Conditions: Asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 214
Healthy volunteers: no

Brief summary:
The objectives of this trial are primarily to evaluate the efficacy and safety of BI 655066/ABBV-066 (risankizumab) as compared to placebo over a 24-week treatment period in severe asthma patients. The primary endpoint is time to first asthma worsening during the planned 24 week treatment period for active vs. placebo treated patients on top of standard of care therapy. Upon demonstration of a meaningful clinical response, another important objective is the identification of biomarkers that can be used to target patients who will likely respond to treatment with BI 655066/ABBV-066 (risankizumab).

Detailed description:

Arms:
arm 1: Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe with 90 milligram/ milliliter (mg/mL) risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20). arm 2: Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe consisting of matching placebo to risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20).

Interventions: intervention 1: placebo intervention 2: risankizumab
Intervention descriptions: intervention 1: Matching placebo for risankizumab intervention 2: Monoclonal IgG antibody

Protocol document:
Prot_000.pdf: 
CLINICAL TRIAL PROTOCOL
Document Number:
c03185695-07
EudraCT No.:
2014-004932-20
BI Trial No.:
1311.14
BI Investigational 
Product:
BI 655066
Title:
A phase IIa, randomized, double-blind, placebo controlled, parallel group study 
to assess the safety and efficacy of subcutaneously administered BI 
655066/ABBV-066 (risankizumab) as add-on therapy over 24 weeks in patients 
with severe persistent asthma.
Brief Title:
Efficacy and safety of BI 655066/ ABBV-066 (risankizumab) in patients with
severe persistent asthma.
Clinical Phase:
IIa
Trial Clinical 
Monitor:
Phone: 
 Fax: 
Coordinating  
Investigator:
Phone:
Status:
Final Protocol (revised protocol based on global amendment 5)
Version and Date:
Version: 6.0
Date: 17 August 2017
Page 1 of 109
Proprietary confidential information.
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 655066
Protocol date:
13 March 2015
Trial number:
1311.14
Revision date:
17 August 2017
Title of trial:
A phase IIa, randomized, double-blind, placebo controlled, parallel group study to 
assess the safety and efficacy of subcutaneously administered BI 655066/ABBV-
066 (risankizumab) as add-on therapy over 24 weeks in patients with severe 
persistent asthma.
Coordinating 
Investigator
Phone: 
Trial sites:
Multi-center, Multi-national
Clinical phase:
IIa
Objectives:
Evaluate efficacy and safety of BI 655066 (risankizumab) compared to placebo in 
patients with severe persistent asthma over a 24-week treatment period.
Methodology:
Randomized, double-blind, placebo-controlled, parallel-group study with 
risankizumab compared to placebo, administered subcutaneously in patients with 
severe persistent asthma.
No. of patients: 
Approximately 200
total entered:
Approximately 200
each treatment:
Approximately 100
Diagnosis :
Severe persistent asthma
Main criteria
for inclusion:
1.    Male or female patients aged at least 18 years but not more than 75 years.
2.    Pre-bronchodilator clinic measured FEV1 of ≥40% and ≤85% of predicted     
normal at the screening visit.
3.   A minimum of one year history of asthma diagnosed by a physician, and 
have FEV1 reversibility as defined by an improvement in FEV1 ≥12% and an 
absolute change of at least 200 ml starting within 15 to 30 minutes after 
administration of 400 µg salbutamol (albuterol) via MDI. Reversibility 
testing is performed at the screening Visit (Visit 1B). 


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 655066
Protocol date:
13 March 2015
Trial number:
1311.14
Revision date:
17 August 2017
If reversibility criteria are not met, the patient may still be randomized if there 
is:

Documented evidence of reversibility with improvement in FEV1
≥12% above baseline and an absolute increase of at least 200 ml in 
the 2 years prior to Visit 2 (randomization visit)
       or

Documented evidence of airway hyperresponsiveness 
(methacholine: PC20 of <8 mg/mL) in the 2 years prior to Visit 2 
(randomization visit)
       or

Documented evidence of airflow variability in clinic FEV1 ≥20% 
between two clinic visits documented in the 12 months prior to visit 
2 (randomization visit).
If reversibility criteria are not met at Visit 1B and if any of the above historic 
data are not available, reversibility testing can be repeated up to twice during 
screening period at separate visits. For the first retest, 400 µg salbutamol via 
MDI should be used, and for the second retest, up to 800 µg salbutamol via 
MDI or 2.5 mg nebulized albuterol should be used.  Reversibility testing must 
not occur on the day of randomization.  Additional guidelines for reversibility 
testing can be found in Appendix 10.1.
4.    Patients must be on at least medium dose inhaled corticosteroids and at least 
one other asthma controller medication for at least one year prior to the date of 
screening.  Asthma therapy must have been documented and must be stable for 
at least 4 weeks prior to the date of screening.
5.    Patients must have documented history of at least one of the following criteria: 
a) two or more severe asthma exacerbations in the last 12 months, or b) one 
severe asthma exacerbation in the last 12 months requiring hospitalization or 
emergency room visit, or c) one severe asthma exacerbation in the last 6 
months not requiring hospitalization or emergency room visit, prior to the date 
of screening visit (Visit 1B).  Patients must not have a severe asthma 
exacerbation in the 6 weeks prior to screening visit.  Patients with only one 
severe asthma exacerbation in the last 6 months (category c, but not a or b) will 
be limited to approximately 25% of the total patient population.
6.    Patients should be a non-smoker or ex-smoker who stopped smoking at least 
one year prior to screening.  Ex-smokers must have a smoking history of less 
than 10-pack years


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 655066
Protocol date:
13 March 2015
Trial number:
1311.14
Revision date:
17 August 2017
Test product(s):
1 mL pre-filled syringe consisting of 90 mg/mL BI 655066
dose:
90 mg, once every 4 weeks: weeks 0, 4, 8, 12, 16, 20
mode of 
administration:
subcutaneous injection
Comparator products:
1 mL pre-filled syringe consisting of matching placebo
dose:
NA
mode of 
administration:
subcutaneous injection
Duration of treatment:
24 weeks (last dose at week 20)
Endpoints
Primary efficacy endpoint:
Time to first asthma worsening during the planned 24-week treatment period. 
Secondary efficacy endpoints:
1.
Annualized rate of asthma worsening during the planned 24-week treatment 
period
2.
Annualized rate of severe asthma exacerbation during the planned 24-week 
treatment period
3.
Weekly ACQ5 score at week 24
4.
Trough FEV1 in-clinic change from baseline at week 24
5.
Post-bronchodilator FEV1 in-clinic change from baseline at week 24
6.
Time to first severe asthma exacerbation during the planned 24-week treatment 
period
7.
Time to first asthma worsening (alternative definition 1) during the planned 
24-week treatment period
 
Safety criteria:
Physical examination, vital signs, safety labs, ECG, and adverse events.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 655066
Protocol date:
13 March 2015
Trial number:
1311.14
Revision date:
17 August 2017
Statistical methods:
For analysis of time to event data for asthma worsening and severe asthma 
exacerbation, Cox’s proportional hazard model will be used for obtaining hazard 
ratio estimations, confidence intervals, and p-values. For analysis of annualized 
rate of asthma worsening and severe asthma exacerbation, a negative binomial 
model accounting for exposure will be used. Weekly ACQ5 score will be analyzed 
using an analysis of covariance (ANCOVA) model. A restricted maximum 
likelihood (REML) based mixed model repeated measures (MMRM) approach will 
be used to analyze mean change from baseline in trough and post-bronchodilator 
FEV1 at week 24.


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FLOW CHART A
Screening 
Period1
Randomized Treatment Period2
Follow-up period2
Visit
1A
1B
2
3
4
5
6
7
8
(EOT)
9
10
11
12
(EOO)
Day
-28 to -22
-21
±6
1
29
±3
57
±3
85     
±3
113   
±3
141
±3
169
±3
197
±4
225
±4
253
±4
281
±4
Week
-4 to -3
-3
0
4
8
12
16
20
24
28
32
36
40
Informed consent3
X
Inclusion/Exclusion criteria
X
X
X
Demographics
X
Med. history/baseline conditions
X
X
Review smoking status
X
X
X
Physical examination
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Laboratory assessments4
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test5
X
X
X
X
X
X
X
X
X
X
X
12-Lead resting ECG
X
X
X
X
X
X
X
Induced sputum6
X
X
X
X
X
Randomization
X
FeNO measurements
X
X
X
X
X
X
X
X
X
X
X
Asthma worsening/exacerbation7
X
X
X
X
X
X
X
X
X
X
X
Dispense rescue medication8
X
X
X
X
X
X
X
X
X
X
E-diary/PEF training9
X
X
Dispense asthma monitor (E-diary)
X
Download E-diary/PEF data
X
X
X
X
X
X
X
X
X
X
Medication washout check10
X
X
X
X
X
X
X
X
X
X
X
Asthma medication log review11
X
X
X
X
X
X
X
X
X
X
X
Pulmonary function tests12
X
X
X
X
X
X
X
X
X
X
X
 
Administer BI 655066 or placebo
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
End of treatment period16
X
End of observation period17
X


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Footnotes:
1.
Visit 1A and Visit 1B must occur on separate days and must be separated by at least one day.  Visit 1A 
is the informed consent visit.  Visit 1B is the screening visit and referred as such throughout the 
protocol.  Screening period is from Visit 1B to Visit 2.
2.
Randomized treatment period will be a total of 24 weeks even if visits within the treatment period are 
missed or rescheduled.  Follow-up period will be a total of 16 weeks.
3.
All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation 
in the trial, which includes medication washout requirements.  
 
4.
For tuberculosis screening, refer to Exclusion Criteria 16.  Fasting is not required for routine labs.  
 
5.
Females (women of child bearing potential only): Serum pregnancy test will be done at the screening 
visit (Visit 1B). Urine pregnancy test (dipstick) will be done at the clinic at all other visits (except Visit 
11) starting at Visit 2.  If urine pregnancy test is positive, serum pregnancy test will be done to confirm 
pregnancy (see Section 6.1).
6.
Sputum samples collected at the screening visit (Visit 1B) will be processed on the same day and the 
primary cytospin slides should be shipped on the same day or no later than the next business day.  The 
central reader will complete the assessment and communicate to the site on patient eligibility (expected 
to take 5 to 7 business days).  Sputum samples from visits other than the screening visit must be 
processed on the same day and shipped.  Sputum induction must be performed only after ECG 
measurements (if applicable at that visit), FeNO measurements, and PFTs are completed.
7.
Asthma worsening check is done by reviewing the downloaded data from the E-diary and also 
verifying with the patient if there has been any change in asthma symptoms since the last clinic visit.
8.
At each clinic visit, starting Visit 1B, study coordinator/nurse must ensure that the patient has access to 
sufficient rescue medication until the next scheduled clinic visit.  The amount of rescue medication 
needed for the next 4 weeks can be estimated based on the use of rescue medication in the past 
4 weeks.  Rescue medication should be salbutamol (albuterol) provided by the Sponsor.
9.
Patients must be trained in the use of E-diary and PEF measurements at Visit 1B, and 2.  If patients are 
non-compliant in the use of E-diary or if they need more training in PEF measurements, additional 
training must be provided during clinic visits in the entire duration of the study.  Proof of additional 
training should be documented.
10. Medication washout check is required for the PFTs.  Medication washout checklist provided in the ISF 
must be completed at each visit.
11. Patients will enter any changes in asthma medications (excluding rescue medication) in a medication
log provided to them at each visit.  At each scheduled visit, the medication log should be collected, 
reviewed, and a new medication log should be dispensed.  At each visit, asthma medication log should 
be checked to see if patients met any of the asthma exacerbation criteria defined in the protocol.
12. All patients will undergo reversibility testing at Visit 1B (see Appendix 10.1 and Inclusion Criteria 4).  
Pre-and post-bronchodilator PFTs will also be performed on other clinic visit days (Visits 2 to 12).  
PFTs must be completed only after ECG measurements (if applicable at that visit), and FeNO 
measurements are completed.  PFT measurements must be completed before sputum induction (if
applicable at that visit).  PFT measurements should be started in the mornings between 6:00 am and 
10:00 am.  Please review additional requirements in Section 5.2.
 
  


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16. If a patient permanently discontinues study medication before the last scheduled dose (Week 20, 
Visit 7), an early EOT visit should be scheduled approx. 4 weeks after the last dose, and all procedures 
listed under Visit 8 should be completed.  At the completion of the EOT, patient will enter the follow-
up period and complete all 4 follow-up visits (Visits 9 to 12, Visit 11 is a phone visit).  During the 
phone call at Visit 11, any adverse events and concomitant therapy will be checked.  Any change in 
asthma medication entered in the asthma medication log will be verified.  If the patient is unable to 
continue all or part of the follow-up period, one additional visit should be scheduled 16 weeks after the 
EOT.
17. If a patient permanently discontinues from the study during the follow-up period, an EOO visit should
be scheduled on the originally scheduled EOO visit date (week 40).


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART A....................................................................................................................6
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................15
MEDICAL BACKGROUND.............................................................................15
1.1
DRUG PROFILE................................................................................................16
1.2
1.2.1
General Pharmacology .......................................................................................16
1.2.2
Toxicology............................................................................................................17
1.2.3
Clinical Experience .............................................................................................17
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....20
RATIONALE FOR PERFORMING THE TRIAL.........................................20
2.1
TRIAL OBJECTIVES........................................................................................20
2.2
BENEFIT - RISK ASSESSMENT.....................................................................20
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................23
OVERALL TRIAL DESIGN AND PLAN .......................................................23
3.1
3.1.1
Administrative structure of the trial .................................................................25
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP...........................................................................................26
SELECTION OF TRIAL POPULATION .......................................................26
3.3
3.3.1
Main diagnosis for trial entry ............................................................................27
3.3.2
Inclusion criteria .................................................................................................27
3.3.3
Exclusion criteria ................................................................................................28
3.3.4
Removal of patients from therapy or assessments...........................................30
Removal of individual patients .............................................................................30
3.3.4.1
Discontinuation of the trial by the Sponsor ..........................................................31
3.3.4.2
4.
TREATMENTS...................................................................................................32
TREATMENTS TO BE ADMINISTERED.....................................................32
4.1
4.1.1
Identity of BI investigational product and comparator product....................32
4.1.2
Method of assigning patients to treatment groups...........................................32
4.1.3
Selection of doses in the trial..............................................................................33
4.1.4
Drug assignment and administration of doses for each patient......................33
4.1.5
Blinding and procedures for unblinding...........................................................34
Blinding.................................................................................................................34
4.1.5.1
Unblinding and breaking the code ........................................................................34
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................34
4.1.7
Storage conditions...............................................................................................34


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4.1.8
Drug accountability.............................................................................................35
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................35
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....35
4.2.2
Restrictions ..........................................................................................................36
Restrictions regarding concomitant treatment ......................................................36
4.2.2.1
Additional treatments............................................................................................37
4.2.2.2
Restrictions on diet and life style..........................................................................37
4.2.2.3
Restrictions for women of childbearing potential.................................................37
4.2.2.4
Restrictions before FeNO measurements:.............................................................37
4.2.2.6
4.3
TREATMENT COMPLIANCE........................................................................37
5.
VARIABLES AND THEIR ASSESSMENT ....................................................39
TRIAL ENDPOINTS..........................................................................................39
5.1
5.1.1
Primary Endpoint ...............................................................................................39
5.1.2
Secondary Endpoints..........................................................................................39
ASSESSMENT OF EFFICACY........................................................................40
5.2
5.2.1
Asthma Exacerbations........................................................................................40
5.2.2
Efficacy Assessments...........................................................................................41
ASSESSMENT OF SAFETY.............................................................................44
5.3
5.3.1
Physical examination ..........................................................................................44
5.3.2
Vital Signs............................................................................................................44
5.3.3
Safety laboratory parameters ............................................................................44
5.3.4
Electrocardiogram ..............................................................................................47
5.3.5
Other safety parameters.....................................................................................48
5.3.6
Assessment of adverse events.............................................................................48
Definitions of AEs ................................................................................................48
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................50
 
APPROPRIATENESS OF MEASUREMENTS..............................................57
5.7
6.
INVESTIGATIONAL PLAN.............................................................................58
VISIT SCHEDULE.............................................................................................58
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................60
6.2
6.2.1
Screening period..................................................................................................60
6.2.2
Treatment period ................................................................................................62
6.2.3
Follow Up Period and Trial Completion...........................................................64


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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................65
STATISTICAL DESIGN - MODEL.................................................................65
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................65
7.2
PLANNED ANALYSES.....................................................................................65
7.3
7.3.1
Primary endpoint analyses.................................................................................65
7.3.2
Secondary endpoint analyses .............................................................................66
7.3.4
Safety analyses.....................................................................................................67
INTERIM ANALYSES ......................................................................................68
7.4
HANDLING OF MISSING DATA ...................................................................68
7.5
RANDOMIZATION...........................................................................................68
7.6
DETERMINATION OF SAMPLE SIZE .........................................................69
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........70
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................70
DATA QUALITY ASSURANCE ......................................................................70
8.2
RECORDS...........................................................................................................70
8.3
8.3.1
Source documents ...............................................................................................71
8.3.2
Direct access to source data and documents.....................................................71
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS71
8.4
8.4.1
Listedness.............................................................................................................71
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................72
STATEMENT OF CONFIDENTIALITY........................................................72
8.5
END OF TRIAL..................................................................................................72
8.6
9.
REFERENCES....................................................................................................73
PUBLISHED REFERENCES............................................................................73
9.1
UNPUBLISHED REFERENCES......................................................................76
9.2
10.
APPENDICES.....................................................................................................78
ADDITIONAL INFORMATION REGARDING 
10.1
INCLUSION/EXCLUSION CRITERIA..........................................................78
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................80


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ABBREVIATIONS
ACQ
Asthma Control Questionnaire
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
ATS
American Thoracic Society
BCG
Bacille Calmette-Guerin
BI
Boehringer Ingelheim
BID
Bis in die (twice daily)
CFC
Chlorofluorocarbon
CRO
Contract Research Organization
CTP
Clinical Trial Protocol
DILI
Drug-Induced Liver Injury
DMC
Data Monitoring Committee
ECG
Electrocardiography
eCRF
Electronic Case Report Form
E-diary
Electronic Diary
EOO
End of Observation
EOT
End of Treatment
ERS
European Respiratory Society
ERT
eResearch Technology
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FeNO
Fractional exhaled Nitric Oxide
FEV1
Forced Expiratory Volume in 1 second
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
HFA
Hydrofluroalkane
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
IL
Interleukin
i.m.
Intra-muscular
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File


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i.v.
intravenous
Kg
Kilograms
mAB
Monoclonal Antibody
MACE
Major Adverse Cardiovascular Event
MedDRA
Medical Dictionary for Drug Regulatory Activities
Mg
Milligrams
MMRM
Mixed Model Repeated Measures
NA
Not Applicable
OCS
Oral corticosteroids
PEF
Peak Expiratory Flow
PFT
Pulmonary Function Test
QD
Quaque die (once daily)
RDC
Remote Data Capture
REML
Restricted Maximum Likelihood
REP
Residual Effect Period
SAE
Serious Adverse Event
s.c.
subcutaneous
SOP
Standard Operating Procedure
TB
Tuberculosis
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit Normal


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Asthma is a common chronic disease with an estimated 300 million affected individuals.  The 
global prevalence ranges from 1 to 18% of the population in different countries.  Asthma is 
the most common chronic disease in childhood, affecting an estimated 6 million children, and 
it is a common cause of hospitalization for children in the United States.  The World Health 
Organization has estimated that 15 million disability-adjusted life years (DALYs) are lost 
annually due to asthma, representing 1% of the total global disease burden. Annual 
worldwide deaths from asthma have been estimated at 250,000.
The clinical features of asthma include recurrent episodes of wheezing, breathlessness, 
chest tightness, and cough.  The physiologic characteristics are derived from inflammation 
of the airway mucosa, often involving the infiltration of eosinophils or neutrophils.
Severe asthma represents a high unmet medical need.  Despite representing a minority of 
all asthma patients, severe asthma patients drive the majority of costs and healthcare 
utilization in asthma.  Furthermore, targeting specific clinical phenotypes/endotypes 
through scientifically rational design is expected to be more successful than broad 
development in severe asthma since the phenotypic heterogeneity is likely driven by 
fundamental differences in underlying mechanisms.  These clinical phenotypes may show 
specific pathophysiological associations leading to classifications of endotypes 
(R14-4225). Accompanying this growing understanding of the diverse nature of asthma is 
the realization that there are also a diverse range of treatment responses dependent on the 
underlying nature of an individual’s disease.  This naturally leads to the concept of the 
personalized therapy regimes for patients with severe asthma that better target their 
individual disease.  Omalizumab (XOLAIR®) is the first biological asthma treatment to 
meet that need in patients with severe allergic asthma (R14-2101).  Numerous potential 
biological agents are in development that show promise in targeting patients with 
particular disease phenotypes / endotypes such as mepolizumab (R14-4224), lebrikizumab
(R14-4226), and dupilumab (R14-4232). These approaches have demonstrated clinical 
benefit in various subsets of asthma, although these agents demonstrated questionable 
clinical utility in broad asthma when tested in a wider population. The success of these 
therapies in defined subsets of asthma highlights the need to further refine treating patients 
in asthma.  To date there has been no therapy developed in successfully addressing 
patients with the known clinical phenotype of neutrophilic asthma despite the fact that this 
phenotype represents a significant portion of severe asthma.  
Cellular heterogeneity has been observed in patients with severe asthma (R14-4187, 
R14-4184). A number of studies have reported increased numbers of neutrophils in the 
airways in patients with severe asthma (P03-08188, P99-03282), asthma exacerbations 
(R14-4216), life threatening severe asthma exacerbations (R98-1426), and fatal asthma 
(R14-4217). However, a causal association between neutrophils and asthma severity has 
been difficult to establish. It is not clear if the increased neutrophils are an indicator of a 
specific inflammatory pattern, a marker of unrecognized airway infection (R14-4215), or 
the consequence of high doses of corticosteroids used by these patients.  Assuming 


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neutrophilic disease is a targetable clinical entity, a novel biological controller medication 
in neutrophilic asthma offers a unique opportunity as no other therapy is approved or is 
near approval in this known clinical phenotype of severe asthma.  
The role of IL-23 in maintaining Th-17 cells that secrete the pro-inflammatory cytokines
IL-17A and F, IL-22, and IFNγ has increasingly been implicated in chronic inflammatory
diseases. The IL-23/Th17 axis is reported to play an important role in the pathogenesis of 
severe asthma (R14-4183, R14-4182).  IL-17A is upstream of the known neutrophil 
attracting chemokines (e.g. IL-8) which promote a known neutrophilic clinical phenotype 
described as steroid resistant.  Recently induced sputum neutrophil cell counts have 
demonstrated high predictive value of severe asthma in unbiased clustering approaches of 
asthma (R14-4315).  It is enticing to propose patients with high levels of sputum 
neutrophils, as a responsive patient population to anti-IL-23 therapy, and testing this 
hypothesis is a primary aim of the current study.  Additionally a readily accessible (e.g. 
serum) diagnostic biomarker or endotype will likely be required to identify a target 
population who benefit from use of anti-IL-23 in severe asthma in further clinical studies 
with this antibody, given the known challenges employing induced sputum assessments in 
large clinical studies.
This study employs asthma worsening as a more frequent event amenable to measurement 
in exploratory phase IIa studies of limited size and duration.  The ultimate key clinical aim 
of the program is to reduce the annual rate of exacerbations in patients with severe 
persistent asthma.  Additionally, improvement in symptoms and symptom control is also 
of clinical importance for severe persistent asthma.  
DRUG PROFILE
1.2
BI 655066 (risankizumab) is a fully human monoclonal antibody (mAb) of the IgG1 subclass 
directed towards IL-23p19. The antibody has been engineered to reduce Fcγ receptor and 
complement binding and potential charge heterogeneity. Risankizumab binds with high 
affinity to human IL-23 and inhibits IL-23 stimulated IL-17 production
 
 
 For this phase 2 trial, risankizumab will be supplied as 
prefilled syringes containing 1 mL of a 90 mg/mL solution for subcutaneous administration.
1.2.1
General Pharmacology
The role of IL-23 in maintaining Th-17 cells that secrete the pro-inflammatory cytokines
IL-17A and F, IL-22, and IFNγ has increasingly been implicated in chronic inflammatory
diseases. In addition to psoriasis, there is evidence that the IL-23/Th17 axis plays an
important role in the pathogenesis of severe asthma (R14-4183, R14-4182). IL-23 has 
been shown to be upregulated in pediatric patients with asthma, and negatively correlated 
with FEV1 (R14-2349).  In animal models of airway hyperreactivity inhibition of 
IL-23p19 demonstrated a protective effect, and interestingly, blockade of IL-23 
unexpectedly reduces the classical Th2 cytokines IL-4, IL-5, IL-13 and IgE in preclinical 
challenge pharmacology models (R14-2348). More recent reports indicate that IL-21 is 
essential in the differentiation of Th2 cells able to secrete Th17 cytokines, and that these 


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cells are specifically pathogenic in severe asthma (P14-14612). Although these 
pluripotent Th2 cells lack the IL-23 receptor, IL-21 is derived from Th17 cells under the 
control of IL-23. Targeting p19 has a theoretical advantage in asthma over targeting the 
p40 subunit of IL-23 in that suppression of IL-12 may be avoided. Although IL-12 
suppression has been associated with risk of malignancy in IL-12 knock-out mice, no 
increased cancer rates have been reported in patients receiving IL-23p40 antibodies for 
psoriasis over a five year period (R13-3518).  Data suggest that a putative risk of infection 
through suppression of the Th1 pathways and IL-23 is possible, and IL-23 has been shown 
to play a role in immune response against specific pathogens like Klebsiella and 
Salmonella (R11-1199, R11-1200). However individuals with genetic perturbations in the 
IL-12/ IL-23 signaling pathway are not broadly immune compromised.  Targeting
IL-23p19 that is devoid of IL-12 inhibition could be a preferable approach for asthma as 
blocking IL-12 could theoretically cause perturbation of the Th1/Th2 balance towards Th2 
disease with negative clinical consequences for a major proportion of asthmatics.  As an 
example, TLR 9 agonists demonstrated clinical benefit in asthma by perturbing the 
Th1/Th2 balance by activating Th1 pathways.  The approach of targeting IL-23, the 
decisive cytokine in Th17 cell propagation, seems to generate a broader suppression of 
inflammatory pathways including not only Th17 cells, but also Th2 responses in 
preclinical models, and therefore may be more advantageous than targeting the 
downstream IL-17 receptor which is a concept currently being clinically tested in severe 
persistent asthma.  
1.2.2
Toxicology
 
 
 
 
 
 
 
 
 
 
 
 
In summary, the toxicology data suggest risankizumab can be safely administered to 
humans, as supported by chronic administration to monkeys for up to 26 weeks. 
 
1.2.3
Clinical Experience
Risankizumab has been evaluated in a completed phase I study where risankizumab was 
studied in a single rising dose trial (1311.1 (U12-3066-01) assessing the safety, tolerability, 
efficacy, PK and PD in male and female patients with moderate to severe psoriasis.  


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Additionally the 1311.2 (c01651292-07), 1311.6 (c01651690-12), and 1311.8 (c02190287-
17) studies evaluating 12-52 week exposure of risankizumab in psoriasis, Crohn’s disease, 
and ankylosing spondylitis respectively are ongoing.  The ongoing review of the safety 
information from these studies taken together with the 12-week unblinded safety data from 
the 1311.2 study in psoriasis enrolling approximately 120 patients treated with risankizumab
was used by an independent Data Monitoring Committee (DMC) to endorse the decision to 
start this study (1311.14) in patients with severe persistent asthma.
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Of interest for potential therapeutic use in asthma, a case report in the literature suggestive of
treatment benefit for patients with concomitant asthma and psoriasis whose asthma control is 
reported to benefit from treatment with STELARA® (R15-0678), but it will be important to 
evaluate treatment effects of risankizumab in an adequate and well controlled study to 
explore these anecdotal observations.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Despite the anticipated approval of new therapies targeting Th2 or eosinophil high asthma 
that will address an important part of the unmet medical need in severe asthma, additional 
therapy is needed to address the remaining unmet need given the high degree of heterogeneity 
in asthma, leaving a significant proportion of severe asthma unaddressed.  
 
 
 This study would 
provide the initial proof of concept for further clinical trials in severe asthma.
TRIAL OBJECTIVES
2.2
The objectives of this trial are primarily to evaluate the efficacy and safety of risankizumab
as compared to placebo over a 24-week treatment period in severe asthma patients.  The 
primary endpoint is time to first asthma worsening during the planned 24-week treatment 
period for active vs. placebo treated patients on top of standard of care therapy.  Additional 
secondary analyses will include time to first severe asthma exacerbation, frequency of asthma 
worsening and severe asthma exacerbation, effects on trough and post-bronchodilator lung 
function (FEV1), and evaluation whether symptomatic benefit can be derived from treatment 
with risankizumab as compared to placebo treated patients. 
 
 
 
 
 
 
 
 
 
 
 
 
BENEFIT - RISK ASSESSMENT
2.3
Severe persistent asthmatics, especially patients who experience frequent exacerbations are
associated with substantial morbidity, mortality, and health-care utilization. Recurrent 
asthma exacerbations are a major problem in severe asthma patients and can predominate in a 
subgroup characterized by neutrophilic airway inflammation.  Neutrophilic asthma may be 


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specifically non-responsive to corticosteroids.  The highest medical value is reduction in
exacerbation and hospitalization frequency, and a further improvement in the control of 
symptoms. In the patient population taking oral corticosteroids (OCS) frequently or 
continuously, reduction or elimination of steroid use would also mitigate the toxicity 
associated with these therapies. Assuming neutrophilic inflammation is relevant for severe 
asthma, neutrophilic severe asthma is currently unaddressed clinically, and it represents both 
an opportunity of a new therapeutic target population and the challenge of identifying 
patients likely to respond to a specific therapy.  Participation in this study may help to 
generate future benefit for larger groups of patients with asthma if risankizumab proves to be 
beneficial in treating this disease.
Although patients enrolled in this study will maintain their standard of care therapy, they will 
have a 50% chance to receive placebo.  Beyond close monitoring of asthma treatment, asthma 
symptoms, clinical laboratories, and clinical evaluations there is no additional potential 
benefit for these patients.  The decision to include a placebo group is essential for the 
evaluation of a treatment effect of risankizumab in severe asthma, and all patients are 
maintained on standard of care therapy.
Clinical data is available from a single rising dose, double-blind, placebo controlled trial with 
risankizumab in patients with moderate to severe psoriasis. In these studies, risankizumab
was generally well tolerated, and there were no clear relationships between the overall 
frequency of AE and treatment groups.  Additional unblinded data, including approximately 
120 patients with 12-week exposure to risankizumab from the ongoing phase II study in 
psoriasis (c01651292-07) was made available for DMC review and a favorable decision was 
made to initiate this study with severe asthma patients.
  
As with any immune modulating agent, risankizumab may impair immune function resulting 
in a risk of infection.  This will be monitored by collection of any AEs during the treatment 
and observation periods. Patients with clinically important active infection will not be 
included in the study. 
The role of IL-23 in tumor immunity is not well established at this time, but an increased risk 
of cancer from an IL-23 antagonist, though considered small, cannot be excluded.
Major adverse cardiovascular events (MACE), including myocardial infarction, 
cerebrovascular accident, and cardiovascular death, may be associated with the anti-IL-12/23 
agents, ustekinumab and briakinumab in patients with psoriasis.  The causal relationship of 
MACE to treatment with these agents is unclear. The overall risk of MACE in the present
study is considered to be low.  Patients will have monitoring of electrocardiography (ECG)
and vital signs.
Local reactions to s.c administered biologic agents are uncommon, and are usually limited to 
redness, swelling or induration at the injection site.  Although rare, a potential for 
drug-induced liver injury is under constant surveillance by Sponsors and regulators as in all 
clinical studies at this stage of clinical development, with no specific increase in risk 
identified for this antibody. Therefore, this study will require timely detection, evaluation, 
and follow-up of laboratory alterations of selected liver laboratory parameters to ensure 
patients´ safety.


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High unmet medical need exists in severe asthma, and the vast majority of mechanisms in 
development focus on Th2 high patients.  However, a significant number of severe asthmatics 
remain unaddressed by current development programs.  The exploration of additional 
mechanisms may provide benefit on top of standard of care.  In conclusion, the benefit-risk 
profile is considered appropriate for this stage of clinical development.  In order to detect any 
safety signals as early as possible, an independent DMC will monitor this study and all other 
studies where patients are receiving risankizumab.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a randomized, double-blind, placebo controlled, parallel group, multicenter study to 
assess the efficacy and safety of risankizumab, an IL-23p19 monoclonal antibody, compared 
to placebo, in patients with severe persistent asthma.  Risankizumab will be administered via 
subcutaneous injection once every 4 weeks (Week 0, 4, 8, 12, 16, and 20) during the 24-week 
treatment period.  The treatment period will be followed by a 16-week follow-up period.  An 
overview of the trial design is presented in Figure 3.1: 1.
After signing the informed consent at the initial visit, patients will enter a screening period
which should last for up to 4 weeks unless extension of the screening period is necessary 
under certain circumstances (see Section 6.1).  Patients who qualify to participate in the study 
will be randomized into a 24-week treatment period in which they will receive either 90 mg 
risankizumab or a matching placebo.   Patients will be evaluated for an additional 16 weeks 
following completion of the randomized treatment period.  An interim analysis is planned 
when the last patient completes the 24-week treatment period (see Section 7.4).  Treatment 
groups will remain blinded until the 16-week follow-up period is completed, and trial 
database is locked.
Figure 3.1: 1 Overview of Trial Design
Visit procedures will be performed as shown in Flow Chart A.  All patients will receive an 
asthma monitor/electronic diary (E-diary) which has an electronic peak flow meter and an 
electronic diary.  The asthma monitor will be dispensed at the screening visit (Visit 1B), and
patients will be required to use the device twice daily (morning and evening) to answer 
questions related to rescue medication use, asthma controller medication use, and also 


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measure Peak Expiratory Flow (PEF).  In addition, patients will complete the first five 
questions in the Asthma Control Questionnaire (ACQ5) in the E-diary once a week.
 
 
  Participation will be blindly stratified by the Interactive Response Technology
(IRT) system.  The number of patients with a history of only one severe asthma exacerbation
in the last 6 months without hospitalization or emergency room visit is limited to 
approximately 25% of the randomized patients (see Section 3.3.2).  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
Pre- and post-bronchodilator pulmonary function tests (PFTs) will be performed at all visits 
on all patients starting at the screening visit.  At the screening visit, the pre- and 
post-bronchodilator measurements will be used to determine reversibility.
Fractional exhaled Nitric Oxide (FeNO) measurements will be done on all patients at all 
visits starting at the screening visit.
Adverse events will be documented throughout the trial, i.e., starting with the informed 
consent to the last clinic visit in the follow-up period.  For further details, please refer to the 
safety Section 5.3.7.
All trial related documentation will be stored by Boehringer Ingelheim (BI) in the Trial 
Master File.  Study relevant documentation at the study sites will be filed in the ISF.


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3.1.1
Administrative structure of the trial
A DMC, independent of the Sponsor will be established to assess the progress of the clinical 
trial, including an unblinded safety and efficacy assessment at intervals specified in the DMC 
charter.  Measures are in place to ensure blinding of the Sponsor and all other trial 
participants.  The DMC can recommend to the Sponsor whether to continue, modify, or stop 
the trial.    The tasks and responsibilities of the DMC will be specified in a charter prior to the 
initiation of the study. The DMC will maintain written records of all its meetings.
The trial is sponsored by AbbVie in the USA and Boehringer Ingelheim (BI) ex-US.  
AbbVie/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 internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
order the materials as needed for the trial, 
-
ensure appropriate training of Local Clinical Monitors (CML), Clinical Research 
Associates (CRAs), and Investigators of participating countries.
Data management and statistical evaluation will be done by BI according to BI SOPs.  Tasks 
and functions assigned in order to organize, manage, and evaluate the trial will be defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A Coordinating Investigator will be nominated and will be responsible to coordinate 
Investigators at different centres participating in this multicenter trial.  Tasks and 
responsibilities will be defined in a contract. Relevant documentation on the participating
Investigators and other important participants, including their curricula vitae, will be filed in 
Trial Master File.
Investigators participating in this study will be pulmonologists, allergists, or physicians who 
have adequate experience with respiratory clinical studies. 
 
 
An external vendor, eResearch Technology, Inc. (ERT), will be contracted to manage 
centralized spirometry.  Spirometry, asthma monitor/E-diary (AM3G), ECG, and FeNO 
measurements are integrated in the Masterscope® CT platform provided by ERT.  Each site 
participating in this study will receive a Masterscope®.  Instructions and procedure manuals 
will be provided in the ISF.
A central laboratory will be responsible for performing the safety laboratory testing 
(Section 5.3.3), and will also provide the logistics in the receipt, storage, and shipment of 
other biological samples collected from patients in this study.
A central vendor will be responsible to provide training to all study sites on sputum induction 
and processing.  This vendor will also function as a central reader to assess the sputum 


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samples for quality, and also characterize them for cellular phenotypes.  A sputum induction 
and processing manual will be provided to all study sites and a copy will be placed in the ISF.
An IRT system from an external vendor will be used for randomization of treatment groups.  
Trial medication supply and re-supplies will be managed by the IRT.  The ability to unblind 
the treatment group will be available via the IRT system.  A copy of the IRT manual will be 
provided in the ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP
The trial design allows the comparison of risankizumab and placebo, on the time to first 
asthma worsening in patients with severe asthma.  The patient population in this study is 
expected to have frequent episodes of asthma worsening and 1-2 asthma exacerbations per 
year despite maximal treatment with the current standard of care.  All patients in the study 
will be on asthma maintenance therapy with stable doses of anti-inflammatory medications 
which must include at least a medium dose inhaled corticosteroid and at least one other 
asthma controller medication, during the entire screening, treatment, and follow-up periods.  
Rescue medication (salbutamol/albuterol) will be provided to all patients for as-needed use 
throughout the course of the trial.
Approximately equal numbers of patients will be randomized to each treatment group.  
Randomization will be stratified with respect to oral corticosteroid use at baseline,
 and history of severe asthma exacerbation.
The data collected in this controlled, double-blind, randomized, placebo-controlled study will 
provide useful information on the efficacy and safety of risankizumab.
SELECTION OF TRIAL POPULATION
3.3
A sufficient number of patients of either sex with the diagnosis of severe persistent asthma 
will be enrolled in the study to ensure that approximately 200 patients are randomized: 
approximately 100 in the active treatment arm and 100 in the placebo arm.  Approximately 
80 study sites will be recruited, and patient recruitment will be competitive.  Eligible patients 
will have the diagnosis of severe asthma being treated with at least medium dose inhaled 
corticosteroids (ICS) and at least one second controller therapy, and who still experience 
frequent exacerbations.  For the purposes of inclusion (e.g. exacerbation history, and baseline 
asthma controller medications), “documented” means previously recorded in the patients’
medical history at the Investigator’s site or at another medical facility.  Patients must be able 
to provide an acceptable sputum sample at screening to allow cellular characterization.
Patient recruitment will end when the Trial Clinical Monitor has determined that sufficient 
number of patients has been randomized.  A log of all patients enrolled in 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 the investigational drug.


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3.3.1
Main diagnosis for trial entry
Outpatients with a history of asthma and who experience frequent exacerbations despite their 
current maintenance treatment with at least a medium dose ICS and at least another asthma 
controller medication are eligible for inclusion if they meet all the inclusion criteria (Section 
3.3.2) and none of the exclusion criteria (Section 3.3.3).
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
1.
Signed informed consent consistent with ICH-GCP guidelines and local 
legislation prior to participation in the trial.  Medication washout and medication 
restrictions are allowed only after signed informed consent is obtained.
2.
Male or female patients aged at least 18 years but not more than 75 years at the 
time of informed consent.
3.
Pre-bronchodilator clinic measured FEV1 of ≥40% and ≤85% of predicted normal 
at the screening Visit 1B, and not lower than 40% of predicted normal at 
randomization visit (Visit 2).  Calculations will be based on Global Lung Function 
Initiative (GLI) formula (R15-0845).
4.
A minimum of one year history of asthma, diagnosed by a physician, and have 
FEV1 reversibility as defined by an improvement in FEV1 ≥12% and an absolute 
change of at least 200 ml starting within 15 to 30 minutes after administration of 
400 µg salbutamol (albuterol) via MDI. Reversibility testing is performed at the 
screening Visit (Visit 1B). 
If reversibility criteria are not met, the patient may still be randomized if there is:
–
Documented evidence of reversibility with improvement in FEV1
≥12% above baseline and an absolute increase of at least 200 ml in the 
2 years prior to Visit 2 (randomization visit)
or
–
Documented evidence of airway hyperresponsiveness (methacholine: 
PC20 of <8 mg/mL) in the 2 years prior to Visit 2 (randomization visit) 
or
–
Documented evidence of airflow variability in clinic FEV1 ≥20% 
between two clinic visits documented in the 12 months prior to visit 2 
(randomization visit).
•
If reversibility criteria are not met at Visit 1B and if any of the above historic data are 
not available, reversibility testing can be repeated up to twice during screening period 
at separate visits. For the first retest, 400 µg salbutamol via MDI should be used, and 
for the second retest, up to 800 µg salbutamol via MDI or 2.5 mg nebulized albuterol 
should be used.  Reversibility testing must not occur on the day of randomization.  
Additional guidelines for reversibility testing can be found in Appendix 10.1.


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5.
Patients must be on at least medium dose ICS (Table 10.1: 1), and at least one 
other asthma controller medication for at least one year prior to the date of 
screening.  Asthma therapy must have been documented and must be stable for at 
least 4 weeks prior to the date of screening.
Note: Some examples of 2nd controller medications are long-acting beta-2-
agonist (LABA), leukotriene receptor antagonist (LTRA) or theophylline.  
Maintenance oral corticosteroid (prednisone or equivalent) with a total daily dose 
of ≤20 mg is also considered as an additional controller therapy.
6.
Patients must have documented history of at least one of the following criteria: a) 
two or more severe asthma exacerbations in the last 12 months, or b) one severe 
asthma exacerbation in the last 12 months requiring hospitalization or emergency 
room visit, or c) one severe asthma exacerbation in the last 6 months not requiring 
hospitalization or emergency room visit, prior to the date of screening visit (Visit 
1B).  Patients must not have a severe asthma exacerbation in the 6 weeks prior to 
screening visit.  Patients with only one severe asthma exacerbation in the last 6 
months (category c, but not a or b) will be limited to approximately 25% of the 
total patient population.
Note: Severe asthma exacerbation is defined as initiation of systemic 
corticosteroids: (prednisone or equivalent) for 3 or more consecutive days for 
asthma. Additionally, for subjects on maintenance systemic corticosteroids, at 
least doubling of the maintenance dose resulting in a total daily dose of ≥20 mg 
for three or more consecutive days will be considered a severe asthma 
exacerbation.
7.
Patients should be non-smokers or ex-smokers who stopped smoking at least one 
year prior to screening.  Ex-smokers must have a smoking history of less than 10-
pack years (see Appendix 10.1).
8.
Patients must be able to perform all trial related procedures including pulmonary 
function tests, and must be able to use the electronic asthma monitor (E-diary).
3.3.3
Exclusion criteria
1.
Patients with a significant disease other than asthma.  A significant disease is 
defined as a disease which in the opinion of the Investigator may a) put the patient 
at risk because of participation in the trial, or b) influence the results of the trial, or 
c) cause concern on the patient’s ability to participate in the trial.
2.
Patients with malignancy for which the patient has undergone resection, radiation, 
or chemotherapy within the past 5 years.  Patients with treated basal cell 
carcinoma or fully cured squamous cell carcinoma are allowed.
3.
Patients with clinically relevant abnormal hematology or blood chemistry
laboratory values at screening if the abnormality defines a significant disease as 
defined in Exclusion Criterion 1.


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4.
Patients who are not able to produce sputum or sputum samples of sufficient 
quality at the screening visit.  Sputum samples with more than 40% squamous 
cells or low viability at the screening visit will be considered of insufficient 
quality.  The central reading center will make the final determination on sputum 
quality.
5.
Patients who have history of intubation for asthma exacerbation within one year of 
the screening visit.
6.
Patients diagnosed with concurrent respiratory disease: presence of a known pre-
existing, clinically important lung condition other than asthma.  This includes 
current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary 
aspergillosis, or diagnoses of emphysema or chronic bronchitis (chronic 
obstructive pulmonary disease other than asthma) or a history of lung cancer.
7.
Recent history (i.e., within 6 months) of myocardial infarction or hospitalization
for cardiac failure during the past year.
8.
Patients who have undergone thoracotomy with pulmonary resection.  Patients 
with a history of thoracotomy for other reasons should be assessed as per 
Exclusion Criterion 1.
9.
Patients who have undergone bronchial thermoplasty or radiotherapy procedure in 
the year prior to screening or have planned procedures during the study.
10.
Patients taking oral corticosteroids with a total daily dose of more than 20 mg
prednisone (or equivalent) in the 6 weeks prior to screening visit.
11.
Pregnant or nursing (lactating) women.
12.
Women of childbearing potential must be ready and able to use highly effective 
methods of birth control per ICH M3 (R2) that result in a low failure rate of less 
than 1% per year when used consistently and correctly from date of screening 
until 20 weeks after last dosing with study medication in this trial. A list of 
contraception methods meeting these criteria is provided in the patient 
information.
Note: Women are considered post-menopausal and not of child bearing potential 
if they have had 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile, i.e. appropriate age range and history of vasomotor 
symptoms, or 6 months of spontaneous amenorrhea with serum FSH levels > 40 
mIU/mL [for U.S. add estradiol < 20 pg/mL]
13.
Patients who have taken an investigational drug within 3 months or six half-lives 
(whichever is greater) prior to the screening visit.
14.
Patients who have been previously randomized in this study.


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15.
Chronic alcohol or drug abuse or any other condition that in the Investigator’s 
opinion makes these patients unreliable or unlikely to complete the trial.
16.
Clinically relevant acute infections or chronic infections including but not limited 
to HIV, viral hepatitis, and (or) tuberculosis or evidence of tuberculosis infection 
as defined by a positive QuantiFERON TB test within 2 months prior to or during 
screening. 
Note: Subjects with a positive QuantiFERON TB test may participate in the study if 
further work up (according to local practice/guidelines) establishes conclusively that 
the subject has no evidence of active tuberculosis.  If presence of latent tuberculosis is 
established, then treatment must have been initiated and maintained according to 
local country guidelines.
17.
Have received any live bacterial or live viral vaccination in the 12 weeks prior to 
the date of screening.  Patients must agree not to receive a live bacterial or live 
viral vaccination during the study and up to 12 months after the last administration 
of study drug.
18.
Have received Bacille Calmette-Guerin (BCG) vaccination in the 12 months prior 
to the date of screening.  Patients must agree not to receive BCG vaccination 
during the study and up to 12 months after the last administration of study drug.
19.
Have received treatment with; a) any dose of ustekinumab (Stelara®), or b) any 
other biological based agents in the 3 months or within 6 times the half-life 
(whichever is longer) prior to the screening visit.
20.
History of allergy/hypersensitivity to a systemically administered biologic agent 
or its excipients, or a known hypersensitivity to β-adrenergic medications.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial treatment if any of the following criteria 
apply:

The patient withdraws consent for study treatment or study participation, without the need 
to justify the decision

The patient needs to take concomitant drugs that interfere with the trial medication, and 
the Investigator wants to discontinue the patient due to safety concerns

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy)

Sponsor decision to discontinue all or portion of the patients for safety or other reasons
Investigator may discontinue a patient from the study for any unexpected medical conditions 
that could compromise patient safety.


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No patient should be discontinued from the trial for a protocol violation before discussion 
with the Local Clinical Monitor.
Patients who are intubated for asthma worsening or exacerbation during the course of the 
study must be discontinued from the study.    In addition, the principal Investigator should 
make an ongoing assessment of the suitability of the patient to continue in the study: any 
discontinuation should be discussed with the Trial Clinical Monitor.
Given the patient’s agreement, the discontinued patient will undergo the procedures for early 
treatment discontinuation and follow-up.  Please refer to Section 6.2 for instructions on early 
discontinuation visits.
For all patients, the reason for withdrawal (e.g. adverse events) must be recorded in the 
electronic case report form (eCRF).  These data will be included in the trial database and 
reported.
A patient should be called as lost to follow-up only after three documented attempts have 
been made to contact the patient.
Discontinuation of the trial by the Sponsor
3.3.4.2
AbbVie/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 enrollment 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 good clinical practice (GCP), the clinical trial protocol (CTP), or the contract 
disturbing the appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
Risankizumab or placebo will be administered subcutaneously.  Risankizumab and the 
matching placebo will be supplied by Boehringer Ingelheim.
4.1.1
Identity of BI investigational product and comparator product
Table 4.1.1: 1
Test Product 1
Substance:
Risankizumab (BI 655066): Anti-human IL-23p19 mAb
Pharmaceutical formulation:
Injection solution of risankizumab (BI 655066) presented in 
a 1 ml pre-filled syringe
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
90 mg risankizumab (BI 655066) in a 1 ml pre-filled syringe
(concentration 90 mg/ml)
Posology
Multiple doses: 6 doses (once every 4 weeks)
Route of administration:
subcutaneous
Table 4.1.1: 2
Test Product 2
Substance:
Placebo
Pharmaceutical formulation:
Injection solution of matching placebo presented in a 1 ml 
pre-filled syringe
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
NA
Posology
Multiple doses: 6 doses (once every 4 weeks)
Route of administration:
subcutaneous
4.1.2
Method of assigning patients to treatment groups
After the patient’s eligibility has been confirmed at Visit 2, each patient will be assigned to a 
treatment group via the IRT. At Visits 2 to 7, the IRT will assign medication boxes to each 
patient (based on the assigned treatment) and each medication box will have a unique 


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number. Site personnel will enter all medication numbers dispensed to each patient in the 
eCRF.  To facilitate the use of the IRT, the Investigator will receive all necessary 
instructions.  Technical features of the treatment allocation are provided in Section 7.6.
4.1.3
Selection of doses in the trial
Each patient will receive six subcutaneous injections of 90 mg each at weeks 0, 4, 8, 12, 16, 
and 20 (i.e., 90 mg q4wk x 6). The selected dose and regimen were based on the available 
safety and tolerability established in completed and ongoing clinical trials to support 
development of risankizumab for other indications.  In a single rising dose study (trial 1311.1
(U12-3066-01)), no clinically relevant safety or tolerability issues were observed with 
risankizumab doses of up to 5 mg/kg i.v. Based on preliminary analysis of concentration 
response, this dose has been predicted to result in robust reduction in psoriatic lesions 
(<0.25 mg/kg) based on data from 1311.1 trial.
Dosing of therapeutic monoclonal antibodies is often based on body size with the perception 
that body weight based dosing would reduce inter-subject variability in drug exposure. While 
this may be warranted in certain cases, most monoclonal antibodies are target-specific, dosed 
in antibody/target excess due to target turnover and offer a relatively large therapeutic 
window. As part of the initial pharmacokinetic analyses (trial 1311.1), there is generally a 
modest contribution of body size to overall pharmacokinetic variability. Inclusion of body 
weight in the model as a regressor (i.e., body-weight based dosing) explains only 13% of 
between subject pharmacokinetic variability of risankizumab with exposures trending higher 
for individuals with lower body weight (55 kg) vs. typical body weight (75 kg) by 25%. This 
underscores the general benefits of fixed-dosing vs. body weight dosing which are considered 
applicable to risankizumab and the aforementioned high drug/target excess (R13-4749, R10-
6267, R13-4753, R13-4750, R13-4754).
In three ongoing phase II trials (trials 1311.2, 1311.6, and 1311.8), multiple s.c. doses of 
risankizumab up to 180 mg are currently being investigated with treatment duration of six 
months or longer. Based on pharmacokinetic modelling of the dosing regimen proposed for 
this trial, drug exposure with 90 mg q4wk treatment is not expected to exceed the levels 
achieved in previous clinical trials
 
Overall, this trial is designed to evaluate the 
efficacy of risankizumab in severe asthma patients using a safe and tolerable dose achieved in 
previous trials and resulting in efficacy in psoriasis.
 
 
4.1.4
Drug assignment and administration of doses for each patient
At the visits as indicated in Flow Chart A, each patient will receive a single dose of 
risankizumab or placebo.  The study medication will be allocated by IRT.  The design will be 
double-blind, and patients will receive injections of risankizumab or placebo. All patients 
will receive a total of 6 subcutaneous injections, one each at week 0, 4, 8, 12, 16, and 20. 
Even though the last dose is administered at week 20, therapeutic coverage is expected to last 
until week 24.  At week 24, the clinic visit is considered as the end of treatment period, and 


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patients will enter a 16-week follow-up period.  Patients will be seen at the clinic at week 28, 
32, and 40, and a phone call at week 36 during the follow-up period.  There will be no study 
drug administration during the follow-up period.  Week 40 will be the last clinic visit and is 
considered as the end of observation.  Instruction for medication handling and administration 
provided in the ISF must be followed.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Patients, Investigators and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial will remain blinded with regard to the randomized treatment 
assignments until after database lock.  The randomization code will be kept secret by Clinical 
Trial Support group until database lock.  When interim analysis is performed (Section 7.4), 
select members of the trial team may be unblinded.
A DMC will be reviewing the trial data periodically (Section 3.1.1), and the committee may 
have access to unblinded data.  Data presented at the DMC will be prepared by an external 
statistician who will have no direct role in this study.
The randomization codes will be provided to bioanalytics group prior to last patient out to 
allow exclusion of samples from the placebo arm for the analyses of pharmacokinetic 
samples. Bioanalytics group will not disclose the randomization code or the results of their 
measurements until the trial is officially unblinded.
Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the Investigator / pharmacist / investigational drug 
storage manager / Sponsor via the 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. A discussion with the 
Sponsor Trial Clinical Monitor should occur (if possible) prior to the decision to unblind any 
study subject.  The reason for unblinding must be documented in the source documents along 
with the date and the initials of the person who broke the code.  Reason for unblinding should 
also be recorded in the eCRF.  In the case of unblinding an individual patient for safety 
reasons, appropriate follow-up of safety related events is required.
4.1.6
Packaging, labelling, and re-supply
Risankizumab and the matching placebo will be provided by the Sponsor.  Syringes pre-filled 
with the study medication will be provided in individual boxes.  Supply of study medication 
will be managed by IRT.  For details of packaging and the description of the label, please 
refer to the ISF.
4.1.7
Storage conditions
Study medication supplies will be kept in their original packaging in a secure limited access 
storage area. Medication must be kept refrigerated in their original packaging.  The 
recommended storage temperature is 2°C to 8°C (36°F to 46° F).  A temperature log must be 


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maintained.  If storage conditions are found to be outside the specified range, the Local 
Clinical Monitor (as provided in the list of contacts in the ISF) must be contacted
immediately.
4.1.8
Drug accountability
The Investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee, 

Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the principal Investigator

Availability of Form 1572 (if applicable)
The Investigator / pharmacist / investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the Sponsor or alternative disposal of unused products.
The 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 
Investigator / pharmacist / investigational drug storage manager 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 return to the 
Sponsor and/or appointed contract research organization (CRO), the Investigator / pharmacist 
/ investigational drug storage manager must verify that all remaining supplies are in the 
Investigator’s possession.  Detailed instructions will be provided for the return/disposal of 
unused study medication.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Rescue medication
Administration of rescue medication is allowed at any time point during the trial except 
during the washout period before clinic visits for PFTs (see Section 4.2.2).  Open-label 
salbutamol (albuterol) will be provided as rescue medication throughout the course of the 
trial: screening (from Visit 1B), treatment, and follow-up periods.  Only the rescue 
medication provided by the Sponsor is to be used by the patients.  Patients must record the 
number of inhalations (puffs) of rescue medication used during the daytime and night-time 
hours in the E-diary.  The salbutamol (albuterol) provided as rescue medication is considered 
a non-investigational medicinal product.


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Emergency procedures
Severe asthma exacerbations would be treated according to best medical practice, but would 
typically include OCS or intra-muscular steroids (and/or antibiotics as appropriate).  These 
patients would be allowed to continue participation in the study.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Table 4.2.2.1: 1
Overview of permitted, restricted, medications and therapies
Drug Class
Washout 
period1
Prior to Visit 
1B
Between 
Visits 1B and 2
Treatment &
Follow-up periods
Corticosteroid (nasal/ocular)
NA
Permitted
Permitted
Permitted
Corticosteroid – oral2
NA
Permitted5
Permitted 
(stable dose)7
Permitted (stable dose) 
& as needed for 
exacerbation
Corticosteroid – i.v., i.m.
NA
Permitted5
Not permitted7
Permitted (as needed 
for exacerbation)
Short-acting β2-adrenergic 
agonist -Inhaled
6 hours
Permitted
Only 
salbutamol 
/albuterol
Only salbutamol 
/albuterol
Long-acting β2-adrenergic
agonist – Inhaled3
12 hours 
/24hours4
Permitted5
Permitted5
Permitted5
Anticholinergic –
Inhaled short acting
6 hours
Permitted5
Permitted5
Permitted5
Anticholinergic –
Inhaled long acting
24 hours
Permitted5
Permitted5
Permitted5
Leukotriene modifier
24 hours
Permitted5
Permitted5
Permitted5
Cromolyn sodium / nedocromil 
sodium
6 hours
Permitted5
Permitted5
Permitted5
Methylxanthines
24 hours
Permitted5
Permitted5
Permitted5
Immunomodulators (e.g. 
methotrexate)
NA
Not Permitted6
Not permitted
Not permitted
Immunotherapy (e.g. sub 
cutaneous or sublingual)
NA
Permitted5
Permitted5
Permitted5
Biologic antagonists (e.g. 
Omalizumab)
NA
Not permitted6
Not permitted
Not permitted
Other investigational drugs
NA
Not permitted6
Not permitted
Not permitted
Footnotes:
1.
Washout period refer to time before in-clinic PFTs on clinic visit days (including Visit 1B).
2.
For patients taking stable maintenance OCS with a total daily dose of ≤20 mg prednisone or equivalent.
3.
Includes fixed dose combination therapy.
4.
12 hours for patients with BID dosing, and 24 hours for patients with QD dosing.
5.
Allowed as stable dose for at least 6 weeks before Visit 1B with no planned changes during the study.
6.
Allowed before Visit 1B with a washout period of 3 months or 6 half-lives whichever is greater.
7.
Use as needed for exacerbations with extension of screening period (see Section 6.1)


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Additional treatments
4.2.2.2
The use of antibiotics is not restricted during the study period for the treatment of asthma 
exacerbations and/or infections.  Investigators should refer to Exclusion Criterion 16 to 
ensure that patients did not have any active infections before entering the trial.
Restrictions on diet and life style
4.2.2.3
Restrictions prior to PFT visits
Medication washout restrictions should be adhered to as shown in Section 4.2.2.1. Please 
also see medication washout criteria in Section 6.1.
On clinic visit days, patients should refrain from strenuous activity for at least 12 hours prior 
to pulmonary function testing and throughout the testing period.  Patients should also avoid 
cold temperatures, environmental smoke, dust or areas with strong odours (e.g. perfumes). 
Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods, and ice-cold 
beverages are not allowed at least 2 hours prior to and during the pulmonary function testing.  
Decaffeinated beverages are acceptable.
Restrictions for women of childbearing potential 
4.2.2.4
Female patients of childbearing potential should use the contraception methods described in 
Section 3.3.3 (Exclusion Criterion 12).
 
 
 
 
 
 
 
 
Restrictions before FeNO measurements:
4.2.2.6
Patients should not drink any fluids or eat any food for about an hour before FeNO 
measurements.  Eating nitrate-containing foods like lettuce are not permitted for about two 
hours before the measurements.
4.3
TREATMENT COMPLIANCE
Patients are required to complete the scheduled clinic visits within the time windows allowed 
in the protocol.  As the administration of study medication is only at the clinic, and the need 
to maintain the required intervals between dosing, it is very important to adhere to the time 


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windows for each visit.  Patients who miss scheduled clinic visit(s) within the time window 
allowed in the protocol will be considered non-compliant.  However, they should be allowed 
to continue in the trial.  Persistent non-compliance will have to be discussed with the Local 
Clinical Monitor.
Patients should be compliant in using the E-diary in the morning and evening.  If E-diary 
compliance is below 75% in the 14 days before Visit 2, randomization visit will be 
rescheduled (see Section 6.1).
Patients should be compliant in taking their daily asthma controller medications during the 
course of the study.  Dose and regimen of the ICS and additional controller medication(s)
should not be changed during the course of the study (screening, treatment, and follow-up
periods) except for treatment of an asthma exacerbation or unless absolutely medically 
necessary.  Baseline treatment should be maintained at the same dose and regimen at it was at 
the time of entry to the study.  If changes are absolutely necessary for reasons other than to 
treat the patient for asthma exacerbation, this should be discussed with the Local Clinical 
Monitor, and well documented in the patient source data including the medical rationale for 
the change from the treating physician.  The follow up period is also an important part of the 
study to assess therapeutic efficacy and changes following the last dose of risankizumab
should be avoided.  After the patient completes the final clinic visit at week-40 (Visit 12), 
Investigator may adjust the dose or change the asthma controller medications without 
consequence to the study objectives.


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint
The primary endpoint of this study is time to first asthma worsening (in days) during the 
planned 24-week treatment period (Section 5.2).  
5.1.2
Secondary Endpoints
1. Annualized rate of asthma worsening during the planned 24-week treatment period
2. Annualized rate of severe asthma exacerbation during the planned 24-week treatment 
period
3. Weekly ACQ5 score at week 24
4. Trough FEV1 in-clinic change from baseline at week 24
5. Post-bronchodilator FEV1 in-clinic change from baseline at week 24
6. Time to first severe asthma exacerbation during the planned 24-week treatment period
7.
Time to first asthma worsening (alternative definition 1) during the planned 24-week 
treatment period
 
 
 
 
 
 


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ASSESSMENT OF EFFICACY
5.2
Asthma Worsening
For the primary endpoint, asthma worsening is defined as the occurrence of any one of the 
following four criteria:
a) Decrease from baseline of ≥30% in morning PEF on at least 2 consecutive days
b) Increase from baseline of ≥50% and an increase of least 4 puffs in daily use of rescue 
medication for at least 2 consecutive days
c) Increase from baseline of ≥0.75 units in ACQ5
d) Severe asthma exacerbations as defined in the protocol (Section 5.2.1).
Asthma worsening (alternative definition 1) has criteria (c) defined as “Increase from 
baseline ≥0.5 units in ACQ5”.
Asthma worsening (alternative definition 2) has criteria (c) defined as “Increase from 
baseline ≥1 units in ACQ5”.
5.2.1
Asthma Exacerbations
The following are protocol definitions for asthma exacerbations based on ATS/ERS criteria 
(R09-2853)
Moderate asthma exacerbation is defined as a physician directed change or addition in 
asthma therapy due to asthma worsening: includes change in the dose/regimen of ICS or 
other asthma controller medications.  For patients on maintenance OCS, increase in total 


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daily dose not meeting the severe asthma exacerbation criteria, will constitute a moderate 
asthma exacerbation.
Severe asthma exacerbation is defined as initiation of systemic corticosteroids (prednisone 
or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on 
maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a 
total daily dose of ≥20 mg for three or more consecutive days will be considered a severe 
asthma exacerbation.
Hospitalization for severe asthma exacerbation is patient requiring hospitalization or 
emergency room/department visit for severe asthma exacerbation.
5.2.2
Efficacy Assessments
Patients will receive an asthma monitor (E-diary) which combines the features of a peak flow 
meter and an electronic diary.  ERT, the central vendor providing the Masterscope® for 
spirometry will also supply the E-diary to all study sites.  Patients will measure the PEF and 
forced expiratory volume in 1 second (FEV1) in the morning and evening.  In addition, 
patients will also enter the number of puffs of rescue medication (salbutamol/albuterol) taken,
in the morning and evening.  Once a day, patient will answer a question in the E-diary to 
confirm if they have taken the regular asthma controller medications.  Once a week, patients
will answer in the E-diary, the first 5 self-administered questions from the ACQ (R00-1157).  
A copy of the ACQ5 can be found in the ISF.
The E-diary will be dispensed at the screening visit (Visit 1B) and patients will use the 
E-diary until the end of observation period (Visit 12).  Instructions and training for the use of 
asthma monitor will be provided at Visits 1B and 2.  Additional training must be provided if 
the patient is non-compliant or if the patient has difficulty in using the E-diary.
Data and measurements collected in the E-diary will be automatically transferred to a central 
server (ERT) each time the patient has completed an assessment on the E-diary.  The 
automated transfer will depend on the availability of the technology in the region, and 
wireless capabilities at the patient’s location.  If the automated transfer cannot be completed 
due to low wireless capabilities, the collected data will be stored in the E-diary and submitted 
during the next automated transfer after a completed assessment, once wireless connection is 
available.  The E-diary also tries to connect to the central server (ERT) once a day to send a 
confirmation signal that the device is working properly: if there should be any data available 
on the device from previous session(s) that were not transmitted due to connection issues, this 
data will be transferred at this time.  In addition, all data collected in the E-diary will be 
downloaded at each clinic visit on to the Masterscope® and transmitted to the central server.  
At each clinic visit the principal Investigator or a delegated study staff should review the 
printed report of all the data downloaded from the E-diary.  When reviewing the report, any 
occurrence of asthma worsening events (Section 5.2) must be identified and discussed with 
the patient.  The principal Investigator is required to sign the printed reports generated from 
the data downloaded in the Masterscope®.  Detailed instructions for the use of the E-diary
will be provided in the ISF.


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Morning and evening recordings in the E-diary should be performed at approximately the 
same time of the day (±30 minutes) between 6:00 am and 9:00 am and 6:00 pm and 9:00 pm, 
respectively.  If the patient did not use the E-diary at the specified time, an alarm will sound 
at 9:00 (am/pm) and 9:30 (am/pm) to remind the patient to enter the data and complete the 
measurements.  If patients forget to use the E-diary in the morning or in the evening, they 
should be instructed to complete the measurements and enter the data if it is still before 
11.59 (am or pm).
The morning measurements should be performed upon arising (after the patient has cleared 
out any mucus), and measurements will be repeated in the evening, both prior to the 
administration of the maintenance ICS and any other asthma controller medication(s).  On 
each occasion, patient should perform three peak expiratory flow maneuvers in the standing 
position.  The highest PEF and the highest FEV1 out of the three acceptable blows, but not 
necessarily the same blow, will be used for evaluation.  On the day prior to the clinic visit and 
on the morning of the clinic visit, patients must adhere to the medication restrictions (Section 
4.2.2.1) that will allow medication washout for the in-clinic PFTs.
During the treatment and follow-up periods, patients will be alerted by the E-diary to contact 
the Investigator if any of the first three asthma worsening criteria (decrease in PEF, increase 
in rescue medication use, or increase in ACQ5 score) specified under the primary efficacy 
endpoint (Section 5.2) are met.  Patients must be instructed to call the study center if they 
receive an alert in the E-diary.  The Investigator or the study coordinator should review the 
asthma symptoms with the patient when the patient contacts the study site.  If deemed 
necessary, the Investigator may schedule an unscheduled clinic visit.  At each clinic visit, the 
Investigator or the delegated study staff is required to review the data from the E-diary 
download in the Masterscope® to verify if any asthma worsening criteria have been met.
For asthma worsening, any event that starts within 7 days from the end date of previous event 
will be considered as the continuation of the previous event, and be collapsed with the 
previous event into one episode.
Treatment of asthma exacerbations including initiation/addition of systemic corticosteroids 
should be done according to the medical judgment of the Investigator or the treating 
physician and should be in line with national and international guidelines.  Patients should be 
instructed to contact the Investigator if they meet any of the asthma exacerbation criteria in 
between clinic visits.  At each clinic visit, the Investigator or the delegated study staff is 
required to discuss with the patient to verify if any of the asthma exacerbation criteria was 
met since the previous clinic visit.
It is the responsibility of the Investigator to report any deterioration of asthma as an AE 
regardless of the definitions provided in this protocol.
For moderate asthma exacerbations, severe asthma exacerbations, and hospitalization for 
severe asthma exacerbations, any event that starts within 7 days from the end date of previous 
event will be considered as the continuation of the previous event, and be collapsed with the 
previous event into one episode.


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Asthma Medication Log
All patients will receive an asthma medication log card from Visit 1B onwards to document 
any changes in asthma controller medications.  During the course of the study, if there is any 
change in the asthma controller medications, patients will record the changes in the asthma 
medication log.  The record should include the name of the medication, start date, end date, 
dose, and route of intake.  Any dose changes in the medications they are already taking for 
asthma will also be recorded in the log.  Any changes to the rescue medication (salbutamol
/albuterol) use must not be recorded in this asthma medication log.  A copy of the asthma 
medication log card will be provided in the ISF.
At each clinic visit starting Visit 2 onwards, patients will bring the asthma medication log
card to the clinic.  The Investigator should review the entries in the medication log and verify 
if the patient met any of the asthma exacerbation criteria defined in the protocol.  The 
medication log card will be collected and placed in the patient file, and a new card will be 
issued at each clinic visit.  If there are no entries in the medication log, the card should be 
marked blank, placed in the patient file, and a new card should be dispensed.  The asthma 
medication log will be signed and dated by the Investigator or study staff before placing it in 
the patient file.
Pulmonary Function Tests
Centralized spirometry services will be made available to all sites by ERT for in-clinic PFTs.  
The spirometers and their use will meet ATS/ERS criteria [P05-12782].  Spirometry will be 
conducted in a seated position.  It is preferable that the same trained individual performs the 
PFTs for a given patient at all visits.  The best of three efforts will be defined as the highest 
FEV1, the highest forced vital capacity (FVC) and the highest PEF, each obtained on any of 
the three blows meeting the ATS/ERS criteria with preferably a maximum of five maneuvers.  
However, a maximum of eight maneuvers will be allowed. The highest FEV1, FVC, and PEF 
will be selected regardless of whether they come from different spirometric maneuvers or 
from the same maneuver. 
For each patient, PFTs should always be done at approximately the same time of the day at 
each clinic visit from Visits 2 to 12. The reference time point will be the time of PFTs at the 
randomization visit (Visit 2).  At Visit 2 pulmonary function testing should be started
between 06.00 am and 10.00 am.  At clinic visits (from Visit 3 onwards), PFTs should be 
scheduled to start ±30 minutes from the start time of the PFTs at Visit 2.  Any deviation from 
this time window should be documented with the reason for deviation.  Every effort must be 
made to not deviate from the ±30 minutes time window.  PFTs should be completed before 
sputum induction (if applicable at that visit) and dosing with study medication if the patient is 
scheduled to be dosed at that particular visit.
At Visits 2 to 10 and at Visit 12, following the completion of three acceptable 
pre-bronchodilator forced expiratory manoeuvers, 400 μg of salbutamol (albuterol) will be 
administered.  There should be at least a 30-second interval between each puff.  
Post-bronchodilator PFTs (three acceptable manoeuvers) will be started 15 to 30 minutes 
after the last puff of salbutamol (albuterol) was inhaled.


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If a patient is unable to complete the PFTs during a visit, this will be noted in the eCRF
indicating the reason for stopping testing.  If rescue medication was administered during the
PFTs (excluding the administration of salbutamol/albuterol for bronchodilation between 
pre- and post-measurements), it should be noted in the eCRF.
ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
A complete physical examination will be completed on all patients at the screening visit 
(Visit 1B), randomization visit (Visit 2), and at Visit 5, Visit 8 (EOT) and Visit 12 (EOO).  
Body weight will be measured on the days when physical examination is scheduled, and 
entered in the eCRF.  Relevant asthma history and atopy status will be captured at the 
screening visit (Visit 1B).  All clinically significant findings at screening will be recorded on
the Medical History / Baseline Condition page in the eCRF.  New clinically significant 
findings or worsening of preexisting conditions detected at subsequent visits will be recorded 
as adverse events on the appropriate eCRF page.
An explanation of the etiology of clinically significant abnormal physical findings must be 
entered on the eCRF.  All relevant (in the opinion of the Investigator) abnormal physical 
findings have to be followed up until they are normalized or sufficiently characterized.
5.3.2
Vital Signs
Pulse rate, systolic and diastolic blood pressure, and body temperature will be measured and 
recorded at the screening visit and all subsequent visits.  Measurements will be obtained
before spirometry testing with the patient seated and rested for at least five minutes.
5.3.3
Safety laboratory parameters
The laboratory tests listed in Table 5.3.3: 1 will be performed at the central laboratory service 
provider, except urine pregnancy test and urinalysis (Stix) that will be performed at the study 
site.  Instructions regarding sample collection, sample handling/processing, and sample 
shipments are provided in the laboratory manual.  For the schedule of routine laboratory tests, 
please see Flow Chart A.  Laboratory results for the samples collected on a clinic visit day 
will not be available on the same day as they have to be shipped to the central laboratory for 
analyses.
When the laboratory results are reported by the central laboratory, the Investigator is required 
to review the reports.  Clinically relevant abnormal laboratory values should be commented
in the eCRF.  It will be responsibility of the Investigator to follow-up with the patient if any 
findings in the laboratory tests need immediate attention.  Laboratory data will be transferred 
from the central laboratory to the Sponsor periodically. If any local regulations prevent the 
transfer of certain laboratory parameters tested in this study to the Sponsor, they will not be 
transferred.  Additional laboratory tests not specified in Table 5.3.3.1 may be performed as 
deemed medically appropriate, and to ensure patient safety.
If screening period is extended, the Investigator should review the laboratory reports from 
baseline (Visit 1B), and make a determination if any lab tests specified in the protocol must 


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be repeated before the randomization visit.  If deemed necessary, test samples should be 
drawn and sent to the central laboratory, and results should be reviewed by the Investigator 
before randomization visit occurs.
During the treatment and follow-up periods, if any of the lab tests specified in the protocol 
must be repeated for patient safety, test samples should be drawn and sent to the central 
laboratory.


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Table 5.3.3: 1
Laboratory tests
Category
Test name
Haematology1
Haematocrit (Hct)
Haemoglobin (Hb)
Glycosylated Hb (HbA1c)2
Red Blood Cell Count/ Erythrocytes
White Blood Cells / Leukocytes
Platelet Count/ Thrombocytes
Diff. Automatic1
Neutrophils (absolute and relative count)
Eosinophils (absolute and relative count)
Basophils (absolute and relative count)
Monocytes (absolute and relative count)
Lymphocytes (absolute and relative count)
Diff. Manual (if Diff. Automatic is abnormal)
Neutrophils, bands (Stabs)
Neutrophils, polymorphonuclear (PMN)
Eosinophils
Basophils
Monocytes
Lymphocytes
Enzymes1
AST(GOT)
ALT(GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Electrolytes1
Calcium
Sodium
Potassium
Chloride
Bicarbonate
Substrates1
Glucose
Creatinine and Creatinine Clearance
eGFR (estimated by CKD-EPI formula)
Bilirubin Total
Bilirubin Direct
Bilirubin Indirect
Albumin
C-Reactive Protein
Cholesterol, total
Triglycerides
LDL-Cholesterol
HDL-Cholesterol
Urea
Urine Pregnancy test (only for female patients of 
childbearing potential) at the clinic, for all scheduled 
clinic visits except Visit 1A and Visit 1B.
Human Chorionic Gonadotropin in the urine


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Table 5.3.3: 1
Laboratory tests (cont.)
Category
Test name
Serum Pregnancy test at screening (Visit 1B) and 
when urine pregnancy test is positive at other visits
Human Serum Chorionic Gonadotropin 
Hormones4
TSH, (free T3 and free T4 in case of 
abnormal TSH results) 
Specific gamma-globulin quantification5
Total IgE
Urinalysis (Stix)1
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urine Bilirubin
Urine RBC/ Erythrocytes
Urine WBC/ Leukocytes
Urine pH
Urine specific gravity
Urine-Sediment (microscopic examination, only if 
urine analysis abnormal)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epithelial Cells
Urine Sed. Crys., Unspecified
Urine Sediment RBC/ Erythrocytes
Urine Sediment WBC/ Leucocytes
Infections screening4
Hepatitis B Surface Antigen (qualitative)
Hepatitis C Antibodies (qualitative)
HIV-1, and HIV-2 Antibody (qualitative)
QuantiFERON-TB Gold
1.
Routine laboratory assessments at visits indicated in Flow Chart A.  
2.
At Visits 2, 5, 8, and 12.  
4.
At screening only (Visit 1B) 
5.
At Visits 2 and 8
5.3.4
Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be performed on all patients at the 
screening visit (Visit 1B) to obtain patient’s baseline condition.  ECG procedure will be 
repeated at the randomization visit (Visit 2), and at Visits 3, 5, 8, 10, and 12.  Additional 
ECGs may be done during the study for safety reasons.   ECG equipment provided by ERT 
(integrated with the Masterscope®) will be used at all the sites for all patients.  ECG printouts
from the Masterscope® will be read and evaluated locally at the respective study centers by a 
physician.   All ECG data will be transmitted electronically to a central server at ERT and 
stored.  If necessary, the data collected in this study will be readily available for additional 
evaluations.  
ECGs will be recorded after the patient has rested for at least 5 minutes in a supine position, 
and will always precede blood sampling and PFTs.  All clinically significant findings at 
screening will be recorded on the medical history/baseline condition page in the eCRF.  All 
clinically significant findings at subsequent visits should be documented on the AE page of 
the eCRF.


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5.3.5
Other safety parameters
Local tolerability at the administration site of the subcutaneous injection will be assessed by 
the Investigator to monitor any swelling, induration, heat, redness, pain, or other findings, 
and will be recorded in the eCRF.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical 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:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Life-threatening in this context 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.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the remote data capture (RDC)
system.  These events should always be reported as SAEs as described in Section 5.3.6.1.


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Adverse events of special interest (AESI)
AESI need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT >3 fold upper limit normal (ULN) combined with an 
elevation of total bilirubin >2 fold ULN measured in the same blood draw sample, and/or

Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “drug-induced liver injury (DILI)
checklist” provided in the RDC system.  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.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE.
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE.
The causal relationship must be provided by the Investigator for all potential trial drugs, i.e. 
the BI trial drug and for all other trial drugs (such as any active comparator or placebo and for 
trial procedure).  The reason for the decision on causal relationship needs to be provided in
the eCRF and on the SAE form.


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5.3.7
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate eCRF by the 
Investigator:
From signing the informed consent onwards through the Residual Effect period (REP), all 
AEs (serious and non-serious), and AESIs will be reported.
All 
AEs which occurred through the treatment phase and throughout the REP will be considered 
as on-treatment (please see Section 7.3.4).  Events which occurred after the REP will be 
considered as post-treatment events.
After the last per protocol contact (Visit 12), the Investigator does not need to actively 
monitor patients for AEs.  However, if the Investigator becomes aware of SAEs or AESIs 
that occurred after the last per protocol contact, the SAEs and AESIs should be reported by 
the Investigator to the Sponsor if considered relevant by the Investigator.
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). In 
specific occasions the Investigator could inform the Sponsor upfront via telephone.  This does 
not replace the requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.


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Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug(s).  The Investigator 
should determine the causal relationship to the trial medication, the trial procedures outlined 
under Section 6.2, and any possible interactions between the investigational drug and a 
non-investigational medicinal product.
The following should also be recorded as an (S)AE in the eCRF and SAE form if they meet 
the SAE criteria:
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.  All (S)AEs, including those persisting after trial completion must be 
followed up until they have resolved, have been sufficiently characterized, or no further 
information can be obtained.
Screening failures
SAEs occurring in patients after having discontinued in the trial due to screening failures, 
i.e. after the screening period and who did not receive any trial medication, are to be reported 
if the Investigator considered the SAE related to the screening procedure.  SAEs which 
occurred during the screening period are to be reported according to standard procedures.
Pregnancy
In the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the Sponsor’s unique entry point (country-
specific contact details will be provided in the ISF). The Pregnancy Monitoring Form for 
Clinical Trials (Part A) should be used. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).


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APPROPRIATENESS OF MEASUREMENTS
5.7
Measurements performed during this trial are standard measurements in patients with severe 
persistent asthma, and will be performed in order to monitor safety aspects or assess 
treatment response in an appropriate way. 
 


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
The trial consists of a screening period, treatment period, and a follow-up period.  Following 
the 3 to 4 week screening period (Visits 1B to Visit 2), patients will be randomized (Visit 2) 
to one of the two treatment groups: risankizumab or placebo.  Additional clinic visits will be 
scheduled every 4 weeks (Visits 3 to 12, with Visit 11 as a phone visit) until week 40.  The 
first 24 weeks after randomization is the treatment period, and this is followed by a 16-week 
follow-up period (Figure 3.1: 1).
Patients should make all efforts to complete the study which includes the 16-week follow-up 
period.  Investigators should encourage treatment compliance, E-diary compliance, and 
adherence to the protocol procedures.  All patients should adhere to the visit schedule as 
specified in Flow Chart A
  Any deviations from the planned visit schedule 
should be documented.
Rescheduling clinic visits and study procedures
Medication washout
Medication washout is necessary for the PFTs.  Visit 1B (screening visit) may be rescheduled 
twice within the permitted time windows due to lack of medication washout compliance.  For 
all other clinic visits, rescheduling is not necessary for lack of medication washout.  
Medication washout checklist provided in the ISF must be completed at each clinic visit. If 
medication washout requirements (Section 4.2.2) are not met it should be recorded in the 
Masterscope®.  Pre- and post-bronchodilator PFT measurements will be performed during 
clinic visits (except Visit 1B) even if medication washout criteria are not met.  If possible, 
patients should be contacted by telephone 2 to 3 days before the clinic visit to remind them 
about the visit schedule and the medication washout requirements.
As reversibility is an inclusion criterion, medication washout must be verified before any 
study procedures begin at Visit 1B.  If washout requirements are not met, the visit will be 
rescheduled and all Visit 1B procedures will be completed at the rescheduled visit when 
washout requirements are met.
Sputum induction
If the patient is unable to produce an adequate sample of the sputum or a sputum sample of 
acceptable quality at Visit 1B (screening visit), a repeat sputum induction may be performed.  
An interval of at least 3 full days should be observed between repeat sputum induction 
procedures.  Sputum induction procedures at Visits 2, 7, 8, and 12 will not be repeated if the 
patient is unable to produce sputum or if the sputum sample quality is not acceptable.
If sputum induction procedure at screening (Visit 1B) needs to be repeated, patient will 
complete only the sputum induction procedure at the repeat visit.  All other Visit 1B 
procedures should have been completed on the originally scheduled Visit 1B date.


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Reversibility testing
At Visit 1B (screening visit) if reversibility criterion is not met, and patient does not have a 
historic reversibility data as defined in Inclusion Criterion 4, reversibility testing can be
repeated twice during the screening period.
If reversibility testing is repeated, patient will complete only the reversibility testing when the 
repeat visit occurs.  All other Visit 1B procedures including sputum induction should have 
been completed on the originally scheduled Visit 1B date.
Asthma exacerbation and respiratory tract infection
If a patient experiences an asthma exacerbation or respiratory tract infection between 
Visits 1A and 1B, Visit 1B will be postponed until 4 weeks following recovery from the 
exacerbation or infection.  If a patient experiences an asthma exacerbation or respiratory tract 
infection between Visits 1B and the randomization visit (Visit 2), randomization will be 
postponed until 4 weeks following recovery from the exacerbation or infection.  Screening 
period may be extended up to six weeks if the patient experiences an asthma exacerbation or 
respiratory tract infection during the screening period.
If patient has an asthma exacerbation or respiratory tract infection during the treatment period 
or follow-up period, study visits will not be rescheduled.  In this case, the investigator will 
make a determination on what study procedures can be completed on the scheduled clinic 
visits.
E-diary compliance
If at the randomization visit (Visit 2), E-diary compliance is below 75% and two completed 
ACQ5 sessions are not available, rescheduling of Visit 2 is required.  The timing of the 
rescheduled visit will depend on the data already available in the E-diary, and what is needed 
to achieve at least 75% compliance.  The goal should be that patient meets the required 
compliance level at the next rescheduled visit.  Rescheduling Visit 2 for lack of E-diary 
compliance is allowed twice.  Screening period may be extended up to four weeks if Visit 2 is 
rescheduled for lack of E-diary compliance.
When patient arrives for Visit 2, the E-diary data should be downloaded first in the 
Masterscope® to determine if the patient met the E-diary compliance criteria.  If the 
compliance criteria are not met, randomization visit must be rescheduled, and no other Visit 2 
procedures should be performed.
The calculation of E-diary compliance during the screening period will be based on the data 
collected in the last 14 days prior to Visit 2. E-diary compliance is derived from the number 
of acceptable sessions. An acceptable session is one in which at least two acceptable PEFs 
were stored and the question on rescue medication use is answered in the E-diary. In addition, 
to meet the required E-diary compliance, at least two ACQ5 sessions in the 14 days prior to 
Visit 2 (including the morning session of Visit 2 before randomization visit) must have been 
completed. ACQ5 will be displayed in the E-diary only once every week as this is a weekly 


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recall. If the patient misses a scheduled ACQ5 session in the E-diary, patient will be able to 
complete the questionnaire in the evening of the same day or in the morning or evening 
sessions in the following day.
Patients should be instructed to maintain full compliance with the E-diary during the entire 
study period.  From Visit 3 onwards, study visits will not be rescheduled for lack of E-diary 
compliance.
Rescheduling clinic visits after randomization
If a clinic visit after Visit 2 and the phone call at Visit 11 is out of the time window allowed 
by the protocol, subsequent visits should occur at the originally scheduled date to ensure a 
24-week treatment period, and a 16-week follow-up period.  Any visits outside the time 
window allowed by the protocol should be discussed with the Local Clinical Monitor.  All 
patients are expected to complete the treatment period in 24 weeks, and the follow-up period 
in 16 weeks.
All clinic visits and the phone call at Visit 11 should be completed at the time window 
allowed in the protocol.  Under extraordinary circumstances, if a scheduled clinic visit is 
delayed (i.e., occurs after the scheduled visit date) during the treatment period, and the visit 
date is more than 14 days from the scheduled visit that was missed, study drug will not be 
administered and the dose should be skipped.  However, all other visit procedures should be 
completed.  Patient will have to wait until the next scheduled visit to receive the next dose of 
study medication.  The time interval between two consecutive doses of the study medication 
must be at least 14 days.
Pregnancy tests
All women of child bearing potential will undergo serum pregnancy test at the screening visit 
(Visit 1B).  Patients who test positive for the serum pregnancy test will be excluded from the 
study.  Urine pregnancy tests will be done at all visits in the clinic starting from Visit 2.  If 
the urine pregnancy test is positive, a serum pregnancy test will be done to confirm 
pregnancy.  If the serum pregnancy test is positive, patient will be discontinued from the 
study.  If serum pregnancy is negative, patient may continue in the study.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening period
At Visit 1A, informed consent will be obtained prior to patient participation in the trial.  
Medication washout procedures are allowed only after the patient signs the informed consent.  
If the patient is willing to provide a sample for pharmacogenomic testing, a separate consent 
must be obtained.  
 
 
  Each patient will be assigned a unique patient number 
and enrollment will be recorded in eCRF.


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Baseline conditions, medical history, and eligibility criteria will be assessed at Visit 1A.  
Concomitant therapy and AE (if any) will be recorded.  Visit 1B will be scheduled.  At the 
conclusion of Visit 1A, patients should receive instructions on medication washout 
requirements for Visit 1B and they should also be briefed about all the procedures to be 
performed at Visit 1B.
Procedures indicated under Visit 1B in Flow Chart A should be completed at Visit 1B.  The 
E-diary will be dispensed at Visit 1B after the patient is trained on how to use the E-diary
including PEF measurements.  An E-diary will be available at all sites exclusively for 
training purposes.  Rescue medication will be provided starting at Visit 1B.  An asthma 
medication log card will be dispensed, and patient will record any change in asthma 
medications (Section 5.2.2).  Patient should be trained on when entries should be made in the 
asthma medication log.
Visit 1B should be scheduled in the morning between 6:00 am and 10:00 to ensure 
completion of the reversibility testing in the morning.  The sequence of procedures in the 
Masterscope® provided by ERT will be ECG followed by FeNO measurements, and then 
PFTs for reversibility testing.  Blood samples should be collected after the ECG procedure is 
completed.  Sputum induction should be done only after completing ECG, FeNO 
measurements, and PFTs for reversibility testing.  The Masterscope® will be used to do the 
PFTs and monitor patient’s lung function during sputum induction.  Processing of the sputum 
samples will be done as specified in a separate sputum procedures manual provided in the 
ISF.  Instructions for shipping of laboratory samples and sputum samples/slides will be 
provided in the manual.
If the patient has met all the eligibility criteria (pending sputum assessment and safety 
laboratory results), randomization visit will be scheduled.  If patients do not meet the sputum 
criteria, they should be informed about their ineligibility and must be marked as screen failed.  
Sputum quality and acceptability will be made by the external vendor who has been 
contracted to make the assessments centrally and the central reader’s decision will be final.
 
 
 
 
 
 
 
 
 
 
 
If rescheduling Visit 1B or Visit 2 is required for reasons specified in Section 6.1, screening 
period can be extended by two weeks unless otherwise a specific period is stated in the 
protocol.  Screening period may be extended by four weeks for administrative reasons after 
consultation with the Local Clinical Monitor.  The typical screening period allowed by the 


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protocol is 3 to 4 weeks 
  
However, if the screening period is extended due to rescheduling allowed per protocol, the 
total screening period should not exceed 10 weeks (informed consent to randomization) 
unless written approval is obtained from the Trial Clinical Monitor.
If screening period is extended for any reasons, the Investigator should review the laboratory 
reports from baseline (Visit 1B), and make a determination if any labs specified in the 
protocol must be repeated before the randomization visit.  If deemed necessary, test samples 
should be drawn and sent to the central laboratory.
Discontinuation during the screening period
If patients discontinue from the study during the screening period, no additional clinic visits 
are required, and they will be marked as screen failures.
Re-screening
Patients may be re-screened once with approval from the Local Clinical Monitor.  Patients 
who met all the inclusion criteria but were screen failed due to acute medical conditions that 
have since been resolved or those who were screen failed for administrative reasons (e.g., 
extended travel, life events) will be good candidates for re-screening.
6.2.2
Treatment period
All eligibility criteria must be checked before proceeding with the randomization visit.  
Patients will be randomized only if their pre-bronchodilator FEV1 is not below 40% 
(Inclusion Criterion 3), met the E-diary compliance criteria (Section 6.1), and were able to 
produce sputum that could be characterized (Exclusion Criterion 4).
Treatment period begins after the patient is dosed with the study medication at Visit 2 and 
ends after completion of the End of Treatment visit (Visit 8) at Week 24.  Each patient will 
be assigned to one of the two treatment groups: risankizumab or placebo.  Procedures listed 
under each visit in Flow Chart A and Flow Chart B should be completed from Visit 2 until 
Visit 8.  Visit windows should be adhered as specified in Flow Chart A.
Patient will be dosed with the study medication every 4 weeks (Visits 2 to 7) in the clinic.  At 
each one of these visits, medication should be administered after completion of all other visit 
procedures.  The study drug will be administered by a physician Investigator or a person who 
is designated by the principal Investigator.  The designated person must be medically 
qualified to administer the injection, and all study drug administration should be under the 
supervision of a physician.  Patients will remain in the clinic for observation for 
approximately an hour after the medication is administered.  The instructions for medication 
handling and administration provided in the ISF must be followed.
All visits during the treatment period should be scheduled in the mornings.  For more 
instructions on the timing of each visit, please refer Section 5.2.2.  Medication washout 
checklist should be completed at each visit.  The sequence of procedures in the Masterscope®
provided by ERT will be ECG followed by FeNO measurements, and then the PFTs.  
 


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  Sputum induction (at 
applicable visits) should be done only after completing ECG, FeNO measurements, and 
PFTs.  The Masterscope® will be used to do the PFTs and monitor patient’s lung function 
during sputum induction.  ECG and sputum induction will be performed only at visits shown 
in Flow Chart A.  Processing of the sputum samples will be done as specified in the manual 
provided in the ISF.  Instructions for shipping of laboratory samples and sputum 
samples/slides will be provided in the respective manuals.  Sputum samples/specimens will 
be assessed by the central reader.
At each visit, data downloaded from the E-diary must be reviewed to check for any asthma 
worsening events (Section 5.2) since the previous clinic visit.  Asthma medication log should 
be reviewed for any changes in asthma medications since the last clinic visit.  Patients should 
be asked if there were any other change in asthma medications or if they had to seek medical 
help (visit to doctor’s office, hospital, etc.) since the previous clinic visit.  Any information 
written in the medication log or collected during the discussion with the patient should be
assessed to see if they meet any of the asthma exacerbation criteria specified in the protocol.
 
  
 
 
 
 
If the scheduled visit does not occur within the protocol allowed time window, follow 
instructions provided in Section 6.1 for rescheduling and study drug administration.  
Unscheduled visits may be arranged if necessary and the procedures completed during the 
unscheduled visit will depend on the circumstances under which the visit was scheduled.
After completion of the End of Treatment visit (Visit 8), all patients will enter the 16-week 
follow-up period.
 
 
 
 
 
 
 
 
 
 
 


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Discontinuation during the treatment period:
If patients discontinue from the study during the treatment period, an EOT visit 
(corresponding to Visit 8) will be scheduled 4 weeks after the last dose of study medication.  
Every effort should be made to complete all the procedures (including sputum induction) 
listed under EOT visit.  After completing the EOT visit, patients should be allowed to enter 
the follow-up period of 16 weeks, and they will complete the four visits (Visit 11 is a phone 
visit) and the associated procedures ending in the End of Observation (EOO) visit.  If the 
patient is not willing to enter the follow-up period, one additional follow-up visit should be 
scheduled 16 weeks after the EOT visit and this will be considered as the EOO visit.  During 
the EOO visit, every effort should be made to complete all procedures listed under the EOO
visit (Visit 12).  
 
6.2.3
Follow Up Period and Trial Completion
The follow-up period extends from week 24 (Visit 8) until week 40 (Visit 12).  The first 
follow-up visit (Visit 9) will be scheduled 4 weeks after the EOT visit.  Visits will be 
scheduled every 4 weeks (Visits 9 to 12, Visit 11 being a phone visit). Procedures for each 
visit can be found in Flow Chart A and Flow Chart B.  Patients will not be dosed with the 
study medication (risankizumab or placebo) during the follow-up visits.  The sequence of 
visit procedures will be the same as in the treatment period.  All visits during the follow-up 
period should be scheduled in the mornings and the criteria for the PFTs including the timing 
will be the same as in the treatment period.  For more instructions on the timing of the PFTs 
at each visit, please refer Section 5.2.2.  Patients will continue to receive the rescue 
medication and will continue to use the E-diary, and the asthma medication log as in the 
treatment period.  The last clinic visit will be at week 40 (Visit 12), and this will mark the 
End of Observation period, and the patient has completed the study.
Discontinuation during the follow-up period:
If patients discontinue from the study during the follow-up period, an EOO visit will be 
scheduled at the date Visit 12 would have been originally scheduled.  All procedures 
scheduled for the EOO visit should be completed during this visit.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is a randomized, double-blind, placebo-controlled, parallel group trial with a 24-week 
treatment period which is followed by a 16-week follow-up period.  Risankizumab will be 
compared to placebo in patients with severe persistent asthma.
The primary endpoint is the time to first asthma worsening during the planned treatment 
period and will be analyzed using Cox-proportional hazards model. Detailed specifications 
are provided in Section 7.3. 
The primary endpoint and secondary endpoints are defined in Section 5.1.
Baseline
The baseline for the diary data: rescue medication, PEF, FEV1 (except ACQ5) is defined as 
the mean of the measurements at corresponding time point (if any) as specified in the 
endpoints in the last two weeks prior to Visit 2, i.e., 14 days prior to the administration of the 
first dose of randomized treatment.
The baseline for ACQ5 is defined as the mean of the last two available measurements in the 
last two weeks prior to Visit 2 (including the morning session before randomization visit), 
i.e., 14 days prior to the administration of the first dose of randomized treatment.
For all clinical spirometry endpoints, the pulmonary function test at the randomization visit 
(Visit 2), measured prior to the first administration of the randomized treatment, is defined as 
baseline.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The following hypotheses will be tested for the primary endpoint with 1-sided α = 0.1:
H0: SBI(t)=SPBO(t), for t>0
H1: SBI(t)>SPBO(t), for t>0,
where S(t) is the probability that a patient has no asthma worsening up to time t, i.e., the 
survival function. The subscripts represent the two treatment groups of either risankizumab or 
placebo.
PLANNED ANALYSES
7.3
7.3.1
Primary endpoint analyses
The primary analyses will be performed in all randomized patients who receive at least one 
dose of treatment.  This set will be called Full Analysis Set (FAS) for all patients.


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Time to first asthma worsening during the planned 24-week treatment period will be analyzed 
using Cox proportional-hazards model including treatment and stratification factor of OCS 
use at baseline as fixed effects to provide hazard ratio, confidence interval, and test statistic to 
compare the treatment groups in FAS.  Kaplan-Meier curves will be provided. For patients 
who prematurely discontinue from the trial during the treatment period not due to consent 
withdrawal, the asthma worsening events collected after treatment discontinuation until 24 
weeks (if available) from the start of the treatment will be included in the analysis.  A 
sensitivity analysis which includes all asthma worsening events during the actual on-
treatment period including 4 weeks after last drug administration will be conducted.
7.3.2
Secondary endpoint analyses
The analyses of secondary endpoints will be performed in FAS.
The annualized rate of asthma worsening and severe asthma exacerbation during the planned 
24-week treatment period will be analyzed using negative binomial regression with logarithm 
of the exposure as an offset.  The analyses will include treatment and the stratification factor 
of OCS use at baseline as fixed effects. The mean number of events per patient year by 
treatment arm, the rate ratio, and corresponding 95% confidence interval will be presented 
along with the p-value.
The same model for primary endpoint will be used to analyze time to first severe asthma 
exacerbation during the planned 24-week treatment period.
An analysis of covariance (ANCOVA) model will be used to analyze ACQ5 score, separately 
for each week (including the secondary endpoint measured at week 24). The model will 
include the fixed categorical effects of treatment and the stratification factor of OCS use at 
baseline, and baseline ACQ5 as a continuous covariate.
Mean change from baseline in trough and post-bronchodilator FEV1 at each clinic visit 
(including secondary endpoint measured at week 24) during the planned treatment period will 
be analyzed using a restricted maximum likelihood (REML)-based mixed model repeated 
measures (MMRM) approach. Analyses will include the fixed, categorical effects of 
treatment, stratification factor of OCS use at baseline, test day, and treatment-by-test day 
interaction, as well as the continuous, fixed covariates of baseline and baseline-by-test day 
interaction. Patient will be considered as a random effect. The planned test days during the 
24-week planned treatment period will be used for values of test day.  An unstructured 
co(variance) structure will be used to model the within-patient errors.  The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. Analyses will be 
implemented using SAS.  The FAS population will be used.  A plot and table over time will 
be provided to describe the profile of trough and post-bronchodilator FEV1.


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the residual effect period 
(REP), a period of 130 days after the last dose of trial medication, will be assigned to the 
treatment period for evaluation.  All treated patients will be included in the safety analysis. 
In general, safety analyses will be descriptive in nature and will be based on BI standards.  
No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’. The residual effect 
period is defined as 130 days. Adverse events that start before first drug intake and 
deteriorate under treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the MedDRA.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.


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Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
  
 
 
 
INTERIM ANALYSES
7.4
Interim analyses may be performed when the last patient completes the 24-week treatment 
period.  The data from interim analysis will allow planning future trials and reporting key 
results.  Select members of the Sponsor trial team will be unblinded during interim analysis.  
Investigators, study site staff, and patients will remain blinded.  No alpha adjustment is 
needed because the primary endpoint will have been reached for all patients in the study. 
More details will be specified in the interim analysis logistics plan.
HANDLING OF MISSING DATA
7.5
For Patient Daily Record data, when the number of salbutamol (albuterol) doses is missing 
but other data are entered on any given day, then these data will be imputed by zero (because 
the presence of other data is interpreted as meaning that the patient did not take rescue 
medication).
Additional details on the imputation of missing data will be specified in the TSAP prior to 
unblinding.
RANDOMIZATION
7.6
Patients will be randomized in blocks to double-blind treatment. Approximately equal 
numbers of patients will be randomized to each treatment group. Randomization will be 
stratified based on OCS use at baseline,
 and history
of severe asthma exacerbation in the past 12 months. BI will arrange for the randomization 
and the packaging and labelling of trial medication.
The randomization list will be generated using a validated system, which involves a 
pseudo-random number generator so that the resulting treatment will be both reproducible 
and non-predictable. The block size will be documented in the clinical trial report.  Access to 
the codes will be controlled and documented.


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DETERMINATION OF SAMPLE SIZE
7.7
Based on the previous studies in asthma with tiotropium: trials 205.416 and 205.417
(U12-2037-01), the proportion of patients with asthma worsening within 6 months, derived 
using the definition in this study, was around 55% in tiotropium treated patients, with history 
of frequent severe asthma exacerbations.  It is assumed that risankizumab would reduce the 
risk of asthma worsening by 40% (HR = 0.6) in patients.  Given 1-sided type-I error α = 0.1, 
this trial requires a total of 89 events and 100 patients per treatment arm to achieve 87% 
power.
Table 7.7: 1
Sample size calculation with 1-sided α = 0.1, event rate = 55% in 
placebo group using nQuery Advisors 6.01 STT0 (log rank test)
Hazard ratio
0.5
0.6
n per group
47
40
100
90
Total number of events needed
38
32
89
80
Power
80%
75%
87%
84%


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
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 and relevant BI Standard Operating Procedures (SOPs).
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract.  As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient 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.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
RECORDS
8.3
Case Report Forms (eCRF) 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.


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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; current medical records must also be available.
For the eCRF, the following data need to be derived from source documents:

Patient identification

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date

Serious adverse events (onset date (mandatory), and end date

Concomitant therapy (start date, changes)

Originals or copies of laboratory results

Completion of Patient’s Participation in the trial

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records or testing conducted specific for a protocol) to support 
inclusion/exclusion criteria does not make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all eCRF, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness is provided. For
risankizumab, this is the current version of the Investigator’s Brochure (c15197475).  The 
current version of this reference document is provided in the ISF. For non-investigational 
medicinal product (salbutamol/albuterol), the reference document is the United States 
prescribing information or another regulatory label document.  The current version of this 


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reference document is provided in the ISF.  No AEs are classified as listed for matching 
placebo, trial design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IEC / IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IEC / IRB, will be done according to local 
regulatory requirements.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
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.
END OF TRIAL
8.6
The end of the trial is defined as the last patient completing the last visit (Visit 12) of the 
follow-up period.
The IEC / competent authority in each participating EU member state needs to be notified 
about the end of the trial or early termination of the trial.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P03-08188 
Holgate ST The ENFUMOSA cross-sectional European multicentre study of 
the clinical phenotype of chronic severe asthma. Eur Respir J 22 (3), 470 - 477 
(2003)
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J 26 (2), 319 - 338 (2005)
P14-07215
Global Initiative for Asthma (GINA) Global strategy for asthma management 
and prevention (updated 2014). http://www.ginasthma.org (2014)
P14-14612
Irvin C, Zafar I, Good J, Rollins D, Christianson C, Gorska MM, et al. 
Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar 
lavage fluid characterizes a population of patients with severe asthma. J 
Allergy Clin Immunol, (2014)
P99-03282
Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF. Neutrophilic 
inflammation in severe persistent asthma. Am J Respir Crit Care Med 160 (5, 
Part 1), 1532 - 1539 (1999)
R00-1157
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and 
validation of a questionnaire to measure asthma control. Eur Respir J 14, 902 -
907 (1999)
R08-5197
Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P. Relationship of the 
type of tobacco and inhalation pattern to pulmonary and total mortality. Eur 
Respir J 5, 1111 - 1117 (1992)
R09-2853
Reddel HK, Taylor DR, Bateman ED, Boulet L, Boushey HA, Busse WW et 
al.  An official American Thoracic Society/European Respiratory Society 
statement: asthma control and exacerbations.  Am J Respir Crit Care Med 180, 
59-99(2009)
R10-6267
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body 
size-based dosing of monoclonal antibodies in adult clinical trials. J Clin 
Pharmacol 49, 1012 - 1024 (2009)
R11-1199
Vosse E van de, Ottenhoff THM. Human host genetic factors in mycobacterial 
and Salmonella infection: lessons from single gene disorders in IL-12/IL-23-
dependent signaling that affect innate and adaptive immunity. Microbes Infect 
8, 1167 - 1173 (2006)


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Happel KI, Dubin PJ, Zheng M, Ghilardi N, Lockhart C, Quinton LJ, et al. 
Divergent roles of IL-23 and IL-12 in host defense against Klebsiella 
pneumoniae. J Exp Med 202 (6), 761 - 769 (2005)
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Papp KA, Griffiths CEM, Gordon K, Lebwohl M, Szapary PO, Wasfi Y, et al. 
PHOENIX 1 Investigators, PHOENIX 2 Investigators, ACCEPT Investigators
Long-term safety of ustekinumab in patients with moderate-to-severe 
psoriasis: final results from 5 years of follow-up. Br J Dermatol 168, 844 - 854 
(2013)
R13-4749
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, et al. A guide to 
rational dosing of monoclonal antibodies. Clin Pharmacokinet 51 (2), 119 -
135 (2012)
R13-4750
Joos B, Trkola A, Kuster H, Aceto L, Fischer M, Stiegler G, et al. Long-term 
multiple-dose pharmacokinetics of human monoclonal antibodies  (MAbs) 
against human immunodeficiency virus type 1 envelope gp120 (MAb 2G12) 
and gp41 (MAbs 4E10 and 2F5).  Antimicrob Agents Chemother 50 (5), 1773 
- 1779 (2006)
R13-4753
Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S. Projecting 
human pharmacokinetics of therapeutic antibodies from  nonclinical data: what 
have we learned?  MAbs 3 (1), 61 - 66 (2011)
R13-4754
Xin Y, Gordon MS, Jin D, Wakshull E, Chen DS, Rosen LS, et al. Population 
pharmacokinetic (PK) analysis supports fixed dosing for the humanized 
monoclonal antibody (huMAb) anti-EGFL7 (MEGF0444A) administered 
intravenously in patients with advanced solid tumors.  47th Ann Mtg of the 
American Society of Clinical Oncology (ASCO), Chicago, 3 - 7 Jun 2011 J 
Clin Oncol 29 (15) (Suppl),, Abstr 2586 (2011)
R14-2101
Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, et al. Benefits 
of omalizumab as add-on therapy in patients with severe persistent asthma 
who are inadequately controlled despite best available therapy (GINA 2002 
step 4 treatment): INNOVATE. Allergy 60, 309 - 316 (2005)
R14-2348
Wakashin H, Hirose K, Maezawa Y, Kagami S, Suto A, Watanabe N, et al. 
IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway 
inflammation in mice. Am J Respir Crit Care Med 178 (19), 1023 - 1032 
(2008)
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Ciprandi G, Cuppari C, Salpietro AM, Tosca MA, Rigoli L, Grasso L, et al. 
Serum IL-23 strongly and inversely correlates with FEV1 in asthmatic 
children. Int Arch Allergy Immunol 159 (2), 183 - 186 (2012)
R14-4182
Seys SF, Grabowski M, Adriaensen W, Decraene A, Dilissen E, Vanoirbeek 
JA, et al. Sputum cytokine mapping reveals an 'IL-5, IL-17A, IL-25-high' 


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pattern associated with poorly controlled asthma.
Clin Exp Allergy 43, 1009 - 1017 (2013)
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Agache I, Ciobanu C, Agache C, Anghel M. Increased serum IL-17 is an 
independent risk factor for severe asthma. Respir Med 104, 1131 - 1137 
(2010)
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Brasier AR, Victor S, Boetticher G, Ju H, Lee C, Bleecker ER, et al. Molecular 
phenotyping of severe asthma using pattern recognition of bronchoalveolar 
lavage-derived cytokines. J Allergy Clin Immunol 121 (1), 30 - 37.e6 (2008)
R14-4187
Hastie AT, Moore WC, Meyers DA, Vestal PL, Li H, Peters SP, et al. NHLBI 
Severe Asthma Research Program (SARP) Analyses of asthma severity 
phenotypes and inflammatory proteins in subjects stratified by sputum 
granulocytes. J Allergy Clin Immunol 125 (5), 1028 - 1036.e13 (2010)
R14-4215
Wood LG, Baines KJ, Fu J, Scott HA, Gibson PG. The neutrophilic 
inflammatory phenotype is associated with systemic inflammation in asthma. 
Chest 142 (1), 86 - 93 (2012)
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Boushey HA, Fahy JV. Basic mechanisms of asthma. Environ Health Perspect 
103 (Suppl 6), 229 - 233 (1995)
R14-4217
Carroll N, Lehmann E, Barret J, Morton A, Cooke C, James A. Variability of 
airway structure and inflammation in normal subjects and in cases of nonfatal 
and fatal asthma. Pathol Res Pract 192, 238 - 248 (1996)
R14-4224
Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. 
Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, 
double-blind, placebo-controlled trial. Lancet 380, 651 - 659 (2012)
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Lotvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, et al.
Asthma endotypes: a new approach to classification of disease entities within 
the asthma syndrome. J Allergy Clin Immunol 127 (2), 355 - 360 (2011) R14-
2101
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Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, et 
al. Lebrikizumab treatment in adults with asthma. N Engl J Med 365 (12), 
1088 - 1098 (2011)
R14-4232
Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. 
Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 
368 (26), 2455 - 2466 (2013)
R14-4315
Moore WC, Hastie AT, Li X, Li H, Busse WW, Jajour NN, et al. National 
Heart, Lung, and Blood Institute's Severe Asthma Research Program Sputum 
neutrophil counts are associated with more severe asthma phenotypes using 
cluster analysis. J Allergy Clin Immunol 133 (6), 1557 - 1563 (2014)


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Amarnani A, Rosenthal KS, Mercado JM, Brodell RT. Concurrent treatment 
of chronic psoriasis and asthma with ustekinumab. J Dermatol Treat 25 (1), 63 
- 66 (2014)
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Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH et al.  Multi-
ethnic reference values for spirometry for the 3-95 year age range: the global 
lung function 2012 equations: report of the Global Lung Function Initiative 
(GLI), ERS Task Force to establish improved lung function reference values.   
Eur Respir J. 40(6):1324-1343 (2012)
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Lamblin C, Gosset P, Leblond IT, Saulnier F, Marquette CH, Wallaert B, 
Tonnel AB. Bronchial neutrophilia in patients with noninfectious status 
asthmaticus. Am J Respir Crit Care Med 157, 394 - 402 (1998)
UNPUBLISHED REFERENCES
9.2
     
c01651292-07
 48 weeks study of three different dose regimens 
of BI 655066 administered subcutaneously in patients with moderate to 
severe chronic plaque psoriasis (randomised, dose-ranging, active-
comparator controlled (ustekinumab), double-blind within dose groups 
of BI 655066). 1311.2. Version: 4.0. 03-Jul-2014.
c01651690-12
.  A phase II, multicenter, randomized, double-
blind, multiple dose, placebo-controlled, parallel-group study to 
evaluate the efficacy, pharmacokinetics and safety of BI 655066, an 
IL-23p19 antagonist monoclonal antibody, in patients with moderately 
to severely active Crohn’s disease, who are naïve to, or were previously 
treated with anti-TNF therapy. 1311.6. Version: 5.0. 04-Dec-2014.
c02190287-17
.  A 48 weeks, phase II, randomized, double-
blind, placebo-controlled, proof of concept and dose finding study of 
three different dose regimens of BI 655066 administered 
subcutaneously in patients with ankylosing spondylitis. 1311.8. 
Version:3.0. 18-Jun-2014.
 
U12-2037-01
. Combined Clinical Trial Report.  BI Trial No. 
205.416 and 205.417.  A Phase III randomized, double-blind, placebo-
controlled, parallel group trial to evaluate efficacy and safety of 
tiotropium inhalation solution delivered via Respimat® inhaler 


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(5μg/day) over 48 weeks as add-on controller therapy on top of usual 
care in patients with severe persistent asthma.  31 Aug 2012.
U12-3066-01
. Safety, tolerability, efficacy, 
pharmacokinetics, and pharmacodynamics of single rising i.v. (Stage 1) 
and s.c. (Stage 2) doses of BI 655066 in male and female patients with 
moderate to severe psoriasis (randomized, double-blind, placebo-
controlled within dose groups). 1311.1. 25-Jan 2012.


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10.
APPENDICES
ADDITIONAL INFORMATION REGARDING INCLUSION/EXCLUSION 
10.1
CRITERIA
Table 10.1: 1
Definition of medium daily doses of ICS adapted from Global 
Initiative for Asthma (GINA) 2014 (P14-07215)
Drug
Medium daily Dose (µg)*
Beclometasone dipropionate (CFC)
>500 - 1000
Beclometasone dipropionate (HFA)
>200 - 400
Budesonide (DPI)
>400 - 800
Ciclesonide (HFA)
>160 - 320
Fluticasone propionate (DPI)
>250 - 500
Fluticasone propionate (HFA)
>250 - 500
Mometasone furoate
>220 - 440
Triamcinolone acetonide
>1000 - 2000
*Protocol requires patients to be on at least medium dose.  There is no restriction on the maximum dose.  
Prescribing information should be carefully reviewed by the Investigator for the correct equivalent dose.
Reversibility testing (P05-12782): At the screening visit (Visit 1B) following the completion 
of three acceptable pre-bronchodilator forced expiratory maneuvers, salbutamol (albuterol)
will be administered to each patient in order to document the degree of reversibility. 
Immediately after (within 10 min) pre-bronchodilator forced expiratory maneuvers and after 
a gentle and incomplete expiration, a dose of 100 μg of salbutamol is inhaled in one breath to 
total lung capacity. The breath is then held for 5–10 s before the subject exhales. Four 
separate doses (total dose 400 μg) are delivered at approximately 30-second intervals (this 
dose ensures that the response is high on the salbutamol dose–response curve). Three 
additional, acceptable post-bronchodilator forced expiratory maneuver tests are recorded
starting ≥15 min to 30 min later after the last dose of salbutamol is inhaled.
If reversibility criteria are not met at Visit 1B and if any of the historic data is not available as 
stated in inclusion criterion 4, reversibility testing can be repeated twice during screening 
period at separate visits. For the first retest, 400 µg salbutamol via MDI should be used, and 
for the second retest, either 800 µg salbutamol via MDI or 2.5 mg nebulized albuterol should 
be used.
During the second retest, the first 400 µg is administered as described above and tested for 
reversibility.  If the patient did not meet the reversibility criteria, another 200 µg salbutamol
is administered and tested for reversibility: post-bronchodilator measurements should begin 
10 to 20 minutes after the last dose of salbutamol is inhaled. If the patient did not meet the 
reversibility criteria after a total of 600 µg salbutamol, another 200 µg salbutamol is 
administered and tested for reversibility: post-bronchodilator measurements should begin 10 
to 20 minutes after the last dose of salbutamol is inhaled.  Reversibility testing must not occur 
on the day of randomization.


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Smoking: calculation of number of pack years
Calculation of pack years based on number of cigarettes:
Pack years =    Number of cigarettes/day     x years of smoking
                                        20
The following equivalents for the tobacco content should be used for smokers other than 
cigarettes smokers (R08-5197):
One plain or filter cigarette = 1 gram of tobacco
One cigar = 5 grams of tobacco
One cheroot or cigarillo = 3 grams of tobacco
One gram of pipe tobacco = 1 gram of tobacco
Calculation of pack years based on tobacco contents:
Pack years =    Number of grams/day     x years of smoking
                                        20


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
22 October 2015
EudraCT number
2014-004932-20
BI Trial number
1311.14
BI Investigational Product(s)
BI 655066
Title of protocol
A phase IIa, randomized, double-blind, placebo 
controlled, parallel group study to assess the safety 
and efficacy of subcutaneously administered BI 
655066 as add-on therapy over 24 weeks in 
patients with severe persistent asthma.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
☒
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
☐
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
☐
Section to be changed
Synopsis
Section 3.3
Section 7.7
Description of change 1
Total number of patients, and patients entered 
changed from 300 to 270, Patients in each 
treatment changed from 150 to 135.
Rationale for change
In studies with tiotropium in asthma, the observed 
event rate in patients treated with tiotropium was 
55%: however, these studies did not have the same 
definition as in this study for the ACQ 
component. The original protocol assumed the 
event rate of 50% to account for the change in the 
way ACQ is administered in this study. After 
additional considerations, due to the exploratory 
nature of the study, a less conservative approach 
was adopted with an assumption of an event rate of 
55% for the primary endpoint. Change in the 


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Number of global amendment
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expected event rate from 50% to 55%, resulted in 
the reduction of sample size.
Section to be changed
Flow Chart A
Description of change 2
Clinic visit 11 replaced with a phone visit.
Footnote #16, added the following: during the 
phone call, any adverse events and concomitant 
therapy will be checked, and any change in asthma 
medication entered in the asthma medication log 
will be verified.
Rationale for change
In order to reduce the burden of multiple clinic 
visits for the patient during the follow-up period, 
Visit 11 at week 36 (16 weeks after the last dose of 
study drug) was converted to a phone visit.
Section to be changed
Flow Chart A
Description of change 3
Removal of AQLQ administration
Rationale for change
Being a proof-of-concept Phase 2a study, data from 
AQLQ may not add much value.  To reduce some 
burden on the patient during clinic visits, the 
questionnaire was removed.
Section to be changed
Description of change 4
 
 
 
 
Rationale for change
 
 
 
 
Section to be changed
Flow Chart A, Footnotes
Description of change 5
Serum pregnancy added to Visit 1B for women of 
child bearing potential.
Rationale for change
To ensure exclusion of patients who are pregnant.  
Also, this was a request made by regulatory 
authorities.


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Section to be changed
Description of change 6
 
 
 
 
 
Rationale for change
 
 
Section to be changed
Description of change 7
 
 
Rationale for change
 
Section to be changed
Section 3.3.2
Section 5.2.1
Description of change 8
Section 3.3.2:
Inclusion criterion #6: first part of severe asthma
exacerbation definition:
Severe asthma exacerbation is defined as initiation 
of systemic corticosteroids: oral (prednisone or 
equivalent) or i.v. for 3 or more consecutive days, 
or a single i.m dose for asthma.
Changed to:
Severe asthma exacerbation is defined as initiation 
of systemic corticosteroids: (prednisone or 
equivalent) for 3 or more consecutive days for 
asthma.


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Number of global amendment
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Section 5.2.1
Definition of severe asthma exacerbation changed
to be consistent with the definition for the same in 
Section 3.3.2
Rationale for change
To be consistent with ATS/ERS definitions.
Section to be changed
Section 3.3.3, Exclusion Criteria #12
Description of change 9
Women of childbearing potential that, if sexually 
active, are unwilling to use a highly effective 
method of birth control which results in a low 
failure rate (i.e. less than 1% per year) when used 
consistently and correctly from date of screening 
until 20 weeks after last dosing with study 
medication in this trial.  Highly effective methods 
of birth control include: ethinyl estradiol containing 
contraceptives, diaphragm with spermicide 
substance, intra-uterine device, and male 
sterilization.
Changed to:
Women of childbearing potential must be ready 
and able to use highly effective methods of birth 
control per ICH M3 (R2) that result in a low 
failure rate of less than 1% per year when used 
consistently and correctly. A list of contraception 
methods meeting these criteria is provided in the 
patient information.
Rationale for change
To allow having a comprehensive list of highly 
effective methods of birth control (available locally 
and aligned with local regulations) in the “patient 
information”.  This change was also requested by 
regulatory authorities.
Section to be changed
Section 3.3.3
Description of change 10
Added the following exclusion criterion:
History of allergy/hypersensitivity to a systemically 
administered biologic agent or its excipients, or a 
known hypersensitivity to β-adrenergic 
medications.
Rationale for change
To exclude patients who are at high risk.  The 
addition of this exclusion criterion was also 
requested by regulatory authorities.
Section to be changed
Section 3.3.4


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Number of global amendment
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Description of change 11
Added:
Investigator may discontinue a patient from the 
study for any unexpected medical conditions that 
could compromise patient safety.
Rationale for change
Additional criterion added to ensure patient safety.  
The addition of this criterion was also requested by 
regulatory authorities.
Section to be changed
Description of change 12
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale for change
 
 
 


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Section to be changed
Section 5.1.3
Description of change 13
Removal of endpoints related to AQLQ
Rationale for change
AQLQ administration was removed from the study.
Section to be changed
Section 5.2.2
Description of change 14
Section 5.2.2, paragraph 3: 
Data and measurements collected in the E-diary 
will be automatically transferred to a central ERT 
(vendor) server at a designated time, once every 
day as technically feasible.  The daily transfer will 
depend on the availability of the technology in the 
region, and wireless capabilities at the patient’s 
location.
Changed to:
Data and measurements collected in the E-diary 
will be automatically transferred to a central 
server (ERT) each time the patient has completed 
an assessment on the E-diary.  The automated 
transfer will depend on the availability of the 
technology in the region, and wireless capabilities 
at the patient’s location.  If the automated transfer 
cannot be completed due to low wireless 
capabilities, the collected data will be stored in the 
E-diary and submitted during the next automated 
transfer after a completed assessment, once 
wireless connection is available.  The E-diary also 
tries to connect to the central server (ERT) once a 
day to send a confirmation signal that the device is 
working properly: if there should be any data 
available on the device from previous session(s) 
that were not transmitted due to connection issues, 
this data will be transferred at this time.
Rationale for change
The timing of the automatic transfer of data from 
patient E-diary to the central server is corrected.
Section to be changed
Table 5.3.3: 1
Description of change 15
a) Urine Pregnancy test (only for female patients of 
childbearing potential) at the clinic, for all scheduled
clinic visits except Visit 1A.
Changed to:
Urine Pregnancy test (only for female patients of 
childbearing potential) at the clinic, for all scheduled 
clinic visits except Visit 1A and Visit 1B.


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b) Urobilinogen test removed from the urinalysis
Rationale for change
a) Urine pregnancy test not required at Visit 1B as 
serum pregnancy test is done.
b) Direct bilirubin is quantitatively measured as 
part of the chemistry profile. 
Section to be changed
Description of change 16
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Rationale for change
 
 
 
 
Section to be changed
Description of change 17
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Number of global amendment
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Rationale for change
 
 
 
Section to be changed
Description of change 18
 


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
 
  
 
 
 
 
 
 
 
 
 
 
 
Rationale for change
 
 
 
 
 
Section to be changed
Description of change 19
 
 
 
 
 
 
 
 
 


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Rationale for change
 
 
Section to be changed
Description of change 20
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Rationale for change
 
 
 
 
 
 
Section to be changed
Description of change 21
Rationale for change
 
Section to be changed
1) Footnotes for Flow Chart A
3) Abbreviations
5) Section 2.3
6) Section 3.1
7) Section 3.3.2
9) Section 4.1.4
10) Section 5.2.2
11) Section 5.2.2
12) Section 5.2.2
13) Section 5.3.3
14) Table 5.3.3: 1
15) Section 5.5
16) Section 6.1
17) Section 6.1
18) Section 6.1
19) Section 6.1
20) Section 6.2.2
21) Section 6.2.3
22) Section 7.1
23) Section 7.3.3
24) Section 7.5


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Description of change 22
1) Footnote #5 now indicates that urine pregnancy 
test will not be done for Visit 11.
Footnote #6: Added “the primary cytospin slides 
should be”.  Footnote on AQLQ deleted.  In 
footnote #12, “PFT measurements should be 
completed” changed to “PFT measurements 
should be started”. Footnote #16 now states that 
Visit 11 is a phone visit.
2) In the column “event and comment”, BI 655066 
administration was changed to BI 655066/Placebo 
administration.  Visit 11 is marked as “NA, Phone 
visit”.
3) AQLQ removed from the abbreviation list.
 
 
 
 
 
 
5) In Section 2.3, paragraph 2, “no additional 
potential additional” changed to “no additional 
potential”.
6) In Section 3.1, paragraph 2, “and trial database 
is locked” was added in the last sentence.
7) In Section 3.3.2, inclusion criteria #3, “Global 
Lung Function” changed to Global Lung Function 
Initiative”.
 
9) In Section 4.1.4, first paragraph, Patients will be 
seen at the clinic at week 28, 32, 36, and 40 during 
the follow-up period


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Changed to
Patients will be seen at the clinic at week 28, 32, 
and 40 and a phone call at week 36 during the 
follow-up period.
10) In Section 5.2.2, the section on AQLQ is 
deleted.
11) In Section 5.2.2, in the section on Pulmonary 
Function Tests, paragraph 2, “At Visits 3 to 12” 
changed to “At clinic visits (from Visit 3 
onwards)”.
12) In Section 5.2.2, in the section on Pulmonary 
Function Tests, paragraph 3, “At Visits 2 to 12” 
changed to “At Visits 2 to 10 and at Visit 12”
13) In Section 5.3.3, paragraph 1, “The laboratory 
tests listed in Table 5.3.3: 1 will be performed at 
the central laboratory service provider”.
Changed to:
“The laboratory tests listed in Table 5.3.3: 1 will be 
performed at the central laboratory service 
provider, except urine pregnancy test and urinalysis 
(Stix) that will be performed at the study site”.
14) In Table 5.3.3: 1, “Serum Pregnancy test (only 
when urine pregnancy test is positive)”
Changed to:
“Serum Pregnancy test at screening (Visit 1B) and 
when urine pregnancy test is positive”
15) In Section 5.5, in the section “Methods of 
Sample Collection”, Sputum will be collected via 
sputum induction procedures described in the 
manual.
Changed to:
Sputum will be collected via sputum induction 
procedures described in the sputum induction and 
processing manual.
16) In section 6.1, “Visits 3 to 12”
Changed to:
“Visits 3 to 12, with Visit 11 as a phone visit”
17) In Section 6.1, in the section on “Medication 
washout”


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For all other visits (Visit 2 to 12), rescheduling is 
not necessary for lack of medication washout.  
Medication washout checklist provided in the ISF 
must be completed at each clinic visit. If 
medication washout requirements (Section 4.2.2) 
are not met (for Visits 2 to 12) it should be 
recorded in the eCRF.  Pre- and post-
bronchodilator PFT measurements will be 
performed during Visits 2 to 12 even if medication 
washout criteria are not met.
Changed to:
For all other clinic visits, rescheduling is not 
necessary for lack of medication washout.  
Medication washout checklist provided in the ISF 
must be completed at each clinic visit. If 
medication washout requirements (Section 4.2.2) 
are not met it should be recorded in the 
Masterscope®.  Pre- and post-bronchodilator PFT 
measurements will be performed during clinic 
visits (except Visit 1B) even if medication washout 
criteria are not met.
17) In Section 6.1, in the section on “Rescheduling 
clinic visits after randomization”
If a clinic visit after Visit 2 is out of the time 
window allowed by the protocol, subsequent visits 
should occur at the originally scheduled date to 
ensure a 24-week treatment period, and a 16-week 
follow-up period.  Any clinic visits outside the time 
window allowed by the protocol should be 
discussed with the Local Clinical Monitor.
Changed to:
If a clinic visit after Visit 2 and the phone call at 
Visit 11 is out of the time window allowed by the 
protocol, subsequent visits should occur at the 
originally scheduled date to ensure a 24-week 
treatment period, and a 16-week follow-up period.  
Any visits outside the time window allowed by the 
protocol should be discussed with the Local 
Clinical Monitor.  
18) In Section 6.1, in the section on “Rescheduling 
clinic visits after randomization”, paragraph 2:
All clinic visits should be completed at the time 


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window allowed in the protocol.  
Changed to:
All clinic visits and the phone call at Visit 11
should be completed at the time window allowed in 
the protocol.  
19) In Section 6.1, in the section on “Pregnancy 
tests”, the following sentence is added:
All women of child bearing potential will undergo 
serum pregnancy test at the screening visit (Visit 
1B).  Patients who test positive for the serum 
pregnancy test will be excluded from the study.  
20) In Section 6.2.2, in the section 
“Discontinuation during treatment period”
After completing the EOT visit, patients should be 
allowed to enter the follow-up period of 16 weeks, 
and they will complete the four clinic visits and the 
associated procedures ending in the End of 
Observation (EOO) visit.
Changed to:
After completing the EOT visit, patients should be 
allowed to enter the follow-up period of 16 weeks, 
and they will complete the four visits (Visit 11 is a 
phone visit) and the associated procedures ending 
in the End of Observation (EOO) visit.
21) In section 6.2.3, 
Clinic visits will be scheduled every 4 weeks 
(Visits 9 to 12). 
Changed to:
Visits will be scheduled every 4 weeks (Visits 9 to 
12, Visit 11 being a phone visit). 
22) In Section 7.1, the text related to AQLQ is 
deleted.
23) In Section 7.3.3, the text related to AQLQ is 
deleted.
24) In Section 7.5, the text related to AQLQ is 
deleted.


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Number of global amendment
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Rationale for change


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Date of CTP revision
04 December 2015
EudraCT number
2014-004932-20
BI Trial number
1311.14
BI Investigational Product(s)
BI 655066
Title of protocol
A phase IIa, randomized, double-blind, placebo 
controlled, parallel group study to assess the safety 
and efficacy of subcutaneously administered BI 
655066 as add-on therapy over 24 weeks in 
patients with severe persistent asthma.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
☐
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
☐
Can be implemented without
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
☒
Section to be changed
Section 3.3.3
Description of change 1
Exclusion criterion 12
Women of childbearing potential must be ready 
and able to use highly effective methods of birth 
control per ICH M3 (R2) that result in a low failure 
rate of less than 1% per year when used 
consistently and correctly. A list of contraception 
methods meeting these criteria is provided in the 
patient information.
Changed to
Women of childbearing potential must be ready 
and able to use highly effective methods of birth 
control per ICH M3 (R2) that result in a low failure 
rate of less than 1% per year when used 
consistently and correctly from date of screening 
until 20 weeks after last dosing with study 
medication in this trial. A list of contraception 
methods meeting these criteria is provided in the 
patient information.


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Rationale for change 1
Clarification that birth control use must continue 
for the 20 weeks after the last dose of study 
medication.


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Number of global 
amendment
3
Date of CTP revision
11 July 2016
EudraCT number
2014-004932-20
BI Trial number
1311.14
BI Investigational 
Product(s)
BI 655066
Title of protocol
A phase IIa, randomized, double-blind, placebo 
controlled, parallel group study to assess the safety and 
efficacy of subcutaneously administered BI 655066
(risankizumab) as add-on therapy over 24 weeks in 
patients with severe persistent asthma.
To be implemented only 
after approval of the IRB / 
IEC / Competent 
Authorities
☒
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
☐
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes 
involve logistical or 
administrative aspects only
☐
Section to be changed
Throughout the document
Description of change 1
BI 655066 changed to risankizumab
Rationale for change 1
New name for BI 655055 added for completeness
Section to be changed
Flow Chart A (Footnote #1)
Section 6.1
Description of change 2
Screening period is defined as the period between Visit 
1B and Visit 2.
Rationale for change 2
Clarification
Section to be changed
Synopsis
Section 3.3
Section 7.2
Section 7.4
Section 7.7
Description of change 3
Total number of patients, and patients entered changed
from 270 to 200, Patients in each treatment changed
from 135 to 100.


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3
Change in statistical parameters and sample size
calculations.
In Section 7.4, “interim analyses will be performed” 
changed to “interim analyses may be performed”.
Rationale for change 3
The sample size for the study was re-evaluated in the 
context of an initial exploratory proof of concept study to 
investigate efficacy and effects in subsets of patients. The 
type-I error was changed from a confirmatory alpha of 
0.05 to 0.1 (1-sided). A change in the type-I error 
resulted in the reduction of sample size.
Change in Section 7.4 still allows the conduct of interim 
analyses.
Section to be changed
Synopsis
Section 3.3.2
Description of change 4
A minimum of one year history of asthma, diagnosed by 
a physician, and have FEV1 reversibility of at least 12% 
and an absolute change of at least 200 mL starting within 
15 to 30 minutes after administration of 400 µg 
salbutamol (albuterol) at the screening Visit 1B (see 
Appendix 10.1).  If reversibility cannot be achieved,
documented evidence of reversibility in the 12 months 
prior to the screening visit is acceptable.
Note: Reversibility testing can be repeated twice 
during the screening period if reversibility cannot 
be achieved at the screening visit and if 
documented evidence of historic reversibility (in 
the past 12 months) is not available.
Changed to
A minimum of one year history of asthma, diagnosed by 
a physician, and have FEV1 reversibility as 
defined by an improvement in FEV1 ≥12% and
an absolute change of at least 200 ml starting 
within 15 to 30 minutes after administration of 
400 µg salbutamol (albuterol) via 
MDI. Reversibility testing is performed at the 
screening Visit (Visit 1B). 
If reversibility criteria are not met, the patient 
may still be randomized if there is:

Documented evidence of reversibility 
with improvement in FEV1 ≥12% above 
baseline and an absolute increase of at 
least 200 ml in the 2 years prior to Visit 


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2 (randomization visit)
         or

Documented evidence of airway 
hyperresponsiveness (methacholine: 
PC20 of <8 mg/mL) in the 2 years prior 
to Visit 2 (randomization visit)
         or

Documented evidence of airflow 
variability in clinic FEV1 ≥20% between 
two clinic visits documented in the 12 
months prior to visit 2 (randomization 
visit).
If reversibility criteria are not met at Visit 1B and if any 
of the above historic data are not available, reversibility 
testing can be repeated up to twice during screening 
period at separate visits. For the first retest, 400 µg 
salbutamol via MDI should be used, and for the second 
retest, up to 800 µg salbutamol via MDI or 2.5 mg 
nebulized albuterol should be used.  Reversibility testing 
must not occur on the day of randomization.  Additional 
guidelines for reversibility testing can be found in 
Appendix 10.1.
Rationale for change 4
To align with current GINA guidelines and current 
practice for reversibility testing in a severe asthma 
patient population with higher degree of fixed airflow.  
History of reversibility increased to allow as reversibility 
testing not routinely performed yearly for this patient 
population with diagnosis of asthma over many years.
Section to be changed
Synopsis
Section 3.3.2
Description of change 5
Patients must be on at least medium dose ICS (Table 
10.1: 1), and at least one other asthma controller 
medication for at least one year prior to the date 
of screening.  Asthma therapy must have been 
documented and must be stable for at least 6 
weeks prior to the date of screening.
Changed to,
Patients must be on at least medium dose ICS (Table 
10.1: 1), and at least one other asthma controller 
medication for at least one year prior to the date 
of screening.  Asthma therapy must have been 
documented and must be stable for at least 4 


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weeks prior to the date of screening.
Rationale for change 5
The requirement for 6 weeks of stable medication was 
changed to 4 weeks to reflect the treatment practice for 
severe asthma patients with frequent exacerbations 
requiring medication adjustments to achieve control.
Number of global 
amendment
3
Section to be changed
Synopsis
Section 3.3.2
Description of change 6
Patients must have documented history of two or more 
severe asthma exacerbations in the 12 months prior to the 
date of screening, but not within 6 weeks prior to 
screening.
Changed to
Patients must have documented history of at least one of 
the following criteria: a) two or more severe asthma 
exacerbations in the last 12 months, or b) one severe 
asthma exacerbation in the last 12 months requiring
hospitalization or emergency room visit, or c) one severe 
asthma exacerbation in the last 6 months not requiring 
hospitalization or emergency room visit, prior to the date 
of screening visit (Visit 1B).  Patients must not have a 
severe asthma exacerbation in the 6 weeks prior to 
screening visit.  Patients with only one severe asthma 
exacerbation in the last 6 months (category c, but not a or 
b) will be limited to approximately 25% of the total 
patient population.
Rationale for change 6
To allow patients with a history of less than 2 
exacerbations in the previous year but at the same time 
where asthma is still not adequately controlled.
Section to be changed
Section 3.1
Section 3.2
Section 7.3.1
Section 7.6
Description of change 7
Description of severe asthma exacerbation history related 
to inclusion criterion # 6
Rationale for change 7
Clarification in sections impacted by change in inclusion 
criterion #6.
Section to be changed
Section 9.1
Section 9.2
Description of change 8
References R04-1001 and R08-0092 deleted.
Reference updated with the revised version of the 


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investigator’s brochure
Rationale for change 8
References that were not applicable are deleted.
Current version of the investigator’s brochure referenced
Section to be changed
Appendix 10.1
Description of change 9
Additional instructions provided for reversibility testing
Rationale for change 9
Additional instructions needed as the inclusion criteria 
for reversibility testing was changed.


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Date of CTP revision
13 October 2016
EudraCT number
2014-004932-20
BI Trial number
1311.14
BI Investigational Product(s)
BI 655066
Title of protocol
A phase IIa, randomized, double-blind, placebo 
controlled, parallel group study to assess the safety 
and efficacy of subcutaneously administered BI 
655066/ABBV-066 (risankizumab) as add-on 
therapy over 24 weeks in patients with severe 
persistent asthma.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
☐
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
☐
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
☒
Section to be changed
Title page, Synopsis
Description of change 1
Changed BI drug or BI investigational product or 
BI 655066 to refer to either names for this 
compound:   BI 655066/ ABBV-066/risankizumab
Rationale for change
In February 2016, AbbVie entered into a license 
agreement with BI related to risankizumab, and in 
October 2016, the US IND for risankizumab 
transitioned from BI to AbbVie.   This protocol 
change reflects that AbbVie will now be the 
Sponsor of this study in the US, as well as the 
modifications to certain study conduct 
responsibilities as a result of that license agreement 
are listed as separate changes below.
Section to be changed
Section 3.1.1
Description of change 2
Changed sponsor from Boehringer Ingelheim (BI)
to AbbVie in the US and BI for all other 
participating countries.
Rationale for change
Refer to rationale for change 1
Section to be changed
Section 3.3.4.2
Description of change 3
Updated text to: “AbbVie/Boehringer Ingelheim 
reserves the right to discontinue the trial overall or 


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at a particular trial site at any time for the following 
reasons”.
Rationale for change
Refer to rationale for change 1
Section to be changed
Description of change 4
 
 
 
 
 
Rationale for change


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Number of global amendment
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Date of CTP revision
17 August 2017
EudraCT number
2014-004932-20
BI Trial number
1311.14
BI Investigational Product(s)
BI 655066
Title of protocol
A phase IIa, randomized, double-blind, placebo 
controlled, parallel group study to assess the safety 
and efficacy of subcutaneously administered BI 
655066/ABBV-066 (risankizumab) as add-on 
therapy over 24 weeks in patients with severe 
persistent asthma.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
☒
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
☐
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
☐
Section to be changed
Protocol Synopsis, Sections 5.1.2, 5.1.3, and 5.2.
Description of change 1
Asthma worsening criteria (ACQ5): increase of 0.5 
units from baseline changed to 0.75 units.  
Addition of secondary and further endpoints.  
Addition of “alternative definitions 1 and 2” for 
asthma worsening in Section 5.2.
Rationale for change
The event rate of asthma worsening and the time to 
first asthma worsening were monitored in a blinded 
manner during the course of the study.  With a 0.5 
units change from baseline in ACQ5, the event rate 
and the number of asthma worsening events were 
primarily driven by change in the ACQ5 score.
Section to be changed
Section 7.3
Description of change 2
Only one stratification factor – OCS use at baseline 
will be included in the primary model as a fixed 
effect. In Section 7.3.2, using baseline ACQ5 as a 
continuous covariate is not a change but a 
clarification.
Rationale for change
The statistical model for analysis of primary,
secondary, and further endpoints include all the 
stratification factors as fixed effects. However, the 


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numbers of patients in one level of two 
stratification factors, i.e., 
 
 with only one 
exacerbation not requiring hospitalization in the 
past 6 month are very low (approximately 10).
Section to be changed
Sections 1.2.2, 1.2.3, 8.4.1, and 9.2
Description of change 3
Reference to Investigator’s Brochure has been 
updated to reflect the current version.
Rationale for change
The study is conducted under the current version of 
the Investigator’s Brochure.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03185695
7.0
clinical-trial-protocol-version-06
A phase IIa, randomized, double-blind, placebo controlled, parallel group study to
assess the safety and efficacy of subcutaneously administered BI 655066
(risankizumab) as add-on therapy over 24 weeks in patients with severe persistent
asthma.
Author-Trial Clinical Monitor
18 Aug 2017 15:08 CEST
Approval-Biostatistics
18 Aug 2017 15:23 CEST
Approval-Therapeutic Area 
18 Aug 2017 15:32 CEST
Author-Trial Clinical
Pharmacokineticist
18 Aug 2017 15:53 CEST
Approval-Team Member Medicine
18 Aug 2017 17:46 CEST
Verification-Paper Signature
Completion
18 Aug 2017 20:06 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03185695
7.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c03567142-01
BI Trial No.:
1311.14
Title:
A phase IIa, randomized, double-blind, placebo controlled, parallel 
group study to assess the safety and efficacy of subcutaneously 
administered BI 655066/ABBV-066 (risankizumab) as add-on 
therapy over 24 weeks in patients with severe persistent asthma.
Including Protocol Amendment 5 [c03185695-07].  
Investigational
Product(s):
BI 655066
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
26 OCT 2017 SIGNED
Version:
Final
Page 1 of 23
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2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................3
2.
LIST OF ABBREVIATIONS ...............................................................4
3.
INTRODUCTION..................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......7
5.
ENDPOINT(S)........................................................................................8
5.1
PRIMARY ENDPOINT ......................................................................................8
5.2
SECONDARY ENDPOINTS..............................................................................8
5.2.1
Key secondary endpoints................................................................................8
5.2.2
(Other) Secondary endpoints .........................................................................8
5.4
OTHER VARIABLES.........................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS...........................................10
6.1
TREATMENTS..................................................................................................10
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................10
6.3
PATIENT SETS ANALYSED..........................................................................13
6.5
POOLING OF CENTRES ................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................15
7.
PLANNED ANALYSIS.......................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........16
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................16
7.3
TREATMENT COMPLIANCE .......................................................................16
7.4
PRIMARY ENDPOINT(S) ...............................................................................17
7.5
SECONDARY AND FURTHER ENDPOINTS..............................................17
7.5.1
Key secondary endpoints..............................................................................17
7.5.2
(Other) Secondary endpoints .......................................................................17
7.7
EXTENT OF EXPOSURE................................................................................19
7.8
SAFETY ANALYSIS.........................................................................................19
7.8.1
Adverse events ...............................................................................................19
7.8.2
Laboratory data.............................................................................................20
7.8.3
Vital signs.......................................................................................................20
7.8.4
ECG ................................................................................................................20
7.8.5
Others .............................................................................................................20
 
8.
REFERENCES.....................................................................................21
10.
HISTORY TABLE...............................................................................23


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LIST OF TABLES
Table 6.2: 1
Important protocol violations...........................................................................11
Table 10: 1
History table .....................................................................................................23


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP
Term
Definition / description
AE
Adverse event
ALQ
Above the assay limit of quantification
ANCOVA
Analysis of Covariance
BLQ
Below the assay limit of quantification
BMI
Body mass index
BRPM
Blinded report planning meeting
CML
Clinical Monitor Local
CRA
Clinical Research Associate
CRF
Case report form
CTP
Clinical Trial Protocol
DBL
Database lock
DCC
Differential Cell Counts
EMEA
European Agency for the Evaluation of Medicinal Products
EoT
End-of-Text
FAS
Full analysis set
ICH
International Council for Harmonisation
GCP
Good clinical practice
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical Quality Review Meeting
NGAL
Neutrophil gelatinase-associated lipocalin
PFT
Pulmonary function test
PT
Preferred term
PV
Protocol violation
RS
Randomised set
SD
Standard deviation


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Term
Definition / description
SOC
System organ class
TSAP
Trial statistical analysis plan
VEGF
Vascular endothelial growth factor


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, and randomization.
SAS® Version 9.4 will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
In section 7.3 of CTP, it indicates that a 95% confidence interval for annualized rate of 
asthma worsening will be presented, however since the sample size calculation is based on a 
1-sided type-I error α = 0.1, an 80% confidence interval will be presented instead.


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT
The primary endpoint of this study is time to first asthma worsening (in days) during the 
planned 24-week treatment period as defined in section 5.2 of CTP.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints 
This section is not applicable as no key secondary endpoints have been specified in the 
protocol.
5.2.2
(Other) Secondary endpoints
The secondary endpoints are defined in section 5.1.2 of CTP.
5.4
OTHER VARIABLES
Demographics and other baseline characteristics

Age, weight, height, race, ethnicity, gender, BMI, smoking history, smoking pack 
years

History of asthma

Concomitant asthma medication

Asthma background characteristics

Sputum cell counts  (absolute and differential) at baseline

Asthma phenotype

Asthma endotype

Lung function measurements at screening and baseline

E-diary measurements at baseline
 
 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
Patients will be randomised at a ratio of 1:1 to one of the following treatment groups:
1. 90 mg BI 655066 administered SC every 4 weeks, up to a total duration of 20 weeks.
2. Placebo administered SC every 4 weeks, up to a total duration of 20 weeks.
The following treatment period will be defined:

Screening period: from the date of informed consent to the date of randomisation -1 
day.

Planned on-treatment period: 24 weeks from the date of randomisation

Planned study period: 40 weeks from the date of randomisation

Actual on-treatment period  
 

Post-treatment period  
 
 

Post-study period: from 20 weeks + 1 day after last dose onwards
6.2
IMPORTANT PROTOCOL VIOLATIONS
A PV is important if it affects the rights or safety of the study subjects or if can potentially 
influence the primary outcome measurement(s) for the respective subjects in a way that is 
neither negligible nor in accordance with the study objectives.
The following table defines the different categories of important PVs. They will be reviewed 
at Medical Quality Review Meetings (MQRMs) conducted periodically based on data 
accumulated during the trial. A list of protocol deviations and of unresolved discrepancies 
will be discussed at the Blinded Report Planning Meetings (BRPMs). The decision whether 
the protocol deviation is an important PV will be made at the final BRPM prior to database 
lock (DBL).


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Table 6.2: 1
Important protocol violations
Category/Code
Description
Example/Comment
Excluded 
from
Automatic / 
Manual
A
Entrance criteria 
not met
A1.1
Age < 18 or >75
Inclusion criteria 2
None
Automatic
A1.2
Pre-bronchodilator 
FEV1 not met at 
Visit 1B or Visit 2
Inclusion criteria 3
None
Automatic
A1.3
History of asthma , 
or FEV1
reversibility not met 
at visit 1B
Inclusion criteria 4
None
Automatic
A1.4
Previous asthma 
therapy not met
Inclusion criteria 5
None
Automatic
A1.5
History of severe 
asthma 
exacerbation not 
met
Inclusion criteria 6
None
Automatic
A1.6
Current smoker; ex-
smoker who 
stopped smoking 
within one year 
prior to screening or 
have a smoking 
history >=10 pack 
years
Inclusion criteria 7
None 
Automatic
A1.7
Not able to perform 
all trial related 
procedures
Inclusion criteria 8
None
Automatic
A2.1
Not able to produce 
sputum, or sputum 
samples of 
insufficient quality
Exclusion criteria 4
None
Automatic
A2.2
Oral corticosteroids 
use criteria not met
Exclusion criteria 10; Systemic 
corticosteroids CRF
None
Automatic
A2.3
Other exclusion 
criteria not met
Other exclusion criteria not met as 
specified in the protocol
None
Automatic
B
Informed consent
B1
Informed consent 
not available/not 
done
Informed consent date missing; no 
signature on ICF
All
Automatic 
and Manual
B2
Informed consent 
too late
Applies to all informed consents. Date 
of informed consent was after the date 
of any study-related procedure, i.e., 
after visit 1A. If patient signed the 
wrong version of ICF and then signed 
None
Automatic 
and Manual


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Category/Code
Description
Example/Comment
Excluded 
from
Automatic / 
Manual
the correct version of ICF with date 
after randomisation, such cases will be 
discussed at MQRM/BRPM/DBL 
meetings.
C
Trial medication 
and randomisation
C1.1
Incorrect trial 
medication taken at 
randomisation
Medication kit assigned not matching 
IVRS assignment at randomisation visit 
(Visit 2)
None
Automatic 
and Manual
C1.2
Incorrect trial 
medication taken
after randomisation
Medication kit assigned not matching 
IVRS assignment after randomisation 
visit (Visit 3 and onwards)
None
Automatic 
and Manual
C2
Non-compliance
C2.1
Interval of two 
infusions of study 
medications <14 
days
Patient did not meet minimum interval 
required for two consecutive infusions 
None
Automatic
C2.2
E-diary non-
compliance at 
baseline
Baseline E-diary compliance < 75% or 
< 2 ACQ5 sessions available
None
Automatic
C2.3
Missing 
administration of 
study drug 
Patients missing doses due to any 
reason
None
Automatic
C3
Medication code 
broken 
inappropriately
To be discussed and decided during 
MQRM/BRPM
None
Manual
D
Concomitant 
medication
D1
Restricted 
medication use
Refer to Table 4.2.2.1: 1 in CTP.
None
Manual
Z
Other
Z1
Serious GCP non-
compliance
Manual PVs reported by CML/CRA. 
Decision to be made during 
MQRM/BRPM
None
Manual
Z2
Other PV affecting 
efficacy and 
possibly safety
Additional PV identified through 
monitoring which impacts the primary 
analysis and possibly patient’s rights or 
safety, e.g., patients on non-stable dose
To be discussed during MQRM/BRPM
None
Manual
Z3
Other PV affecting 
safety only
None
Manual


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6.3
PATIENT SETS ANALYSED

Randomised set (RS):
This patient set includes all randomised patients, whether treated or not.

Full analysis set (FAS):
This patient set includes all patients in the randomised set who receive at least one 
dose of investigational treatment.
 
 
The RS will be used for patient disposition, demographic, and baseline characteristics. 
The FAS will be used for the primary efficacy evaluation and all safety evaluations.
 
 
 


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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
E-diary data
The 24-hour rescue medication use (AM + PM) will be calculated for each day by adding the 
AM and PM puffs. An interval (AM or PM) that is missing leads to a missing 24-hour total 
and will be used as missing when calculating the weekly mean.
In-clinic pulmonary function testing data
If a patient takes rescue medication at a clinic visit before pre-bronchodilator pulmonary 
function tests (PFT), any measurements taken on and after the time of the rescue medication 
use will be set to missing. If the time of rescue medication use is unknown, data for the entire 
visit will be set to missing. If a patient takes rescue medication at a clinic visit after pre-
bronchodilator PFTs, the measurements taken on and after the time of rescue medication use 
will be used. 
Concomitant medication dates 
The imputation rules will be described in the technical TSAP. 
AE dates
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”). (1)


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Sputum cell counts
Missing sputum cell count data will not be imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The definition of baseline values is defined in Section 7.1 of the CTP.
 
 


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max. 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient 
set whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category “missing” will be displayed only if there are actually missing values.
 
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
A table of the number (%) of patients with concomitant diagnoses by system organ class 
(SOC) and preferred term (PT) will be included along with a supporting listing. Concomitant 
diagnoses will be coded with the most recent version of MedDRA in effect at database lock.
Frequency tables (%) will be presented for medical history of interest and asthma background 
characteristics.
Pulmonary medication will be summarized as the number (%) of patients taking pulmonary 
medications at baseline. The number (%) of patients who have dose reduction in maintenance 
therapy will also be summarized. 
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
Treatment compliance (%) = number of drug administrations / [(date of last drug 
administration – date of first drug administration) / 28 + 1] * 100%
E-diary compliance (%) for PEF = (number of PEF sessions / 2) / (date of discontinuation 
from the study – date of randomisation + 1) * 100%
E-diary compliance (%) for rescue medication = (number of rescue medication record / 2) / 
(date of discontinuation from the study – date of randomisation + 1) * 100%


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E-diary compliance (%) for ACQ5 = number of ACQ5 record / [(date of discontinuation from 
the study – date of first drug administration) / 7 + 1] * 100%
7.4
PRIMARY ENDPOINT(S)
The analyses of primary endpoint will be performed as described in section 7.3.1 of CTP.
 
 
 
 
 
 
7.5
SECONDARY AND FURTHER ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
(Other) Secondary endpoints
The analyses of secondary endpoints will be performed as described in section 7.3.2 of CTP.
 
 
 
 


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7.7
EXTENT OF EXPOSURE
Extent of exposure, including days on treatment, follow-up time and observation time, will be 
summarized using descriptive statistics for days of exposure as well as number (%) of 
patients whose exposure falls in the categories with 4-week intervals.
On treatment (days) = drug stop date – drug start date + 28
Follow-up time (days) = max(0, date of discontinuation from the study – drug stop date – 28)
Observation time (days) = date of discontinuation from the study – drug start date + 1
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the FAS. 
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of patients with AEs and NOT on the number of 
AEs.
Furthermore, for analysis of AE attributes such as duration, severity, etc., multiple AE 
occurrence data on the CRF, will be collapsed into AE episodes provided that all of the 
following applies:
•
The same MedDRA lowest level term was reported for the occurrences
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)
•
Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence
For further details on summarization of AE data, please refer to the guideline 'Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries' (3) 
[001-MCG-156].
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake till 130 days 


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after last drug intake will be assigned to the randomised treatment. All adverse events 
occurring before first drug intake will be assigned to ‘screening’ and all adverse events 
occurring after last drug intake + 130 days will be assigned to ‘post-treatment’ (for listings 
only). For details on the treatment definition, see Section 6.1.
An overall summary of adverse events will be presented.
The frequency of patients with adverse events will be summarised by treatment, primary SOC
and PT. Separate tables will be provided for patients with other significant adverse events 
according to ICH E3 (4), and for patients with serious adverse events.
The SOCs will be sorted according to the standard sort order specified by EMEA, PTs will be 
sorted by frequency (within SOC).
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (5).
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
ECGs were collected with an adverse event recorded if the readout was associated with any 
clinical finding.
7.8.5
Others
Not applicable, there are no other safety analyses.
 
 
 
 
 
 


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8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
 
 
3
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON.
4
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version.
5
001-MCG-157: "Display and Analysis of Laboratory Data", current version, IDEA 
for CON.
 


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
26-Oct-17
None
This is the final TSAP without any 
modification