally acting medications which 
might counter or influence the objective of the trial (e.g., NSAID, 
antihistamine), or medications known to provoke/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 Visit 2/Day 1 and are 
planned to remain so for the duration of this trial.
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 Visit 2/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 Visit 2/Day 1 or throughout the trial.
Oral corticosteroids
Not permitted within 4 weeks prior to Visit 2/Day 1 or throughout the trial.
Prosorba® Column
Not permitted within 6 months of the Screening Visit.
Leflunomide 
Not permitted. Must be withdrawn at least 8 weeks prior to Visit 2/Day 1.


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Abbreviations: IL=interleukin; IV=intravenous; NSAID=nonsteroidal anti-inflammatory drugs; PUVA= psoralen with 
ultraviolet light; TNF=tumor necrosis factor; UVA=ultraviolet A light; UVB=ultraviolet B light; WHO=World Health 
Organization.
4.2.2.2
Restrictions on diet and life style
Moisturizers/emollients containing retinoids and the use of tanning beds are not allowed 
during the trial.
4.2.2.3
Restrictions regarding women of childbearing potential 
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 trial requires immediate interruption of trial 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 treatment.
Women of childbearing potential must use the contraception methods described in the patient 
information for 6 months after the last dose of trial drug. Acceptable methods of birth control 
include, for example, birth control pills, intrauterine devices (IUDs), surgical sterilization, 
vasectomized partner. 
Women of childbearing potential are defined as:
•
Having experienced menarche and 
•
Not postmenopausal (12 months with no menses without an alternative medical 
cause) and 
•
Not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy).
•
Women must not breast-feed for at least six months after the last adalimumab 
treatment.
4.2.2.4
Restrictions regarding male participants of reproductive potential
Male participants with female partner(s) of child-bearing potential must agree to use a 
medically acceptable method of contraception during the trial described in the patient 
information 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, 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 patients 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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4.3
TREATMENT COMPLIANCE
Compliance will be assured by the observation of trial medication administration (see 
Flow Chart) by dedicated trial personnel considered qualified to perform or observe the s.c. 
injections. 
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. 
Patients who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) will 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.
ASSESSMENTS
Please refer to the Flow Chart for the schedule of assessments for the trial.
5.1
ASSESSMENT OF EFFICACY
The following assessments will be made at the time points indicated in the Flow Chart for the 
purposes of calculating the PASI, sPGA, 
 scores.
5.1.1
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 (Table 10.2: 2).
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 represent 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, Table 10.2: 4)
5.1.2
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 patient’s disease state at the time of the assessments, 
without comparison to any of the patient’s previous disease states (dynamic), whether at 
baseline or at a previous visit (Appendix 10.2, Table 10.2: 1).


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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
ASSESSMENT OF SAFETY
At the Screening Visit, the medical examination will include documentation of patient 
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 other visits, it will include review of vital signs, 12-lead ECG, laboratory tests, 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).
5.2.1
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, body weight, skin, 
head, neck, throat, lymph nodes, cardiovascular and neurological systems, thyroid gland, 
musculoskeletal system/limbs, respiratory tract and abdomen. Clinically relevant abnormal 
findings will be reported as baseline conditions or AEs.
5.2.2
Vital signs
Vital signs will be assessed at the visits indicated in the Flow Chart.
Blood pressure, respiratory rate, and pulse rate measurements should be taken following at 
least 5 minutes rest while the patient is in a sitting position. The patient’s body temperature 
will also be recorded. The 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 (see 
Section 5.2.6.2).


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5.2.3
Safety laboratory parameters
The laboratory tests listed in Table 5.2.3: 1 will be analysed by a central laboratory. The 
central laboratory provider will also provide the materials for blood sampling. Instructions for 
the labelling, 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 5.2.6.1); however, if the laboratory value abnormality is consistent with a current 
diagnosis, it will be documented accordingly.
Table 5.2.3: 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)
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)


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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)
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)
Hepatitis B (HBsAg, anti-HBc)
Hepatitis C (anti-HCV)
HIV-1 and HIV-2 antibody (qualitative, where 
mandated by local authorities, at the discretion of the 
Investigator where clinically indicated)
Screening for infections (at screening, Visit 14, EOT, 
and optional retest at Unscheduled 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; GGT=gamma-glutamyl transferase; GOT=glutamic-oxaloacetic transaminase; GPT=glutamic pyruvic 
transaminase; Hb=hemoglobin; HBsAg= hepatitis B surface antigen; Hct=hematocrit; HIV=human immunodeficiency 
virus; IGRA=interferon gamma-release assay; PPD=purified protein derivative; RBC=red blood cell; 
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.
5.2.4
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.


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5.2.5
Other safety parameters
5.2.5.1
Local tolerability
The assessment of injection site reactions will be done by the Investigator/designee in blinded 
fashion 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.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
-
requires inpatient hospitalisation or 
-
requires prolongation of existing hospitalisation,
-
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 appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.6, subsections “ AE Collection” and AE reporting to sponsor and 
timelines”


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In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined 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 (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g., the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, 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

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 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
2. Anaphylactic reactions
3. Serious infection (defined as infections requiring i.v. antibiotics or meeting the regulatory 
definition of an SAE)
4. Hypersensitivity reactions
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgement 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 trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the 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 trial drug administration), until the individual patient’s end of trial: 
-all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
-the investigator does not need to actively monitor the patient for AEs but should only 
report related SAEs and related AESIs of which the investigator may become aware of by 
any means of communication, e.g., phone call. Those AEs should however, not be 
reported in the CRF.


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Figure 5.2.6.2: 1
Adverse event collection
The REP is defined as 10 weeks after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment. 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 unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the investigator could inform the sponsor / sponsor 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, if applicable. 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 BI SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only.All (S)AEs, including those 


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persisting after individual patient’s end of trial must be followed up until they have resolved, 
have been assessed as “chronic” or “stable” , or no further information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s / 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.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Plasma samples of BI 695501 or adalimumab will be obtained from each patient at the visits 
specified in the Flow Chart and Table 5.3.1: 1.


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Table 5.3.1: 1
Pharmacokinetic estimated sample time points
Visit
Week
Day
PTM [h]
PK Sample
ADA/nAb samples
2
Baseline
1
-1
within 3 hours
before drug administration
X (predose)
3
2
8
168
X (predose)
6
8
50
1176
X (predose)
8
12
78
1848
X (predose)
8a
81
1920
72 hours ± 12 hours 
after the Week 12 dosing
8b
83
1968
120 hours ± 12 hours 
after the Week 12 dosing
8c
85
2016
168 hours ± 12 hours
after the Week 12 dosing
8d
88
2088
240 hours ± 12 hours
after the Week 12 dosing
9
14
92
2184
336 hours ± 3 hours 
after the Week 12 dosing
AND within 3 hours
before Week 14 dosing
X (predose)
11
18
120
2856
within 3 hours
before drug administration
X (predose)
13
22
148
3528
X (predose)
17
30
204
4872
X (predose)
17a
207
4944
72 hours ± 12 hours
after the Week 30 dosing
17b
209
4992
120 hours ± 12 hours
after the Week 30 dosing
17c
211
5040
168 hours ± 12 hours
after the Week 30 dosing
17d
214
5112
240 hours ± 12 hours
after the Week 30 dosing
18
32
218
5208
336 hours ± 3 hours
after the Week 30 dosing 
AND within 3 hours
before Week 32 dosing
X (predose)
22
40
274
6552
within 3 hours
before drug administration
X (predose)
27
50 / EoT
344
8232
no restrictions
X
28
58 / SFU
400
9576
no restrictions
X
Abbreviations: ADA=anti-drug antibody; EoT=End-of-Treatment; nAb=neutralizing antibody; PK=pharmacokinetic; 
PTM=Planned Time; SFU=Safety Follow-up.
It needs to be ensured that samples indicated to be taken before drug administration (predose) 
in the table above will be taken before the next injection is given. It will be essential for the 


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Investigator or designated staff to document the exact date and time when each sample was 
taken and the time of administration of the most recent dose preceding the sample in the 
eCRF. Pharmacokinetic parameters will be evaluated using noncompartmental analysis 
methods according to the derivations defined in the TSAP.
The sponsor will offer the patient a Home Health Care (HHC) service to support the patient 
with compliance to the multiple blood draws at specific points in time for this study. This 
service includes a qualified home healthcare professional (nurse) who will visit the patient 
outside of the clinic (at home or at an alternative location to be specified by the patient and 
agreed by the study team) to collect specific blood samples required after Visit 8 (Visits 8a-d) 
and after Visit 17 (Visits 17a-d), avoiding the requirement for the patient to come to the clinic 
to have these samples collected. 
5.3.2
Methods of sample collection
Full instructions for collection, labelling, storage and shipment of samples are provided in the 
Laboratory Manual.
In the event of early withdrawal from the trial, every effort should be made to take a PK 
sample as part of the early withdrawal procedures, if possible, with date and time of sample 
and time of dose prior to this sample recorded.
Estimated blood volumes are shown in Section 6.1.
5.3.3
Analytical determinations
Plasma concentrations of BI 695501 and adalimumab will be measured using a validated 
method.
After completion of the trial, selected PK samples may be retained and may be analyzed for 
the presence of species (e.g., soluble proteins or small molecule entities) potentially 
interfering with the analysis method or for generation of ADA positive control material and 
stability testing for use in future assays. Retained samples may also be used to further 
characterize the immune response (e.g., isotyping of ADA) if required and as additional assay 
methods are developed. The results of any additional ADA analyses of the retained samples 
(i.e., analyses not already specified in this protocol) will be reported separately from the CTR. 
All remaining trial samples will be discarded after completion of the additional investigations 
upon written authorisation by the sponsor, but not later than 5 years after the final CTR has 
been signed.
5.3.4
Pharmacokinetic – pharmacodynamic relationship
Not applicable. 
5.4
ASSESSMENT OF BIOMARKER(S)
Not applicable. 


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5.5
OTHER ASSESSMENTS
5.5.1
Assessment of immunogenicity
5.5.1.1
Plasma sampling for anti-drug-antibodies characterisation
For characterization of human anti-BI 695501 or anti-adalimumab antibodies (ADA), 
approximately 3 mL of blood will be collected in a dipotassium ethylenediaminetetraacetic 
acid (K2EDTA) anticoagulant blood drawing tube at time points indicated in Flow Chart and 
Table 5.3.1: 1.
Full instructions for collection, labelling, storage and shipment of samples are provided in the 
Laboratory Manual.
After completion of the trial, selected immunogenicity (ADA and nAb) samples may be 
retained and may be analyzed for the presence of species (e.g., soluble proteins or small 
molecule entities) potentially interfering with the analysis method or for generation of ADA 
positive control material and stability testing for use in future assays. Retained samples may 
also be used to further characterize the immune response (e.g., isotyping of ADA) if required 
and as additional assay methods are developed. The results of any additional ADA analyses 
of the retained samples (i.e., analyses not already specified in this protocol) will be reported 
separately from the CTR. 
All remaining trial samples will be discarded after completion of the additional investigations 
upon written authorisation by the sponsor, but not later than 5 years after the final CTR has 
been signed.
Estimated blood volumes are shown in Section 6.1.
5.5.1.2
Plasma sampling for neutralizing antibody characterisation
For characterization of human neutralizing anti-BI 695501 or adalimumab antibodies (nAb), 
approximately 6 mL of blood will be collected in a K2EDTA anticoagulant blood drawing 
tube at the same time points as ADA samples are collected. 
Full instructions for collection, labelling, storage and shipment of samples are provided in the 
Laboratory Manual.
Neutralizing antibodies will be detected in human plasma samples using validated methods.
5.6
APPROPRIATENESS OF MEASUREMENTS
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. 
Measurement of the drug concentrations is necessary for the determination of the PK profile. 
Determination of ADAs and nAbs will support the PK, efficacy and safety analysis.


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Therefore, the appropriateness of all measurements applied in this trial is assured.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
A schedule of assessments is provided in the Flow Chart.
Visits will be scheduled as close as possible to the preplanned schedule: 
•
No visit window is permitted for Visit 2 (Day 1).
•
A visit window of ± 2 days is permitted from Visit 3 up to Visit 8
•
Visit 9 has to be scheduled exactly 14 days after Visit 8
•
A visit window of ± 3 days is permitted for Visit 10 to Visit 17
•
Visit 18 has to be scheduled exactly 14 days after Visit 17
•
A visit window of ± 3 days is permitted for Visit 19 to Visit 27
•
A visit window of ± 3 days is permitted for Visit 28
•
Trial medication will be administered at Day 1, with the second injection 7 days later, and 
subsequent injections every 2 weeks thereafter (± 2 days up to Week 12, ± 3 days from 
Week 14 to Week 48).
Note: The below trial medication administration time points will need to be strictly followed 
as shown. 
Trial medication at Week 14 (Visit 9) 
should be administered exactly 14 days after Week 12 Visit (Visit 8).
Trial medication at Week 32 (Visit 18) 
should be administered exactly 14 days after Week 30 Visit (Visit 17).
On trial medication administration days, all assessments should be performed prior to 
administration, unless otherwise specified. Laboratory samples must be drawn prior to trial 
medication injection.
Questionnaires will be completed at the site by the patient before any investigations or 
discussions about their disease with the clinic staff and may only be recorded by a trial 
nurse/Investigator on behalf of the patient if the patient has difficulty writing during the visit 
or is unable to read. This must be documented clearly in the patient notes.
The total estimated volume of blood that will be drawn from each patient during the course of 
the trial is shown in Table 6.1: 1.


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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
8
24
Hematology
3
8
24
ADAs
3
12
36
nAbs
6
12
72
Pharmacokinetics
3
20
60
Infection screen
4
1
4
TB test
3
3
9
Approximate total
229
Abbreviations: ADAs=anti-drug antibodies; nAbs=neutralizing ADAs; TB=tuberculosis.
It should also be noted that additional samples may be required if medically indicated, e.g., at unscheduled visits to follow
safety findings.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
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 trial site will enter the screened patient into the system using the 
IRT. Patients can be re-screened in case they have failed an eligibility assessment at 
screening that is fulfilled at a later date during the recruitment period of the trial. Screen 
failure patients may be rescreened once based on Investigator judgment and prior permission 
from medical monitor of the trial (see Section 3.3.4). All assessments have to be repeated for 
the rescreened patients. 
The procedures and assessments performed at screening are shown in the Flow Chart. 
Once patients have completed screening and have met all the inclusion criteria and none of 
the exclusion criteria, treatment kit assignment can occur using the IRT system.
6.2.2
Treatment period(s)
The trial medication will be administered at the site on days when trial assessments will be 
performed. Trial medication will be administered at Visit 2 (Day 1), at Visit 3 (± 2 days), and 
then every 2 weeks from Visit 4 onward. 
The procedures and assessments performed at Visit 2 through Visit 8 are shown in the 
Flow Chart. 
At Visit 9 (the beginning of Week 14), patients with at least a partial response (PASI50) at 
Week 14 will be randomized to one of two sequences (1:1) according to the stratification 
factors (see Section 4.1.3 for details).
Other procedures and assessments performed at Visit 9 through Visit 26 are shown in the 
Flow Chart. 


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End-of-Treatment procedures and assessments will be performed at Visit 27 as shown in the 
Flow Chart.
Safety Follow-up procedures and assessments will be performed at Visit 28 as shown in the 
Flow Chart.
6.2.3
Follow-up period and trial completion
End-of-Treatment Visit
Patients who prematurely discontinue the trial at any time after Day 1 (but do not withdraw 
their consent) will be required to have all of the evaluations for the Week 50 Visit as soon 
after trial discontinuation as possible. 
Every effort should be made for all patients who complete the total 50-week treatment period, 
or who discontinue the trial early, to return for an SFU Visit at Week 58 or 10 weeks after the 
last treatment administration. 
Unscheduled visit assessments
Patients may attend the trial site for unscheduled visits at any time for additional safety 
monitoring at the discretion of the Investigator.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a randomized, double-blind, parallel-arm, multiple-dose, active comparator, multi-
center, multi-national trial. 
Trial objectives are as stated in Section 2.1.1.
7.2
NULL AND ALTERNATIVE HYPOTHESES
For the primary endpoint analysis the BE margins 80% – 125% on the ratio scale will be 
applied. 
The two endpoints are considered coprimary (i.e., the trial is considered positive if the results 
for both endpoints are simultaneously positive), therefore no multiplicity-adjustment with 
respect to the alpha level will be performed.
The tests for PK similarity will be performed with respect to switching versus continuous 
Humira.
The hypotheses for the primary endpoint analysis can be written as follows:
H01:
Ratio of the means of AUCτ, 30-32 (switching arm versus continuous Humira®
arm) is less than 80% or more than 125%
H11:
Ratio of the means of AUCτ, 30-32 (switching arm versus continuous Humira®
arm) is within [80%, 125%]
and
H02:
Ratio of the means of Cmax, 30-32 (switching arm versus continuous Humira®
arm) is less than 80% or more than 125%
H12:
Ratio of the means of Cmax, 30-32 (switching arm versus continuous Humira®
arm) is within [80%, 125%]
A (one-sided) significance level 4.9% was chosen to ensure overall type I error control at 5%, 
in light of the adapted analysis strategy (details are described in the TSAP).
7.3
PLANNED ANALYSES
Pharmacokinetic parameters of a patient will be included in the statistical analyses of PK 
endpoints if they are not flagged for exclusion due to a protocol violation relevant to the 
evaluation of PK. Whether a protocol violation is considered relevant will be decided no later 
than in the Data Review Meeting (DRM) prior to the data snapshot. Exclusion of a patient’s 
data will be documented in the CTR.
Relevant protocol violations within the time period critical for primary endpoint evaluation 
(i.e., from Visit 2 to 18) may be:


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•
Incorrect trial medication taken, i.e., the patient received at least one dose of trial 
medication the patient was not assigned to.
•
Incorrect or incomplete dose of trial medication taken.
•
Missed doses of trial medication.
•
Use of restricted medications with suspected impact on PK.
•
Missed plasma samples during the dosing interval from Week 12 to Week 14 or from 
Week 30 to Week 32:
o
at two consecutive timepoints during Visits 8a-d and 17a-d
o
before dosing at Week 12, 14, 30 or 32.
Further criteria that may lead to exclusion of subjects or individual plasma concentrations 
from the calculation of PK parameters or exclusion of PK parameters from statistical analyses 
may be specified in the TSAP and in the minutes of the Data Review Meeting.
The PKS includes all patients in the Treated Set (TS, see below) who provide at least one 
primary PK parameter that was not excluded according to the description above. 
All efficacy analyses will be based on the Per Protocol Set (PPS). 
The PPS consists of all patients 
•
who were randomized to double-blinded treatment
•
who received at least one dose of double-blinded trial medication, and 
•
who have all efficacy measures relevant for at least one secondary efficacy endpoint, 
measured prior to randomization (last non-missing value prior to randomization) and at 
least once post-randomization.
•
who have followed the CTP in all essential criteria: 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 secondary efficacy 
endpoint. Important protocol violations may include: Incorrect trial medication taken, 
violation of treatment compliance, violation of inclusion/exclusion criteria. Protocol 
violations will be assessed on a case-by-case basis. Further details on the definition of the 
different analysis sets will be provided in the TSAP. 
All patients treated with at least one dose of trial medication administered in the randomized
phase will be included in the safety evaluation (TS).
All patients treated with at least one dose of Humira® during the run-in period will be 
included in the Run-in Treated Set (RTS).
The primary, secondary and further analysis results will be presented based on the double-
blind randomization (continuous Humira® arm and switching arm).
7.3.1
Primary endpoint analyses
The analyses will be performed on the PKS and done ‘as treated’. 
The PK similarity of the two treatments (switching arm versus continuous Humira® arm) will 
be tested for the primary parameters AUCτ, 30-32 and Cmax, 30-32 (see Section 2.1.2 for details). 


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The ratios of the means including their two-sided 90.2% CIs will be calculated. The 
confidence interval will be calculated according to Fiellers theorem [R12-1809]. As stated in 
[R12-1809, chapter 10.2.1], equivalence will be concluded if Fieller’s 90.2% confidence 
interval for the ratio of means is included in the equivalence range 80.00% – 125.00% and
||
	
 1

> ,
which is equivalent to rejecting both null hypotheses. Thereby  refers to the LSMean of the 
reference treatment, 	 is the residual standard deviation from the ANCOVA model (M1) 
below, nT and nR are the final sample sizes in the test and reference arm, respectively, and 
= 4.9%.
The statistical model used for the analysis of AUCτ, 30-32 and Cmax, 30-32 will be an analysis of 
covariance (ANCOVA) model on the original scale. This model will include effects 
accounting for:
•
Treatment (switching arm versus continuously Humira® arm)
•
Logarithm of rPASI, where rPASI is the ratio of PASI at Week 14 and PASI at Week 1 
(continuous value) 
•
Weight at Week 14 (continuous value)
•
Stage, where stage represents the two parts of the study prior to and after the blinded 
sample size reassessment (categorical, 1 or 2)
•
AUCτ, 12-14 or Cmax, 12-14 (continuous value)
as a source of variation. As the measurements at Week 14 will be prior to randomization and 
all patients will have received the same treatment with the reference treatment only, the 
covariates listed above are all considered adequate baseline values.
All effects will be considered as fixed. The model is described by the following equation:
(M1)
response (AUCτ or Cmax) = overall mean + treatment effect + log(rPASI) + 
weight at Week 14 + stage + AUCτ, 12-14 or Cmax, 12-14 + random error.
where the random errors are assumed to be independent and normally distributed with zero 
mean and variance σk
2 where k is either test or reference treatment.
Prior to analysis, the data will be log-transformed (see M1). In other words, the dependent 
variable of the primary endpoint analysis model is the primary endpoint, as stated in the M1 
formula. The analysis will then be adjusted for the covariates as stated in M1. The model will 
be implemented with the SAS® procedure PROC MIXED in conjunction with the LSMEANS 
statement. The LSMEANS statement is used to estimate the treatment. LSMeans of the 
switching and non-switching arm which will be used to construct the point estimate for the 
ratio of means. The 90.2% CI will be derived based on Fieller’s theorem.
All patients that finished Week 32 Visit at or before the cut-off date will be allocated to 
stage 1. All other patients (i.e., all patients that at cut-off date do not have a finished Week 32 
Visit) will be allocated to stage 2.


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7.3.2
Secondary endpoint analyses
7.3.2.1
Secondary PK endpoint analyses
The secondary PK endpoint Cmin, 30-32 will be analyzed in the same way as the primary 
endpoints (see Section 7.3.1). However, only the mean ratio and CIs will be calculated and 
presented. No formal comparison to margins will be performed.
The secondary PK endpoint tmax, 30-32 will be analyzed in a descriptive manner only.
7.3.2.2
Secondary efficacy endpoint analyses
All secondary efficacy endpoint analyses will be based on the PPS and incomplete or missing 
data will be handled as described in Section 7.3.2.
The analysis of efficacy endpoints (see Section 2.1.3) will be based on asymptotic method. 
The difference in proportions will be calculated as the difference between the observed 
proportions in each treatment group. Conficence intervals for the difference of proportions 
will be obtained using the Wald method, which is based on the asymptotically normal 
approximation to the distribution of the observed sample proportions.
The 90% and 95% CIs will be provided.
7.3.2.3
Secondary immunogenicity endpoint analyses
All secondary immunogenicity endpoint analyses will be based on the TS. All secondary 
immunogenicity endpoints will be summarized descriptively.
For analysis of the secondary endpoint dedicated to safety, see Section 7.3.4.


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7.3.4
Safety analyses
The safety analyses will be descriptive in nature. The analyses will be performed based on the 
TS and RTS. 
The proportion of patients with drug-related AEs during the treatment phase will be analyzed 
as a secondary safety endpoint. 
For the proportion of patients with AESIs, risk ratios and 95% CIs will be provided in 
addition.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced.
Safety measurements (such as ECG, vital signs or laboratory parameters) and AEs as well as 
local tolerability assessments will be assigned to treatments, based on the actual treatment at 
the time of the measurement, or on the recorded time of AE onset (concept of treatment 
emergent AEs). That is, measurements and AEs recorded prior to first trial drug 
administration will be assigned to 'screening'; those between the first Humira® intake and up 
to the drug administration on Week 14 will be assigned to “run-in” period. All AEs occurring 
between start of treatment and end of the REP will be considered ‘treatment-emergent’ with 
respect to the randomized treatment arm. Adverse events that start before first drug intake 
and deteriorate under treatment will also be considered as ‘treatment-emergent’ (with respect 
to the randomized treatment arm).
Laboratory assessments after the first dose of trial medication up to a period of 10 weeks after 
the last dose of the trial medication will be assigned to the treatment phase for evaluation. 
Laboratory values will be compared to their reference ranges and frequency tables by visit
will be provided for the number of patients within and outside the reference range.
Vital signs, physical examinations, 12-lead ECG, or other safety-relevant data observed at 
screening, baseline, during the course of the trial and at the end-of-trial evaluation will be 
assessed with regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
The PK parameters listed in Sections 2.1.2, 2.1.3, 2.1.4 for patients in the switching arm and 
in the US-licensed Humira®-continuous arm will be calculated using non-compartmental 
methods according to the relevant SOP of the sponsor and as described in the TSAP.
PKS will be used for the statistical analysis of PK parameters. Plasma concentrations will be 
analyzed descriptively for all patients in the run-in treated set (RTS). Moreover, PK 
parameters will be also descriptively analyzed for patients in the RTS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of PK parameters. Concentrations used in the PK calculations 
will be in the same format provided in the bioanalytical report, that is, to the same precision 
of decimal places or significant figures as provided in the bioanalytical report.


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If a measured level for a given PK sample is BLQ then 1/2 LLOQ of the bioanalytical assay 
(0.0125 µg/mL) will be used for the parameter calculations. For samples taken at baseline 
(visit 2) BLQ values will not be replaced by 1/2 LLOQ.
If all plasma concentrations of an intensive PK interval (week 12-14 and/or week 30-32) 
will be replaced by ½ LLOQ, both Cmax and Cmin of the respective dosing interval will 
equal ½ LLOQ. The corresponding tmax and tmin will be the actual time of the first plasma 
sample in this dosing interval. 
Both analyte plasma concentrations and PK parameters for the switching arm and in the US-
licensed Humira®-continuous arm will be listed and presented graphically as appropriate. 
At least the following descriptive statistics will be calculated for plasma concentrations as 
well as for all PK parameters: N, arithmetic mean, standard deviation, minimum, median, 
maximum, Q1, Q3 (Q1 and Q3 only for PK parameters), arithmetic coefficient of variation 
(CV), geometric mean, and geometric CV. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then, the individual PK values as well as the descriptive statistics will 
be reported with three significant digits in the CTR.
For the statistical analysis of the PK endpoints please refer to Section 7.3.1.
7.4
INTERIM ANALYSES
7.4.1
Blinded review of sample size
The blinded, pooled AUCτ, 30-32 or Cmax, 30-32 will be monitored to verify the sample size 
assumptions. 
Due to the uncertainty about the PK variability, a sample size re-assessment procedure as 
described in Friede and Kieser (P04-05360) and Golkowski et al (R16-4933) has been 
considered for this study. The initially planned total sample size is 170 PK evaluable patients 
(i.e., patients in the PKS and all necessary covariates are available). This is also set to be the 
minimum sample size for the trial.
For this study a maximum sample size to be recruited is set to 350. Taking into account the 
drop-out rates as described above this translates to a maximum of approximately 246 PK 
evaluable patients at Week 32.
After (approximately) 86 patients have had their Week 32 primary endpoints assessment and 
are PK evaluable the variability of AUCτ, 30-32 and Cmax, 30-32 will be re-estimated based on the 
data of those 86 patients. This adequately allows the determination of the variability relevant 
for sample size (re-)calculation, which is in line with the primary endpoint analysis strategy. 
In order to mirror the primary endpoint analysis strategy the variability will be estimated after 


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stage 1 as the residual variance from the model as stated in Section 7.3.1 but, due to the 
blinded assessment, without the covariates ‘Treatment’ and ‘Stage’.
More details will be specified in the TSAP. In addition, the TSAP will provide justification 
which demonstrates that the overall type I error is maintained.
No formal statistical testing for efficacy will be performed.
7.5
FINAL ANALYSIS
The final analysis as described above will take place when all data are available, clean and 
the database is locked. 
7.6
HANDLING OF MISSING DATA
7.6.1
Pharmacokinetic data
Handling of missing PK data will be performed according to the relevant SOP of the sponsor 
(001-MCS-36-472). 
For the non-compartmental analysis, concentration data identified with no sample (NOS), no 
valid result (NOR) or not analysed (NOA) will generally not be considered for the 
evaluations (calculations and graphical representation). 
Descriptive statistics of concentrations at specific time points are calculated only when at 
least 2/3 of the individuals have concentrations within the validated concentration range. The 
overall sample size to decide whether the “2/3 rule” is fulfilled is based on the total number 
of samples that were drawn at the specific time point (i.e., below the limit of quantitation 
[BLQ] (only if not replaced by ½ LLOQ of the bioanalytical assay), NOR, NOA and NOS 
are included).
7.6.2
Efficacy data
For the analysis of secondary efficacy endpoints, missing PASI75 and sPGA data will be 
imputed using the multiple imputation (MI) method.
However, all patients who discontinue treatment, are lost-to-follow-up or have any severe 
violation related to any therapy that may significantly impact efficacy assessment (Table 
4.2.2.1: 1) prior to the secondary efficacy endpoints assessment will be considered as a non-
responder. This is referred to as ‘NRI’. 
For more details refer to the TSAP.
7.6.3
Safety data
For the aim of safety analysis, in case of missing AE relationship status, an AE will be 
considered as related. 


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For other endpoints, rules for handling of missing data will be specified in the TSAP, if 
necessary.
7.7
RANDOMISATION
On Day 1, all patients meeting the eligibility criteria will be entered and receive Humira®
during the run-in phase. At the beginning of Week 14, patients with at least a partial response 
(PASI50) will be randomized at 1:1 to either receive Humira® until Week 48 or alternatively 
receive BI 695501 and Humira® until Week 48. Patients not achieving at least a PASI50 
response at Week 14 will be considered as non-responders and will be discontinued from the 
trial. At Week 14, the randomization will be stratified by the level of their Week 14 response 
(≥ PASI50 to < PASI75 and ≥ PASI75). 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 except for unblinded 
qualified staff who will prepare and administer trial medication. The block sizes of the 
randomization will be documented in the CTR.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized 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 patients 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.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 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.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
eCRFs for individual 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 patient 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 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 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
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 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 Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analysing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and 
the banking facility are therefore assessed to be qualified for the storage and use of 
biological samples and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed insent.
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 30 days 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.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).


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8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI). 
A 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 central laboratory service and an Interactive Response Technology (IRT) vendor will be 
used in this trial. Details will be provided in the IRT Manual and Central Laboratory Manual, 
available in the ISF.
Pharmacokinetic, ADA, and nAb sample analysis will be performed by 
 


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P04-05360
Friede T, Kieser M. Blinded sample size reassessment in non-inferiority 
and equivalence trials. Statistics in Medicine 2003; 22:995-1007.
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.
R11-1259
Menter A, Griffiths CEM. Psoriasis 2: current and future management of 
psoriasis. Lancet 2007; 370:272-284.
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.
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, labeling 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)
R16-4933
Golkowski D, Friede T and Kieser M. Blinded sample size re-estimation in 
crossover bioequivalence trials. Pharmaceutical Statistics 2014; 13;157-
162.
R16-5078
Humira® (adalimumab) injection, for subcutaneous use (AbbVie) (U.S. 
prescribing information, revised: 10/2016 website 
rxabbvie.com/pdf/humira.pdf.
R96-3541
Fredriksson T, Pettersson U. Severe psoriasis - oral therapy with a new 
retinoid. Dermatologica 1978; 157:238-244.
R12-1809
Hauschke D Steinijans V Pigeot I. Bioequivalence studies in drug 
development: methods and applications. Chichester: John Wiley & Sons; 
2007.


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9.2
UNPUBLISHED REFERENCES
U13-1096-01
 
Pharmacokinetics and safety of BI 695501 in healthy subjects: a 
randomized, open-label, single dose, parallel arm, active-comparator 
clinical Phase I study. 1297.1, 24 Jan 2013.
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.
c09477818-01
Randomized, single-dose, parallel-arm, open-label Phase I trial to 
investigate and compare the pharmacokinetics, safety and tolerability of BI 
695501 administered subcutaneously via pre filled syringe or autoinjector 
(VOLTAIRE-AI). 1297.6 Final Primary Analysis Report. 26 Aug 2016.


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10.
APPENDICES
10.1
CLINICAL EVALUATIONS OF LIVER INJURY
10.1.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.6 (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, LDH, cholinesterase, haptoglobin, PT or INR, CK, CK-
MB (assessed only if CK is greater than ULN at the DILI visit), coeruloplasmin, α-1 
antitrypsin, transferin, amylase, lipase, fasting plasma glucose, cholesterol, triglycerides
Serology
•
Hepatitis A (Anti-IgM, Total Anti-Hep A), Hepatitis B (HbsAg, Anti-HBs, DNA), 
Hepatitis C (Anti HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Total Anti-
Hep D if HBsAg positive), 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, and Anti mitochondrial antibody if overall hepatitis 
serology is negative or non-reactive
Hormones, tumor marker
•
TSH
Hematology
•
CBC w/Reticulocytes (WBC, differentials, RBC, MCV, MCH, MCHC and Reticulocytes)


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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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10.2
EFFICACY ASSESSMENTS
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
Table 10.2: 1 sPGA Rating Scale for Overall Psoriatic Disease
Table 10.2: 2 Body Surface Area Involved in Psoriasis


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Table 10.2: 3 Dermatology Life Quality Index


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Table 10.2: 4 PASI


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10.3
MEDICATION BLINDING PROCEDURE FOR THIRD PARTY 
BLINDING
This is a double-blind trial, therefore patients, Investigators, and trial personnel (except the 
trial personnel administering, receiving and handling the trial medication at site) will remain 
blinded with regard to the randomized treatment assignments until after database lock. 
To prevent unblinding, a designated unblinded 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 personnel. At the time of return to the sponsor or local destruction, the designated 
unblinded person must verify that no supplies remained at the trial site. 
The unblinded trial personnel administering the trial medication will not be involved in any 
other trial assessments or procedures.
A description of the trial medication is provided in Table 4.1.1: 1 and Table 4.1.1: 2.
Patient blinding procedure
Trial medication will be administered by unblinded trial personnel 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.
(NOTE: all personnel noted below will have signed the Site Personnel Signature Log, clearly 
outlining each individual’s responsibility). 


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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 
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:
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 
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 


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blinding procedures for blinded and unblinded study CRAs will be provided during a CRA 
Meeting. Training in study blinding procedures for blinded and unblinded site staff will be 
provided at the Investigators’ Meeting; during workshop or WebEx sessions, separately 
designed for blinded and unblinded study personnel in which CRAs will participate, as well. 
Part of both workshops will review the Medication Blinding Procedures, with blinding 
procedures described. For the rest of site staff, who did not participate in an Investigators’ 
Meeting, applicable training in study blinding procedures will be provided by a blinded CRA 
during the Site Initiation Visit, based on information in Study Protocol, Medication Blinding 
Procedures and Pharmacy Manual. Such training is a part of study specific agenda for Site 
Initiation Visit, as well as slide presentation prepared for the visit. All training will be 
documented.


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10.4
POTENTIAL DRUG-INDUCED LIVER INJURY (DILI) CHECKLIST


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
17 Nov 2017
EudraCT number
2016-002254-20
BI Trial number
1297.9
BI Investigational Product(s)
BI 695501
Title of protocol
VOLTAIRE-X: Pharmacokinetics, safety, 
immunogenicity and efficacy 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.
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
X
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request 
for approval
Can be implemented without IRB / IEC / Competent Authority approval 
as changes involve logistical or administrative aspects only
Section to be changed
Title Page
Description of change
Lay Title revised
Rationale for change
Lay description of protocol revised for clarity. 
Section to be changed
Synopsis (Trial site[s]), 3.3
Description of change
Number of clinical sites revised from 75 to 80. 
Rationale for change
Number of sites updated. 
Section to be changed
Synopsis (Methodology), 3.1
Description of change
Description of “Visit Days” changed to “Visit #” for 
Weeks 12-14 and 30-32. 
Rationale for change
Changed to “visits” in case days are revised. 
Section to be changed
Synopsis (Methodology), 3.1
Description of change
Drug and dosing sequence by Week/Visit # added. 
Rationale for change
Text revised for clarity of dosing sequence. 
Section to be changed
Flow Chart list of assessments, Flow Chart Footnote 
6
Description of change
TB testing added to Week 14 and EoT visits; 
procedures to follow if positive TB results are 
obtained at screening or post-screening have been 
added. 
Rationale for change
Additional testing added to monitor TB positivity at 


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EoT. 
Section to be changed
Flow Chart
Description of change
Contact IRT added to EoT visit
Rationale for change
Missed procedure for EoT added. 
Section to be changed
Flow Chart (Cont’d)
Description of change
Change permitted window visit to “0” days
Rationale for change
Corrected a previous error. 
Section to be changed
Flow Chart, Footnote 10, Section 5.3.1
Description of change
Added collection of PK samples that may be 
performed by home healthcare nurse at sub-visits.
Rationale for change
Added for clarity. 
Section to be changed
Abbreviations
Description of change
List of Abbreviations updated as necessary.
Rationale for change
Consistency with revisions. 
Section to be changed
2.1.4
Description of change
PK endpoints added. 
Rationale for change
PK endpoints added for accuracy and completeness. 
Section to be changed
3.1
Description of change
The text: “the end of the treatment period” deleted. 
Rationale for change
Text revisions made for clarity. 
Section to be changed
3.3.2
Description of change
“Pre-treatment call” deleted from Inclusion Criterion 
#1. 
Rationale for change
Deleted to avoid confusion. 
Section to be changed
3.3.3
Description of change
Units for calculated creatinine clearance corrected in 
Exclusion Criterion #23. 
Rationale for change
Units corrected. 
Section to be changed
Table 4.1.1: 1, Table 4.1.1: 2
Description of change
Posology revised. 
Rationale for change
Posology revised for clarity. 
Section to be changed
Table 4.1.1: 1, Table 4.1.1: 2, Section 4.1.4
Description of change
Site of administration added. 
Rationale for change
Site of administration added for clarity and for 
consistency with labelling. 


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Section to be changed
Table 4.2.2.1: 1
Description of change
Live attenuated vaccine not permitted up to “5” 
months revised to “3” months. 
Rationale for change
Corrected to be aligned with the label and with other 
studies for the same molecule. 
Section to be changed
5.2
Description of change
Deleted “(including IGRA at SFU)”. 
Rationale for change
Change made to be consistent with Flow Chart.
Section to be changed
Table 5.2.3: 1
Description of change
Screening for hepatitis clarified; screening for 
infections added to Visit 14, EoT, and optional retest 
at Unscheduled visit. 
Rationale for change
Additional TB testing added for monitoring.
Section to be changed
Table 5.3.1: 1
Description of change
Revised Visit 17 PK samples from Week “17” to 
Week “30” and Visit 18 PK samples from Week “18” 
to Week “32”; PK sampling time windows revised 
from “3” hours to “12” hours at Visits 8a-d and 
17a-d. 
Rationale for change
Revised for accuracy. 
Section to be changed
Table 6.1: 1
Description of change
Number of samples and volumes revised due to TB 
tests added at Visits 14 and EoT.
Rationale for change
Revised for accuracy with updated testing. 
Section to be changed
6.2.3
Description of change
Deleted text noting that patients will be followed for 
efficacy assessments until Week 50. 
Rationale for change
Deleted since most patients will receive other 
treatments following the End-of-Treatment Visit. 
Section to be changed
7.3
Description of change
Number of missed plasma samples from Week 12 to 
14 or Week 30 to 32 revised to two consecutive 
timepoints during Visits 8a-d and 17a-d; deleted “at 
more than three timepoints”
Rationale for change
This scenario is redundant based on the other two 
defined criteria. 
Section to be changed
7.3.2.1
Description of change
Cmin revised to Cmin, 30-32. 
Rationale for change
Changes made for clarity and accuracy. 


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Section to be changed
7.4.3
Description of change
Section number revised to 7.5; description of final 
analyses revised. 
Rationale for change
Changes made for clarity and accuracy. 
Section to be changed
8.7
Description of change
Changed bioanalytical lab from 
 to 
Rationale for change
Change in laboratories. 
Section to be changed
10.1.2
Description of change
Clinical chemistry, serology, and hematology 
assessments changed to be consistent with Section 
10.4. 
Rationale for change
Revisions made for internal consistency. 
Section to be changed
Figure 10.2: 5
Description of change
Nail assessment deleted. 
Rationale for change
Nail assessment not performed in this trial. 
Section to be changed
11.1
Description of change
Description of Global Amendment 1 and summary of 
changes added. 
Rationale for change
Description of changes and rationales added per 
template.
11.2
GLOBAL AMENDMENT 2
Date of amendment
25 Jul 2019
EudraCT number
2016-002254-20
BI Trial number
1297.9
BI Investigational Product(s)
BI 695501
Title of protocol
VOLTAIRE-X: Pharmacokinetics, safety, 
immunogenicity and efficacy 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.
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
X
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


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Section to be changed
Synopsis (Statistical methods), Sections 3.1, 4.1.5,
7.2, 7.3.1, 7.3.2.1, 7.3.5, 7.4.1, 7.8, 9.1.
Description of change
The primary statistical method and sample size 
calculations have been updated based on the blinded
sample size re-assessment (BSSR) (the study is still 
fully blinded)
Rationale for change
The results of the BSSR revealed that the 
assumptions underlying the statistical analysis model 
in the current CTP version 2 were not valid.
 
 
 Therefore, the pre-specified primary 
statistical analysis (ANCOVA on the log scale) is 
considered inappropriate in this specific case. This 
amendment is changing the statistical analysis of the 
primary endpoints to adequately reflect the 
underlying data distribution. The primary endpoints 
AUCτ, 30-32 and Cmax, 30-32 are to be evaluated on the 
untransformed original scale instead of on the 
logarithmic scale. No primary analysis with week 32 
data, there will be only one final analysis with all 
data.
Section to be changed
Synopsis (Statistical methods)
Description of change
Confidence intervals updated to 90.2; Text revised to 
address the changes on pre-specified primary 
statistical analysis
Rationale for change
See above
Section to be changed
Sections 3.1, 7.4.2, 7.5
Description of change
The primary analysis when the last patient has 
completed their Week 32 assessment has been 
deleted.
Rationale for change
See above 
Section to be changed
Section 4.1.5
Description of change
Blinding of the study staff involved in the primary 
analysis when the last patient has completed their 
Week 32 assessment has been deleted.
Rationale for change
See above 
Section to be changed
Section 7.2
Description of change
1st paragraph deleted: This is equivalent to comparing 
the 90% two-sided confidence intervals (CI) for the 
ratio of geometric means with the boundaries 80.00% 


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to 125.00% used in the evaluation of PK similarity.
New paragraph added: A (one-sided) significance 
level 4.9% was chosen to ensure overall type I error 
control at 5%, in light of the adapted analysis strategy 
(details are described in the TSAP).
Means description updated (geometric deleted)
Rationale for change
See above
Section to be changed
Section 7.3
Description of change
Paragraph 1: Sentence deleted: “The Pharmacokinetic 
Set (PKS) is defined as follows.”
Paragraph 3: It was added that further criteria might 
be specified also “in the minutes of the Data Review
Meeting.”
Rationale for change
Paragraph 1: Corrected a previous error.
Paragraph 3: Adapted to the actual procedure.
Section to be changed
Section 7.3.1
Description of change
Paragraph 2 added:The confidence interval will be 
calculated according to Fiellers theorem [R12-1809]. 
As stated in [R12-1809, chapter 10.2.1], equivalence 
will be concluded if Fieller’s 90.2% confidence 
interval for the
is included in the 
equivalence range 80.00% – 125.00% and
||
	
 1

> ,
which is equivalkent to rejecting both null 
hypotheses. Thereby  refers to the LSMean of the 
reference treatment, 	 is the residual standard 
deviation from the ANCOVA model (M1) below, nT
and nR are the final sample sizes in the test and 
reference arm, respectively, and = 4.9%.
Logarithmic scale replaced by Original.
LSMEANS statement updated as follows:
The LSMEANS statement is used to estimate the 
treatment. LSMeans of the switching and non-
switching arm which will be used to construct the 
point estimate for the ratio of means. The 90.2% CI 
will be derived based on Fieller’s theorem. 


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Rationale for change
See above
Section to be changed
Section 7.3.2.1
Description of change
gMean ratio replaced by Mean ratio
Rationale for change
See above
Section to be changed
Section 7.3.5
Description of change
Paragraph 2 was replaced by:
PKS will be used for the statistical analysis of PK 
parameters. Plasma concentrations will be analyzed 
descriptively for all patients in the run-in treated set 
(RTS). Moreover, PK parameters will be also 
descriptively analyzed for patients in the RTS.
Paragraph 4 was added: 
If a measured level for a given PK sample is BLQ 
then 1/2 LLOQ of the bioanalytical assay (0.0125 
µg/mL) will be used for the parameter calculations. 
For samples taken at baseline (visit 2) BLQ values 
will not be replaced by 1/2 LLOQ.
Paragraph 5 was added:
If all plasma concentrations of an intensive PK 
interval (week 12-14 and/or week 30-32) will be 
replaced by ½ LLOQ, both Cmax and Cmin of the 
respective dosing interval will equal ½ LLOQ. The 
corresponding tmax and tmin will be the actual time 
of the first plasma sample in this dosing interval. 
Sentence added in paragraph 7:
(Q1 and Q3 only for PK parameters) 
Rationale for change
Paragraph 2: RTS will be used for the descriptive 
analysis of PK concentrations and PK parameters to 
also include patients with plasma concentrations and 
PK parameters determined only during the run-in 
period.
Paragraph 4: BLQ values will be replaced by 1/2 
LLOQ at visits other than baseline to acknowledge 
the intrinsic property of adalimumab to elicit high 
titer immunogenic responses with strong impact on 
drug exposure
Paragraph 5: If all plasma conentrations during the 


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intensive PK interval are replaced by ½ LLOQ the 
observed parameters Cmax and Cmin (and tmax and tmin) 
are identical in order to include also patients with low 
plasma concentrations in the analysis of these 
parameters.
Additional sentence in paragraph 7: Section adapted 
according to SOP
Section to be changed
Section 7.6.1
Description of change
Sentence added: (only if not replaced by ½ LLOQ of 
the bioanalytical assay).
Rationale for change
Added for consistency and clarity. See also rationale 
for change in section 7.3.5
Section to be changed
Section 7.8
Description of change
 
 
 
 
 
 
 
 
 
 
Rationale for change
Sample size determination is updated based on the 
change of the statistical analysis for primary 
endpoints
Section to be changed
Section 9.1
Description of change
New reference added: R12-1809, Hauschke D 
Steinijans V Pigeot I. Bioequivalence studies in drug 
development: methods and applications. Chichester: 
John Wiley & Sons; 2007.
Rationale for change
Added for clarity. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c16011431
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clinical-trial-protocol-version-03
VOLTAIRE-X: Pharmacokinetics, safety, immunogenicity and efficacy 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 Trial Leader
26 Jul 2019 12:23 CEST
Author-Trial Clinical
Pharmacokineticist
26 Jul 2019 13:13 CEST
Approval-Team Member Medicine
26 Jul 2019 14:27 CEST
Approval-
 Medical Affairs
26 Jul 2019 18:58 CEST
Author-Trial Statistician
29 Jul 2019 07:56 CEST
Verification-Paper Signature
Completion
05 Aug 2019 16:53 CEST


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(Continued) Signatures (obtained electronically) 
 
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SAP_001.pdf: 
Statistical Analysis Plan 
 
PROTOCOL 1297.9 
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Document: 
\\ieedc-
nas01a\BIOSdata\Boehringer_Ingelheim\BI_695501\CXA26389\Biostatistics\Documentation\SAP
Author: 
 
Version Number: 
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Version Date:
03SEP2019
Template No:  CS_TP_BS016  Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
Copyright © 2009, 2010, 2012, 2016, 2018 
 All rights reserved. The contents of this document are confidential and proprietary 
to
Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
1297.9 
 
PHARMACOKINETICS,  SAFETY,  IMMUNOGENICITY  AND  EFFICACY  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: V2.1, 03SEP2019 
 
 
 










Statistical Analysis Plan 
 
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Version Date:
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Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
Copyright © 2009, 2010, 2012, 2016, 2018 
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 Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
STATISTICAL ANALYSIS PLAN REVIEWED BY 
Boehringer Ingelheim 
Team Role
Trial Statistician 
Project Statistician
Project Programmer 
Clinical Program 
 
Clinical Project 
 
Trial Pharmacokineticist
ADA/nAb specialist
Regulatory
Project Medical Writer
Pharmacovigilance, Risk Management Physician 
Project Clinical Pharmacokineticist
 
Team Role
Senior Reviewer
Biostatistician
 Programmer
Project 
Global Therapeutic Medical Advisor  
Medical Writer
 
 
OUTPUT TEMPLATES SIGNATURE PAGE 
Please refer to Output Templates V2.0 (Dated 02AUG2019) for Protocol 1297.9. 
 
 
 
 
 
 
 


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Version Date:
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Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
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MODIFICATION HISTORY 
Version 
Date of the 
Document Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
03 September 2018 
 
Not Applicable – First Version 
2.0 
02 August 2019 
 
Adaptation of primary endpoint 
analysis strategy 
Deletion of primary analysis 
after the last patient has 
completed their Week 32 
assessment. 
2.1 
03 September 2019 
 
Update of Appendix 7 -
Laboratory Assessments 
 
 
 


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Table of Contents 
1.  INTRODUCTION ............................................................................................................................. 15 
2.  STUDY OBJECTIVES ...................................................................................................................... 15 
2.1. 
Primary Objective ...................................................................................................................................... 15 
2.2. 
Secondary Objectives ................................................................................................................................ 15 
3.  STUDY DESIGN ............................................................................................................................... 15 
3.1. 
General Description ................................................................................................................................... 15 
3.2. 
Schedule of Events ..................................................................................................................................... 16 
3.3. 
Changes to Analysis from Protocol ............................................................................................................ 17 
4.  PLANNED ANALYSES .................................................................................................................... 17 
4.1. 
Blinded Review of Sample Size .................................................................................................................. 17 
4.2. 
Primary Analysis .............................................................................................. Error! Bookmark not defined. 
4.3. 
Final Analysis ................................................................................................... Error! Bookmark not defined. 
5.  ANALYSIS SETS .............................................................................................................................. 17 
5.1. 
All Subjects Enrolled Set [ENR] .................................................................................................................. 18 
5.2. 
Run‐in Treated Set [RTS] ............................................................................................................................ 18 
5.3. 
All Subjects Randomized Set [RND] ........................................................................................................... 18 
5.4. 
Treated Set [TS] ......................................................................................................................................... 18 
5.5. 
Pharmacokinetic Set [PKS] ......................................................................................................................... 19 


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5.6. 
Per‐Protocol Analysis Set [PPS] .................................................................................................................. 21 
6.  GENERAL CONSIDERATIONS ..................................................................................................... 22 
6.1. 
Reference Start Date and Study Day .......................................................................................................... 22 
6.2. 
Baseline ..................................................................................................................................................... 23 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 23 
6.4. 
Windowing Conventions ............................................................................................................................ 23 
6.5. 
Statistical Tests .......................................................................................................................................... 24 
6.6. 
Common Calculations ................................................................................................................................ 24 
6.7. 
Software Version ....................................................................................................................................... 24 
7.  STATISTICAL CONSIDERATIONS ............................................................................................. 24 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 24 
7.2. 
Multicenter trial ........................................................................................................................................ 25 
7.3. 
Missing data .............................................................................................................................................. 25 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 25 
7.5. 
Active‐Control Studies Intended to Show Non‐inferiority or Equivalence .................................................. 25 
7.6. 
Examination of Subgroups ......................................................................................................................... 26 
8.  OUTPUT PRESENTATIONS ......................................................................................................... 26 
9.  DISPOSITION AND WITHDRAWALS ....................................................................................... 26 
9.1. 
Important Protocol Deviations .................................................................................................................. 27 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................... 28 
10.1. 
Derivations ............................................................................................................................................ 31 


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11. 
SURGICAL AND MEDICAL HISTORY ..................................................................................... 33 
12. 
MEDICATIONS ............................................................................................................................ 34 
13. 
TRIAL MEDICATION EXPOSURE ........................................................................................... 35 
13.1. 
Derivations ............................................................................................................................................ 36 
14. 
TRIAL MEDICATION COMPLIANCE ...................................................................................... 36 
14.1. 
Derivations ............................................................................................................................................ 37 
15. 
BLINDED REVIEW OF SAMPLE SIZE .................................................................................... 39 
16. 
PHARMACOKINETIC DATA .................................................................................................... 41 
16.1. 
General Pharmacokinetic considerations ............................................................................................... 41 
16.2. 
Pharmacokinetic endpoints ................................................................................................................... 41 
16.2.1. 
Primary  Pharmacokinetic variables and derivations ............................................................................. 41 
16.2.2. 
Secondary  Pharmacokinetic variables and derivations ......................................................................... 42 
16.2.3. 
Handling of Missing Data ....................................................................................................................... 42 
16.2.4. 
Change of PK parameters names ........................................................................................................... 43 
16.2.5. 
Analysis of Pharmacokinetic variables ................................................................................................... 44 
16.2.6. 
Analysis of Primary pharmacokinetic Endpoints .................................................................................... 44 
16.2.7. 
Analysis of secondary and further pharmacokinetic variables ............................................................... 46 
17. 
EFFICACY OUTCOMES .............................................................................................................. 47 
17.1. 
Secondary Efficacy Endpoints ................................................................................................................ 47 
17.1.1. 
Missing Data Method for Secondary Efficacy Endpoints ........................................................................ 47 
17.1.1.1. 
Missing Data Method: Non‐Responder Imputation and Multiple Imputation .................................... 47 


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17.1.1.2. 
Multiple Imputation ........................................................................................................................... 48 
17.1.1.3. 
Non Responder Imputation ................................................................................................................ 49 
17.1.2. 
Analysis of Secondary Efficacy Endpoints ............................................................................................... 50 
17.1.2.1. 
Secondary Efficacy Variables and Derivations .................................................................................... 52 
18. 
SAFETY OUTCOMES .................................................................................................................. 54 
18.1. 
Adverse Events ...................................................................................................................................... 55 
18.1.1. 
Adverse Event Specific Derivation .......................................................................................................... 55 
18.1.1.1. 
Treatment Emergent Adverse Event .................................................................................................. 55 
18.1.1.2. 
Risk ratio ............................................................................................................................................ 56 
18.1.2. 
All TEAEs ................................................................................................................................................ 56 
18.1.2.1. 
Intensity ............................................................................................................................................. 56 
18.1.2.2. 
Relationship to Trial Medication ........................................................................................................ 57 
18.1.3. 
TEAEs Leading to Discontinuation of Trial Medication ........................................................................... 57 
18.1.4. 
Serious Adverse Events .......................................................................................................................... 57 
18.1.5. 
Adverse Events Leading to Death ........................................................................................................... 57 
18.1.6. 
Other Safety Endpoints and Adverse Events Of Special Interest ............................................................ 57 
18.1.6.1. 
Reported by Investigator ................................................................................................................... 58 
18.1.6.2. 
Serious Infections ............................................................................................................................... 58 


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18.1.6.3. 
Hypersensitivity Reactions ................................................................................................................. 58 
18.1.6.4. 
Drug Induced Liver Injury (DILI) .......................................................................................................... 59 
18.1.6.5. 
Anaphylactic reactions ....................................................................................................................... 59 
18.1.7. 
Aes Occuring After the Last Injection For Subjects Discontinued Due to Lack of Efficacy ....................... 59 
18.2. 
Injection‐site reactions .......................................................................................................................... 59 
18.3. 
Deaths ................................................................................................................................................... 60 
18.4. 
Laboratory Evaluations .......................................................................................................................... 60 
18.4.1. 
Laboratory Specific Derivations ............................................................................................................. 61 
18.4.2. 
Laboratory Reference Ranges and Abnormal Criteria ............................................................................ 61 
18.4.3. 
Other safety laboratory evaluations ...................................................................................................... 62 
18.4.3.1. 
Pregnancy test ................................................................................................................................... 62 
18.4.3.2. 
Tuberculosis test ................................................................................................................................ 62 
18.5. 
ECG Evaluations ..................................................................................................................................... 62 
18.6. 
Vital Signs .............................................................................................................................................. 62 
18.7. 
Physical Examination ............................................................................................................................. 62 
19. 
IMMUNOGENICITY .................................................................................................................... 63 
19.1. 
Missing data methods for immunogenicity ............................................................................................ 63 
19.2. 
Analysis of immunogenicity variables .................................................................................................... 63 
20. 
References ................................................................................................................................................. 65 


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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 
anti‐HCV 
Hepatitis C antibodies 
AST 
 
Aspartate aminotransferase 
AUC 
 
Area under the curve 
BI 
 
Boehringer Ingelheim 
BLQ 
 
Below the limit of quantitation 
CI 
 
Confidence interval 
Cmax   
Maximum concentration of the analyte in plasma 
Cmin   
Minimum concentration of the analyte in plasma 
CTP 
 
Clinical trial protocol 
CTR 
 
Clinical trial report 
CV 
 
Coefficient of variation 
DB 
 
Double‐Blind 
DILI 
 
Drug‐induced liver injury 
 
 
 
ECG 
 
Electrocardiogram 
eCRF   
electronic Case Report Form 
EoT 
 
End‐of‐Treatment 
HBsAg   
Hepatitis B surface antigen 
HCV 
 
Hepatitis C virus 
HIV 
 
Human immunodeficiency virus 
ICH 
 
International Council for Harmonisation 
IGRA   
Interferon gamma‐release assay 
IV 
 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
 
Multiple imputation 
nAb 
 
Neutralizing antibody 
NOA 
 
Not analysed 
NOP 
 
No Peak 
NOR 
 
No valide result 


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NOS 
 
No sample 
NRI 
 
Non‐responder imputation 
PASI    
Psoriasis Area and Severity Index 
PK  
 
Pharmacokinetic(s) 
PKS  
 
Pharmacokinetic Set 
PPD  
 
Purified protein derivative 
PPS 
 
Per‐Protocol Analysis Set 
RA 
 
Rheumatoid arthritis 
RI 
 
Run‐in 
RTS 
 
Run‐in Treated Set 
TS 
 
Treated Set 
SAE 
 
Serious adverse event 
SFU 
 
Safety Follow‐up 
SOP 
 
Standard operating procedure 
SPC 
 
Summary of product characteristics 
sPGA   
Static Physician’s Global Assessment 
TB 
 
Tuberculosis 
Tmax   
Time to reach maximum concentration 
ULN 
 
Upper limit of normal 
US 
 
United States 
WHO   
World Health Organisation 
 
 
 


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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of pharmacokinetics 
(PK) safety, immunogenicity and efficacy data for Protocol 1297.9. 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 3.0, dated 25th July 2019. 
2. STUDY OBJECTIVES 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of this trial is to assess the PK similarity between patients receiving United States (US)-
licensed Humira® continuously vs those who switch between BI 695501 and US-licensed Humira®, in patients 
with moderate to severe chronic plaque psoriasis. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objectives of this trial are to descriptively compare the: 
 
safety,  
 
immunogenicity, and  
 
efficacy  
profiles between patients receiving US-licensed Humira® continuously vs those who switch between BI 695501 
and US-licensed Humira®. 
3. STUDY DESIGN 
3.1. 
GENERAL DESCRIPTION 
 
This is a 58-week, multiple-dose, active comparator trial with a single-arm run-in period of 14 weeks duration for 
all entered subjects, followed by a randomized, double-blind, two-arm period of 34 weeks. The total treatment 
period will be 48 weeks followed by 10 weeks of safety follow-up. 
All entered subjects will have a planned run-in period of 14 weeks during which they will be treated with US-
licensed Humira®. Approximately 240 subjects will be entered into the run-in US-licensed Humira® arm. 
At the beginning of Week 14 (Day 92), subjects achieving at least a 50% reduction in Psoriasis Area and Severity 


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Index (PASI50) response will be randomized in a 1:1 ratio to either continue receiving US-licensed Humira® 
(continuous US-licensed Humira® arm) until Week 48 or receive BI 695501/US-licensed Humira®/BI 695501 
alternately for three periods (switching arm) in a blinded fashion. The randomization will be stratified by the level 
of their Week 14 response (PASI50 to <PASI75 or ≥ PASI75). In the switching arm, the first two periods of 
switching will be of 4 weeks (2 injections) duration, and the third treatment period will be of 10 weeks (5 
injections) duration, with an extension period of 16 weeks beyond the Week 32. All subjects will continue to 
receive 40 mg US-licensed Humira® or BI 695501 every other week until the end of the treatment period (Week 
48).  
Those subjects not achieving at least PASI50 at Week 14 will be discontinued from any further treatment in the 
study, but will undergo the End-of-Treatment (EoT) and Safety Follow-Up (SFU) for safety.  
Subjects will undergo intensive PK sampling between Weeks 12-14 (Days 78-92), and Weeks 30-32 (Days 204-
218) to assess PK similarity between the two arms.  
Table A: 
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 
No change from protocol. 
4. PLANNED ANALYSES 
The following analyses will be performed for this study: 
 
Blinded review of sample size (after approximately 86 subjects have the Week 32 endpoints assessment 
and are PK evaluable) 
 
Final Analysis (after Database lock, based on all available data) 
This document will provide details for Blinded review of sample size and Final Analysis. 
The analysis described in the TSAP will be performed by 
 Biostatistics following Sponsor Authorization of 
the Statistical Plan, Sponsor Authorization of Analysis Sets and Data Snapshot/Database Lock. 
4.1. 
BLINDED REVIEW OF SAMPLE SIZE 
The Blinded review of sample size will be performed when the two primary endpoints, PK parameters AUCτ, 30-32 
and Cmax, 30-32, are available for approximately 86 PK evaluable subjects (cf. definition of PKS in Section 5.5). The 
analysis will be done on verified data, no open queries reside on the data used for the analysis.  
The PK parameterswill be determined by BI in a blinded fashion and then send to 
 for analysis. This 
analysis will be performed by a blinded statistician in order to evaluate the variability to assess whether the 
initially planned sample size will be increased or not; this analysis will also include descriptive statistics for AUCτ, 
30-32 and Cmax, 30-32, AUCτ, 12-14 and Cmax, 12-14. If the new calculated sample size is lower than the initial one, the 
initially planned sample size will be kept, i.e., 240 subjects to obtain approximatively 170 PK evaluable subjects. 
A maximum sample size to be recruited is set to 350 subjects to obtain approximatively 246 PK evaluable 
subjects. 
Regarding the difference between the number of enrolled subjects and the number of PK evaluable subjects, it is 
assumed that approximately 80% of subjects achieve PASI50 at Week 14 (and thus will be randomized into the 
double blind trial part) and that the PK non-evaluable drop-out rate is about 10% to 15%, leading to an overall 
drop-out rate of approximately 30%. 
 
5. ANALYSIS SETS 
Agreement and authorization of subjects included/excluded from each analysis set will be conducted prior to the 


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unblinding for Final analysis. For the BSSR this will bedone at the data base snapshot date.  
5.1. 
ALL SUBJECTS ENROLLED SET [ENR] 
The all subjects enrolled (ENR) set will contain all subjects who provide informed consent for this trial. 
5.2. 
RUN‐IN TREATED SET [RTS] 
The Run-in Treated Set (RTS) will contain all subjects in the ENR set treated with at least one dose of Humira® 
during the run-in period. 
If there is any doubt whether a subject was treated or not, the subject will be assumed treated for the purposes of 
analysis. 
5.3. 
ALL SUBJECTS RANDOMIZED SET [RND] 
The all subjects randomized (RND) set will contain all subjects in the ENR set who were randomized to trial 
medication. 
For analyses and displays based on RND, subjects will be classified according to randomized treatment. 
5.4. 
TREATED SET [TS] 
The Treated Set (TS) will contain all subjects in the RND set treated with at least one dose of trial medication 
administered in the randomized phase. 
If there is any doubt whether a subject was treated or not, the subject will be assumed treated for the purposes of 
analysis. 
For analyses and displays based on TS: 
- 
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. 
Fully incorrectly treated: Subject who received the wrong treatment at each visit from W14 to W48. 
Partially incorrectly treated: Subject who received at least once the wrong treatment and at least once the good one 
from W14 to W48. A listing of AEs for partially incorrect treated subjects will be performed.  


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5.5. 
PHARMACOKINETIC SET [PKS] 
The Pharmacokinetic Set (PKS) includes all patients from the Treated Set (TS) who provide at least one primary 
PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK according to the 
description below. 
 
 
Deviations from visit windows 
Visit  windows in the CTP were defined for operative reasons. If deviations from these windows will lead to 
exclusion from analysis of PK endpoints will be assessed and decided no later than the blinded Data Review 
Meeting. 
Relevant protocol violations within the time period critical for primary endpoint evaluation (i.e., from Baseline to 
W32-Visit 18) may be: 
 
 
Incorrect trial medication taken, i.e., the subject received at least one dose of trial medication the subject 
was not assigned to 
If a patient took the medication he/she was not assigned to (e.g. received Humira when BI 695501 was scheduled 
or vice versa) during the study until including visit 17, PK parameters after incorrect intake of trial medication will 
be excluded from statistical analysis. 
 
 
Incomplete dose of trial medication taken 
For incomplete dose of trial medication the same rules as for missed doses will be applied. 
 
 
Missed doses of trial medication 
A delay of dose by 7 days or more (resulting in a dosing interval length of 21 days or longer) will be considered as 
a missed dose.  
 
 
Missed doses during run-in phase (until including visit 8) 
If one dose until including visit 6 was missed, PK parameters of dosing interval week 12-14 (intensive PK interval 
run-in phase) will be included in the statistical analysis. 
If more than one dose was missed until including visit 8, PK parameters of intensive PK interval in run-in phase 
will be excluded from statistical analysis. 
If dose at visit 7 was missed, PK parameters of intensive PK interval in run-in phase  will be excluded from 
statistical analysis. 
If dose at visit 8 was missed, PK parameters of intensive PK interval in run-in phase will not be calculated. 
 


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 
Missed doses during randomized phase 
If one dose from including visit 9 until including visit 15 was missed, PK parameters will be included in the 
statistical analysis. 
If more than one dose was missed until including visit 17, PK parameters of dosing interval week 30-32 (intensive 
PK interval in randomized phase) will be excluded from statistical analysis. 
If dose at visit 16 was missed, PK parameters of intensive PK interval in randomized phase will be excluded from 
statistical analysis. 
If dose at visit 17 was missed, PK parameters of intensive PK inteval in randomized phase will not be calculated. 
If doses are missed from including visit 18 until end of the study, PK parameters will be included in the statistical 
analysis. 
 
 
Use of restricted medications with suspected impact on PK 
If Methotrexate was used once or repeatedly within 7 days prior to visit 2 or during the study until including visit 
18, PK parameters will be excluded from statistical analysis. 
If Methotrexate was used after visit 18 (week 32), PK parameters will be included in the statistical analysis.  
 
 
Missed plasma samples during the dosing interval from Week 12 to Week 14 or from Week 30 to 32 
If two consecutive samples during visits 8a-d or 17a-d are missing, AUCτ and Cmax of the affected intensive PK 
interval will not be calculated. 
If pre-dose samples at visit 8 and/or 9 are missing, AUCτ,12-14 will not be calculated.. 
If pre-dose samples at visit 17 and/or 18 are missing, AUCτ,30-32 will not be calculated. 
 
 
Missing drug administration or missing PK sampling date or time 
Rules below will be applied for missing drug administration or missing PK sampling date and time if missing data 
could not be imputed (see Section 7.3). 
 
 
Missing drug administration date or time of visit 8 or 17 
If dosing date or time of visit 8 or 17 is missing, PK parameters of the affected intensive PK interval will not be 
calculated. 
 
 
Missing drug administration date or time of visit 9 or 18 
If dosing date or time of visit 9 or 18 is missing, AUCτ of the affected intensive PK interval will not be calculated. 
 


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 
Missing drug administration date or time (all visits except visit 8, 9, 17 and 18) 
If dosing date or time is missing for any other visit except visits 8, 9, 17 and 18, PK parameters will be calculated 
and included in the statistical analysis. 
 
 
Missing PK sampling date or time 
Visits 8, 9, 17, or 18: 
If PK sampling date or time of visit 8 or 17 is missing, PK parameters of the affected intensive PK interval will not 
be calculated. 
If PK sampling date or time of visit 9 or 18 is missing, AUCτ of affected intensive PK interval will not be 
calculated.  
 
Visits 2, 3, 6, 11, 13, 22, 27 and 28: 
If PK sampling date or time for PK samples is missing for visits 2, 3, 6, 11, 13, 22, 27 and 28, PK parameters will 
be calculated and included in statistical analysis. 
 
 
Deviations from PK sampling times 
PK sampling windows in the CTP were defined for operative reasons. Deviations will not necessarily lead to 
exclusion from analyis of PK endpoints. 
 
Whether a protocol violation is considered relevant for the assessment of PK will be decided no later than in the 
blinded Data Review Meeting prior to the data snapshot. Exclusion of a patient’s data will be documented in the 
CTR. 
For analyses and displays based on PKS, subjects will be classified according to treatment received. 
5.6. 
PER‐PROTOCOL ANALYSIS SET [PPS] 
The Per-Protocol Analysis Set (PPS) will contain all subjects in the TS 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, for 
violations that can only be assessed with unblinded data (i.e. incorrect treatment medication taken). The important 
protocol violations relevant for efficacy until Week 32 inclusive may include but are not limited to: 
 
Incorrect trial medication taken, i.e., at least one kit number used and recorded on the eCRF before Week 
32 does not correspond to the randomized treatment group.  
 
Severe violation of treatment compliance prior to Week 32: medical team will review subjects with 
treatment compliance strictly below 80% and strictly above 120% (refer to Section 14.1) and decide if 
the violation is severe. 


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 
Severe violation of inclusion/exclusion criteria 
o 
Exclusion criterion 2: Prior exposure to any biologic therapies for any auto-immune diseases 
(e.g.,: RA, Psoriasis, and Crohn’s disease). 
o 
Exclusion criterion 6: Subjects 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 trial, or less 
than 30 days (or less than 5 half-lives, whichever is longer) since ending another investigational 
device or drug trial(s), or receiving other investigational treatment(s). 
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. 
 
A listing of each patient with the information included/excluded from the PPS and the reasons will be provided to 
BI. Then a Blinded Set Review Meeting will be done between BI and 
 to discuss and confirm which 
subjects are to be excluded from the PPS. This meeting could be done at the same time as the Data Review 
Meeting. 
Important protocol violations will be defined before unblinding for Final analysis. 
For analyses and displays based on PPS, subjects will be classified according to randomized treatment. 
6. GENERAL CONSIDERATIONS 
6.1. 
REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/stop day of assessments 
and events.  
Two reference start dates are defined: 
 
Reference Run-in Start Date: this reference start date is defined as the day of the first dose of Humira® 
(Day 1 is the day of the first dose of Humira®).  
 
Reference Double-Blind Start Date: this reference start date is defined as the day of the first dose of 
treatment after randomization (planned day is Day 92 ). 
The two reference start dates will appear in every listing where an assessment date or event date appears. 
 
The Study Day is calculated as follows: 


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 
If the date of the event is on or after the reference start date then:  
Study Day = (date of event – reference start date) + 1. 
 
 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference start date). 
 
In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, and 
Study Day, and any corresponding durations will be presented based on the imputations specified in APPENDIX 
2. 
6.2. 
BASELINE 
Baseline is defined as the last non-missing measurement taken prior to the Reference date: Reference Run-in Start 
Date (Run-in Baseline) or Reference Double-Blind Start Date (Double-Blind Baseline). 
The immunogenicity, laboratory and safety analysis will be performed separately for both defined baselines 
(Reference Run-in Start Date  and Reference Double-Blind Start Date). Otherwise, baseline is defined as the last 
non-missing measurement taken prior to reference Run-in start date (including unscheduled assessments).  
In the case where the last non-missing measurement and the reference 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 7, 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 secondary efficacy endpoints (refer to Section 17.1.1.1) and DILIs (refer to Section 18.1.6.4). 
Treatment early termination data will be included in the End-of-Treatment visit in by-visit table summaries and 
by-visit graphs, according to the protocol. 
Listings will include scheduled, unscheduled, and retest data as collected in the eCRF database. 
6.4. 
WINDOWING CONVENTIONS  
Unless otherwise specified, visit data as recorded in the database will be used for the analysis. No visit windowing 
recalculation will be performed for this trial. 


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6.5. 
STATISTICAL TESTS 
 
Confirmatory: 
Regarding the PK analyses the confidence intervals will be 90.2%. 
 
Descriptive: 
Regarding the efficacy analyses the confidence intervals will be 90% and 95%. Regarding the safety analyses the 
confidence intervals will be 95%. 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 
 
Relative change from baseline (%) will be calculated as: ((Test Value at Visit X – Baseline Value)/ 
Baseline Value) x 100. 
6.7. 
SOFTWARE VERSION 
 
Analyses provided by 
 will be conducted using SAS version 9.4 or higher. Analyses provided by BI will be 
using Phoenix WinNonlin Version 6.3 or higher and SAS Version 9.4 or higher. 
 
7. STATISTICAL CONSIDERATIONS 
7.1. 
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN 
ANALYSES 
The following covariates and factors are used in Blinded review of sample size and the analyses of PK. For details 
of their inclusion in the models, see the specific analysis section. 
Treatment (switching arm versus continuously Humira® arm) – except for the Blinded review of sample size 
Logarithm* of rPASI, where rPASI is the ratio of PASI at Week 14 and PASI at Week 1 


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Weight at Week 14 
Stage (1 for subjects who finished Week 32 prior to the blinded sample size reassessment versus 2 for the other 
ones) – except for the Blinded review of sample size 
AUCτ, 12-14 or Cmax, 12-14 
*natural logarithm 
7.2. 
MULTICENTER TRIAL 
This trial will be conducted by multiple investigators at multiple centers internationally, approximatively 
80 clinical sites across approximatively 9 countries. Randomization will be stratified by the level of their Week 14 
PASI response (≥ PASI50 to < PASI75 and ≥ PASI75). No stratification by site was planned because of the small 
number of subjects to be randomized per site. 
7.3. 
MISSING DATA 
Missing PK data will be handled as described in Section 16.2.3 of this analysis plan. 
Missing safety data will not be imputed if not mentioned otherwise.  
Missing efficacy data will be handled as described in Section 17.1.1 of this analysis plan.  
Calculation for a partial date is described in APPENDIX 2. 
7.4. 
MULTIPLE COMPARISONS/ MULTIPLICITY 
This trial has two primary endpoints: AUCτ, 30-32 and Cmax, 30-32. These two endpoints are considered coprimary (i.e., 
the trial is considered positive if the results for both endpoints are simultaneously positive), therefore no 
multiplicity-adjustment with respect to the alpha level will be performed. 
7.5. 
ACTIVE‐CONTROL STUDIES INTENDED TO SHOW NON‐INFERIORITY OR 
EQUIVALENCE 
The primary objective of the trial is to assess the PK similarity between a treatment arm in which  patients will be 
receiving United States (US)-licensed Humira® continuously and a treatment arm where patients will switch 
multiple times between BI 695501 and US-licensed Humira®. The relevant PK endpoints are: AUCτ, 30-32 and Cmax, 
30-32. The statistical description of these analyses is presented in Section 16.2 of this SAP. 


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7.6. 
EXAMINATION OF SUBGROUPS 
Not applicable. 
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 and BI. 
9. DISPOSITION AND WITHDRAWALS 
Disposition and withdrawals will be presented at the Final Analysis. 
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) 
 
Run-in Treated Set (RTS) 
 
Treated Set (TS) 
 
Pharmacokinetic Analysis Set (PKS) 
 
Per Protocol Analysis Set (PPS) 
The reasons for exclusion from the analysis sets will be listed. 
The following subject disposition and withdrawals will be presented for the ENR set: 
 
Screened 
 
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. 
 
Enrolled but not treated by Humira® during run-in period 
 
Treated by Humira® during run-in period 
 
Discontinued from treatment during Run-In period strictly before Day 92 (Week 14) , primary reason for 


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premature discontinuation from treatment during Run-In period strictly before Day 92 (Week 14) 
 
Randomized 
 
Randomized but not treated 
 
Treated by post-randomization treatment 
 
Completed treatment at Day 330 (Week 48) 
 
Completed the trial 
 
Discontinued from post-randomization treatment, primary reason for premature discontinuation from 
post-randomization treatment (i.e., after Day 92 (Week 14) and strictly before Day 344 (Week 50)) 
 
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. 
 
Enrolled but not treated by Humira® during run-in period 
 
Treated by Humira® during run-in period 
 
Treated by post-randomization treatment 
 
Randomized 
 
Randomized but not treated 
 
Completed treatment at Day 330 (Week 48) 
 
Completed the trial 
9.1. 
IMPORTANT PROTOCOL DEVIATIONS 
 
Protocol violations as defined in Section 5.6 leading to exclusion from the PPS, will be tabulated and listed for the 
TS. 
Protocol violations as defined in Section 5.5 leading to exclusion from the PKS will be tabulated and listed for the 
TS. 
 
The full protocol deviations log will be attached to the clinical study report. 
 


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10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
No statistical testing will be carried out for demographic or other baseline characteristics.  
The following demographic characteristics at Run-in Baseline will be reported at Blinded review of sample size 
for PKS and at Final Analysis for RTS, TS and PKS: 
 
Age (years) at Informed Consent 
 
First age category at Informed Consent  
o 
Adolescent (< 18 years): AGE < 18 – no subject expected 
o 
Adults (18-64 years): 18<= AGE < 65 
o 
Adults (65-79 years): 65<= AGE < 80 
o 
Adults (Over 80 years): 80<= AGE – no subject expected 
 
Second age category at Informed Consent 
o 
AGE < 65 years 
o 
AGE >= 65 years 
 
Third age category at Informed Consent 
o 
AGE < 65 years 
o 
65 <= AGE < 76 
o 
76 <= AGE <80 
o 
AGE >= 80 
 
Gender 
o 
Male 
o 
Female 
 
Country 
 
Ethnicity 
o 
Hispanic or Latino 
o 
Not Hispanic or Latino 
o 
Not reported 
o 
Unknown 
 
Race 
o 
American Indian or Alaska Native 
o 
Asian 


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o 
Black or African American 
o 
Native Hawaiian or Other Pacific Islander 
o 
White 
o 
Other 
 
Height at baseline (cm) 
 
The following demographic characteristics will be reported at Run-in Baseline at Final Analysis for RTS and will 
be reported at Run-in Baseline and Double-Blind Baseline at Blinded review of sample size for PKS and at Final 
Analysis for RND, TS and PKS: 
 
Childbearing potential 
o 
Post-Menopausal 
o 
Surgically Sterile 
o 
Childbearing Potential (includes tubal ligation) 
 
Weight at baseline (kg) 
 
BMI at baseline (kg/m2) 
 
The following efficacy baseline characteristic will be reported at Run-in Baseline at Final Analysis for RTS and 
will be reported at Run-in Baseline and Double-Blind Baseline at Blinded review of sample size for PKS and at 
Final Analysis for TS, PPS and PKS: 
 
PASI score as collected in the eCRF 
 
The following efficacy baseline characteristics will be reported at Run-in Baseline at Final Analysis for RTS and 
will be reported at Run-in Baseline and Double-Blind Baseline at Final Analysis for TS and PPS: 
 
Static Physician’s Global Assessment of psoriasis (sPGA) score at baseline 
 
 
 
The following other baseline characteristics will be presented at Run-in Baseline at Final Analysis for RTS and 
will be reported at Run-in Baseline and Double-Blind Baseline at Final Analysis for TS: 
 
Infection screen (Hepatitis B (HBsAg anti-HBc), hepatitis C (anti-HCV), HIV) 
 
Chest X-Ray result 
 
Tuberculosis (TB) test (IGRA or PPD testing) 
 
Physical examination (general appearance, skin, head, neck, throat, lymph nodes, cardiovascular and 
neurological systems, thyroid gland, musculoskeletal system/limbs, respiratory tract and abdomen) 


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 
Vital signs at baseline (Body temperature, blood pressure and pulse rate) 
 
12-lead-electrocardiogram at baseline: 
o 
Normal 
o 
Abnormal, not clinically significant 
o 
Abnormal, clinically significant 
 
Proportion of subjects with positive Anti-Drug Antibody (ADAs) result at baseline 
 
Proportion of neutralizing anti-drug antibodies results at baseline 
 
Accountability for missing data will be displayed in case of any missing entries. 
 
 
 


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10.1. 
DERIVATIONS 
Conversion factors: 
o 
1 pound (lbs) = 0.453592 kilograms (kg) 
o 
1 inch (in) = 2.54 centimeters (cm) 
o 
Fahrenheit degree (°F) = 1.8 x Celsius degree (°C) + 32 
(1 °F = -17.22222 °C) 
 
BMI (kg/ m²) = weight (kg)/(height (m)²) 


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 
PASI: 
The PASI is a tool that provides a numeric scoring for subjects’ 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 4 body regions. 
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. 
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 represent 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 


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11. SURGICAL AND MEDICAL HISTORY 
Surgical and Medical History information will be presented at Final Analysis for the RTS and TS. 
Surgical and Medical History will be coded using MedDRA version 20.0 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. 
 
 
Run-in period 
o 
Prior medical history, surgeries, and procedures:  
 
Start date and stop date of medical history, surgeries, and procedures is prior to or at 
screening date 
o 
Concomitant medication:  
 
Start date of medical history, surgeries, and procedures prior to the date of first dose of 
randomized medication 
AND 
 
End date of medical history, surgeries, and procedures after the screening date or were 
ongoing at the date of first dose of randomized medication 
 
 
 


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 
Post-randomization period 
o 
Concomitant medical history, surgeries, and procedures:  
 
Start date of medical history, surgeries, and procedures prior to or on the end of 
treatment date 
AND 
 
End date of medical history, surgeries, and procedures on or after the date of first dose 
of randomized medication or were ongoing at end of treatment date 
 
For rescreened subject 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 
General considerations 
Medications will be presented at Final Analyses for the RTS and TS. 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.  
 
 
 
 
Run-in period 
o 
Prior medications:  
 
Start date and stop date of medication is prior to date of first dose of trial medication 
o 
Concomitant medication:  
 
Start date of medication prior to randomization (i.e. randomization Visit included)  
AND 
 
End date of medication on or after the date of first dose of trial medication (start day of 
run-in period) or were ongoing at randomization Visit 


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 
Post-randomization period 
o 
Concomitant medication:  
 
Start date of medication prior to or on the end of treatment date 
AND 
 
End date of medication on or after the date of first dose of randomized medication or 
were ongoing at end of treatment date 
13. TRIAL MEDICATION EXPOSURE 
 
Exposure to trial medication will be presented at Final Analysis for the RTS, TS and PKS. 
 
 
Run-in period: 
The presentation will be on the RTS: 
The proportion of subjects treated by Humira® at each Run-in period planned visit (administration on Week 1, 
Week 2, Week 4, Week 6, Week 8, Week 10 and Week 12) will be presented. 
Descriptive statistics of the number of injections of Humira® per subject will be presented. 
Number of subjects per categories of duration of exposure to Humira®, patient time (years) per categories of 
duration of exposure to Humira®, and descriptive statistics for duration of exposure to Humira® will be presented. 
Exposure categories: ≥ 1 day, ≥ 2 weeks, ≥ 4 weeks, ≥ 6 weeks, ≥ 8 weeks, ≥ 10 weeks and ≥ 12 weeks. 
These analyses will be presented globally and per randomized treatment group (i.e. subjects will be allocated to 
either not-randomized if they are not randomized at week 14 or to the randomized treatment group if they are 
randomized at week 14). 
 
 
 
 
 
Overall trial period: 
The presentation will be on the TS: 
The proportion of subjects treated with trial medication (Run-in period Humira® or randomized trial  medication) 
at each planned visit (administration on Week 1, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 14, 
Week 16, Week 18, Week 20, Week 22, Week 24, Week 26, Week 28, Week 30, Week 32, Week 34, Week 36, 


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Week 38, Week 40, Week 42, Week 44, Week 46 and Week 48) will be presented. 
Descriptive statistics for the number of trial medication injections per subject during the trial will be presented. 
Number of subjects per categories of duration of exposure to trial medication, patient time (years) per categories of 
duration of exposure to trial medication, and descriptive statistics for duration of exposure to trial medication will 
be presented. 
Exposure categories: ≥ 1 day, ≥ 2 weeks, ≥ 4 weeks, ≥ 6 weeks, ≥ 8 weeks, ≥ 12 weeks, ≥ 16 weeks, ≥ 22 weeks, ≥ 
28 weeks, ≥ 34 weeks, ≥ 40 weeks, ≥ 48 weeks. 
These analyses will be presented globally and per randomized treatment group (i.e. subjects will be allocated to 
either not-randomized if they are not randomized at week 14 or to the randomized treatment group if they are 
randomized at week 14). 
13.1. 
DERIVATIONS 
The date of first and last Run-in period Humira® administration and the date of first and last trial post-
randomization treatment administration will be taken from the eCRF page “Trial Medication Injection”. 
Duration of Run-in period Humira® exposure (days) = Date of last Run-in period Humira® injection - Date of first 
Run-in period Humira® injection + 1. 
Duration of Run-in period Humira® exposure (weeks) = Duration of Run-in period Humira® exposure (days) / 
7. 
Patient Year Run-in period Humira® Exposure (year) = Cumulative duration of Run-in period Humira®  
exposure in days per subjects / 365.25 
 
 
 
Duration of any trial medication exposure (days) = Date of last trial medication injection - Date of first trial 
medication injection + 1. 
Duration of any trial medication exposure (weeks) = Duration of any trial medication exposure (days) / 7. 
Patient Year trial medication exposure (year) = cumulative duration of any trial medication exposure in days 
per subjects / 365.25 
 
14. TRIAL MEDICATION COMPLIANCE  
Compliance to trial medication will be presented at Final Analysis for the TS and PKS. 


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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: 
Compliance at visit N = Yes if the question “Was full dose given” is answered “Yes”. 
 
 
 
No else 
 
 ‘Overall’ compliance will be calculated as follows: 
Overall compliance (%) = (Number of administered injections)*100/Planned number of injections 
Where 
 
 
 


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Planned usage 
Trial Period 
Run-in Period 
Visit N 
1 
2 
3 
4 
5 
6 
7 
8 
Week 
 
1 
2 
4 
6 
8 
10 
12 
Number of injections 
at visit N 
0 
2 
1 
1 
1 
1 
1 
1 
Planned cumulative 
number of injections 
in trial 
0 
2 
3 
4 
5 
6 
7 
8 
 
Trial Period 
Double-Blind Period 
 
Visit N 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Week 
14 
16 
18 
20 
22 
24 
26 
28 
30 
Number of injections at 
visit N 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Planned cumulative 
number of injections in 
trial 
9 
10 
11 
12 
13 
14 
15 
16 
17 
 
 
 


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Trial Period 
Extension Period 
 
Visit N 
18 
19 
20 
21 
22 
23 
24 
25 
26 
Week 
32 
34 
36 
38 
40 
42 
44 
46 
48 
Number of injections at 
visit N 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Planned cumulative 
number of injections in 
trial 
18 
19 
20 
21 
22 
23 
24 
25 
26 
 
15. BLINDED REVIEW OF SAMPLE SIZE 
The blinded, pooled AUCτ, 30-32 or Cmax, 30-32 will be monitored to verify the sample size assumptions. 
Due to the uncertainty about the PK variability, a sample size re-assessment procedure as described in Friede and 
Kieser [1] and Golkowski et al [2] has been considered for this study. The initially planned total sample size is 170 
PK evaluable subjects (i.e., subjects in the PKS and all necessary covariates are available). This is also set to be 
the minimum sample size for the trial, denoted as Nmin. 
For this study a maximum sample size to be recruited is set to 350. Taking into account the drop-out rates as 
described above this translates to a maximum of approximately 246 PK evaluable subjects at Week 32, denoted as 
Nmax. 
After (approximately) 86 subjects have had their Week 32 primary endpoints assessment and are PK evaluable the 
variability of AUCτ, 30-32 and Cmax, 30-32 will be re-estimated based on the data of those n1 = 86 subjects. This 
adequately allows the determination of the variability relevant for sample size re-calculation, which is in line with 
the primary endpoint analysis strategy. In order to mirror the primary endpoint analysis strategy the variability will 
be estimated after stage 1 as the residual variance from the model of ANCOVA as stated in Section 16.2.6 but, due 
to the blinded assessment, without the covariates ‘Treatment’ and ‘Stage’. 
The model will be: 
 
Response (AUCτ, 30-32 or Cmax, 30-32) = overall mean + logarithm* of rPASI + weight at Week 14 + (AUCτ, 12-14 or 
Cmax, 12-14) + random error 
*Natural logarithm 
where: 
rPASI  is the ratio of PASI at Week 14 and PASI at Week 1 (continuous value). If PASI at Week 14 is zero, then 
the score from this Week 14 will be set to 0.05 (otherwise the logarithm is not defined) 
 


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This model will be implemented for both primary endpoints. 
The maximum of the two estimated residual variances from the two models, ߪොଵ
ଶ, together with the same 
assumption for the treatment difference as before (i.e. 8% on the ratio scale) will then be employed to calculate the 
updated total number ܰ෡ required to achieve at least 80% power. To this end, the power/sample size calculation 
method by Fieller’s theorem as described in [3, chapter 10.3.1] will be used. 
This functionality is implemented in the function sampleN.RatioF from the R package PowerTOST (v. 1.4-3). 
That is, the following function call will be used to calculate ܰ෡  
sampleN.RatioF(alpha=0.049, CV=
ఙభ
ෞ
௠, theta0=0.92, targetpower=0.8, design=”parallel”), 
where m is the predicted mean response of a patient with average covariate values (LSMean) and theta0 represents 
the mean ratio assumed for sample size (re-)calculation. 
In this study the final sample size shall not be lower than the initially planned size Nmin and therefore the 
resulting final total sample size N෡୤ is not smaller than the maximum of the two numbers Nmin and N෡. In addition, a 
maximum sample size Nmax as described above will be used as cap, i.e. N෡୤ൌmin ሺmax൫N୫୧୬, N෡൯, N୫ୟ୶ሻ. The 
second stage, i.e. the study part after the blinded sample size reassessment of the study should thus include nଶൌ
 N෡୤െnଵ PK evaluable patients. 
BI has performed simulations to assess the actual type I error rate in the context of the planned blinded sample size 
re-estimation procedure in order to justify that the overall type I error is maintained.  
The document of these simulations is presented in 0. 
 
The ouputs of this analysis will provide: 
- 
the two estimated residual variances from the two models (including corresponding  CV)  
- 
ܰ෡ 
- 
n2 
- 
CV for AUCτ and Cmax both at Week 14 and at Week 32. Note: here, it is considered as descriptive, i.e. no 
model applied here. Also include number of observations used. 
- 
Number of subjects in PKS 
 


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16. PHARMACOKINETIC DATA 
All PK analyses will be performed for the PKS. 
Descriptive statistics of plasma concentrations and PK parameters will be also done on RTS. For PK parameter 
analysis on RTS the same rules regarding exclusion as for PKS will be applied. 
16.1. 
GENERAL PHARMACOKINETIC CONSIDERATIONS 
The PK parameters will be calculated according to the BI SOP ‘Standards and processes for analyses performed 
within Clinical Pharmacokinetics/ Pharmacodynamics’ [001-MCS-36-472] (see APPENDIX 4). Parameters, 
which are taken directly from the observed plasma concentration (e.g. Cmin, Cmax, Cpre, C50, C58) will be excluded 
from descriptive statistics and statistical analysis of PK endpoints if the corresponding plasma concentration is 
flagged to be excluded from descriptive statistics. 
For technical reasons if PK blood sample at visit 9 or 18 is taken before 336 h after preceding dose and the plasma 
concentration of visit 9 or 18 is higher or equal than the preceding plasma concentration, then the time of the PK 
sample at visit 9 or 18 will be set to 336 h. 
Only concentration values within the validated concentration range and actual sampling times will be used for the 
calculation of PK parameters. Concentrations used in the PK calculations will be in the same format provided in 
the bioanalytical report (that is, to the same number of decimal places provided in the bioanalytical report). 
If a measured level for a given PK sample is BLQ then 1/2 LLOQ of the assay (0.0125 µg/mL) will be used for the 
parameter calculations. For samples taken at baseline (visit 2) BLQ values will not be replaced by 1/2 LLOQ. 
For data presentation the following conventions will apply: 
All the sampling visits performed after an incorrect (not as randomized) administration of trial drug will be 
reported and flagged in the table. The flagged sampling results will be excluded from the descriptive statistics and 
from the figures. The planned and actual times are listed in a separate table in the CTR. In case a concentration 
value is excluded from the statistical and/or pharmacokinetic evaluation, it will be flagged appropriately in the 
respective concentration-time table. 
The individual values as well as descriptive statistics are reported with 3 significant digits. 
16.2. 
PHARMACOKINETIC ENDPOINTS 
16.2.1. PRIMARY  PHARMACOKINETIC VARIABLES AND DERIVATIONS 
Pharmacokinetics will be assessed as the primary objective in this trial. 
The primary pharmacokinetic endpoints are: 
 
AUCτ, 30-32 (Area under the adalimumab plasma concentration-time curve over the dosing interval of 
Week 30-32) 
 
Cmax, 30-32  (Maximum observed adalimumab plasma concentration during the dosing interval Week 30-32) 


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16.2.2. SECONDARY  PHARMACOKINETIC VARIABLES AND DERIVATIONS 
The secondary pharmacokinetic endpoints are: 
 
 
Cmin, 30-32 (Minimum observed adalimumab plasma concentration during the dosing interval Week 30-32) 
 
tmax, 30-32  (Time to maximum observed adalimumab plasma concentration during the dosing interval Week 
30-32) 
 
16.2.3. HANDLING OF MISSING DATA 
Handling of missing PK data will be performed according to the relevant SOP of the sponsor. 
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA will generally not be 
considered (calculations and graphical representation). Descriptive statistics of concentrations at specific visits will 
be calculated only when at least 2/3 of the individuals have concentration measurements within the validated 
concentration range of the assay (that means between lower and upper limit of quantification as reported in the BA 
transfer) or BLQ values have been replaced by ½ LLOQ of the bioanalytical assay. The overall sample size to 
decide whether the “2/3 rule” is fulfilled will be based on the total number of samples actually drawn and not 
flagged as taken after an incorrect (not as randomized) administration of trial drug for that visit (i.e., BLQ (only if 
not replaced by ½ LLOQ of the bioanalytical assay), NOR, NOS, NOA and NOP are included). 


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If actual PK sampling date is missing the dosing date of the the same visit  will be used instead. 
If actual PK dosing date is missing the PK sampling date of the the same visit will be used instead. 
If actual dosing time is missing and the dosing and PK sampling dates are identical then the PK sampling time of 
the the same visit will be used instead. 
If actual PK sampling time for pre-dose PK samples is missing and the dosing and PK sampling dates are identical 
then the dosing time of the same visit will be used instead 
If actual PK sampling time for sub-visits 8a-d or 17a-d is missing, the clock-time of preceding dosing will be used 
instead. Missing PK sampling dates of sub-visits 8a-d and 17a-d will not be replaced. 
If it is not possible to impute missing date or times, the respective date or time will stay missing. 
Imputed administration or PK sampling date and times will be listed in Appendix 14.2 of the CTR. 
If weight is missing at Week 14 the last available measurement which is closest to week 14 used as Week 14 
weight. 
16.2.4. CHANGE OF PK PARAMETERS NAMES 
Due to technical reasons parameter names in Appendix 14.2 will differ from the CTP and the remaining CTR 
sections (refer to table 16.2.2: 1). 
 
Table 16.2.2: 1 
 
Appendix 14.2 
Description 
Cmax,12‐14 
Cmax,12 
Maximum observed adalimumab plasma 
concentration during the dosing interval Week 12‐14 
tmax,12‐14 
tmax,12 
Time to maximum observed adalimumab plasma 
concentration during the dosing interval Week 12‐14 
Cmin,12‐14 
Cmin,12 
Minimum observed adalimumab plasma concentration 
during the dosing interval Week 12‐14 
tmin,12‐14 
tmin,12 
Time to minimum observed adalimumab plasma 
concentration during the dosing interval Week 12‐14 
AUCτ,12‐14 
AUCτ,12
Area under the adalimumab plasma concentration‐
time curve over the dosing interval of Week 12‐14
Cmax,30‐32 
Cmax,30 
Maximum observed adalimumab plasma 
concentration during the dosing interval Week 30‐32 
tmax,30‐32 
tmax,30 
Time to maximum observed adalimumab plasma 
concentration during the dosing interval Week 30‐32 


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Cmin,30‐32 
Cmin,30 
Minimum observed adalimumab plasma concentration 
during the dosing interval Week 30‐32 
tmin,30‐32 
tmin,30 
Time to minimum observed adalimumab plasma 
concentration during the dosing interval Week 30‐32 
AUCτ,30‐32 
AUCτ,30 
Area under the adalimumab plasma concentration‐
time curve over the dosing interval of Week 30‐32
 
16.2.5. ANALYSIS OF PHARMACOKINETIC VARIABLES 
Descriptive statistics of plasma concentrations and PK endpoints, as well as the tables and graphs for the 
pharmacokinetic noncompartmental analyses, will follow specific definitions of this SAP or, otherwise, the BI 
standard procedure “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics” [001-MCS-36-472] (see APPENDIX 4). 
16.2.6. ANALYSIS OF PRIMARY PHARMACOKINETIC ENDPOINTS 
Pharmacokinetic parameters of a patient will be included in the statistical analyses of PK endpoints (ANCOVA) if 
they are not flagged for exclusion due to a protocol violation relevant to the evaluation of PK. 
The primary objective of this trial is to test the hypothesis of PK similarity between the switching arm and 
continuous Humira® arm) on the two PK parameters: AUCτ, 30-32 and Cmax, 30-32. 
The test for PK similarity will be performed with respect to the switching vs. continuous Humira® arm. 
For the primary endpoint analysis the BE margins 80% – 125% on the ratio scale will be applied.  
The hypotheses for the primary endpoint analysis can be written as follows: 
 
H01: Ratio of the means of AUCτ, 30-32 (switching arm versus continuous Humira® arm) is less than 80% 
or more than 125% 
 
H11: Ratio of the means of AUCτ, 30-32 (switching arm versus continuous Humira® arm) is within [80%, 
125%] 
and 
 
H02: Ratio of the means of Cmax, 30-32 (switching arm versus continuous Humira® arm) is less than 80% or 
more than 125% 
 
H12: Ratio of the means of Cmax, 30-32 (switching arm versus continuous Humira® arm) is within [80%, 
125%] 
A significance level of 4.9% was chosen to ensure overall type I error control at 5%, in light of the adapted 
analysis strategy. Details are provided in APPENDIX 5.  
The two endpoints are considered coprimary (i.e., the trial is considered positive if the results for both endpoints 
are simultaneously positive), therefore no multiplicity-adjustment with respect to the alpha level will be 
performed. 


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The statistical model used for the analysis of AUCτ, 30-32 and Cmax, 30-32 will be an analysis of covariance 
(ANCOVA) model. This model will include effects accounting for: 
 
Treatment (switching arm versus continuously Humira® arm) 
 
Logarithm* of rPASI, where rPASI is the ratio of PASI at Week 14 and PASI at Week 1 (continuous 
value). If PASI at Week 14 is zero, then the score from this Week 14 will be set to 0.05 (otherwise 
the logarithm* is not defined). Note that this imputation is only done for the purpose of creating the 
covariate used in this PK analysis.  
 
Weight at Week 14 (continuous value) 
 
Stage, where stage represents the two parts of the study prior to and after the blinded sample size 
reassessment (categorical, 1 or 2) 
 
AUCτ, 12-14 or Cmax, 12-14 (continuous value) 
* Natural logarithm 
as a source of variation. As the measurements at Week 14 will be prior to randomization and all subjects will have 
received the same treatment with the reference treatment only, the covariates listed above are all considered 
adequate baseline values. 
All effects will be considered as fixed. The model is described by the following equation: 
(M1)  
response (AUCτ, 30-32 or Cmax, 30-32) = overall mean + treatment effect + logarithm* of rPASI + weight 
 
at Week 14 + stage + (AUCτ, 12-14 or Cmax, 12-14) + random error. 
* Natural logarithm 
where the random errors are assumed to be independent and normally distributed with zero mean and variance σ². 
The analysis will then be adjusted for the covariates as stated in M1. The model will be implemented with the 
SAS® procedure PROC MIXED in conjunction with the LSMEANS statement. The LSMEANS statement is used 
to estimate the treatment LSMeans of the switching and non-switching arms which will be used to construct the 
point estimate for the ratio of means. The CI will be derived based on Fieller’s theorem ([3], chapter 3.3.3.1 and 
0): 


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All subjects that finished Week 32 Visit at or before the cut-off date will be allocated to stage 1. All other subjects 
(i.e., all subjects that at cut-off date do not have a finished Week 32 Visit) will be allocated to stage 2. 
 
Equivalently ([3], chapter 10.2.1) to rejecting both null hypotheses for the primary endpoints, PK similarity 
between Switching arm and Continuous Humira® arm will be concluded if the two-sided 90.2% Fieller CI for the 
ratio of the means is fully contained within the standard equivalence limits of 80.00% to 125.00% and  
|ܻഥோ|
ߪොට1
݊ோ
൐ݐଵିఈ,ௗ௙ 
where ܻതோ refers to the LSMean of the reference treatment, ߪො is the residual standard deviation from the ANCOVA 
model (M1), df are the residual degrees of freedom of (M1) and  = 4.9%. 
16.2.7. ANALYSIS OF SECONDARY 
 VARIABLES 
The secondary PK endpoint Cmin, 30-32 will be analyzed in the same way as the primary endpoints However, only 
the mean ratio and CIs will be calculated and presented. 
No formal comparison to margins will be performed. 
The secondary PK endpoint tmax, 30-32 will be analyzed in a descriptive manner only. 


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17. EFFICACY OUTCOMES  
17.1. 
SECONDARY EFFICACY ENDPOINTS 
All efficacy analyses will be performed for the PPS. 
17.1.1. MISSING DATA METHOD FOR SECONDARY EFFICACY ENDPOINTS 
17.1.1.1. Missing Data Method: Non‐Responder Imputation and Multiple Imputation 
For the secondary efficacy analysis, missing PASI score at Week 32 and static Physician’s Global Assessment 
(sPGA) at Week 32 data will be imputed using a combination of non-responder imputation (NRI) and multiple 
imputation (MI) methods. PASI and sPGA will be log-transformed using natural logarithm in the models. 
As the same missing data method will be applied on the PASI score and the sPGA, these two endpoints will be 
named SCORE in this Section 17.1.1.  
Unscheduled visits are in general not included in the analysis in this approach. However if a planned visit was 
missing and an unscheduled visit was performed within this visit window (refer to CTP section 6.1). 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 secondary 
efficacy analysis. 
 
Table 1: Application of NRI / MI for the analysis on the PPS  
 
prior to/on Week 32 
Secondary efficacy analysis (PPS) 
Discontinued treatment#  
Did NOT discontinue treatment 
SCORE computable using observed data at Week  32 
NRI applied 
Observed 
SCORE NOT computable using observed data at Week  32 
NRI applied 
MI applied 
 
# lost to follow‐up (according to eCRF record for “End of Treatment” or “Trial Completion”) is also included here, or subjects who took a therapy 
that may significantly impact efficacy assessment prior to this time‐point. 
 


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The following steps will be followed: 
17.1.1.2. Multiple Imputation 
 
STEP 1: 
 
 
Creation of monotone missing data datasets: 
A monotone missing data structure means the variables have a specific order and that missing data always occur at 
the end of data records. Once a variable measurement is missing, all subsequent variable measurements are 
missing. 
A non-monotone missing data structure means the missingness of data doesn’t depend on the order of the 
variables. Once a variable measurement is missing, the following variable measurements might be recorded or 
missing.  
The first step of the multiple imputation is to transform a non-monotone missing data structure to a monotone one. 
Intermediate missing variables will be multiple imputed using the Markov Chain Monte Carlo (MCMC) method 
and assuming Missing At Random (MAR) and multivariate Normality. The SAS procedure PROC MI with the 
MCMC option will be used. 
The number of burn-in iterations before the first imputation and between each imputation has been identified 
based on approximately 90% of subject data up to Week 32 and fixed to 200. 
This step will be performed on the longitudinal continuous PASI score and sPGA score (between Week 0 and 
Week 32). 
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. 
One thousand imputations will be performed. A SAS dataset will be provided and will contain 1000 databases 
with a monotone missing data structure regarding the SCORE (PASI or sPGA) variables at each visit. 


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 
Creation of non-missing data datasets: 
 
The datasets, now with monotone missing data, will be imputed further using sequential regression, with the 
following model for each visit by treatment: 
 
Log(SCORE) = + WeightW14 + Stage + <log(Pasi Previous baseline score) + Log(Pasi Post-baseline score) > 
 
That means, if the screening visit is Visit 1 and score (PASI or sPGA) at Visit v is denoted Sv, then for example 
the model to impute 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 effects of: 
Treatment (switching arm versus continuously Humira® arm) 
Weight at Week 14 (continuous value) 
Stage, where stage represents the two parts of the study prior to and after the blinded sample size reassessment 
(categorical, 1 or 2) 
The PASI75 and sPGA ≤ 1 at Week 32 will then be calculated for each of the multiple imputed datasets.The PASI 
and sPGA at Week 32 will be the only imputed values used in the next analyses. The missing PASI and sPGA 
values at previous visits and at baseline were imputed only in order to make the W32 imputation possible but will 
be used nowhere else. 
17.1.1.3. Non Responder Imputation 
 
STEP 2: 


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The imputed PASI75 and sPGA at Week 32 will be set to non-responder at Week 32 if the subject: 
 
discontinue treatment prior to Week 32 (including death) 
 
are lost-to-follow-up (according to eCRF record for “End of Treatment” or “Trial Completion”)  prior to 
Week 32 
 
have any severe violation related to any therapy that may significantly impact efficacy assessment prior to 
Week 32 
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: 
o 
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. 
o 
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. 
 
17.1.2. ANALYSIS OF SECONDARY EFFICACY ENDPOINTS 
 
The difference in proportions will be calculated between the two treatment arms as the difference between the 
observed proportions in each treatment group. Confidence intervals for the difference of proportions will be 
obtained using the Wald method, which is based on the asymptotically normal approximation to the distribution of 
the observed sample proportions. 
The 90% and 95% CIs will be provided. 
 
The difference in proportion will be calculated as: ݌ଵെ݌ଶ 
This confidence interval formula is: 
ܥܫఈ/ଶൌሺ݌ଵെ݌ଶሻേݖఈ/ଶൈඨ݌ଵൈሺ1 െ݌ଵሻ
݊ଵ
൅݌ଶൈሺ1 െ݌ଶሻ
݊ଶ
 
where: 
p1 = Observed proportion of subjects in the switching arm 
p2 = Observed proportion of subjects in the continuous Humira® arm 
α =  
10% for 90% CI bounds 
 
5% for 95% CI bounds 


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zα/2 =  
1.64 for 90% CI bounds 
 
1.96 for 95% CI bounds 
n1 = Number of subjects in the switching arm 
n2 = Number of subjects in the continuous Humira® arm 
 


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17.1.2.1. Secondary Efficacy Variables and Derivations 
The proportion of subjects with a PASI75 response will be assessed at Week 32. 
 
 
Relative change of PASI score (%) at Week 32 =  (PASI score at baseline – PASI score at Week 32)/ 
PASI score at baseline x 100 
In case of baseline value equal to 0 and non-missing value recorded at Week 32, then the change is set to 0% for 
the corresponding visit. 
In this case, baseline is only the baseline value obtained before Reference Run-in Start Date. Baseline value 
obtained before Reference Double-blind Start Date is not used here. 
 
 
PASI75 at Week 32: 
o 
Yes if relative change of PASI score at Week 32 ≥ 75 
o 
No if relative change of PASI score at Week 32 < 75 
 
The proportion of subjects with a static Physician’s Global Assessment (sPGA) ≤ 1 (clear or almost clear) will be 
assessed at Week 32. 


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18. SAFETY OUTCOMES 
For the Final analysis, safety analyses will be done on overall Trial period (W1-W58) and separately on Run-in 
Period (W1-W14) and Post-Randomization Period (W14-W58). 
The overall Trial analysis, Double-Blind Period analysis and Post-Randomization Period analysis will be 
performed for the TS. The Run-in Period analysis will be performed for the RTS. 
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 and further objective in this trial. 


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The safety endpoint is defined as the proportion of subjects with drug-related Adverse Events (AEs). This safety 
endpoint is considered a secondary endpoint in this trial. 
Other safety endpoints are: 
 
Proportion of subjects with AEs, Serious AEs (SAEs), and AEs of Special interest (AESIs) 
 
Proportion of subjects with injection site reactions 
18.1. 
ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA central coding dictionary, Version 20.0 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. 
18.1.1. 
ADVERSE EVENT SPECIFIC DERIVATION 
18.1.1.1. Treatment Emergent Adverse Event 
According the period analysed, 3 derivations of the Treatment Emergent Adverse Events (TEAEs) will be used. 
For the overall Trial analysis: 
o 
TEAEs are defined as AEs that started or worsened on or after the first dose of Humira® and 
prior to the last dose of trial post-randomization medication + 10 weeks (W58). 
o 
Non-TEAEs will be classified as “Screening” if AE start date is strictly prior the first dose of 
Humira® date. Non-TEAEs will be classified as “Post treatment” if AE start date is strictly after 
the last dose of trial post-randomization medication date + 10 weeks. 
For the Post-Randomization Period analysis: 
o 
TEAEs are defined as AEs that started or worsened on or after the first dose of trial post-
randomization medication and prior to the last dose of trial post-randomization medication + 10 
weeks (W58). 
o 
Non-TEAEs will be classified as “Screening” if AE start date is strictly prior the first dose of 
trial post-randomization medication date. Non-TEAEs will be classified as “Post treatment” if 
AE start date is strictly after the last dose of trial post-randomization medication date + 10 
weeks. 
For the Run-in Period analysis 
o 
TEAEs are defined as AEs that started or worsened on or after the first dose of Humira® and 


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prior to the first dose of trial post-randomization medication +10 weeks. 
o 
Non-TEAEs will be classified as “Screening” if AE start date is strictly prior the first dose of 
Humira® date. Non-TEAEs will be classified as “Post treatment” if AE start date is strictly on or 
after the first dose of trial post-randomization medication date +10 weeks. 
 
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. 
18.1.1.2. Risk ratio 
Risk ratios and associated 95% exact confidence interval will be presented for adverse events of special interest. 
18.1.2. 
ALL TEAES  
Number of subjects, percentages, and number of events 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.  
18.1.2.1. Intensity 
Intensity is classed as mild/ moderate/ severe (increasing intensity). TEAEs starting after the first dose of Humira® 
or trial post-randomization medication (according to the analyzed period) 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. 


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18.1.2.2. 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 
relationship to trial medication within that period will be used in the corresponding relationship summaries. 
All drug related AEs will be listed. 
18.1.3. 
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 by SOC and PT. 
The AEs causing treatment modification or drug withdrawal will be listed. 
18.1.4. 
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 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. 
A summary of related SAEs by SOC and PT will also be prepared. 
The SAEs and Non-SAEs will be listed. 
18.1.5. 
ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events that 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. 
18.1.6. 
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: 
 


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Adverse Event : 
AESI 
Other safety 
endpoint 
     Serious infections 
√ 
√ 
     Hypersensitivity reactions 
√ 
√ 
     Drug induced liver injury 
√ 
√ 
     Injection site reactions 
 
√ 
     Anaphylactic reactions 
√ 
√ 
18.1.6.1. 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. 
18.1.6.2. 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. 
18.1.6.3. 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 
to “Yes” information from the Adverse Events page of the eCRF as a flag. 


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18.1.6.4. 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 18.4.1). 
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. 
18.1.6.5. 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. 
18.1.7. 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. 
18.2. 
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 


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each injection site reaction (Swelling / Hardening / Heat / Redness / Pain / Itching / Bruising / Other). 
 
Injection-site reactions will be listed. 
 
18.3. 
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. 
18.4. 
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 7. 
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 analyzed period up to the end of the period (periods described in 
Section 18) will be assigned to the treatment phase for evaluation. Moreover, tables about DILI and  hemoglobin 
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) 
 
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: 


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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. 
18.4.1. 
LABORATORY SPECIFIC DERIVATIONS 
Log ALT = logarithm to base 10 scale of the multiple of the ULN of ALT 
Log AST = logarithm to base 10 scale of the multiple of the ULN of AST 
Log TBL = logarithm to base 10 scale of the multiple of the ULN of TBL.  
Note: Bilirubin value instead of TBL will be used. 
 
Potential Hy’s law categories: 
o 
Category 1: ALT or AST >=3xULN and TBL >=2xULN within the same sample 
o 
Category 2: TBL >=2xULN within 30 days after transaminase peak (ALT or AST >=3 ULN) 
 
Potential Hy’s Law subjects are defined as subjects with laboratory data in at least one Potential Hy’s law 
categories at any time point of the trial. 
 
Drug induced liver injury (DILI): 
o 
Normal liver function at Baseline is defined as AST and ALT and Total Bilirubin values 
measured at baseline are each <= respective ULN. 
o 
For post baseline visits: 
 
Subjects with normal liver function at Baseline and (AST and/or ALT ≥3 times ULN 
and TBL ≥2 times ULN within the same sample). 
 
Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN 
18.4.2. 
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. 


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18.4.3. 
OTHER SAFETY LABORATORY EVALUATIONS 
18.4.3.1. Pregnancy test 
Descriptive table will present pregnancy results for females by visit on TS. 
The pregnancy results will be listed as well. 
18.4.3.2. Tuberculosis test 
Descriptive table will present Tuberculosis (TB) test results by visit on TS. 
The TB test results will be listed as well. 
18.5. 
ECG EVALUATIONS 
Results from ECGs will be summarized by visit to the categories as recorded in the eCRF page “12-Lead-ECG” 
(“Normal”, “Abnormal, not clinically significant” and “Abnormal, clinically significant”). 
ECG evaluations will also be listed. 
18.6. 
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) 
 
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. 
18.7. 
PHYSICAL EXAMINATION 
Incidence of evaluation categories (Normal, Abnormal) at baseline and post-baseline visits will be provided for 


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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. 
19. IMMUNOGENICITY 
 
19.1. 
MISSING DATA METHODS FOR IMMUNOGENICITY 
Missing data will not be imputed. 
19.2. 
ANALYSIS OF IMMUNOGENICITY VARIABLES 
Immunogenicity will be assessed as secondary and further objectives in this trial. All Immunogenicity analyses 
will be performed based on (i) RTS without patients being randomized (if feasible) and (ii) TS.  
There will be no formal statistical comparisons between the treatment groups for Immunogenicity data. 
The handling of retests, unscheduled and end of trial measurements are described in Section 6.3. 
 
The following analyses will be performed:Number and frequency of subjects with ADA / neutralizing ADA 
sampling results by actual treatment arm and visit*: 
o 
Negative 
o 
Positive 
o 
Total reportable (= sum of Negative and Positive) 
o 
Not Reportable (= samples which should have been taken per protocol but no result is available 
(due to many reasons). Samples from subject that discontinued (drop-outs) or subjects that have 
not reached a defined time-point yet, are not considered non-reportable but reduce the number of 
total samples available) 
o 
Total (= sum of Total Reportable and Not Reportable) 
Descriptive statistics of ADA and nAb titer will be provided by actual treatment arm and visit when available. 
* where ADA/nAb samples have been taken, i.e. Visits 2, 3, 6, 8, 9, 11, 13, 17, 18, 22, 27 and 28. Note that 
patients from the RTS that have not been randomized, by definition, do not have all values available for Visit 11 
onwards, see CTP. 
The ADA and nAbs results will be listed as well. 
ADA and nAbs results listing restricted to the subjects treated at least once with the incorrect trial treatment will 


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be provided. 
From those assessments, the secondary immunogenicity endpoints are: 
 
The proportion of subjects with ADAs at Week 32 (Visit 18). 
 
ADA titer of subjects with ADAs at Week 32 (Visit 18). 
 
The proportion of subjects with neutralizing Antibody (nAb) at Week 32 (Visit 18) 
 
nAb titer of subjects with nAbs at Week 32 (Visit 18). 
All other time points are considered further immunogenicity endpoints. 
 
The following figures will be provided for Immunogenicity data (only for TS): 
 
Time course (Bar Chart) of ADA development (percent positive subjects) over time (by planned study 
day) for all treatments. 
 
Box plot (with whiskers) of titer within ADA positive subjects over time (by planned study day) (one 
graph) – the log2 scale will be used 
 
Box plot (with whiskers) of titer within ADA positive subjects at each ADA timepoint (multiple graphs) 
– the log2 scale will be used 
 
Time course (Bar Chart) of nAb development (percent positive subjects) over time (by planned visit day) 
for all treatments 
 
Box plot (with whiskers) of titer within nAb positive subjects over time (by planned study day) (one 
graph) – the log2 scale will be used 
 
Box plot (with whiskers) of titer within nAb positive subjects at each ADA timepoint (multiple graphs) – 
the log2 scale will be used 
 
 


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20. REFERENCES  
ICH E9 – Statistical Principles for Clinical Trials (Issued 1998) 
[1] Friede T, Kieser M. Blinded sample size reassessment in non-inferiority and equivalence trials. Statistics in 
Medicine 2003; 22, 995-1007.  
[2] Golkowski D, Friede T and Kieser M. Blinded sample size re-estimation in crossover bioequivalence trials. 
Pharmaceutical Statistics 2014; 13, 157-162. 
[3] Hauschke D Steinijans V Pigeot I. Bioequivalence studies in drug development: methods and applications. 
Chichester: John Wiley & Sons; 2007. 
[4] Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis Group; 2010.