A Multicenter, Open-Label, Non-Randomized Study to Assess the Pharmacokinetics, Tolerability, and Safety of a Single Subcutaneous Administration of Icatibant in Children and Adolescents With Hereditary Angioedema
Phase: PHASE3
Conditions: Hereditary Angioedema (HAE)
Sponsor: Shire

Cli nic al Tr i al Prot oc ol:  H G T- FI R-0 8 6
St u d y Title:
A M ultice nter, O pe n -La bel, N o n -Ra n d o mize d St u d y  t o Assess t he 
P har mac o ki netics, T olera bilit y , a n d Safety of a Si n gle S u bc uta ne o us 
A d mi nistrati o n of Icati ba nt i n C hil dre n a n d A d olesce nts wit h 
Here ditar y  A n gi oe de ma
St u d y N u m ber:
H G T -FI R- 0 8 6
St u d y P h ase:
III
Pr o d uct N a me:
Icati ba nt ( Firazyr ® )
I n dic ati o n:
Here ditar y  a n gi oe de ma
I n vesti g at ors:
M ultice nter
S p o ns or:
S hire Or p ha n T hera pies, I nc.
S p o ns or C o nt act:
3 0 0 S hire Wa y  
Le xi n gt o n, M A  0 2 4 2 1 U S A
Me dic al M o nit or:
 M D, P h D
S hire H u ma n Ge netic T hera pies ( H G T), I nc.
M o bile:  
 
Date
Ori gi n al Pr ot oc ol:
1 4 J u ne 2 0 1 1
A m e n d me nt 1
0 5 A u g ust 2 0 1 1
A m e n d me nt 2
0 6 Marc h 2 0 1 2
A m e n d me nt 3
1 9 J u ne 2 0 1 3 
C o nfi de nti alit y St ate me nt
T his d oc u me nt is t he pr o prietar y  a n d c o nfi de ntial pr o perty of 
S hire H u ma n Ge netic T hera pies, I nc.  
P P D
P P D
P P D

Icatibant (Firazyr®)
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SYNOPSIS
Sponsor:
Shire Orphan Therapies, Inc.
Name of Finished Product:
Icatibant (Firazyr®)
Study Title:
A Multicenter, Open-Label, Non-Randomized Study to Assess the Pharmacokinetics, 
Tolerability, and Safety of a Single Subcutaneous Administration of Icatibant in Children 
and Adolescents with Hereditary Angioedema 
Study Number:
HGT-FIR-086
Study Phase: III
Investigational Product; Dose; and Mode of Administration: 
Single dose of icatibant 0.4 mg/kg subcutaneous (SC) up to a maximal dose of 30 mg
Comparator; Dose; and Mode of Administration:
Not applicable
Study Objectives: 
The objectives of this study are:

To investigate the pharmacokinetics (PK), tolerability, and safety of a single 
subcutaneous (SC) dose of icatibant in children and adolescents with hereditary 
angioedema (HAE) 

To evaluate the efficacy of a single SC dose of icatibant in children and 
adolescents with HAE.

To evaluate the effect on reproductive hormone levels after a single SC dose of 
icatibant in children and adolescents with HAE. 
Other objectives of this study are:

To evaluate the continued safety of icatibant in pubertal/postpubertal children after 
repeated exposures.

To evaluate the efficacy of icatibant in the treatment of acute HAE attacks in 
pubertal/postpubertal children after repeated exposures.

To evaluate the effect on reproductive hormone levels in pubertal/postpubertal 
children after repeated exposures. 
Study Endpoints: 
Primary endpoints:

The PK profile of icatibant after a single SC injection in pediatric subjects (in 
prepubertal children with an acute attack of HAE and pubertal/postpubertal 
children with or without an acute attack of HAE).

The tolerability and safety of SC icatibant as assessed by injection site reactions, 

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adverse events, vital signs, electrocardiogram (ECG) recordings, physical 
examination, clinical laboratory parameters (serum chemistry [including liver 
function tests], hematology, urinalysis), reproductive hormone levels, and 
immunogenicity (anti-icatibant antibodies).
Secondary endpoints (only for subjects treated with icatibant during a HAE attack):
Time to onset of relief of symptoms and time to minimal symptoms, as measured by 
investigator- and subject-reported outcomes

For subjects 2 to less than 18 years of age: investigator assessment and scoring of 
cutaneous, abdominal and laryngeal symptoms of acute HAE attacks by an 
investigator-rated symptom score.

For subjects 4 years of age and older: subject self-assessment of HAE related pain 
using the Faces Pain Scale-Revised (FPS-R).

For subjects less than 4 years of age: investigator assessment of HAE-related pain 
(cutaneous, abdominal and laryngeal) using a validated pain scale (Faces, Legs, 
Activity, Cry, and Consolability [FLACC].
Incidence of rescue medication use.
Proportion of subjects with worsened intensity of clinical HAE symptoms between 2 and 
4 hours after treatment with icatibant.
Study Design:
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, 
and safety, including effect on reproductive hormones, of a single SC administration of 
icatibant in pediatric subjects with HAE.
The study will enroll children and adolescents from 2 to less than 18 years of age, divided 
into 2 groups: prepubertal (Tanner stage I) and pubertal/postpubertal (Tanner stages II to 
V). 
At least 10 prepubertal children and at least 20 adolescents (including 10 treated during a 
HAE attack) must be enrolled in the study.
Study Methodology:
A subject’s classification as prepubertal or pubertal/postpubertal will be determined at 
screening and, if appropriate, at the time of the first icatibant-treated HAE attack.  
Subjects classified as pubertal/postpubertal at screening will not require further evaluation 
of pubertal status during the study, whereas subjects classified as prepubertal at screening 
will have their pubertal status reassessed at the time of their first icatibant-treated attack 
visit.
After a qualifying screening period, the PK, safety/tolerability, and efficacy of treatment 
with SC icatibant will be evaluated in at least 20 subjects (10 prepubertal and 10 
pubertal/postpubertal subjects) who present with cutaneous, abdominal, or laryngeal 
symptoms of an acute attack of HAE.  Subjects should initiate treatment with icatibant 
within 12 hours of the onset of symptoms; however, there are no prespecified attack 
severity criteria that are required for treatment.  Subjects with attacks considered to be 

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mild, moderate, or severe are all potentially eligible to receive treatment with icatibant.  
The PK and safety/tolerability of SC icatibant will be evaluated in at least 10 additional 
pubertal/postpubertal subjects who meet screening criteria and receive treatment with SC 
icatibant in the absence of a current acute HAE attack.
Initially, enrollment and dosing of pubertal/postpubertal subjects will precede that of 
prepubertal subjects. After the first 4 subjects in the pubertal/postpubertal group have 
been treated with icatibant (whether during or in the absence of attack), PK, 
safety/tolerability, and efficacy (as appropriate) will be reviewed by an independent Data 
and Safety Monitoring Board (DSMB).  The DSMB review of the first 4 subjects shall be 
completed prior to continuing enrollment of additional pubertal/postpubertal subjects, 
treatment of second and third HAE attacks in pubertal/postpubertal subjects, and initiating 
enrollment of subjects in the prepubertal group.
Subjects will receive treatment with a single SC administration of icatibant on Day 1 and
will be monitored closely in the hospital/study center for at least 6 to 8 hours after 
treatment. Subjects will undergo PK and safety assessments; efficacy assessments will be 
performed if treatment occurs during an acute HAE attack.  All subjects will have serum 
reproductive hormone measurements.  
A subject may be discharged after completion of assessments at 6 hours post treatment, if 
deemed medically stable in the investigator’s clinical judgment and, if applicable, the 
subject’s HAE symptoms have resolved (the subject’s investigator-rated symptom score 
must be zero, denoting the absence of symptoms).  If HAE symptoms have not completely 
resolved at 6 hours (ie, the investigator-rated symptom score is >0), the subject shall 
remain in the hospital/study center for at least 8 hours after icatibant administration for 
further evaluation.
Telephone follow-up will occur at both 24 and 48 hours after treatment.  
Subjects will return to the hospital/study center for scheduled assessments on Day 8 and 
for a follow-up visit on Day 90.
After having received initial treatment with icatibant, either during or in the absence of an 
attack, at least 10 pubertal/postpubertal subjects who subsequently experience an acute 
HAE attack may continue to receive treatment with icatibant as a single SC administration 
per attack for a total of 3 eligible icatibant-treated attacks.  Further treatment with 
icatibant is contingent upon presentation of an acute cutaneous, abdominal, or laryngeal 
attack of HAE at least 7 days after prior treatment.  All primary and secondary outcomes
as above (including anti-icatibant antibodies and reproductive hormones) will be 
measured in these pubertal/postpubertal subjects after each administration.  Note that for 
some of the pubertal/postpubertal subjects who receive further treatment, ie, those who 
provided PK and safety/tolerability measurements without an attack, their first icatibant-
treated attack will represent their second on-study exposure to icatibant for safety analysis 
purposes.
The investigator will schedule a telephone contact approximately 6 months after Day 1 of 
each icatibant-treated attack to obtain specific updates concerning pubertal 
changes/milestones.

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Study Population: 
The study will enroll a sufficient number of children and adolescents with HAE to ensure 
study completion of 30 subjects.  The study population to provide efficacy, PK, and 
safety/tolerability measurements will consist of at least 20 subjects from 2 to less than 
18 years of age of whom at least 10 are prepubertal and at least 10 are 
pubertal/postpubertal at the time of their first icatibant-treated acute cutaneous, 
abdominal, or laryngeal attack of HAE.  An additional 10 subjects who are 
pubertal/postpubertal at the time of enrollment, but who are not experiencing a current 
HAE attack, will provide PK and safety/tolerability measurements only.
Study Inclusion and Exclusion Criteria:
Subjects must meet all of the following criteria to be considered eligible for enrollment:
1. Two to <18 years of age (ie, from the second birthday through the day prior to the 
eighteenth birthday) at the time of enrollment and treatment with icatibant.
-
Prepubertal and pubertal/postpubertal subjects experiencing an acute cutaneous, 
abdominal, or laryngeal HAE attack treated with icatibant as part of this study. 
-
Pubertal/postpubertal subjects with HAE who are treated with icatibant as part of 
this study, but not during an attack. 
2. Documented diagnosis of HAE type I or II.  Diagnosis may be on the basis of 
historical data: family history, characteristic attack manifestations, recurrent attacks, 
historical C1-INH deficiency, and exclusion of other forms of angioedema.  Inclusion 
will be permitted initially based on medical history only if a clear diagnosis has been 
made based on all of the preceding criteria.  However, the diagnosis must be 
confirmed prior to treatment by documented immunogenic and/or functional C1-INH 
deficiency (C1-INH protein level below the lower limit of normal and/or functional 
level <50% of normal) as performed by the Sponsor’s central laboratory.
3. Informed consent (and subject assent as appropriate) signed by the subject’s parent(s) 
or legal guardian(s).
Subjects who meet any of the following criteria will be excluded from the study:
1. Diagnosis of angioedema other than HAE.
2. Participation in another clinical trial that involves use of any investigational product 
(drug or device) within 30 days prior to study enrollment or at any time during the 
study. 
3. Any known factor/disease that might interfere with the treatment compliance, study 
conduct, or result interpretation.
4. Congenital or acquired cardiac anomalies that interfere significantly with cardiac 
function.
5. Treatment with angiotensin converting enzyme (ACE) inhibitors within 7 days prior to 
treatment.
6. Use of hormonal contraception within the 90 days prior to treatment.
7. Androgen use (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone 
within the 90 days prior to treatment).
8. Pregnancy or breastfeeding. 
9. A physical condition that interferes with pubertal status determination.

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Study Duration:
At minimum, the duration of a subject’s active participation in the study will consist of 
single day dosing with 90-day follow-up.  
Once eligibility is established at screening, the subject will be enrolled into the study but 
will enter a period of inactive participation of variable duration until such time as the 
subject experiences an acute attack of HAE and is offered treatment.  For those 
pubertal/postpubertal subjects who will be treated without an attack, eligibility will be 
established at screening and the subject will be immediately enrolled and treated with 
icatibant.  At the time of enrollment, the subject will enter a 90-day period of active 
participation which will consist of treatment with a single SC administration of icatibant 
on Day 1 through follow-up at Day 90.  
After receiving the first treatment with icatibant with or without an attack (N=20), at least 
10 pubertal/postpubertal subjects who present with subsequent attacks of acute HAE will 
continue to receive treatment with icatibant for a total of 3 attacks each.  Thus, the period 
of active participation in the study for prepubertal subjects will be approximately 90 days, 
while that for pubertal/postpubertal subjects could be a maximum of approximately 270 or 
360 days (3 separate active periods of approximately 90 days for those treated with 
icatibant during an attack; 4 separate active periods for those treated without an attack), 
with each active period separated by periods of inactive participation of variable duration.  
The period of active participation may be shorter if pubertal/postpubertal subjects have 
recurrent HAE attacks in between the Day 8 and Day 90 visits for a prior icatibant-treated 
HAE attack.  Telephone follow-up will occur approximately 6 months after each icatibant-
treated attack.
Once the tenth prepubertal subject and the twentieth pubertal/postpubertal subject have 
completed the 6-month follow-up after the initial treatment, and the tenth 
pubertal/postpubertal subject has completed the 6-month follow-up after his or her third 
and final treatment for an attack, the study will be closed. 
Pharmacokinetic Variables:
Individual patient PK variables for icatibant and major metabolites will be determined 
from the respective plasma concentration time profiles where appropriate, using 
noncompartmental methods. 
A population PK model will be derived to evaluate the correlation of key covariates (ie 
age, body weight, gender) on the pharmacokinetic profile of icatibant.
Primary and secondary pharmacokinetic parameter estimates will be reported and include 
time to peak concentration (Tmax), actual peak (Cmax) and minimum (Cmin) concentrations, 
clearance (CL/F), actual area under the plasma concentration-time curve (AUC0-last and 
AUC0-inf), mean residence time (MRT), volume of distribution at steady state (Vss/F) and 
elimination half-life (t1/2).
Safety Assessments:
Safety will be assessed by standard criteria including physical examination, vital signs, 
ECGs, clinical laboratory evaluations (clinical chemistry [including liver function tests], 
hematology, urinalysis), and immunogenicity (presence of anti-icatibant antibodies), 
recording of concomitant medications, and monitoring of adverse events.  Local 
tolerability will be assessed by evaluation of reactions at the site of icatibant 
administration (injection site).  Levels of reproductive hormones will be assessed in 

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female (follicle stimulating hormone [FSH], luteinizing hormone [LH], estradiol, 
progesterone) and male (FSH, LH, testosterone) subjects.
Efficacy Assessments:  
Efficacy will be assessed using both investigator- and subject-reported outcomes, 
depending on the subject’s age.  Investigators will assess and score symptoms of acute 
cutaneous, abdominal, and laryngeal attacks of HAE for all subjects using an 
investigator-rated symptom score.  Subjects who are 4 years of age or older will perform a 
self-assessment of HAE-related pain using the FPS-R instrument. Subjects who are 
younger than 4 years of age will have symptoms assessed by the investigator only; 
including an assessment of HAE-related pain (cutaneous, abdominal, and laryngeal) using 
the FLACC scale.  The time of initial symptom relief as assessed by the investigator will 
be recorded for all subjects.
(Efficacy assessments will not be performed for those pubertal/postpubertal subjects 
treated with icatibant in the absence of an HAE attack).
Statistical Methods: 
Summary statistics for continuous variables will include the number of subjects, the mean, 
median, standard deviation, and range.  For PK parameters, the coefficient of variation 
and geometric mean also will be provided.  
For categorical data, summaries will include counts and percentages.  For time-to-event 
data, the median time to event and other summary statistics will be estimated using 
Kaplan-Meier methodology.
The following populations will be used in the analysis:

The Efficacy Population will consist of those subjects who were treated with 
icatibant for their first and any additional attacks

The PK Population will consist of those subjects who were treated with icatibant 
and had sufficient icatibant plasma concentration time measurements to derive 
primary PK parameters. 

The Safety Population will consist of those subjects who were treated with 
icatibant at least once
Subject disposition, demographic and baseline characteristics and medical history will be 
summarized separately for the Efficacy Population and the Safety Population.  
Efficacy analyses will be based on the Efficacy Population. Efficacy endpoints, including 
change from baseline when appropriate, will be summarized descriptively.  The primary 
efficacy endpoint is the time to onset of symptom relief measured using the investigator-
rated symptom score.  The time to onset of symptom relief is defined as the earliest time 
post treatment at which there is a 20% improvement in the average post-treatment 
symptom score with no worsening of any single component score. 
Plasma concentrations of icatibant by time point and the PK parameters will be 
summarized descriptively.
Safety and tolerability analyses will be based on the Safety Population.  The assessment of 
safety will be based mainly on the frequency of adverse events.  Adverse events will be 

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summarized by presenting the number and percentage of subjects having any adverse 
event, having an adverse event in each body system, and having each individual adverse 
event using the Medical Dictionary for Regulatory Activity (MedDRA).  Adverse events 
also will be tabulated by severity and relationship to treatment.
Local tolerability will include symptoms at the injection site and will be assessed 
separately from general reports of adverse events.  Local tolerability will be tabulated and 
summarized according to the type and severity of the injection site reaction.
The change from baseline in the secretion of reproductive hormones and the change from 
baseline in HAE symptoms (as reported by the investigator or subject) will be summarized 
descriptively.
Date of Amended Protocol: 19 June 2013 

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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................2
TABLE OF CONTENTS...........................................................................................................9
LIST OF IN-TEXT TABLES ..................................................................................................12
LIST OF APPENDICES..........................................................................................................13
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................14
1
INTRODUCTION ...........................................................................................................16
1.1
Disease Background...............................................................................................16
1.2
Previous Clinical Studies.......................................................................................17
1.2.1
Pharmacokinetics of Icatibant......................................................................17
1.2.2
Overview of the Safety and Efficacy of Sc Icatibant in Clinical Studies....18
1.2.3
Investigations of Potential Effects of Bradykinin Inhibition on 
Reproductive Function.................................................................................19
1.3
Rationale for Dose Selection .................................................................................20
2
STUDY OBJECTIVES....................................................................................................22
2.1
Objectives ..............................................................................................................22
2.2
Other Objectives ....................................................................................................22
3
STUDY ENDPOINTS.....................................................................................................23
3.1
Primary Endpoints .................................................................................................23
3.2
Secondary Endpoints .............................................................................................23
4
INVESTIGATIONAL PLAN..........................................................................................25
4.1
Overall Study Design and Plan..............................................................................25
4.1.1
Study Design................................................................................................25
4.1.2
Study Methodology......................................................................................25
4.1.3
Study Assessments.......................................................................................26
4.1.3.1
Initial Treatment.................................................................................27
4.1.3.2
Subsequent Treatment........................................................................28
4.2
Rationale for Study Design....................................................................................29
4.3
Study Duration.......................................................................................................29
5
STUDY POPULATION SELECTION ...........................................................................31
5.1
Study Population....................................................................................................31
5.2
Inclusion Criteria ...................................................................................................31
5.3
Exclusion Criteria ..................................................................................................31
6
STUDY TREATMENT...................................................................................................33
6.1
Description of Treatment .......................................................................................33
6.1.1
Investigational Product ................................................................................33
6.1.2
Comparator ..................................................................................................33
6.2
Treatment Administered ........................................................................................33

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6.3
Selection and Timing of Dose for Each Subject....................................................33
6.4
Method of Assigning Subjects to Treatment Groups.............................................33
6.5
Blinding..................................................................................................................34
6.6
Concomitant Medication Usage.............................................................................34
6.7
Rescue Therapy......................................................................................................34
6.8
Restrictions ............................................................................................................35
6.8.1
Fluid and Food Intake..................................................................................35
6.8.2
Subject Activity Restrictions .......................................................................35
6.9
Treatment Compliance...........................................................................................35
6.10
Packaging and Labeling.........................................................................................35
6.11
Storage and Accountability....................................................................................36
6.12
Investigational Product Retention at Study Site ....................................................36
7
STUDY PROCEDURES .................................................................................................37
7.1
Informed Consent...................................................................................................37
7.2
Study Entrance Criteria..........................................................................................37
7.3
Confirmation of Study Eligibility..........................................................................37
7.4
Demographics ........................................................................................................37
7.5
Medical History .....................................................................................................37
7.6
Menstrual Cycle History........................................................................................38
7.7
Height and Weight .................................................................................................38
7.8
Pubertal Status Determination ...............................................................................38
7.9
Investigational Product Administration.................................................................38
7.10
Pharmacokinetic Assessments ...............................................................................38
7.10.1
Pharmacokinetic Variables ..........................................................................38
7.10.2
Pharmacokinetic Sampling ..........................................................................39
7.10.3
Bioanalytical Method...................................................................................39
7.11
Efficacy Assessments.............................................................................................39
7.11.1
Investigator Symptom Score........................................................................39
7.11.2
Subject Self-assessment of Pain ..................................................................40
7.11.3
Investigator Assessment of Pain..................................................................40
7.11.4
Initial Symptom Relief.................................................................................40
7.12
Reproductive Hormone Assessments ....................................................................40
7.13
Safety Assessments................................................................................................41
7.13.1
Physical Examination ..................................................................................41
7.13.2
Vital Signs....................................................................................................41
7.13.3
Electrocardiography.....................................................................................41
7.13.4
Clinical Laboratory Tests.............................................................................41
7.13.5
Local Tolerability ........................................................................................42

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7.13.6
Immunogenicity...........................................................................................42
7.13.7
Pregnancy Testing........................................................................................43
7.14
Sample Collection, Storage, and Shipping ............................................................43
7.15
Recording of Concomitant Medications................................................................43
7.16
Recording of Adverse Events ................................................................................43
7.17
Adverse Events Assessments.................................................................................43
7.17.1
Definitions of Adverse Events and Serious Adverse Events.......................43
7.17.1.1
Adverse Event....................................................................................43
7.17.1.2
Serious Adverse Event.......................................................................45
7.17.2
Classification of Adverse Events and Serious Adverse Events...................45
7.17.2.1
Clarification between Serious and Severe .........................................45
7.17.3
Relatedness of Adverse Events and Serious Adverse Events......................46
7.17.4
Procedures for Recording and Reporting Adverse Events ..........................46
7.17.4.1
Adverse Event Monitoring and Period of Observation......................46
7.17.4.2
Reporting Serious Adverse Events ....................................................47
7.18
Pregnancy...............................................................................................................48
7.19
Abuse, Overdose, and Medication Error................................................................48
7.20
Removal of Subjects from the Trial or Investigational Product ............................49
7.20.1
Safety-Related Study Stopping Rules..........................................................49
7.21
Appropriateness of Measurements.........................................................................50
8
STUDY ACTIVITIES .....................................................................................................52
8.1
Screening (Day of Informed Consent to Pretreatment on Day 1)..........................52
8.2
Pretreatment (Baseline) Assessments (Day 1, No Attack) ....................................52
8.3
Pretreatment (Baseline) Assessments (Day 1, Initial and Subsequent Attacks)....53
8.4
No Attack...............................................................................................................53
8.4.1
Treatment Period (Day 1 to Day 8 [± 1 Day]).............................................53
8.5
Initial Attack ..........................................................................................................54
8.5.1
Treatment Period (Day 1 to Day 8 [± 1 Day]).............................................54
8.5.2
Follow-up Visit (Day 90 ±7 days) ...............................................................55
8.5.3
Telephone Contact (Month 6 ±7 days) ........................................................56
8.6
Subsequent Attacks (Pubertal/Postpubertal Subjects Only) ..................................56
8.6.1
Treatment Period (Day 1 to Day 8 [± 1 Day]).............................................56
8.6.2
Follow-up Visit (Day 90 ±7 days) ...............................................................57
8.6.3
Telephone Contact (Month 6 ±7 days) ........................................................57
9
QUALITY CONTROL AND ASSURANCE .................................................................58
10
PLANNED STATISTICAL METHODS ........................................................................59
10.1
General Considerations..........................................................................................59
10.2
Determination of Sample Size ...............................................................................59

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10.3
Analysis Populations..............................................................................................59
10.4
Demographics and Baseline Characteristics..........................................................60
10.5
Pharmacokinetic Analysis......................................................................................60
10.5.1
Estimation of PK Parameters.......................................................................60
10.5.1.1
Noncompartmental Modeling ............................................................60
10.5.1.2
Compartmental Modeling Using Population Methods ......................61
10.6
Safety and Tolerability Analyses...........................................................................61
10.7
Efficacy Analyses ..................................................................................................62
10.8
Other Analyses.......................................................................................................63
10.9
Data Monitoring and Interim Analysis ..................................................................63
10.10 Handling of Missing Data......................................................................................63
11
ADMINISTRATIVE CONSIDERATIONS....................................................................64
11.1
Investigators and Study Administrative Structure.................................................64
11.2
Institutional Review Board or Independent Ethics Committee Approval .............64
11.3
Ethical Conduct of the Study.................................................................................64
11.4
Subject Information and Consent/Assent...............................................................64
11.5
Subject Confidentiality ..........................................................................................65
11.6
Study Monitoring...................................................................................................66
11.7
Case Report Forms and Study Records .................................................................66
11.7.1
Critical Documents ......................................................................................66
11.8
Data and Safety Monitoring Board........................................................................67
11.9
Protocol Violations/Deviations..............................................................................67
11.10 Premature Closure of the Study.............................................................................68
11.11 Access to Source Documentation ..........................................................................68
11.12 Data Generation and Analysis ...............................................................................68
11.13 Retention of Data...................................................................................................69
11.14 Financial Disclosure...............................................................................................69
11.15 Publication and Disclosure Policy .........................................................................69
12
LIST OF REFERENCES.................................................................................................70
LIST OF IN-TEXT TABLES
Table 4-1
Study Periods..............................................................................................26
Table 7-1
List of Clinical Laboratory Tests................................................................42
Table 7-2
Adverse Event Severity..............................................................................45
Table 7-3
Adverse Event Relatedness ........................................................................46

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LIST OF APPENDICES
Appendix 1
Study Schedule of Events (No Attack).......................................................71
Appendix 2
Study Schedule of Events (Initial Icatibant-treated Attack).......................75
Appendix 3
Study Schedule of Events (Subsequent Icatibant-treated Attacks) ............80
Appendix 4
Modified Sexual Maturation Scale.............................................................83
Appendix 5
Faces Pain Scale-Revised (FPS-R).............................................................84
Appendix 6
Faces, Legs, Activity, Cry, and Consolability Scale (FLACC) .................85
Appendix 7
Protocol Signature Page .............................................................................86
Appendix 8
Summary of Changes for Amendment 3....................................................87

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ACE
angiotensin converting enzyme
AE
adverse event
AUC
area under the curve extrapolated to zero
BMI
body mass index
BSA
body surface area
C1-INH
C1 esterase inhibitor (human)
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CL/F
total body clearance 
Cmax
maximum observed plasma concentration
Cmin
minimum plasma drug concentration
CRF
case report form
CRO
contract research organization
CYP
cytochrome P450
DHEA
dehydroepiandrosterone
DHEA-S
dehydroepiandrosterone sulfate
DSMB
Data and Safety Monitoring Board
EC50
half maximal effective concentration
ECG
electrocardiogram
e-diary
electronic diary
EMA
European Medicines Agency
FDA
United States Food and Drug Administration
FFP
fresh frozen plasma
FLACC
Faces, Legs, Activity, Cry, and Consolability (comportmental pain scale)
FPS-R
Faces Pain Scale-Revised
FSH
follicle stimulating hormone
GAM
general additive model
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GnRH
gonadotrophin releasing hormone
HAE
hereditary angioedema
hCG
human chorionic gonadotropin

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Abbreviation
Definition
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug Application
IRB
Institutional Review Board
IV
intravenous(ly)
kg
kilogram(s)
LBW
lean body weight
LC-MS
liquid chromatography–mass spectrometry
LH
luteinizing hormone
LOCF
last observation carried forward
LOQ
limit of quantification
MedDRA
Medical Dictionary for Regulatory Activity 
mg
milligram
mL
milliliter(s)
mm
millimeters
MRT
mean residual time
ng
nanogram(s)
NSAID
non-steroidal anti-inflammatory drug
PD
pharmacodynamic
PK
pharmacokinetic(s)
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System®
SC
subcutaneous
SHBG
sex hormone binding globulin
SOC
system organ class
t1/2
terminal elimination half-life
TBW
total body weight
Tmax
time to maximum concentration
US
United States
VAS
visual analog scale
Vss
volume of distribution at steady state
WHO-DD
World Health Organization Drug Dictionary

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1
INTRODUCTION
1.1
Disease Background
Bradykinin is responsible for the clinical symptoms of hereditary angioedema (HAE), causing 
increased vascular permeability, vasodilation, and contraction of visceral smooth muscle.  HAE 
is a rare autosomal dominant disorder characterized clinically by recurrent and self-limiting 
attacks of edema of the skin, gastrointestinal tract, and larynx.  Its prevalence is estimated at 
1:10,000 to 1:50,000.1
HAE is caused by either a quantitative (Type I) or qualitative (Type II) deficiency of C1 
inhibitor.  C1 inhibitor functions in several biochemical pathways, including inhibition of C1 
complement auto-activation, inactivation of coagulation factors XIIa, XIIf, XIa, and inhibition of 
activated kallikrein.  After a triggering event, the deficiency in C1 inhibitor results in accelerated 
release of bradykinin by its cleavage from high molecular weight kininogen by activated 
kallikrein.  Bradykinin is the principal mediator of the increased vascular permeability 
characteristic of HAE.  
Icatibant is a synthetic decapeptide with a structure similar to bradykinin that acts as an 
antagonist of the bradykinin B2 receptor.2, 3 It is highly specific for the B2 receptor, and is 
characterized by high potency in vitro and in vivo, and sufficient biological half-life to allow 
systemic administration by subcutaneous (SC) injection.4, 5 Inhibition of bradykinin action 
through use of a B2 receptor antagonist is a therapeutic strategy for treatment of clinical 
symptoms of HAE, and represents the rationale for use of icatibant in treatment of acute attacks 
of angioedema in HAE patients.  In adults, SC icatibant 30 mg has been shown to produce a 
rapid and durable response in the treatment of cutaneous, abdominal, and laryngeal attacks of 
acute HAE.  A single SC injection is generally sufficient for rapid relief of symptoms of acute 
HAE attacks irrespective of edema location.  Repeated use of icatibant over time for treatment of 
multiple acute HAE attacks in adults produces a consistent response at each attack, with no 
diminution of efficacy.  When self-administered by adults experiencing an acute HAE attack, 
icatibant also produces a rapid and safe treatment response.
The management of HAE in pediatric patients is complex.  The age at onset, the frequency and 
duration of symptoms, as well as the severity of attacks all exhibit substantial inter-individual 
variation.  Although acute episodes of HAE may occur at any age, the median age at first 
symptomatic HAE attack is estimated to range between 4 to 11 years (reviewed by Farkas).6  
Subcutaneous edema of the extremities, face, neck, torso, and genitals is the most common, and 
usually the earliest, manifestation of HAE seen in children.  In the gastrointestinal tract, 
submucosal edema may be associated with colicky abdominal pain, nausea, vomiting, and 
diarrhea.  In a large pediatric cohort, increased frequency and severity of HAE symptoms were 
reported at between 3 and 6 years of age and at around puberty, and were attributed to 
physiological changes which occur during these periods of development.6  
Though infrequent compared to cutaneous and abdominal manifestations, attacks of acute HAE 
involving the larynx may result in submucosal edema of the upper airways and risk of death by 
asphyxiation if undiagnosed and/or untreated.  In comparison to adults, asphyxia may ensue 
more rapidly in children because of smaller airway diameter.

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Prompt control of attacks, short-term prophylaxis, "intermittent" prophylaxis, long-term 
prophylaxis and emergency therapy are recommended for the management of pediatric HAE.6
Treatment options for children with HAE according to current guidelines include 
antifibrinolytics, attenuated androgens, and C1 inhibitor (C1-INH) replacement therapy.  Current 
guidelines favor antifibrinolytics for long-term prophylaxis because of their safety profile 
relative to attenuated androgens.  The preferred antifibrolytic agent, where approved for use, is 
tranexamic acid, though -aminocaproic acid is sometimes also used for this purpose.  C1-INH 
replacement therapy has been used successfully for management of acute attacks of HAE in 
children; however, its use in children is associated with the same drawbacks (ie, requirement for 
intravenous [IV] administration, potential to elicit hypersensitivity reactions, possible 
transmission of blood-borne infectious agents) as in adults.
1.2
Previous Clinical Studies
1.2.1
Pharmacokinetics of Icatibant
The pharmacokinetic (PK) properties of icatibant have been characterized extensively in studies 
using both IV and SC administration to healthy adult subjects and adult subjects with HAE.  The 
PK profile of icatibant in adults with HAE (JE049-2101) is similar to that in healthy adults.
After SC administration of a single 30 mg dose of icatibant to healthy adult subjects (N=96), a 
mean (± standard deviation) maximum plasma concentration (Cmax) of 974 ± 280 ng/mL was 
observed after approximately 0.75 hours.  The mean area under the concentration-time curve 
(AUC0-∞) after a single 30 mg dose was 2165 ± 568 ng•hr/mL, with no evidence of accumulation 
of icatibant after three 30 mg doses administered 6 hours apart.  
Plasma clearance after SC administration of icatibant was 245 ± 58 mL/min with a mean 
elimination half-life of 1.4 ± 0.4 hours and volume of distribution at steady state (Vss) of 
29.0 ± 8.7 L.  The information obtained from Phase III clinical studies clearly demonstrated that 
SC icatibant 30 mg is a clinically safe and effective treatment for attacks of acute angioedema 
across a wide range of subject demographics, including age, sex, and body weight. 
Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are 
primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug.  
Icatibant is not degraded by oxidative metabolic pathways, and is not an inhibitor of major 
cytochrome P450 (CYP) isoenzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 
3A4) and is not an inducer of CYP 1A2 and 3A4.
Clinical PK studies demonstrate that for mild to moderate impairment of renal or hepatic 
function no dose adjustment is necessary.  In 10 subjects with hepatorenal syndrome (glomerular 
filtration rate (GFR) 30 to 60 mL/min), clearance of icatibant was not dependent on renal 
function.  Icatibant clearance in subjects with a wide range of hepatic impairment (Child-Pugh 
score ≥7 and ≤15) was similar to that in healthy subjects.

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1.2.2
Overview of the Safety and Efficacy of Sc Icatibant in Clinical Studies
Despite the rarity of HAE, a robust clinical dataset supports the safety of icatibant.  As of 
18 April 2013, a total of 2214 doses of SC icatibant have been administered in clinical trials.  In 
Phase I-III studies, icatibant has been administered by a healthcare professional to 177 healthy 
subjects and to 269 subjects with HAE.  In completed Phase III studes, the maximum number of 
icatibant-treated attacks in a single subject was 142 (over approximately 3 years) in JE049-2102, 
22 (over approximately 1.5 years) in JE049-2103, and 34 (over approximately 3 years) in HGT-
FIR-054.  
Icatibant has been well tolerated in all clinical studies. Nonserious reactions (erythema, swelling, 
burning sensation, itching, warmth, and cutaneous pain) at the injection site were the most 
commonly reported adverse effects in clinical studies, and occurred transiently in almost all 
subjects after SC injection of icatibant. These reactions were self resolving and typically mild to 
moderate in severity. Icatibant was generally non-immunogenic. Over repeated treatment for 
multiple attacks in the 3 controlled Phase III studies, transient positivity in test results for the 
presence of anti-icatibant antibodies was observed in rare cases. No hypersensitivity or 
anaphylactic reactions were reported with use of icatibant. 
Collectively, across the 3 controlled Phase III studies, subjects on icatibant had a faster median 
time to onset of symptom relief (2.0, 2.5, and 2.0 hours, respectively) compared to tranexamic 
acid (12.0 hours) and placebo (4.6 and 19.8 hours).  The treatment effect of icatibant was 
confirmed by secondary efficacy endpoints.  In subgroup analyses of data pooled across these 
3 controlled Phase III studies, the time to onset of symptom relief and time to onset of primary 
symptom relief were similar regardless of age group, sex, race, weight or whether or not the 
subject used androgens or antifibrinolytic agents.  A consistent treatment response was observed 
across repeated attacks in studies HGT-FIR-054, JE049-2102, and JE049-2103, during which a 
total of 237 subjects were treated with 1, 383 doses of SC icatibant for 1278 acute attacks of 
HAE.  
Thus, the clinical data supports the favorable benefit-risk profile of icatibant as a treatment for 
acute attacks of HAE. 
The recommended dose of icatibant in adults is 1 SC injection of 3 mL (30 mg) administered in 
the abdominal area for the treatment of acute attacks of HAE.  In case of insufficient relief or 
recurrence of symptoms, a second injection of icatibant can be administered after 6 hours.  No 
more than 3 injections of icatibant should be administered in a 24-hour period.  In clinical trials, 
a single SC injection of icatibant was generally sufficient to treat an acute HAE attack.  No 
differences in the efficacy or safety of icatibant in clinical trials have been observed between 
sexes; no dose adjustments for adult males or females are necessary. 
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of icatibant.

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1.2.3
Investigations of Potential Effects of Bradykinin Inhibition on Reproductive 
Function
In nonclinical studies performed in rat and dog, high repeated doses of icatibant have been 
associated with effects on sexual organs and sexual maturation.  These findings are consistent 
with published data showing a role of bradykinin action through B2 receptors in the control of 
reproductive hormone release. 
Completed juvenile toxicology study in sexually immature rats involving fertility assessment 
over the course of 7-weeks of administration of icatibant (3.0, 9.0, or 25 mg/kg/day) elicited 
effects on reproductive organs and impaired fertility. These findings on reproductive tissues in 
males to be largely expected due to the known effects of antagonizing the bradykinin B2 receptor 
and were seen to be partially or fully reversibleduring the dose-free recovery period. 
Nonclinical evaluation of icatibant in rats demonstrated icatibant-related effects on hormone 
levels with secondary effects observed on reproductive organs in a 26-week rat toxicity study 
(JE049-0163) at dose levels of 3.0 and 9.0 mg/kg/day. However, these findings did not result in 
a functional deficit in terms of the mating performance and fertility of the male rat at doses lower 
than 9.0 mg/kg.  Additionally, the dose regimen utilized in this study represents an exaggeration 
of the clinical use of icatibant, thereby minimizing the impact of the findings to what would 
potentially be observed in a clinical setting.
A retrospective analysis, prompted by nonclinical observations, of serum levels of gonadotrophic 
hormone levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) in 16 male 
and 16 female healthy volunteers in an Phase I study (JE049-1103) showed no clinically 
important changes from baseline in levels of FSH and LH after administration of 3 SC doses 
(30 mg each) of icatibant 6 hours apart on Day 1 followed by single SC doses (30 mg) on Day 8 
and Day 15. 
Phase 1 study (HGT-FIR-062) was a double-blind, randomized, placebo-controlled, single center 
study to assess the effect of icatibant on serum reproductive hormone levels in male and 
premenopausal female healthy adult subjects and seminal fluid analysis in healthy male adult 
subjects.  This study was intended to definitively determine the effect of repeated administration 
of 3 SC doses of icatibant 30 mg on reproductive hormone levels in adults prior to any 
investigational use in pediatric subjects per the recommendation of the European Medicines 
Agency (EMA).  Subjects were randomized to receive icatibant or placebo as a single SC 
injection at 6 hour intervals 3 times daily on Days 1, 4, and 7 of the treatment week (total 
9 doses/week) with an approximately 8 week follow-up phase.  
Thirty-nine adult subjects (16 females and 23 males) were enrolled and treated in Study 
HGT-FIR-062; 32 subjects completed the study in its entirety (7 subjects did not return for 
follow-up visits).  No negative trends were seen with regard to the results of basal or 
gonadotrophin releasing hormone (GnRH)-stimulated reproductive hormone assessments in 
female and male subjects treated with icatibant or placebo.  Though the number of subjects 
participating was small, and the study was not powered for statistical significance, a suppressive 
effect of icatibant on GnRH-stimulated reproductive hormone concentrations was not generally 
observed in either sex.  Overall, there were no clinically significant changes from baseline in 

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basal and GnRH-stimulated concentrations of reproductive hormones (estradiol, progesterone, 
prolactin, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), sex 
hormone binding globulin (SHBG), FSH, and LH in females and testosterone, DHEA, DHEA-S, 
SHBG, FSH, LH, and Inhibin-B in males) in response to treatment with icatibant.  Additionally, 
there were no significant effects of icatibant on the concentration of luteal phase progesterone, an 
indicator of ovulation status and luteal function, or on menstrual cycle length in females, and 
there were no significant effects of icatibant on semen parameters in males.  
Adrenal cortex function in male and female subjects, as assessed by serum cortisol 
concentrations, was unaffected by treatment with icatibant. 
1.3
Rationale for Dose Selection
Icatibant has not been evaluated in clinical trial subjects below the age of 18 years.  The 
proposed study will be the first in which icatibant is administered to pediatric subjects for 
treatment of acute HAE attacks.  All subjects in the proposed study will receive a single, 
weight-adjusted dose of 0.4 mg/kg per attack as a SC injection up to a maximum dose of 30 mg.  
This dose regimen was selected to target an exposure (Cmax and area under the curve [AUC]) 
comparable to that observed in adults treated with icatibant.  Only 1 dose of icatibant will be 
permitted for treatment of a single attack.   
The 0.4 mg/kg dose was derived from pharmacokinetic/pharmacodynamic (PK/PD) modeling of 
data from a study (JE049-1001), which investigated the inhibitory potential of icatibant at 
various IV infusion doses and regimens after bradykinin challenge in healthy male subjects.  The 
PK and PD data sets were used to model the PK/PD relationship of icatibant using a sigmoidal 
Emax model.  A high degree of concordance of half maximal effective concentration (EC50) 
values was obtained for each of the PD parameters studied (heart rate, blood pressure, and 
cutaneous blood flow) with the majority of values being between 8.54 and 9.77 ng/mL.  Thus, a 
mean EC50 value of 9.5 ng/mL (7.3 nM) was used for subsequent PK/PD simulation.  Based on 
the PK/PD modeling, IV icatibant doses of 0.4 mg/kg and 0.8 mg/kg were predicted to provide 
duration of therapeutic effect of as much as 9 or 13 hours, respectively, when infused over 0.5 to 
1 hour.  These results supported a minimum effective dose of 0.4 mg/kg to treat acute attacks of 
HAE.  This corresponds to a dose of 30 mg of icatibant in a 75 kg subject.  
A subsequent Phase II (JE049-2101) dose-ranging proof of concept efficacy study in HAE 
subjects was then conducted that examined the efficacy of doses ranging from 0.4 to 0.8 mg/kg 
IV (ie, 30 to 60 mg in a 75 kg person) and 30 to 45 mg SC.  The results of this study indicated 
that SC administration of icatibant 30 mg produced a rapid onset of symptom relief and that 
45 mg SC showed no improvement in efficacy over 30 mg SC.  
As a result of clinical exploration of the efficacy, safety and exposure-response relationship of 
icatibant, a single SC administration of 30 mg icatibant (10 mg/mL formulation) was selected 
and consistently employed in the Phase III studies in adult HAE subjects.  The totality of 
available efficacy information obtained from the Phase III clinical studies demonstrates that a 
single SC 30 mg dose of icatibant provides a sufficient magnitude and duration of effect to 
clinically manage the majority of acute attacks in adult HAE subjects across a wide range of 

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demographics.  Therefore, 0.4 mg/kg SC is considered an appropriate dose to study the 
tolerability, safety and PK of icatibant in the pediatric population. 

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2
STUDY OBJECTIVES
2.1
Objectives 
The objectives of this study are:
•
To investigate the PK, tolerability, and safety of a single SC dose of icatibant in children and 
adolescents with HAE.
•
To evaluate the efficacy of a single SC dose of icatibant in children and adolescents with 
HAE.
•
To evaluate the effect on reproductive hormone levels after a single SC dose of icatibant in 
children and adolescents with HAE. 
2.2
Other Objectives 
Other objectives of this study are:
•
To evaluate the continued safety of icatibant in pubertal/postpubertal children after repeated 
exposures.
•
To evaluate the efficacy of icatibant in the treatment of acute HAE attacks in 
pubertal/postpubertal children after repeated exposures.
•
To evaluate the effect on reproductive hormone levels in pubertal/postpubertal children after 
repeated exposures.

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3
STUDY ENDPOINTS
3.1
Primary Endpoints
Primary endpoints:
•
The PK profile of icatibant after a single SC injection in pediatric subjects (in prepubertal 
children with an acute attack of HAE and pubertal/postpubertal children with or without an 
acute attack of HAE).
•
The tolerability and safety of SC icatibant as assessed by injection site reactions, adverse 
events, vital signs, ECG recordings, physical examination, clinical laboratory parameters 
(serum chemistry [including liver function tests], hematology, urinalysis), reproductive 
hormone levels, and immunogenicity (presence of anti-icatibant antibodies). 
3.2
Secondary Endpoints
Secondary endpoints (only for subjects treated with icatibant during a HAE attack):
Time to onset of relief of symptoms and time to minimal symptoms, as measured by 
investigator- and subject-reported outcomes
•
For all subjects (2 to <18 years of age): investigator assessment and scoring of cutaneous, 
abdominal, and laryngeal symptoms of acute HAE attacks by an investigator-rated 
symptom score.
-
The time to onset of relief of symptoms, defined as the earliest time at which at least a 
20% improvement is seen in the average post-treatment score with no worsening of 
any single component score.
-
The time to minimal symptoms, defined as the earliest time post treatment when all 
symptoms are either mild or absent based on the investigator-rated symptom score.
•
For subjects ≥4 years of age only: subject self-assessment of HAE-related pain using the 
Faces Pain Scale-Revised (FPS-R).
-
The time to onset of relief of symptoms, defined as the earliest time at which the post-
treatment score improves by at least one level.
-
The time to minimal symptoms, defined as the earliest time at which the post-
treatment score improves to zero (or no pain).

For subjects <4 years of age only: investigator assessment of HAE-related pain 
(cutaneous, abdominal, and laryngeal) using a validated pain scale (Faces, Legs, Activity, 
Cry, and Consolability [FLACC].
-
The time to onset of relief of symptoms, defined as the earliest time at which a 20% 
improvement is seen in the total post-treatment score.
-
The time to minimal symptoms, defined as the earliest time at which the total post-
treatment score improves to zero.

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Incidence of rescue medication use.
Proportion of subjects with worsened intensity of clinical HAE symptoms between 2 and 4 hours 
after treatment with icatibant.

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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
4.1.1
Study Design
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, and 
safety, including effects on reproductive hormones, of a single SC administration of icatibant in 
pediatric subjects with HAE.
The study will enroll children and adolescents from 2 to less than 18 years of age, divided into 
2 groups: prepubertal (Tanner stage I) and pubertal/postpubertal (Tanner stages II to V).
At least 10 prepubertal children and at least 20 adolescents (including 10 treated during a HAE 
attack) must be enrolled in the study.
4.1.2
Study Methodology
A subject’s classification as prepubertal or pubertal/postpubertal will be determined at screening 
and, if appropriate, at the time of the first icatibant-treated HAE attack.  Subjects classified as 
pubertal/postpubertal at screening will not require further evaluation of pubertal status during the 
study, whereas subjects classified as prepubertal at screening will have their pubertal status 
reassessed at the time of their first icatibant-treated attack visit.
After a qualifying screening period, the PK, safety/tolerability, and efficacy of treatment with SC 
icatibant will be evaluated in at least 20 subjects (10 prepubertal and 10 pubertal/postpubertal 
subjects) who present with cutaneous, abdominal, or laryngeal symptoms of an acute attack of 
HAE.  Subjects should initiate treatment with icatibant within 12 hours of the onset of 
symptoms; however, there are no prespecified attack severity criteria that are required for 
treatment.  Subjects with attacks considered to be mild, moderate, or severe are all potentially 
eligible to receive treatment with icatibant.  
The PK and safety/tolerability of SC icatibant will be evaluated in at least 10 additional 
pubertal/postpubertal subjects who meet screening criteria, but receive treatment with SC 
icatibant in the absence of a current acute HAE attack.
Initially, enrollment and dosing of pubertal/postpubertal subjects will precede that of prepubertal 
subjects. After the first 4 subjects in the pubertal/postpubertal group have been treated with 
icatibant (whether during or in the absence of attack), PK, safety/tolerability, and efficacy (as 
appropriate) will be reviewed by an independent Data and Safety Monitoring Board (DSMB). 
The DSMB review of the first 4 subjects shall be completed prior to continuing enrollment of 
additional pubertal/postpubertal subjects, treatment of second and third HAE attacks in 
pubertal/postpubertal subjects, and initiating enrollment of subjects in the prepubertal group.
Subjects will receive treatment with a single SC administration of icatibant on Day 1 and will be 
monitored closely in the hospital/study center for at least 6 to 8 hours after treatment. Subjects 
will undergo PK and safety assessments; efficacy assessments will be performed if treatment 

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occurs during an acute HAE attack.  All subjects will have serum reproductive hormone 
measurements.  
A subject may be discharged after completion of assessments at 6 hours post treatment, if 
deemed medically stable in the investigator’s clinical judgment and, if applicable, the subject’s 
HAE symptoms have resolved (the subject’s investigator-rated symptom score must be zero, 
denoting the absence of symptoms).  If HAE symptoms have not completely resolved at 6 hours 
(ie, the investigator-rated symptom score is >0), the subject shall remain in the hospital/study 
center for at least 8 hours after icatibant administration for further evaluation.
Telephone follow-up will occur at both 24 and 48 hours after treatment.  
Subjects will return to the hospital/study center for scheduled assessments on Day 8 and for a 
follow-up visit on Day 90.
After having received initial treatment with icatibant, either during or in the absence of attack, at 
least 10 pubertal/postpubertal subjects who subsequently experience an acute HAE attack may 
continue to receive treatment with icatibant as a single SC administration per attack for a total of 
3 eligible icatibant-treated attacks.  Further treatment with icatibant is contingent upon 
presentation of an acute cutaneous, abdominal, or laryngeal attack of HAE at least 7 days after 
prior treatment.  All primary and secondary outcomes as above (including anti-icatibant 
antibodies and reproductive hormones) will be measured in these pubertal/postpubertal subjects 
after each administration.  Note that for some of the pubertal/postpubertal subjects who receive 
further treatment, ie, those who provided PK and safety/tolerability measurements without an 
attack, their first icatibant-treated attack will represent their second on-study exposure to 
icatibant for safety analysis purposes.
The investigator will schedule a telephone contact approximately 6 months after Day 1 of each 
icatibant-treated attack to obtain specific updates concerning pubertal changes/milestones.
4.1.3
Study Assessments
The study will consist of the following periods (Table 4-1).
Table 4-1
Study Periods
Study Periods
Screening 
Day of informed consent through pretreatment on Day 1 
No attack (Pubertal/postpubertal subjects only)
    Treatment 
Day 1
    Post Treatment
Day 1 through Day 8 (± 1 day)
    Follow-up
Day 9 through Day 90 (±7 days)
    Telephone Contact
Month 6 (± 7 days) from Day 1 

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Table 4-1
Study Periods
Study Periods
Initial icatibant-treated attack (All subjects)
    Treatment 
Day 1
    Post Treatment
Day 1 through Day 8 (± 1 day)
    Follow-up
Day 9 through Day 90 (±7 days)
    Telephone Contact
Month 6 (± 7 days) from Day 1 of the attack
Two additional icatibant-treated attacks for a total of 3 icatibant-treated attacks 
(Pubertal/postpubertal subjects only)
    Treatment 
Day 1
    Post Treatment
Day 1 through Day 8 (±1 day)
    Follow-up
Day 9 through Day 90 (±7 days)
    Telephone Contact
Month 6 (± 7 days) from Day 1 of the attack
The study will include a screening period to determine subject eligibility.  Eligibility will be 
evaluated after the subjects’ parent(s)/legal guardian(s) and the subject (if applicable) provide 
informed consent/assent.  
Study activities at screening will include confirmation of diagnosis of HAE type I or II by review 
of the subject’s medical history and documentation of C1-INH deficiency indicative of HAE 
Type I or II.  A blood sample will be collected for C1-INH testing.  Other assessments performed 
at screening will include concomitant medication use, physical examination (including height 
and weight), pubertal status determination, vital signs, electrocardiogram (ECG), and a urine 
pregnancy test in female pubertal/postpubertal subjects.
4.1.3.1
Initial Treatment
In previously screened, eligible subjects who present with an attack of acute HAE, baseline 
clinical assessments for PK, safety, and efficacy will be performed on Day 1 at pretreatment.  
The initial severity and type of attack (ie, cutaneous, abdominal, or laryngeal) will be determined 
by the investigator.  The investigator will complete baseline assessments at pretreatment of the 
symptoms of the acute HAE attack (including a separate assessment of HAE-related pain in 
subjects younger than 4 years of age), and adherence to inclusion/exclusion criteria will be 
reconfirmed.  Subjects who are 4 years of age or older will perform a self-assessment of 
HAE-related pain.  Other baseline assessments performed at pretreatment will include physical 
examination, pubertal status determination (only for those subjects classified as prepubertal at 
screening), height and weight, vital signs, collection of samples for clinical laboratory tests 
(serum chemistry [including liver function tests], hematology, urinalysis), urine pregnancy test 
for pubertal/postpubertal females, baseline PK and immunogenicity assessments, and baseline 

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measurement of reproductive hormones (FSH, LH, estradiol, and progesterone in females and 
FSH, LH, and testosterone in males). 
On Day 1, subjects will be administered a single dose of icatibant as an abdominal SC injection 
within 12 hours after the onset of the acute attack.  The time of investigational product 
administration on Day 1 will be designated as Time 0.  All post-treatment assessments will be 
calculated from the time of investigational product administration.  PK, safety, and efficacy 
assessments will be performed on Day 1 after treatment at the time points indicated in the study 
schedules of events (Appendix 1, Appendix 2, Appendix 3).  These assessments will consist of 
physical examination, vital signs, ECG, clinical laboratory tests (serum chemistry [including 
liver function tests], hematology, urinalysis), injection site reactions, and measurement of 
reproductive hormones (FSH, LH, estradiol, and progesterone in females and FSH, LH, and 
testosterone in males) in all subjects.  The investigator will complete assessments of symptoms 
of the acute attack of HAE for all subjects (including a separate assessment of HAE-related pain 
in subjects younger than 4 years of age).  Subject who are 4 years of age or older will also 
complete a self-assessment of HAE-related pain.
Eligible pubertal/postpubertal subjects who undergo treatment with icatibant in the absence of an 
acute HAE attack will receive single dose of icatibant as an abdominal SC injection on Day 1 
and undergo PK and safety assessments as for subjects who receive treatment with icatibant 
during an attack.  (Efficacy assessments will not be performed for those pubertal/postpubertal 
subjects treated with icatibant in the absence of an HAE attack.)
A safety follow-up contact to assess the subject’s condition will occur by telephone at 24 (±4) 
hours and 48 (±4) hours after treatment with icatibant (for a subject who remains hospitalized, 
this safety follow-up will be conducted in person).
Rescue medication use will be assessed through 48 (±4) hours after treatment.  With exception of 
icatibant, any medicinal product may be used as rescue medication, at the discretion of the 
treating physician.
Subjects will return to the hospital/study center to undergo safety assessments, including 
physical examination, vital signs, and clinical laboratory tests (serum chemistry [including liver 
function tests], hematology, urinalysis), evaluation of injection site reactions, immunogenicity, 
and measurement of reproductive hormones on Day 8 (±1 day) after treatment.
Subjects will be followed over a 90-day period after initial treatment.  All subjects will provide 
blood samples for immunogenicity testing and measurement of reproductive hormone levels at 
the Day 90 (±7 days) visit and undergo safety assessments including physical examination, vital 
signs, and clinical laboratory tests (serum chemistry, hematology, and urinalysis).  Additionally, 
females of childbearing potential will undergo urine pregnancy testing.
4.1.3.2
Subsequent Treatment
Subsequent treatment with icatibant may be offered to pubertal/postpubertal subjects who have 
received initial treatment and who present subsequently with an attack at least 7 days after prior 
treatment. In the event that a subsequent attack occurs at least 7 days after prior treatment, but 
within the window (±1 day) allowed for performance of Day 8 assessments associated with a 

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prior attack, the Day 8 assessments may also serve as the pretreatment (baseline) assessments for 
the subsequent attack. Subjects will be eligible for treatment with icatibant until a total number 
of at least 10 adolescents have been treated with icatibant for a total of 3 acute attacks (ie, after 
the first icatibant-treated attack, only pubertal/postpubertal subjects may receive further 
treatment with icatibant for up to 2 subsequent attacks of acute HAE).  Except for PK 
determinations, all primary and secondary outcomes, including immunogenicity, are to be 
measured after each administration.  Safety, reproductive hormones, and other assessments in 
association with subsequent attacks of acute HAE will be performed on Day 90 (±7 days) after 
treatment (each treatment for a subsequent attack will require its own Day 90 follow up visit; 
however, if a subsequent attack occurs within 7 days of the Day 90 follow-up visit for the 
previous attack, the assessments on Day 8 and Day 90 may be combined). Note that for some of 
the pubertal/postpubertal subjects who receive further treatment, ie, those who provide PK and 
safety/tolerability measurements without experiencing a current attack, their first icatibant-
treated attack will represent their second on-study exposure to icatibant for safety analysis 
purposes.
The investigator will schedule a telephone contact approximately 6 months after Day 1 of each 
icatibant-treated attack to obtain updates concerning pubertal changes/milestones.  If this 
prescheduled telephone contact date should occur within the 90-day follow-up period (ie, Day 1 
through Day 90) of a subsequent attack, this prescheduled contact may be omitted.
In addition, for all subjects who remain enrolled in the study for longer than 6 months, a 
telephone contact will be scheduled every 6 months to collect information concerning HAE 
attacks not treated with icatibant in the study.
All assessments are outlined in full in the study schedules of events in Appendix 1, No Attack, 
Appendix 2, Initial Icatibant-treated Attack, and Appendix 3, Subsequent Icatibant-treated 
Attacks.    
4.2
Rationale for Study Design
This study has an open-label, single arm design.  
The study is intended to determine the PK profile of SC icatibant when administered to children 
and adolescents with HAE and to identify an optimal pediatric dosing regimen.  
In addition, the study is intended to establish the tolerability and safety of icatibant in children 
and adolescents, particularly with respect to potential effects on reproductive development, and 
to demonstrate the effectiveness of icatibant in relieving the symptoms of acute HAE attacks.  
Therefore, this study will help determine whether icatibant can address an unmet medical need 
for a safe and effective treatment for acute attacks of HAE in pediatric patients. 
4.3
Study Duration
At minimum, the duration of a subject’s active participation in the study will consist of single 
day dosing with 90-day follow-up.  

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Once eligibility is established at screening, the subject will be enrolled into the study but will 
enter a period of inactive participation of variable duration until such time as the subject 
experiences an acute attack of HAE and is offered treatment.  For those pubertal/postpubertal 
subjects who will be treated without an attack, eligibility will be established at screening and the 
subject will be immediately enrolled and treated with icatibant.  At the time of enrollment, the 
subject will enter a 90-day period of active participation which will consist of treatment with a 
single SC administration of icatibant on Day 1 through follow-up at Day 90.  
After receiving the first treatment with icatibant with or without an attack (N=20), at least 
10 pubertal/postpubertal subjects who present with subsequent attacks of acute HAE will 
continue to receive treatment with icatibant for a total of 3 attacks each.  Thus, the period of 
active participation in the study for prepubertal subjects will be approximately 90 days, while 
that for pubertal/postpubertal subjects could be a maximum of approximately 270 or 360 days 
(3 separate active periods of approximately 90 days for those treated with icatibant during an 
attack; 4 separate active periods for those treated without an attack), with each active period 
separated by periods of inactive participation of variable duration.  The period of active 
participation may be shorter if pubertal/postpubertal subjects have recurrent HAE attacks in 
between the Day 8 and Day 90 visits for a prior icatibant-treated HAE attack.  Telephone follow-
up will occur approximately 6 months after each icatibant-treated attack.
Once the tenth prepubertal subject and the twentieth pubertal/postpubertal subject have 
completed the 6-month follow-up after the initial treatment, and the tenth pubertal/postpubertal 
subject has completed the 6-month follow-up after his or her third and final treatment for an 
attack, the study will be closed. 

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5
STUDY POPULATION SELECTION
5.1
Study Population
The study will enroll a sufficient number of children and adolescents with HAE to ensure study 
completion of 30 subjects.  The study population to provide efficacy, PK, and safety/tolerability 
measurements will consist of at least 20 subjects from 2 to less than 18 years of age, at least 
10 of whom are prepubertal and at least 10 of whom are pubertal/postpubertal at the time of their 
first icatibant-treated acute cutaneous, abdominal, or laryngeal attack of HAE.  An additional 
10 subjects who are pubertal/postpubertal at the time of enrollment, but who are not experiencing 
a current HAE attack, will provide PK and safety/tolerability measurements only.
5.2
Inclusion Criteria
Subjects must meet all of the following criteria to be considered eligible for enrollment.
1. Two through <18 years of age (ie, from the second birthday until the day prior to the 
eighteenth birthday) at the time of the subject’s first HAE attack treated with icatibant as part 
of this study.
-
Prepubertal and pubertal/postpubertal subjects experiencing an acute cutaneous, 
abdominal, or laryngeal HAE attack treated with icatibant as part of this study. 
-
Pubertal/postpubertal subjects with HAE who are treated with icatibant as part of this 
study, but not during an attack. 
2. Documented diagnosis of HAE type I or II.  Diagnosis may be on the basis of historical data: 
family history, characteristic attack manifestations, recurrent attacks, historical C1-INH 
deficiency, and exclusion of other forms of angioedema.  Inclusion will be permitted initially 
based on medical history only if a clear diagnosis has been made based on all of the 
preceding criteria.  However, the diagnosis must be confirmed prior to treatment by 
documented immunogenic and/or functional C1-INH deficiency (C1-INH protein level 
below the lower limit of normal and/or functional level <50% of normal) as performed by the 
Sponsor’s central laboratory.
3. Informed consent (and subject assent as appropriate) signed by the subject’s parent(s) or 
legal guardian(s).
5.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study:
1. Diagnosis of angioedema other than HAE.
2. Participation in another clinical trial that involves use of any investigational product (drug or 
device) within 30 days prior to study enrollment or at any time during the study. 
3. Any known factor/disease that might interfere with the treatment compliance, study conduct, 
or result interpretation.
4. Congenital or acquired cardiac anomalies that interfere significantly with cardiac function. 
5. Treatment with angiotensin converting enzyme (ACE) inhibitors within 7 days prior to 
treatment.
6. Use of hormonal contraception within the 90 days prior to treatment.

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7. Androgen use (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) within 
the 90 days prior to treatment.
8. Pregnancy or breastfeeding.
9. A physical condition that interferes with pubertal status determination.

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6
STUDY TREATMENT
6.1
Description of Treatment
6.1.1
Investigational Product
Icatibant is prepared as a sterile, isotonic, and acetate buffer solution containing sodium chloride, 
acetic acid, sodium hydroxide and water for SC injection, adjusted to pH 5.5 0.3.  The solution 
does not contain any preservative.  
The product is supplied as a 10 mg/mL (free base) solution in 3-mL glass syringes, with 
elastomeric stoppers, tip cap, plunger rod, and backstop.  A fluid-dispensing connector will be 
used to secure a 1-mL or 3-mL syringe to the glass syringe.  A single dose (see Section 6.2) will 
be withdrawn and administered by SC injection.
6.1.2
Comparator
Not applicable to this study.
6.2
Treatment Administered
All subjects will receive treatment with icatibant as a single, weight-adjusted dose of 0.4 mg/kg 
up to a maximum of 30 mg administered in the abdominal region as a SC injection.
Pubertal/postpubertal subjects are potentially eligible to receive treatment with icatibant in the 
absence of an attack, and to receive treatment with icatibant for a total of 3 attacks of acute HAE.  
Thus, a maximum of 4 doses of icatibant may be administered to a pubertal/postpubertal subject 
in the study, while all prepubertal subjects will receive a single dose of icatibant.
6.3
Selection and Timing of Dose for Each Subject
All subjects, whether treated during or in the absence of an acute attack of HAE, will be 
administered a single SC injection of icatibant.
Subjects treated for an acute attack of HAE should receive icatibant within 12 hours after the 
onset of the attack.  There are no prespecified attack severity criteria that are required for 
treatment.  Subjects with attacks considered to be mild, moderate, or severe are all potentially 
eligible to receive treatment with icatibant.   
Subsequent treatment with icatibant for up to 2 additional attacks of acute HAE, for a total of 
3 attacks, will be offered to pubertal/postpubertal subjects contingent upon having been treated 
for an initial attack and presenting with a subsequent acute attack at least 7 days after prior 
treatment (see Section 4.1.3).  
6.4
Method of Assigning Subjects to Treatment Groups
Not applicable to this study.  All subjects will be administered icatibant at a weight-adjusted dose 
of 0.4 mg/kg SC up to a maximum of 30 mg per treatment.  

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6.5
Blinding
Not applicable to this open-label study.
6.6
Concomitant Medication Usage
All prescription and over-the-counter medications that are being taken by subjects during the 
study are regarded as concomitant medications and must be documented on the case report form 
(CRF) following informed consent.
Use of the following concomitant medications is allowed during the study:
•
All chronically administered medications, except for treatments of HAE, are allowed, but the 
dose and regimen must have been stable for at least 1 month before the first dose of icatibant 
in this study.
•
Prophylactic therapies for HAE (eg, anti-fibrinolytics or C1-INH) other than attenuated 
androgens will be allowed, but therapies known to attenuate an acute HAE attack (eg, 
C1-INH concentrate, fresh-frozen plasma [FFP]) must not be used during the attack being 
treated with icatibant unless these are required as rescue medications (see Section 6.7).  An 
exception is that fibrinolysis inhibitors may be given in a subject’s usual, stable prophylactic 
regimen. 
Use of the following concomitant medications is forbidden within 90 days prior to treatment, and 
for 90 days after receiving treatment with icatibant:
•
ACE inhibitors.
•
Androgens or attenuated androgens (eg, stanozolol, danazol, oxandrolone, 
methyltestosterone, testosterone).
•
Hormonal contraceptives (acceptable contraception during the study for sexually active 
females will consist of abstinence or a double barrier method such as condom plus 
diaphragm, condom or diaphragm plus spermicide, condom or diaphragm plus intrauterine 
device).
6.7
Rescue Therapy
For the purposes of this protocol, rescue therapy is any medication used after the administration 
of icatibant which, in the opinion of the investigator, is immediately necessary to alleviate acute 
symptoms which are judged by the investigator as resultant from the current HAE attack.  
Repeat administration of icatibant for treatment of a single attack is not allowed in this study.  
The determination of the necessity for rescue therapy will be at the discretion of the investigator.  
With the exception of icatibant, any medicinal product may be used as rescue medication at the 
discretion of the treating physician.
Rescue therapies will include agents to control the HAE attack, such as C1-INH inhibitor 
concentrates.  C1-INH therapy has been used safely for the treatment of acute attacks in the 

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pediatric setting.6  If C1-INH concentrates are unavailable, FFP may be used.7  A kallikrein 
inhibitor, ecallantide, approved only in the USA, is indicated for use in patients 16 years of age 
and older. 
Other acceptable rescue therapies for acute attacks include palliative medications that are 
intended to ameliorate the symptoms (eg, pain, nausea) of angioedema rather than to control the 
HAE attack itself.  If pain medication is required, the investigator may administer intravenous or 
prescription-strength non-steroidal anti-inflammatory drugs (NSAIDs) for mild to moderate pain 
and administer morphine sulfate (or opiate equivalent) intravenously or intramuscularly at a dose 
of 0.05 mg/kg (or an equivalent dose if another opiate medication is used).  Anti-emetics may 
also be prescribed as necessary to treat nausea.  Acceptable rescue therapies may also include 
epinephrine, intravenous fluids, or other medicinal products.
Medications provided for rescue therapy will be denoted as rescue medications on the 
appropriate CRF.  Antihistamines (diphenhydramine, loratadine, cetirizine, etc) and 
glucocorticoids are considered ineffective for the alleviation of an acute HAE attack.  If 
administered during an acute attack that occurs during the study, they should be recorded as 
concomitant medications but will not be considered as rescue medications.  
If rescue medication is provided, the investigator will document the drug name, amount, time, 
route of administration, frequency, and duration administered.
6.8
Restrictions
Subjects are not to receive treatment with any investigational product(s) other than icatibant or 
any investigational device(s) at any point during this study.
6.8.1
Fluid and Food Intake 
No specific restrictions on fluid or food intake apply for this study.
6.8.2
Subject Activity Restrictions
No specific restrictions on subject activity apply for this study.
6.9
Treatment Compliance
During this study, the investigational product will be administered at the hospital/study center 
under controlled conditions; therefore, full subject compliance with treatment is anticipated.
6.10
Packaging and Labeling
The investigational product will be packaged as 3-mL solution in a pre-filled 3-mL syringe made 
of clear type-I glass.  The back stopper consists of bromobutyl coated with fluorocarbon 
polymer.  Front closure is achieved by means of a luer-lock adaptor that allows secure 
attachment of the needle.  Secondary packaging consists of 1 icatibant syringe, labeled in a tray 
with a 25-guage needle placed inside a plain white carton, also labeled.  A fluid-dispensing 

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adaptor will be used to secure a 1-mL or 3-mL syringe to the glass syringe for withdrawal of 
icatibant.
See the Pharmacy Manual for additional details.
6.11
Storage and Accountability
The following information should be considered when storing and using the investigational 
product.
The investigational product will be shipped at 2° to 8°C.  Icatibant 10 mg/mL formulated for SC 
administration should be stored at or below 25°C.  The syringes must not be frozen.
The disposition of all investigational product delivered to a principal investigator must be 
recorded on a subject-by-subject basis by completing the clinical trial material accountability 
log.  The date and time of administration of the investigational product must be documented on 
the appropriate CRF.
The principal investigator, clinical research coordinator, or designee (eg, pharmacist) must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 
loss/damaged and return or destruction of used/unused product is complete, accurate, and ready 
for review at each monitoring visit and/or audit. 
The sites must ensure that the investigational product is available for the monitor to inventory 
and prepare for return shipment to the sponsor or designee, if required. 
6.12
Investigational Product Retention at Study Site
The process for destruction of investigational product must be determined and documented 
during the study start-up phase.  
If the investigational product is to be destroyed by the study sites, sites must follow their own 
process/policy that describes such activities.  All drug destruction processes will be documented 
and the sites must retain copies of these documents within the site regulatory binder.  The sites 
must ensure that the clinical trial material accountability and destruction log is complete, 
accurate, and ready for review and/or audit at each monitoring visit.  
All manifests documenting shipments of investigational product must be retained as well copies 
of any investigational product return forms.  
See the Pharmacy Manual for additional details.

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7
STUDY PROCEDURES
Detailed descriptions of subject evaluations required for this protocol are described in this 
section.  These evaluations will be performed during the indicated days and weeks of the study 
(see the study schedules of events in Appendix 1, No Attack, Appendix 2, Initial 
Icatibant-treated Attack, and Appendix 3, Subsequent Icatibant-treated Attacks).    
All data collected are to be recorded on the appropriate CRF or electronic diary (e-diary) page.
Details for study procedures including sample collection are described in the Operations Manual 
for this study.
7.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent must be obtained 
from the subject’s parent(s) or legal guardian(s) and assent from the subject (if applicable).
The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the subject, the subject’s parent(s), or the subject’s legal guardian(s) by the 
investigator or designee in accordance with the guidelines described in Section 11.4.  
Documentation and filing of informed consent documents should be completed according to 
Section 11.4.
7.2
Study Entrance Criteria
At screening, each subject will be reviewed for eligibility against the study entrance criteria.  
Subjects who do not meet the study entrance criteria will not be allowed to participate in the 
study.  The reason(s) for the subject’s ineligibility for the study will be documented.
7.3
Confirmation of Study Eligibility
Subject eligibility according to the study inclusion and exclusion criteria will be confirmed at the 
screening and pretreatment (baseline) visits on the basis of review of the study entrance criteria.
7.4
Demographics
Subject demographic information including gender, date of birth, and race will be collected prior 
to the subject receiving the first dose of investigational product. 
7.5
Medical History
Medical history will be recorded in the CRF.  Details of prior HAE attacks (eg, typical 
frequency, symptom duration, onset of relief, and type and frequency of medical interventions 
required) will be obtained at screening through pretreatment on Day 1.  Other important medical 
events, menstrual cycle history in females (see Section 7.6), and concomitant medication and 
illnesses will be recorded at other visits on the appropriate CRF pages.  Any existing medical 
condition present prior to the time of the first dose will be reported as medical history.

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7.6
Menstrual Cycle History
A menstrual cycle history will be determined historically for female subjects and will be 
recorded in the CRF.  The timing of the blood sampling with respect to the menstrual cycle must 
be known to inform the interpretation of any potential changes in reproductive hormones in 
adolescent females, because of the normal cyclical rise and fall of reproductive hormones of the 
menstrual cycle.
Instructions for investigators:
To assist in this determination, investigators should obtain the following information and 
document in the CRF.
•
Age of menarche
•
Normal duration of menstrual flow 
•
Normal interval in between menstrual periods 
•
Date of last onset of bleeding 
•
Prospectively ask female subjects to write down subsequent dates of onset of bleeding and 
cessation of bleeding between Day 1 and Day 90
•
Date of ovulation (sometimes called ovulation pain, mid-cycle pain or mittelschmerz) may 
also be documented if subjects can identify this feeling
7.7
Height and Weight
Height and weight will be recorded for all subjects.  
7.8
Pubertal Status Determination
The investigator will perform an examination for all subjects to determine whether they are 
prepubertal or pubertal/postpubertal.  A description of the sexual maturation scale described by 
Marshall and Tanner8, 9 is provided in Appendix 4.
7.9
Investigational Product Administration
Subjects will receive treatment with icatibant as a single, weight-adjusted dose of 0.4 mg/kg 
administered as an abdominal SC injection up to a maximum dose of 30 mg.  Treatment with 
icatibant should be administered within 12 hours of onset of an acute HAE attack.  
Pubertal/postpubertal subjects that present with a subsequent attack at least 7 days after prior 
treatment (see Section 4.1.3) may receive further treatment with icatibant for a total of 3 attacks.
7.10
Pharmacokinetic Assessments 
7.10.1
Pharmacokinetic Variables
Individual patient PK variables for icatibant and major metabolites will be determined from the 
respective plasma concentration time profiles where appropriate, using noncompartmental 
methods. 

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A population PK model will be derived to evaluate the correlation of key covariates (ie, age, 
body weight, gender) on the PK profile of icatibant.
Pharmacokinetic variables will be determined by full sampling and noncompartmental methods 
where possible, and elsewhere by sparse sampling (at least 4 to 7 time points) and a population 
PK approach using nonlinear mixed effects modeling software.  
Primary and secondary pharmacokinetic parameter estimates will be reported and include time to 
peak concentration (Tmax), actual peak (Cmax) and minimum (Cmin) concentrations, clearance 
(CL/F), actual area under the plasma concentration-time curve (AUC0-last and AUC0-inf), mean 
residence time (MRT), volume of distribution at steady state (Vss/F) and elimination half-life 
(t1/2).
The methods to be used for estimation of PK parameter values are described in Section 10.5.1.
7.10.2
Pharmacokinetic Sampling
Sampling for PK assessments will be collected according to the schedule of events provided in 
Appendix 1 (No Attack) and Appendix 2 (Initial Icatibant-treated Attack).
The time of investigational product administration on Day 1 will be designated as Time 0.  All 
post-treatment assessments will be calculated from the time of investigational product 
administration.  Detailed sample collection, processing, and shipping instructions will be 
provided in the study Operations Manual.
Blood samples for determination of plasma concentrations of icatibant in pubertal/postpubertal 
subjects will be collected on Day 1 at pretreatment, and at 15 (±5) minutes, 30 (±5) minutes, 
45 (±5) minutes, 1 hour (±10) minutes, 2 hours (±10) minutes, 4 (±0.5) hours, and 6 (±0.5) after 
treatment.
Blood samples for determination of plasma concentrations of icatibant in prepubertal subjects 
will be collected on Day 1 at pretreatment, and at 15 (±5) minutes, 30 (±5) minutes, 2 hours 
(±10) minutes, 4 (±0.5) hours, and 6 (±0.5) hours after treatment.
7.10.3
Bioanalytical Method
Plasma samples will be assayed for concentrations of icatibant and its metabolites (M1 and M2) 
using a validated method (see Section 7.21).
7.11
Efficacy Assessments
7.11.1
Investigator Symptom Score 
The investigator will use a symptom score to assess the severities of symptoms of acute 
cutaneous, abdominal, and laryngeal attacks of HAE using the following 5-point scale.  
Symptom scores will be recorded on Day 1 at pretreatment and at predetermined time points 
after treatment.  Results will be recorded in the CRF.

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Investigator-rated Symptom Score
0 = none; absence of symptoms
1 = mild (no to mild interference with daily activities)
2 = moderate (moderate interference with daily activities)
3 = severe (severe interference with daily activities)
4 = very severe (very severe interference with daily activities)
For attacks classified as cutaneous and/or abdominal, investigator-rated symptom scores will be 
collected for 8 symptoms:  abdominal tenderness, nausea, vomiting, diarrhea, skin pain, 
erythema, skin irritation, and skin swelling.  
For attacks classified as laryngeal, investigator-assessed symptom scores will be collected for 
13 symptoms:  abdominal tenderness, nausea, vomiting, diarrhea, skin pain, erythema, skin 
irritation, skin swelling, dysphagia, voice change, breathing difficulties, stridor, and asphyxia.  
7.11.2
Subject Self-assessment of Pain 
Subjects who are at least 4 years of age will self-assess HAE-related pain using the FPS-R.  A 
copy of the FPS-R is provided in Appendix 5.  
FPS-R self-assessment data will be recorded in an e-diary.  Subjects will record self-assessments 
on Day 1 at pretreatment and at predetermined time points after treatment while at the 
hospital/study center, and after their discharge to home.  Subjects will return the e diary to the 
hospital/study center at the scheduled visit on Day 8.  
Subjects will receive detailed instruction on when and how to use the e-diary from the 
investigator and/or clinical site personnel.
7.11.3
Investigator Assessment of Pain
Subjects who are below 4 years of age will undergo investigator assessment of HAE-related pain 
(cutaneous, abdominal, and laryngeal) using the FLACC comportmental pain scale.  A copy of 
the FLACC scale is provided in Appendix 6.
7.11.4
Initial Symptom Relief
The investigator will be asked to record the date and time when overall subject improvement was 
first noted and mark the date and time accordingly in the CRF.
7.12
Reproductive Hormone Assessments
Reproductive hormone levels will be measured in all subjects.  Blood samples will be collected 
to assess FSH, LH, estradiol, and progesterone in females, and FSH, LH, and testosterone in 
males.  

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7.13
Safety Assessments
7.13.1
Physical Examination
Physical examinations will include a review of the subject’s general appearance as well as 
evaluation of the body systems.  Any clinically significant abnormal change in findings will be 
recorded as an adverse event (AE) on the appropriate CRF.  The physical examination will 
include the following:
-
General appearance
-
Eye, ears, nose, throat 
-
Lymph nodes
-
Cardiovascular
-
Skin
-
Abdomen 
-
Neurological
-
Spine and extremities
-
Lungs
7.13.2
Vital Signs
Vital signs are to be recorded for all subjects and will include pulse, blood pressure, respiration 
rate, and temperature. 
7.13.3
Electrocardiography
A standard 12-lead ECG will be performed after 10 minutes at rest when the patient is seated or 
supine.  ECG results will be read locally at the clinical site.  Abnormalities will be recorded.
7.13.4
Clinical Laboratory Tests
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing.  The clinical laboratory tests to be performed are listed in Table 7-1. 

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Table 7-1
List of Clinical Laboratory Tests
Hematology:
-
Hematocrit 
-
Hemoglobin 
-
Mean corpuscular hemoglobin 
-
Mean corpuscular hemoglobin 
concentration 
-
Mean corpuscular volume 
-
Platelet count
-
Red blood cell count 
-
White blood cell  count with 
differential 
Urinalysis: 
-
Appearance
-
Bilirubin
-
Color
-
Glucose
-
Ketones
-
Nitrite 
-
Occult blood
-
pH
-
Protein
-
Specific gravity
Serum Chemistry:
-
Albumin 
-
Alkaline phosphatase 
-
Alanine aminotransferase
-
Aspartate aminotransferase 
-
Calcium 
-
Carbon dioxide 
-
Chloride 
-
Creatinine
-
Creatine kinase 
-
Gamma-glutamyl transferase 
-
Glucose
-
Lactate dehydrogenase 
-
Phosphorus
-
Potassium 
-
Sodium 
-
Total bilirubin
7.13.5
Local Tolerability
Injection site reactions (erythema, swelling, burning sensation, itching/pruritis, warm sensation, 
cutaneous pain, or other) will be evaluated by the investigator or other medically qualified 
personnel when the subject is at the hospital/study center, and the diameter of any erythema or 
swelling will be measured.  
After discharge, the subject (or the subject’s parent/legal guardian on behalf of the subject as 
appropriate) will be interviewed about injection site reactions, either in person or by telephone 
contact.  
7.13.6
Immunogenicity
The immunogenicity of icatibant will be assessed.  Serum samples for immunogenicity testing 
will be collected for determination of anti-icatibant antibodies.  Serum samples will be analyzed 
for anti-icatibant antibodies at Shire or at a designated laboratory.  Details concerning sample 
collection and preparation will be provided in the study Operations Manual.
Samples will be stored frozen at -65°C or below if not shipped on the day of collection.  Details 
for shipping will be provided in the study Operations Manual.

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7.13.7
Pregnancy Testing
Female subjects of childbearing potential (ie, those who have experienced menarche) will 
undergo pregnancy testing at time points specified in the study schedule of events (Appendix 1, 
Appendix 2, and Appendix 3).  All pregnancy testing will be conducted using a urine human 
chorionic gonadotropin (hCG) test kit.  The test will be performed and interpreted by the study 
personnel at the hospital/study center at the time of the visit.
7.14
Sample Collection, Storage, and Shipping
Blood samples will be collected via venipuncture.  Use of an indwelling catheter is encouraged 
for collection of serial blood samples for PK assessments when feasible.  Use of a topical local 
anesthetic (such as EMLA or LMX) is acceptable to make the procedure more tolerable for 
children, provided that the timing of this application does not interfere with blood sample 
collection.  Subjects will be in a seated or supine position during blood collection.
All samples will be stored and secured in a way that assures that unauthorized access is 
prohibited and the samples are not lost, allowed to deteriorate, or are accidentally or illegally 
destroyed.  Detailed sample collection, processing, and shipping instructions will be provided in 
the study Operations Manual.
7.15
Recording of Concomitant Medications 
All medications administered to the study subjects from the time of informed consent through the 
follow-up visit 90 (±7) days after investigational product administration are regarded as 
concomitant and will be documented in the CRF.  Concomitant medications are defined in 
Section 6.6.  
7.16
Recording of Adverse Events
Adverse events will be collected over an observation period from the time of treatment until the 
follow-up visit 90 (±7) days after investigational product administration (or until the event has 
resolved/stabilized or an outcome is reached, whichever comes first).  Adverse event monitoring 
and the period of observation defined for this study are described in Section 7.17.4.1.  
7.17
Adverse Events Assessments  
7.17.1
Definitions of Adverse Events and Serious Adverse Events
7.17.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
a clinical study, whether or not considered investigational product related.  This includes an 
exacerbation of a pre-existing condition.  However, anyexacerbation or worsening of symptoms 
of an acute HAE attack treated with icatibant is considered a result of the underlying disease and 
will not be considered an adverse event (unless meeting the criteria for a serious adverse event, 
see Section 7.17.1.2).

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Adverse events include:
•
Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study (with the exception of HAE).
•
Intercurrent illnesses.
•
Drug interactions.
•
Events related to or possibly related to concomitant medications.
•
Clinically significant abnormal laboratory values (this includes significant shifts from 
baseline within the range of normal that the investigator considers to be clinically important).
•
Clinically significant abnormalities in physical examination, vital signs, and weight.
The investigator must record all AEs in the CRF, regardless of the severity or relationship to 
investigational product.  The investigator should treat subjects with AEs appropriately and 
observe them at suitable intervals until the events stabilize or resolve.  Adverse events may be 
discovered through observation or examination of the subject, questioning of the subject, 
complaint by the subject, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become clinically significantly out of 
range.  In the event of an out-of-range value, the laboratory test should be repeated until it 
returns to normal or stabilizes, or can be medically explained, and the subject’s safety is not at 
risk.
Additional illnesses present at the time when informed consent is given until the time of 
treatment are regarded as concomitant illnesses and will be documented on the medical history 
page of the CRF.  Illnesses first occurring or detected on or after treatment, and worsening of a 
concomitant illness during the study, are to be regarded as adverse events and must be 
documented as such in the CRF.
The treated HAE attack is defined as any symptoms occurring in treated subjects within 48 hours 
of the onset of symptoms.  A clinically relevant worsening of the signs and symptoms of a 
treated attack is considered to be related to the underlying disease of HAE, and will be collected 
in the appropriate CRF separately from general reports of adverse events unless meeting the 
criteria of a serious adverse event.  Symptoms reoccurring more than 48 hours after an initial 
attack will be considered a new attack, and will also not be reported as AEs.  Attacks not treated 
with icatibant will be documented in the appropriate CRF at the Day 90 visit; they are considered 
to be pre-existing disease and will not be documented as AEs.
Local tolerability will include symptoms at the site of icatibant administration (injection site) and 
will be assessed separately from general reports of AEs.  Injection site reactions will be 
documented in the “local tolerability” page of the CRF.  Injection site reactions that have been 
reported previously with icatibant included erythema, swelling, burning sensation, itching, 
warmth and pain and were generally, mild to moderate, transient, and resolved without sequelae. 
Injection site reactions that do not meet the criteria of a serious adverse event will not need to be 
additionally reported as AEs.

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7.17.1.2
Serious Adverse Event
A serious adverse event (SAE) is any AE occurring at any dose that results in any of the 
following outcomes:
•
Death.
•
Is life-threatening.
•
Requires hospitalization.
•
Requires prolongation of existing hospitalization.
•
A persistent or significant disability or incapacity. 
•
A congenital anomaly or birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  A life-threatening AE is defined as an AE that placed the 
subject, in the view of the initial reporter, at immediate risk of death from the adverse event as it 
occurred (ie, it does not include an AE that, had it occurred in a more severe form, might have 
caused death).
7.17.2
Classification of Adverse Events and Serious Adverse Events
The severity of AEs will be assessed by the investigator as mild, moderate, or severe based on 
the definitions shown in Table 7-2. The severity of AEs and SAEs should be recorded on the 
appropriate CRF page as mild, moderate, or severe.
Table 7-2
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.
7.17.2.1
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (eg, severe headache).  This is not the same as “serious,” which is based on 
the outcome or action criteria usually associated with events that pose a threat to life or 
functioning.  Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.

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7.17.3
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product is to be determined by the investigator 
based on the following definitions (see Table 7-3).  
Table 7-3
Adverse Event Relatedness
Relationship to Product(s)
Definition
Not Related
Unrelated to investigational product
Possibly Related
A clinical event or laboratory abnormality with a reasonable 
time sequence to administration of investigational product, but 
which could also be explained by concurrent disease or other 
drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable 
time sequence to administration of investigational product, 
unlikely to be attributable to concurrent disease or other drugs 
and chemicals and which follows a clinically reasonable 
response on de-challenge.  The association of the clinical event 
or laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds.
Definitely related
The event follows a reasonable temporal sequence from 
administration of the investigational product, follows a known 
or suspected response pattern to the investigational product, is 
confirmed by improvement upon stopping the investigational 
product (de-challenge), and reappears upon repeated exposure 
(re-challenge).  Note that this is not to be construed as requiring 
re-exposure of the subject to investigational product; however,
the determination of definitely related can only be used when 
recurrence of event is observed.
7.17.4
Procedures for Recording and Reporting Adverse Events
7.17.4.1
Adverse Event Monitoring and Period of Observation
Adverse events will be monitored continuously.  For the purposes of this study, the safety 
observation period will extend from the time of treatment with investigational product until the 
subject’s final evaluation after treatment.  For subjects who complete the study, the final 
evaluation of AEs will occur at the follow-up visit performed 90 (±7) days after treatment with 
investigational product.  
If the investigator considers it necessary to report an AE in a subject after the end of the safety 
observation period, he or she should contact the sponsor to determine how the AE should be 
documented and reported.  

Ic ati b a nt ( Fir az yr ® )
Cli nic al Tri al Pr ot oc ol A m e n d me nt 3: H G T - FI R-0 8 6
1 9 J u ne 2 0 1 3
S hire
C o nfi de nti al
4 7
7. 1 7. 4. 2
Re p orti n g Seri o us A d verse E ve nts
A n y  S A E , re gar dless of relati o ns hi p t o i n vesti gati o nal pr o d uct, w hic h occ urs i n a s u bject after 
i nf or me d c o nse nt, s h o ul d be rec or de d by t he cli nical site o n a seri o us a d verse e ve nt f or m.  T he 
S A E m ust be c o m pletel y  descri be d o n t he s u bject’s C R F, i ncl u di n g t he j u d g me nt of t he 
i n vesti gat or as t o t he relati o ns hi p of t he S A E t o t he i n vesti gati o nal pr o d uct.  
T he i n vesti gat or will pr o m ptl y  s u p ply all i nf or mati o n i de ntifie d a n d re q ueste d b y t he s p o ns or ( or 
c o ntract researc h or ga nizati o n [ C R O]) re gar di n g t he S A E .  T he i n vesti gat or m ust re p ort t he 
seri o us a d verse e ve nt t o t he S hire P har mac o vi gila nce a n d Ris k Ma na ge me nt De part me nt A N D t o 
t he S hire Me dical M o nit or o n a n S A E f or m.  T his f or m m ust be c o m plete d a n d fa xe d or e maile d 
wit hi n 2 4 h o urs of t he i n vesti gat or’s lear ni n g of t he e ve nt t o:
S hire P h ar m ac o vi gil a nce a n d Ris k M a n a ge me nt De p art me nt:
F A X:  
( W orl d wi de) O R
( N ort h A meric a)
E m ail: 
A N D
S hire Me dic al M o nit or: 
, M D, P h D
F A X: 
( U S A)
P P D
A n y  f oll o w-u p i nf or mati o n m ust als o be c o m plete d o n a n S A E f or m a n d fa xe d or e maile d t o t he 
sa me n u m bers liste d a b o ve.
P P D
P P D
P P D
P P D
P P D

Ic ati b a nt ( Fir az yr ® )
Cli nic al Tri al Pr ot oc ol A m e n d me nt 3: H G T - FI R-0 8 6
1 9 J u ne 2 0 1 3
S hire
C o nfi de nti al
4 8
I n t he e ve nt of a se vere a n d u ne x pecte d, fatal, or life -t hreate ni n g S A E , t he cli nical site m ust 
c o ntact t he S hire Me dical M o nit or b y  tele p h o ne; t his is i n a d diti o n t o c o m pleti n g a n d 
tra ns mitti n g t he S A E f or m as state d a b o ve.  T he f oll o wi n g pr o vi des c o ntact i nf or mati o n f or t he 
S hire Me dical M o nit or. 
If an S A E is assesse d as se vere a n d u ne x pecte d, or life-t hreate ni n g, c o ntact:
If a n S A E is assesse d as se vere a n d u ne x pecte d, or life-t hre ate ni n g, c o nt act:
 M D, P h D
S hire H u m a n Ge netic T her a pies, I nc.
3 0 0 S hire W a y
Le xi n gt o n, M A 0 2 4 2 1 U S A
Tele p h o ne:  
M o bile:  
F a x: 
( U S A)
T he i n vesti gat or m ust pr o m ptl y  re p ort all re q uire d i nf or mati o n t o t he Instit uti o nal Re vie w B oar d 
(IR B )/I n de pe n de nt Et hics C o m mittee (IE C).  It is t he res p o nsi bilit y  of t he s p o ns or t o e ns ure t hat 
eac h i n vesti gat or recei ves a c o p y of a n y C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces ( CI O M S I)/ Me d Watc h re p ort t hat has bee n s u b mitte d t o t he a p pr o priate re g ulat or y  
a ge ncies n otif yi n g t he m of a n u ne x pecte d relate d S A E .  
T he i n vesti gat or or s p o ns or m ust e ns ure t hat t he I R B/I E C recei ves a c o p y of t he re p ort a n d t hat a 
c o p y is als o file d wit hi n t heir st u d y files.
7. 1 8
Pre g n a nc y
Pre g na nc y  a n d lactati o n are e xcl usi o n criteria f or t his st u d y.  T he s p o ns or m ust be n otifie d i n t he 
e ve nt of a pre g na nc y occ urri n g d uri n g t he c o urse of t he st u d y a n d t hr o u g h 1 8 0 da ys after t he 
s u bject’s last d ose of i n vesti gati o nal pr o d uct.  Pre g na nc y is n ot t o be re p orte d as a n A E ; t he 
pre g na nc y  re p orti n g f or m s h o ul d be use d t o re p ort t he pre g na nc y.  T he pre g na nc y will be 
f oll o we d u p t hr o u g h deli ver y or fi nal o utc o me.
7. 1 9
A b use, O ver d ose, a n d Me dic ati o n Err or
•
A b use – Persiste nt or s p ora dic i nte nti o nal i nta ke of i n vesti gati o nal me dici nal pr o d uct at a 
d ose hi g her t ha n prescri be d per pr ot oc ol ( b ut bel o w t he d ose defi ne d f or o ver d ose) or w he n 
use d f or n o n -me dical p ur p ose (e g, alteri n g o ne’s state of c o nsci o us ness).
•
Mis use
P P D
– I nte nti o nal or u ni nte nti o nal use of i n vesti gati o nal me dici nal pr o d uct ot her t ha n as 
directe d or i n dicate d at a n y  d ose, w hic h is at or bel o w t he d ose defi ne d f or o ver d ose ( N ote:  
t his i ncl u des a sit uati o n w here t he pr o d uct is n ot use d as directe d at t he d ose prescri be d by 
t he pr ot oc ol).
P P D
P P D
P P D
P P D
P P D

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•
Overdose – No clinical information on overdose is available.  A dose of 3.2 mg/kg 
(approximately 8 times the therapeutic dose) caused transient erythema, itching or 
hypotension in healthy subjects.  No therapeutic intervention was necessary.
•
Medication Error – A mistake made in prescribing, dispensing, administration and/or use of 
the investigational medicinal product.
7.20
Removal of Subjects from the Trial or Investigational Product
A subject’s participation in the study may be discontinued at any time at the discretion of the 
investigator.  The following may be justifiable reasons for the investigator to remove a subject 
from the study:
•
Non-compliance, including failure to appear at one or more study visits.
•
The subject was erroneously included in the study.
•
The subject develops an exclusion criterion. 
•
The subject suffers an intolerable adverse event.
•
The study is terminated by the sponsor.
•
The study is closed prior to the subject’s first eligible attack.
The subject, the subject’s parent(s), or the subject’s legal guardian(s) acting on behalf of the 
subject is free to withdraw consent and discontinue participation in the study at any time without 
prejudice to further treatment.
If a subject or the subject’s parent(s) or the subject’s legal guardian(s) acting on behalf of the 
subject, discontinues participation in the study, or the subject is discontinued by the investigator, 
the subject completion/discontinuation CRF describing the reason for discontinuation must be 
completed.  Any AEs experienced up to the point of discontinuation must be documented in the 
CRF.  If AEs are present when the subject withdraws from the study, the subject will be re-
evaluated within 30 days of withdrawal.  All ongoing SAEs at the time of withdrawal will be 
followed until resolution.
7.20.1
Safety-Related Study Stopping Rules  
The Data and Safety Monitoring Board (see Section 11.8 for a description of the DSMB and its 
role) may elect to suspend the study until the DSMB can review any death that is drug or 
disease-related or unexplained, or if there is an unexpected drug-related severe AE.
Following the review of safety data, the study will be either:
•
Resumed unchanged
•
Resumed with modifications to the protocol 
•
Terminated
Subject safety will be monitored on a continuous basis during this study until the last subject 
completes his or her last scheduled study visit/assessment.  

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Additional information on safety monitoring can be found in Section 11.8.
7.21
Appropriateness of Measurements
The safety assessments used in this study are standard and will provide a detailed measure of the 
safety of icatibant in the pediatric population. 
The measures of serum reproductive hormone concentration are accepted measures for assessing 
the function of reproductive organs.  
Plasma samples will be assayed for concentrations of icatibant and its 2 major metabolites 
(M1 and M2) using a validated high-performance liquid chromatography/tandem mass 
spectrometry (LC-MS/MS) method with a lower limit of quantification of 1 ng/mL and a range 
from 1 to 1000 ng/mL (Analytical Report SHR10-002).  Pharmacokinetic variables will be 
determined by full sampling and noncompartmental methods where possible, and elsewhere by 
sparse sampling (at least 4 to 7 time points) and a population PK approach using non-linear 
mixed effects modeling software.
The symptom score used in efficacy assessments in this study is an investigator-rated measure of 
symptom severity based on a standard 5-point scoring system (0-absence of symptoms, 1-mild, 
2-moderate, 3-severe, 4-very severe)  capturing symptoms of acute attacks of HAE that have 
been identified and validated to assess efficacy in adults.  For attacks classified as abdominal or 
cutaneous, investigator-rated symptom scores are collected for 8 symptoms:  abdominal 
tenderness, nausea, vomiting, diarrhea, skin pain, erythema, skin irritation, and skin swelling.  
For attacks classified as laryngeal, investigator-assessed symptom scores are collected for 
13 symptoms:  abdominal tenderness, nausea, vomiting, diarrhea, skin pain, erythema, skin 
irritation, skin swelling, dysphagia, voice change, breathing difficulties, stridor, and asphyxia.  
In all pediatric subjects in the present study, irrespective of age, the investigator-rated symptom 
score will provide an appropriate means to measure the severity of primary symptoms (eg, 
cutaneous and/or abdominal pain, cutaneous swelling, or laryngeal symptoms) of acute attacks of 
HAE at pretreatment and the change in symptom severity, if any, after treatment with icatibant.
Though subject-reported outcomes such as the symptom score and visual analog scale (VAS) 
have been employed successfully as efficacy measures in clinical studies of icatibant in adults, 
the use of these subject-reported outcomes in children poses special challenges.  The Faces Pain 
Scale is a validated, self-reported measure used to assess the intensity of children's pain in a wide 
variety of clinical contexts.10  The Faces Pain Scale-Revised (FPS-R) was adapted from the 
original FPS in order to make it possible to score pain on a widely accepted 0-to-10 metric.11  
The scales are suitable for use in assessment of the intensity of children's acute pain from age 
4 onward, are simple to administer, and require no specialized equipment other than the 
standardized images of faces.  Use of the FPS-R is planned for this study, and will provide an 
appropriate means to measure pain associated with acute attacks of HAE in pediatric subjects 
who are at least 4 years of age.
Young children (ie, those below the age of 4 years) frequently lack the verbal and cognitive 
skills necessary to report physical discomfort and pain intensity.  Behavioral cues are the primary 

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indicators of pain in children who are unable to report pain or follow instructions in the use of 
assessment tools.  The FLACC instrument comprises 5 categories of behavior (face, legs, 
activity, cry, and consolability) to assess pain in preverbal children or children with limited 
verbal capability.12, 13 Each category is scored on a 0-to-2 scale which results in a total score 
from 0 to 10.
Collectively, the measures employed in this study are expected to allow for assessment of the PK 
profile, tolerability, safety, and efficacy of icatibant in the pediatric population.

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8
STUDY ACTIVITIES
8.1
Screening (Day of Informed Consent to Pretreatment on Day 1)  
•
Informed Consent/Assent
•
Inclusion/Exclusion Criteria
•
Medical History
•
Documentation of HAE attack(s) not treated with icatibant*
•
Confirmation of documented HAE diagnosis (via the sponsor’s central laboratory)
•
Measurement of C1-INH 
•
Pubertal status determination
•
Physical examination
•
Vital signs
•
ECG
•
Height and weight
•
Urine pregnancy test (in females of childbearing potential)
•
Recording of concomitant medications
*For all subjects who remain enrolled in the study for longer than 6 months, a telephone contact 
will be scheduled every 6 months to collect information concerning HAE attacks not treated with 
icatibant in the study.
8.2
Pretreatment (Baseline) Assessments (Day 1, No Attack)
The following assessments will be performed for subjects who will be treated with icatibant in 
the absence of a current HAE attack.  All evaluations and sample collections must be performed 
prior to treatment.
•
Medical history 
•
Confirm inclusion/exclusion criteria 
•
Pubertal status determination (only if the subject was classified as prepubertal at the time of 
the screening visit)
•
Menstrual cycle history (in pubertal/postpubertal females only)
•
Physical examination
•
Vital signs
•
Height and weight
•
Clinical laboratory tests (serum chemistry, hematology and urinalysis)
•
Urine pregnancy test (in females of childbearing potential)
•
Reproductive hormone assessments
•
Pharmacokinetic sampling
•
Immunogenicity evaluation
•
Recording of concomitant medications

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8.3
Pretreatment (Baseline) Assessments (Day 1, Initial and Subsequent Attacks)
The following assessments will be performed at both initial and subsequent icatibant-treated 
attacks unless otherwise indicated.  All evaluations and sample collections must be performed 
prior to treatment.
•
Medical history (at initial attack only)
•
Confirm inclusion/exclusion criteria 
•
Pubertal status determination (only if the subject was classified as prepubertal at the time of 
the screening visit)
•
Menstrual cycle history (in pubertal/postpubertal females only)
•
Physical examination
•
Vital signs
•
ECG (at subsequent attacks only)
•
Height and weight
•
Subject self-assessment of HAE-related pain (in subjects 4 years of age and older) using 
e-diary FPS-R
•
Investigator assessment of HAE symptoms
•
Investigator assessment of HAE-related pain (in subjects younger than 4 years of age only) 
using FLACC
•
Clinical laboratory tests (serum chemistry, hematology and urinalysis)
•
Urine pregnancy test (in females of childbearing potential)
•
Reproductive hormone assessments
•
Pharmacokinetic sampling (at pretreatment for initial attack only)
•
Immunogenicity evaluation
•
Recording of concomitant medications
•
Assessment of adverse events (at pretreatment for subsequent attacks only)
8.4
No Attack
8.4.1
Treatment Period (Day 1 to Day 8 [± 1 Day])
•
Investigational product administration (Day 1, Time 0)
•
Physical examination (Day 1, 6 [±0.5] hours) (or 8 [±0.5] hours if the subject is not 
discharged***) post dose and Day 8 [±1 day])
•
Vital signs (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours) (or 8 [±0.5] hours if the subject is 
not discharged***) post dose and Day 8 [±1 day])
•
ECG (Day 1, 6 [±0.5] hours (or 8 [±0.5] hours if the subject is not discharged***) post dose) 
•
Clinical laboratory tests (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])
•
Reproductive hormone assessments (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])
•
Injection site reaction evaluation (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours) (and 8 [±0.5] 
hours if the subject is not discharged**) post dose, Day 2 (24 [±4] hours), Day 3 (48 [±4] 
hours), and Day 8 [±1 day])

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•
Sampling for PK assessments in pubertal/post pubertal subjects (Day 1, 15 [±5] minutes, 
30 [±5] minutes, 45 [±5 minutes], 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] 
hours, 6 [±0.5] hours post dose)
•
Safety follow-up contact (Day 2 (24 [±4] hours), Day 3 (48 [±4] hours) by telephone (If a 
subject remains hospitalized, this safety follow-up will be conducted in person.)
•
Immunogenicity evaluation (Day 8 [±1 day])
•
Menstrual cycle history (Day 8 [±1 day] in pubertal/postpubertal females)
•
Recording of concomitant medications 
•
Assessment of adverse events 
*A subject may be discharged after completion of all assessments at 6 hours post treatment, if 
deemed medically stable in the investigator’s clinical judgment.   If this is the case, the 
assessments scheduled for 8 hours post treatment will be omitted.
8.5
Initial Attack 
8.5.1
Treatment Period (Day 1 to Day 8 [± 1 Day])
•
Investigational product administration (Day 1, Time 0)
•
Physical examination (Day 1, 6 [±0.5] hours) (or 8 [±0.5] hours if the subject is not 
discharged***) post dose and Day 8 [±1 day])
•
Vital signs (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours) (or 8 (±0.5) hours if the subject is 
not discharged***) post dose and Day 8 [±1 day])
•
ECG (Day 1, 6 [±0.5] hours (or 8 [±0.5] hours if the subject is not discharged***) post dose)
•
Subject self-assessment of HAE-related pain (in subjects 4 years of age and older) using 
e-diary FPS-R (Day 1, 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] hours, 6 [±0.5] 
hours and 8* [±0.5] hours post dose, Day 2 (24 [±4] hours), Day 3 (48 [±4] hours)
•
Investigator assessment of HAE symptoms (Day 1, 1 hour [±10 minutes], 2 hours 
[±10 minutes], 4 [±0.5] hours, 6 [±0.50] hours (and 8 [±0.5] hours if the subject is not 
discharged**) post dose)
•
Investigator assessment of HAE-related pain (in subjects younger than 4 of age only) using 
FLACC (Day 1, 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] hours, 6 [±0.5] hours 
(and 8 [±0.5] hours if the subject is not discharged**) post dose)
•
Clinical laboratory tests (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])
•
Reproductive hormone assessments (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])
•
Injection site reaction evaluation (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours (and 8 [±0.5] 
hours if the subject is not discharged**) post dose, Day 2 (24 [±4] hours), Day 3 (48 [±4] 
hours), and Day 8 [±1 day])
•
Sampling for PK assessments in pubertal/post pubertal subjects (Day 1, 15 minutes [±5 
minutes], 30 minutes [±5 minutes], 45 minutes [±5 minutes], 1 hour [±10 minutes], 2 hours 
[±10 minutes], 4 [±0.5] hours, 6 [±0.5] hours post dose at initial attack only)
•
Sampling for PK assessments in prepubertal subjects (Day 1, 15 minutes [±5 minutes], 
30 minutes [±5 minutes], 2 hours [±10 minutes], 4 [±0.5] hours, 6 [±0.5] hours post dose at 
initial attack only)

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•
Safety follow-up contact (Day 2 (24 [±4] hours), Day 3 (48 [±4] hours) by telephone (If a 
subject remains hospitalized, this safety follow-up will be conducted in person.)
•
Immunogenicity evaluation (Day 8 [±1 day])
•
Menstrual cycle history (Day 8 [±1 day] in pubertal/postpubertal females)
•
Recording of concomitant medications 
•
Assessment of adverse events 
*A subject may be discharged after completion of all assessments at 6 hours post treatment, if 
deemed medically stable in the investigator’s clinical judgment and the subject’s HAE symptoms 
have resolved (the subject’s investigator-rated symptom score = zero, denoting the absence of 
symptoms).  
If this is the case, the assessments scheduled for 8 hours post treatment will be omitted with the 
exception of subject self-assessment of HAE-related pain using the e-diary FPS-R. 
**If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s 
investigator-rated symptom score ≠ zero) and the subject is not to be discharged after completion 
of assessments at the 6-hour time point, the assessments indicated will be performed at both 
6 AND 8 hours post treatment.
***If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s 
investigator-rated symptom score ≠ zero) and the subject is not to be discharged after completion 
of assessments at the 6-hour time point, the assessments indicated will be performed at either 
6 OR 8 hours post treatment.
8.5.2
Follow-up Visit (Day 90 ±7 days)
In the event that a subject has a subsequent HAE attack within the 90 day follow-up period for 
the first treatment, the date of the Day 90 follow-up visit for the first treatment remains the same.  
Each subsequent treatment will have a corresponding Day 90 follow-up visit. 
•
Physical examination
•
Vital signs
•
Height and weight
•
Clinical laboratory tests (serum chemistry, hematology, and urinalysis)
•
Urine pregnancy test (in females of childbearing potential)
•
Reproductive hormone assessments
•
Immunogenicity evaluation 
•
Menstrual cycle history (in pubertal/postpubertal females)
•
Recording of concomitant medications
•
Assessment of adverse events
•
Documentation of HAE attack(s) not treated with icatibant

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8.5.3
Telephone Contact (Month 6 ±7 days) 
The scheduled telephone contact will document pubertal changes/milestones, if any.
•
Pubarche
•
Menarche (females only)
•
Changes in menstrual cycle (females only)
•
Pregnancy (females and male partner)
8.6
Subsequent Attacks (Pubertal/Postpubertal Subjects Only)
Pubertal/postpubertal subjects may receive treatment for up to 2 subsequent HAE attacks, 
contingent upon having been treated for an initial attack and presenting with a subsequent acute 
attack of at least 7 days after prior treatment (see Section 4.1.3).  
Each treatment for a subsequent attack will require a Day 90 follow up visit.  If a subsequent 
attack occurs within 7 days of the Day 90 follow-up visit for the previous attack, the assessments 
on Day 8 and Day 90 will be combined.   
8.6.1
Treatment Period (Day 1 to Day 8 [± 1 Day])
•
Investigational product administration (Day 1, Time 0)
•
Physical examination (Day 1, 6 [±0.5] hours (or 8 (±0.5) hours if the subject is not 
discharged***) post dose and Day 8 [±1 day]) 
•
Vital signs (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours (or 8 [±0.5] hours if the subject is 
not discharged***) post dose and Day 8 [±1 day])
•
ECG (Day 1, 6 [±0.5] hours (or 8 [±0.5] hours if the subject is not discharged***) post dose)
•
Subject self-assessment of HAE symptoms in subjects 4 years of age and older using e-diary 
FPS-R (Day 1, 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] hours, 6 [±0.5] hours 
and 8* [±0.5] hours post dose, Day 2 (24 [±4] hours), Day 3 (48 [±4] hours))
•
Investigator assessment of HAE symptoms (Day 1, 1 hour [±10 minutes], 2 hours [±10 
minutes], 4 [±0.5] hours, 6 (±0.5) hours [and 8 (±0.5) hours if the subject is not discharged**] 
post dose)
•
Clinical laboratory tests (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])
•
Reproductive hormone assessments (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])
•
Injection site reaction evaluation (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours (and 8 [±0.50] 
hours if the subject is not discharged**) post dose, Day 2 (24 [± 4] hours), Day 3 (48 [±4] 
hours), and Day 8 [±1 day])
•
Safety follow-up contact (Day 2 (24 [±4] hours], Day 3 (48 [±4] hours) by telephone (If a 
subject remains hospitalized, this safety follow-up will be conducted in person.)
•
Immunogenicity evaluation (Day 8 [±1 day])
•
Menstrual cycle history (Day 8 [±1 day] in pubertal/postpubertal females)
•
Recording of concomitant medications
•
Assessment of adverse events 

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*A subject may be discharged after completion of all assessments at 6 hours post treatment, if 
deemed medically stable in the investigator’s clinical judgment and the subject’s HAE symptoms 
have resolved (the subject’s investigator-rated symptom score = zero, denoting the absence of 
symptoms).  
If this is the case, the assessments scheduled for 8 hours post treatment will be omitted with the 
exception of subject self-assessment of HAE-related pain using the e-diary FPS-R. 
**If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s 
investigator-rated symptom score ≠ zero) and the subject is not to be discharged after completion 
of assessments at the 6-hour time point, the assessments indicated will be performed at both 
6 AND 8 hours post treatment.
***If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s 
investigator-rated symptom score ≠ zero) and the subject is not to be discharged after completion 
of assessments at the 6-hour time point, the assessments indicated will be performed at either 
6 OR 8 hours post treatment.
8.6.2
Follow-up Visit (Day 90 ±7 days)
•
Physical examination
•
Vital signs
•
Height and weight
•
Clinical laboratory tests (serum chemistry, hematology, and urinalysis)
•
Urine pregnancy test (in females of childbearing potential)
•
Reproductive hormone assessments
•
Immunogenicity evaluation
•
Menstrual cycle history (in pubertal/postpubertal females)
•
Recording of concomitant medications
•
Assessment of adverse events
•
Documentation of HAE attack(s) not treated with icatibant
8.6.3
Telephone Contact (Month 6 ±7 days) 
The scheduled telephone contact will document pubertal changes/milestones, if any.
•
Pubarche
•
Menarche (females only)
•
Changes in menstrual cycle (females only)
•
Pregnancy (females and male partner)

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9
QUALITY CONTROL AND ASSURANCE
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
Clinical sites will be monitored by the sponsor or its designee to ensure the accuracy of data 
against source documents.
The required data will be captured in a validated clinical data management system that is 
compliant with the Food and Drug Administration (FDA) 21 Code of Federal Regulations (CFR) 
Part 11 Guidance.  The clinical trial database will include an audit trail to document any 
evidence of data processing or activity on each data field by each user.  Users will be trained and 
given restricted access, based on their role(s) in the study, through a password-protected 
environment.
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the sponsor or its designee.  If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Pharmacovigilance database.

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10 PLANNED STATISTICAL METHODS
10.1
General Considerations
All statistical analyses will be performed using SAS® statistical software (SAS Institute, North 
Carolina, USA) except for the population PK modeling which will be performed with
nonlinear mixed effect modeling software (eg, Phoenix NLME module, Pharsight Corp.). A
separate analytic plan will be developed to support the analysis of PK data. The analysis
methods for all other study data (disposition, demographic and pretreatment characteristics, 
efficacy variables, and safety variables) will be detailed in the statistical analysis plan (SAP).
Data will be summarized with respect to disposition, demographic, pretreatment characteristics, 
PK variables, safety variables, and efficacy variables.  Summary statistics for continuous 
variables will include the number of subjects, the mean, median, standard deviation, and range.  
For PK parameters, the coefficient of variation and geometric mean also will be provided.  For 
categorical data, summaries will include counts and percentages.  For time to event data, the 
median time to event and other summary statistics will be estimated using the method of Kaplan 
and Meier.
10.2
Determination of Sample Size
The study will enroll a sufficient number of children and adolescents to ensure study completion 
of 30 subjects.  The study population is planned to consist of at least 10 prepubertal and 
20 pubertal/postpubertal subjects from 2 to less than 18 years of age.  Though empirically 
derived and not based on a formal sample size calculation, this sample size will provide basic 
information concerning the PK, tolerability and safety, and efficacy of icatibant in children and 
adolescents with HAE.
10.3
Analysis Populations
The following populations will be used in the analysis:
•
The Efficacy Population will consist of those subjects who were treated with icatibant for 
their first and any additional attacks.
•
The PK Population will consist of those subjects who were treated with icatibant and had 
sufficient icatibant plasma concentration time measurements to derive primary PK 
parameters. 
•
The Safety Population will consist of those subjects who were treated with icatibant at least 
once
All efficacy analyses will be performed on the Efficacy Population.  The corresponding tabular 
summaries and listings will be presented by the subject stratification group at enrollment (ie, 
prepubertal group or pubertal/postpubertal group) and icatibant-treated attack number.
The PK analyses will be based on the PK Population.  

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Safety and tolerability analyses will be based on the Safety Population.  All tabular summaries
and listings within this population will be presented by the subject stratification group and 
icatibant exposure number.
10.4
Demographics and Baseline Characteristics
Demographic data and pretreatment characteristics will be summarized separately for the Safety 
Population and the Efficacy Population.
10.5
Pharmacokinetic Analysis
A primary objective of the study is to investigate the PK of a single SC injection of icatibant in 
pediatric subjects.  All PK analyses will use the PK population.
Plasma concentrations of icatibant and metabolites (ie, M1 and M2) and actual blood sampling 
times will be listed by subject and sampling time.  Plasma concentrations will be summarized 
using descriptive statistics (number, mean and standard deviation).  Pharmacokinetic parameters 
for icatibant and metabolites will be listed by subject and will be summarized using descriptive 
statistics (number, mean, standard deviation, coefficient of variation, geometric mean, minimum, 
median, maximum).  Individual and mean plasma concentrations of icatibant and metabolites 
versus time will be displayed on linear and semi-logarithmic axes.
10.5.1
Estimation of PK Parameters
10.5.1.1
Noncompartmental Modeling
For subjects in whom the number of samples is sufficient to permit noncompartmental modeling, 
individual and mean PK parameters will be computed for icatibant and metabolites (M1 and M2) 
using standard noncompartmental methods, where possible, using the WinNonLin software 
package (Pharsight Corp., Mountain View, CA).  For descriptive statistical tabulation of mean 
plasma concentrations and graphical displays, nominal collection times will be used, while all 
PK analysis and parameter calculations will use actual collection times.  Plasma concentrations 
<LOQ will be treated as 0 for the calculation of the descriptive statistics for plasma 
concentrations at each sampling time.  For the pharmacokinetic analysis, plasma concentrations 
<LOQ that occurred from pre-dose to the first concentration ≥LOQ will be treated as 0 and those 
that occur thereafter will be treated as missing.
Pharmacokinetic parameter estimates will include, where appropriate:  icatibant and metabolite 
concentrations at each sampling time, time to peak concentration (Tmax), actual peak (Cmax) and 
minimum (Cmin) concentrations, CL/F, AUC0-last and AUC0-inf, MRT, volume of distribution at 
steady state (Vss/F) and elimination half-life (t1/2).
The distribution of continuous data will be evaluated using parametric tests.  A transformation, 
such as logs, will be used where appropriate.  Multiple regression analysis, with an appropriate 
transformation on the dependent variable, will be used to assess the contribution of potential PK 
covariates while controlling for demographic covariates (eg, subject’s age and gender) to the 
inter-subject variability of icatibant PK parameters.  The multivariable analysis will be 

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considered the primary statistical analysis.  A p-value of 0.05 will be considered statistically 
significant for all analyses.
10.5.1.2
Compartmental Modeling Using Population Methods 
Nonlinear mixed effects modeling will be used to define individual subject profiles and if 
possible, parameter estimates.  The structural PK model will be developed and validated using 
PK information obtained from adult subjects and will enable delineation of the impact of age-
dependent changes on icatibant disposition.  Development of this model will allow for 
characterization and better prediction of the dose-concentration-exposure relationship for 
icatibant in pediatric subjects.  Population PK modeling will be performed with nonlinear mixed 
effect modeling software (eg, NONMEM, Globomax LLC or WinNonMix, Pharsight Corp.).  
The program will estimate the inter- and intra-individual variability of PK parameter estimates.  
Both weight-normalization and allometric scaling principles will be evaluated.  For selecting 
preliminary meaningful covariates the general additive model (GAM) analysis will be used.  
Variables to be considered will include (but are not limited to):  age, sex, ethnicity, total and lean 
bodyweight (TBW, LBW), body mass index (BMI), and body surface area (BSA).
Monte Carlo simulation experiments based on the model(s) developed above may be performed 
by a validated simulation software program (eg, Trial Simulator, Pharsight Corp.) to assess the 
response patterns for various dosage regimens of icatibant treatments in the pediatric population.
10.6
Safety and Tolerability Analyses
Another key objective of the study is to investigate the safety and tolerability of a single SC dose 
of icatibant in pediatric subjects treated with icatibant for the first time or treated with icatibant 
more than once. The corresponding analyses will be based on the Safety Population.
The safety and tolerability parameters include AEs, vital signs, ECG, local tolerability at the 
injection site, reproductive hormone levels, immunogenicity, and standard hematology, serum 
chemistry, and urinalysis.
Adverse events will be categorized using MedDRA Version 8.1. The assessment of safety will 
be based mainly on the frequency of treatment emergent AEs. Adverse events will be 
summarized by system organ class (SOC) and preferred term. The number and proportion of 
subjects experiencing an AE will be tabulated by the stratification group and icatibant exposure
number.  Adverse events by SOC and preferred term also will be tabulated by severity and by 
relationship to treatment. In the case of multiple occurrences of the same AEs (at the preferred 
term level) in an individual subject, the AE that is classified as the most severe (ie, maximum 
severity) will be identified for the analysis by severity and the AE that has the highest 
relationship to investigational product will be identified for the analysis by relationship. Serious 
adverse events will be provided in a data listing.
Laboratory data will be listed by subject, stratification group and icatibant exposure number. 
Subjects with newly occurring abnormalities outside the normal range will be flagged and listed
separately. Observed values and changes from pretreatment values will be summarized by the 

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stratification group and icatibant exposure number. Shift tables will also be tabulated by 
stratification group, icatibant exposure number, and study time point.
Vital signs data will be listed by subject, stratification group, and icatibant exposure number. 
Furthermore, observed values and changes from baseline will be summarized by stratification 
group and icatibant exposure number. Shift tables may be presented, utilizing reference ranges. 
Subjects with notably abnormal values will be identified and listed separately along with their 
values.
Local tolerability will be tabulated and summarized according to the type and severity of the 
injection site reaction.
The impact of icatibant on the reproductive hormone levels will be assessed by presenting 
tabular summaries for FSH, LH, estradiol, and progesterone for females, and FSH, LH, and 
testosterone for males.  The change from baseline values will also be summarized.  Subjects with 
newly occurring abnormalities outside the normal range will be flagged and listed separately.
Data from other tests (eg, immunogenicity, ECG) will be listed and summarized as appropriate.
10.7
Efficacy Analyses
Efficacy analyses will be performed on the Efficacy Population. The primary efficacy endpoint 
is the time to onset of symptom relief measured using the investigator-reported symptom score. 
The investigator will report symptom scores at pretreatment and 1, 2, 4, and 6 hours post 
treatment, and at 8 hours post treatment for subjects who had not shown complete resolution of 
HAE symptoms at 6 hours. Eight symptoms will be assessed for abdominal and cutaneous 
attacks, and 13 symptoms will be assessed for laryngeal attacks. Time to onset of symptom 
relief is defined as the earliest time post treatment at which there is a 20% improvement in the 
average post-treatment symptom score with no worsening of any single component score. The 
median time and the 95% confidence interval will be calculated using the Kaplan-Meier 
methodology.
A tabular summary of the average investigator-reported symptom score and the change from 
baseline in the average investigator-reported symptom score will be presented by the 
stratification group and the icatibant treated attack number. An alternative analysis will focus on 
the time to minimal symptoms and is defined as the time from study drug administration to the 
earliest time post treatment when all symptoms are either absent or mild. The median time and 
95% confidence interval will be calculated using Kaplan-Meier methodology. 
For individual investigator-reported symptom scores, a shift table from baseline will be 
presented for each post-treatment time point.  The analysis will be repeated to assess shift in the 
individual symptom scores from the 2 hour time-point.  Also, for individual symptoms that are 
moderate or worse at pretreatment, the median and 95% confidence interval will be presented for 
the time to the symptom being mild or absent. 
Two subsets of subjects, those 4 years of age or older and those below 4 years of age, will have 
assessment of pain using the FPS-R and FLACC instruments, respectively. For subjects ≥4 years
of age, the time to onset of symptom relief is defined as the earliest time at which the post-

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treatment score improves by at least one level.  The time to onset of symptom relief for subjects 
<4 years of age is defined as the earliest time at which a 20% improvement is seen in the total 
post-treatment score. Additionally, time to minimal symptoms defined as the earliest time at 
which the post-treatment score (or total post-treatment score for FLACC) improves to zero, will 
be analyzed. The time to onset of symptom relief and time to minimal symptoms will be 
analyzed using the same methods as the primary efficacy endpoint. 
10.8
Other Analyses
The number and percentage of subjects who received rescue medications before the onset of 
symptom relief will be summarized by the stratification group and icatibant-treated attack 
number.  Time to first use of rescue medication prior to symptom relief will be calculated from 
the time of investigational product administration to the first use of rescue medication prior to 
the onset of symptom relief.  The median time and the 95% confidence interval will be 
calculated using Kaplan-Meier methodology if there are at least 5 subjects for a given attack who 
used rescue medication prior to attaining symptom relief.
10.9
Data Monitoring and Interim Analysis
A DSMB will be set up to review the safety, tolerability, PK, and efficacy data on an ongoing 
basis.  The DSMB is described in Section 11.8; its goal will be to assess the risk/benefit of 
icatibant treatment in this pediatric population.  
An analysis of the data for DSMB review is planned after the first 4 subjects in the 
pubertal/postpubertal group have been treated, and will be repeated at subsequent time points as 
specified in the DSMB charter.  Because no formal hypothesis testing is planned, multiplicity 
concerns regarding repeated analyses are not an issue.
Based on the anticipated sequence of data being generated in the study, an initial interim analysis 
of the data from pubertal/postpubertal patients (N=20) is planned.  It is expected that this will be 
followed by an interim analysis of data from prepubertal patients (N=10), and then by a final 
analysis to include the data of patients treated for subsequent attacks.  This sequence is based on 
the anticipated sequence of data being generated during the study and may be modified to fit the
actual study conduct.
10.10 Handling of Missing Data
Individual pretreatment symptom scores, FPS-R scores, and FLACC scores will be assigned a 
value of zero. For missing post-treatment scores, imputation will be employed using the Last 
Observation Carried Forward (LOCF) approach. The pretreatment values may also be used in the 
imputation. For missing or partial rescue medication dates, the imputation will be performed 
such that the earliest possible time post treatment will be assigned to the rescue medication use. 
A similar approach will be followed to determine treatment emergent AEs in case of missing or 
partial AE dates. 

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11 ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the investigator must provide the sponsor with a completed Form 
FDA 1572 or Investigator Agreement.  Investigational product may be administered only under 
the supervision of the investigator listed on this form.  Curriculum vitae must be provided for the 
investigator and sub-investigators listed on Form FDA 1572 or the Investigator Agreement.
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions.  The investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the investigator must provide the sponsor with a copy of the 
written IRB/IEC approval of the protocol and the informed consent form.  This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the sponsor on the cover page of the protocol.
Status reports must be submitted to the IRB/IEC at least once per year.  The IRB/IEC must be 
notified of completion of the study.  Within 3 months of study completion or termination (or as 
required), a final report must be provided to the IRB/IEC.  A copy of these reports will be sent to 
the study clinical monitor.  The investigators must maintain an accurate and complete record of 
all submissions made to the IRB/IEC, including a list of all reports and documents submitted.  
Serious drug-related AEs which are reported to the US FDA or other Regulatory agencies 
(Investigational New Drug [IND] Safety Reports) must be submitted promptly to the IRB/IEC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonisation (ICH) GCP Guidelines Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
11.4
Subject Information and Consent/Assent
Before enrolling in the clinical study, the subject and/or the subject’s parent(s) or legal 
guardian(s) must consent to participate after the nature, scope, and possible consequences of the 
clinical study have been explained in a form understandable to him or her.
An informed consent form (assent form, if applicable) that includes information about the study 
will be prepared and given to the subject or the subject’s parent(s) or legal guardian(s).  

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This document will contain all FDA and ICH-required elements, as well as other elements 
required by ethics committees, if applicable, or as per country legal requirements.  The informed 
consent (or assent form, if applicable) form must be in a language understandable to the subject 
or the subject’s parent(s) or legal guardian(s) and must specify who informed the subject, the 
subject’s parent(s), or the subject’s legal guardian(s).
After reading the informed consent document, the subject or the subject’s parent(s) or legal 
guardian(s) must give consent in writing.  Consent must be confirmed at the time of consent by 
the personally dated signature of the subject, the subject’s parent(s) or the subject’s legal 
guardian(s) and by the personally dated signature of the person conducting the informed consent 
discussions.
If the subject or the subject’s parent(s) or legal guardian(s) is unable to read, oral presentation 
and explanation of the written informed consent form and information to be supplied must take 
place in the presence of an impartial witness.  Consent must be confirmed at the time of consent 
orally and by the personally dated signature of the subject or by a local legally recognized 
alternative (eg, the subject’s thumbprint or mark) or by the personally dated signature of the 
subject’s parent(s) or the subject’s legal guardian(s).  The witness and the person conducting the 
informed consent discussions must also sign and personally date the informed consent document.  
It should also be recorded and dated in the source document that consent was given.
A copy of the signed and dated consent document(s) must be given to the subject or the subject’s 
parent(s) or the subject’s legal guardian(s).  The original signed and dated consent document will 
be retained by the investigator.
The investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Subject Confidentiality
Subject names will not be supplied to the sponsor.  Only the subject number and subject initials 
will be recorded in the CRF, if applicable according to local laws and regulation, and if the 
subject name appears on any other document, it must be obliterated before a copy of the 
document is supplied to the sponsor.  Study findings stored on a computer will be stored in 
accordance with local data protection laws.  The subjects will be told that representatives of the 
sponsor, a designated CRO, the IRB/IEC, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws.  The investigator will maintain a personal subject identification list (subject numbers with 
the corresponding subject names) to enable records to be identified.

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11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed.  Review of 
the CRFs for completeness and clarity, cross-checking with source documents, and clarification
of administrative matters will be performed.
The study will be monitored by the sponsor or its designee.  Monitoring will be performed by a 
representative of the sponsor (Clinical Study Monitor) who will review the CRFs and source 
documents.  The site monitor will ensure that the investigation is conducted according to 
protocol design and regulatory requirements by frequent site visits and communications (letter, 
email, telephone, and facsimile).
11.7
Case Report Forms and Study Records
Case report forms (paper or electronic) are provided for each subject.  All forms must be filled 
out by authorized study personnel.  All corrections to the original CRF entry must indicate the 
reason for change.  The investigator is required to sign the CRF after all data have been captured 
for each subject.  If corrections are made after review and signature by the investigator, he or she 
must be made aware of the changes, and his or her awareness documented by resigning the CRF.
11.7.1
Critical Documents
Before the sponsor initiates the trial (ie, obtains informed consent from the first subject), it is the 
responsibility of the investigator to ensure that the following documents are available to the 
sponsor or its designee:
•
Applicable local regulatory documentation (eg, completed Form FDA 1572 [Statement of 
Investigator], signed, dated, and accurate.
•
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed within 
24 months of study initiation).
•
Copy of investigator(s) and sub-investigator(s) current medical license (indicating license 
number and expiration date).
•
Signed and dated agreement of the final protocol.
•
Signed and dated agreement of any amendment(s), if applicable.
•
Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed by
name, number and date of approval or re approval: protocol, any amendments, Subject 
Information/Informed Consent Form, and any other written information to be provided 
regarding subjects recruitment procedures.
•
Copy of IRB/IEC approved Subject Information/Informed Consent Form/any other written 
information/advertisement (with IRB approval stamp and date of approval).
•
Current list of IRB/IEC Committee members/constitution (dated within 12 months prior to 
study initiation).
•
Financial Disclosure Form signed by investigator(s) and sub-investigator(s).
•
Current laboratory reference ranges (if applicable).
•
Certification/QA scheme/other documentation (if applicable).

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Regulatory approval and notification as required must also be available.  The protocol will not be
initiated until regulatory approval and notification are obtained; these are the responsibility of the 
sponsor.
11.8
Data and Safety Monitoring Board
In view of the role of bradykinin and B2 receptors in reproductive development, the study will 
use an external DSMB.  The DSMB will provide an ongoing, independent review and 
assessment of the safety data to protect the interests and safety of subjects participating in the 
study.  The DSMB will adhere to a prospectively determined charter which will be proposed by
sponsor and approved by the DSMB.  The charter will define the membership of the DSMB, the 
responsibilities of the DSMB and the sponsor, describe the conduct of meetings, and define the 
data to be reviewed.  
Enrollment of pediatric subjects in the proposed study will be stratified into 2 groups (2 years of 
age to the older prepubertal children, and pubertal/postpubertal children to those less than 
18 years of age).  It is planned that subjects in both groups will receive an icatibant dose 
(0.4 mg/kg to a maximum dose of 30 mg) selected to target an exposure comparable to that 
observed in adults treated with icatibant.  Initially, enrollment and dosing of 
pubertal/postpubertal subjects will precede that of prepubertal subjects.  After the first 4 subjects 
in the pubertal/postpubertal group have been treated, icatibant concentration measurements and 
PK analysis, safety, tolerability, and efficacy data will be reviewed and assessed by the DSMB.  
This review must be completed prior to initiating enrollment of subjects in the prepubertal group.  
As the outcome of its review, the DSMB may make a recommendation to continue enrolling 
subjects in the pubertal/postpubertal group, to initiate dosing of subjects in the prepubertal group, 
or to administer a different dose, or to terminate the study. 
11.9
Protocol Violations/Deviations
The investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to subjects.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.
A record of subjects screened, but not entered into the study, is also to be maintained.  No 
protocol waivers or exemptions will be considered by the sponsor during the study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the investigator will contact the sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.  

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Any departures from the protocol must be fully documented as a protocol deviation.  Protocol 
deviations will need to be reviewed by the medical monitor and may also need to be submitted to 
the IRB/IEC.
Protocol modifications will only be initiated by the sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.10 Premature Closure of the Study
If the sponsor, investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable risk to 
subjects, the study may be terminated after appropriate consultation between the sponsor and the 
investigator.  In addition, a decision on the part of the sponsor to suspend or discontinue 
development of the investigational product may be made at any time.  Conditions that may 
warrant termination of the study or site include, but are not limited to:
•
The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled in 
the study
•
Failure of the investigator to comply with pertinent global regulations
•
Submission of knowingly false information from the study site to the sponsor or other 
pertinent regulatory authorities
•
Insufficient adherence by the Investigator to protocol requirements
11.11 Access to Source Documentation
Regulatory authorities, the IRB/IEC, or the sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, cross-checking with 
source documents, and clarification of administrative matters may be performed.
11.12 Data Generation and Analysis
The clinical database will be developed and maintained by a CRO or an electronic data capture 
technology provider as designated by Shire.  The sponsor or its designee will be responsible for 
performing study data management activities. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 8.1 or higher.  Concomitant medication will be coded using the World Health 
Organization Drug Dictionary (WHO-DD) (2004, Q4). Centralized laboratories will be 
employed as described in the study manual to aid in consistent measurement of efficacy and 
safety parameters.

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11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  The sponsor will notify the investigator if these documents must be 
retained for a longer period of time.  It is the responsibility of the sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained.
11.14 Financial Disclosure
The investigator should disclose any financial interests in the sponsor as described in 21 CFR 
Part 54 prior to beginning this study.  The appropriate form will be provided to the investigator 
by the sponsor, which will be signed and dated by the investigator, prior to the start of the study, 
at the end of the study, and one year post-study (or site) closure.  Changes in status concerning 
financial interests during the study and after its completion will be disclosed by the Investigator 
in accordance 21 CFR Part 54.   
11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the sponsor and not 
previously published are considered confidential and will remain the sole property of the 
sponsor.  The investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies.  In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the sponsor with complete test results and all data developed 
in the study in a timely manner.
The investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire, 
provided Shire a copy of the draft document intended for publication, and obtained the written 
consent of Shire for such publication.  All information obtained during the conduct of this study 
will be regarded as confidential.  Shire will use the information for registration purposes and for 
the general development of the drug.

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12 LIST OF REFERENCES
1. Bowen T, Cicardi M, Bork K, et al. Hereditary angiodema: a current state-of-the-art review, 
VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, 
Therapy, and Management of Hereditary Angioedema. Annals of Allergy Asthma 
Immunology 2008;100:S30-40.
2. Davis AE, 3rd. New treatments addressing the pathophysiology of hereditary angioedema. 
Clinical and Molecular Allergy 2008;6:2.
3. Knolle J, Breipohl G, Henke S, Wirth K, Scholkens B. New and highly potent bradykinin 
antagonists. Agents and Actions Supplement 1992;38 ( Part 1):559-64.
4. Hock FJ, Wirth K, Albus U, et al. Hoe 140 a new potent and long acting 
bradykinin-antagonist: in vitro studies. British Journal of Pharmacology 1991;102:769-73.
5. Wirth K, Hock FJ, Albus U, et al. HOE 140 a new potent and long acting 
bradykinin-antagonist: in vivo studies. British Journal of Pharmacology 1991;102:774-7.
6. Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy, Asthma 
and Clinical Immunology 2010;6:18.
7. Zuraw BL. Clinical practice. Hereditary angioedema. New England Journal of Medicine 
2008;359:1027-36.
8. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of 
Disease in Childhood 1969;44:291-303.
9. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of 
Disease in Childhood 1970;45:13-23.
10. Bieri D, Reeve RA, Champion GD, Addicoat L, Ziegler JB. The Faces Pain Scale for the 
self-assessment of the severity of pain experienced by children: development, initial 
validation, and preliminary investigation for ratio scale properties. Pain 1990;41:139-50.
11. Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain 
Scale-Revised: toward a common metric in pediatric pain measurement. Pain 
2001;93:173-83.
12. Manworren RC, Hynan LS. Clinical validation of FLACC: preverbal patient pain scale. 
Pediatric Nursing 2003;29:140-6.
13. Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for 
scoring postoperative pain in young children. Pediatric Nursing 1997;23:293-7.

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Appendix 4 Modified Sexual Maturation Scale
Stage
Female Breast Stage
Female Pubic Hair Stage a
Male Genital Stage
Male Pubic Hair Stage a
1
Preadolescent
Elevation of papilla 
only.
No pubic hair.
Testes, scrotum, and penis 
are of about the same size 
and proportion as in early 
childhood.
No pubic hair.
2
Breast bud stage; 
elevation of breast and 
papilla as a small 
mound, enlargement of 
areolar diameter.
Sparse growth of long, slightly 
pigmented downy hair, straight 
or only slightly curled, appearing 
on the pubis.  Do not consider 
hair on the labia.
The scrotum and testes have 
enlarged and there is a 
change in the texture of the 
scrotal skin.  There is also 
some reddening of the 
scrotal skin.
Sparse growth of long, slightly 
pigmented downy hair, straight 
or only slightly curled, appearing 
chiefly at the base of the penis.
3
Further enlargement of 
breast and areola, with 
no separation of their 
contours.
Considerably darker, coarser, 
and more curled; spreads 
sparsely over the conjunction of 
the pubes.
Growth of the penis has 
occurred, at first mainly in 
length but with some 
increase in breadth.  There 
has been further growth of 
testes and scrotum.
Considerably darker, coarser, 
and more curled; spreads 
sparsely over the junction of the 
pubes.
4
Projection of areola and 
papilla to form a 
secondary mound 
above the level of the 
breast.
Hair is adult in type, but the area 
covered by it is still considerably 
smaller than in most adults. 
There is no spread to the medial 
surface of the thighs.
Penis further enlarged in 
length and breadth with 
development of glans.  Tests 
and scrotum further 
enlarged.  Further darkening 
of the scrotal skin.
Hair is adult in type, but the area 
covered by it is still considerably 
smaller than in most adults. 
There is no spread to the medial 
surface of the thighs.
5
Mature stage; 
projection of papilla 
only, owing to 
recession of the areola 
to the general contour 
of the breast.
Adult in quantity and type, 
distributed as an inverse triangle.  
Spread to the medial surface of 
the thighs, but not up the linea 
alba or elsewhere above the base 
of the inverse triangle.
Genitalia adult in size and 
shape.  No further 
enlargement takes place 
after stage 5 is reached.
Adult in quantity and type, 
distributed as an inverse triangle.  
Spread to the medial surface of 
the thighs, but not up the linea 
alba or elsewhere above the base 
of the inverse triangle.
a
Pubic hair development reflects adrenal function, not hypothalamic/gonadal function.  The descriptions used in this table are intended to provide guidance 
for the investigators and may not align with descriptions of pubic hair and pubertal stage in other sources.

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Appendix 5 Faces Pain Scale-Revised (FPS-R)

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Appendix 6 Faces, Legs, Activity, Cry, and Consolability Scale (FLACC)
FLACC SCALE (FACE, LEGS, ACTIVITY, CRY, CONSOLABILITY)
FACE
0
No 
particular 
expression 
or smile
1
Occasional grimace or frown
Withdrawn
Disinterested
2
Frequent to constant frown
Clenched jaw
Quivering chin
LEGS
0
Normal 
position
or
Relaxed
1
Uneasy
Restless
Tense
2
Kicking
or
Legs drawn up
ACTIVITY
0
Lying 
quietly
Normal 
position
Moves 
easily
1
Squirming
Shifting back/forth
Tense
2
Arched
Rigid
or
Jerking
CRY
0
No cry 
(awake or 
asleep)
1
Moans or whimpers
Occasional complaint
2
Crying steadily
Screams or sobs
Frequent complaints
CONSOLABILITY
0
Content 
Relaxed
1
Reassured by occasional 
touching, hugging, or 
‘talking to’. 
Distractible
2
Difficult to console or comfort
The FLACC is a behavioral pain assessment scale suitable for use in preverbal children and 
children with limited verbal capability.
Instructions:
1.
Rate patient in each of the 5 measurement categories
2.
Add together.
3.
Document total pain score.

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Appendix 8 Summary of Changes for Amendment 3
1. Amendment Summary and Rationale
Shire submitted a Paediatric Investigation Plan (PIP) modification request (EMEA-000408-
PIP01-08-M04) to the Paediatric Committee (PDCO) of the European medicines Agency on 22 
February 2013. Shire proposed to modify the study parameters for HGT-FIR-086 in order to 
facilitate enrollment and make the study less burdensome for recruitment of pediatric subjects. 
The request for PIP modification received a positive PDCO opinion on 17 May 2013. 
The revised study design includes the following:
•
Pubertal/postpubertal patients: The number of pubertal/postpubertal patients participating in 
the study will remain at 20 (single dose icatibant with 3-month follow-up); however, 10 
patients will be treated with icatibant during an HAE attack; while the other 10 patients will 
be treated without an attack (ie, will be evaluated for PK, tolerability and safety, but not for 
efficacy).
•
Prepubertal patients: The number of prepubertal patients will be reduced from 16 to 10. The 
Sponsor will continue to actively enroll this pediatric subset in HGT-FIR-086; however, 
given the significant enrolment challenges, the completion of the study in this particular 
subset is deferred until December 2017.
•
Specific follow-up: Pubertal/postpubertal subjects, including both those treated during an 
attack or not, may be offered further open-label treatment with icatibant for any subsequent 
HAE attacks that occur at least 7 days after prior treatment.  As a consequence of the 
difficulty in enrolling patients in the study, open-label treatment will be continued until a 
total number of 10 adolescents (instead of 15) have been treated with icatibant for at least 3 
eligible acute attacks.  The follow up phase is not part of the PIP; however, this will be a 
post-approval commitment.
Shire believes that the proposed study modifications will still allow for the generation of an 
adequate safety, PK, and efficacy dataset in pediatric subjects and therefore will continue to 
fulfill the overall objective of the pediatric program.
2. Detailed Summary of Changes for the Amendment
This is a section that has been updated to describe the changes from the previous protocol 
version.  Significant changes and additions to the protocol text are captured below. 
Changes in grammar, spelling, punctuation, format, minor editorial changes (including 
re-ordering of text or other edits for consistency and clarity), updates to the list of abbreviations 
and cross-references, and edits to the Introduction (Section 1) are not reflected in the change 
summary.
Bold text indicates new text. Strikethrough text indicates deleted text.

Ic ati b a nt ( Fir az yr ® )
Cli nic al Tri al Pr ot oc ol A m e n d me nt 3: H G T - FI R-0 8 6
1 9 J u ne 2 0 1 3
S hire
C o nfi de nti al
8 8
C H A N G E S T O T E X T
C ha n ge: C ha n ge t o Me dical M o nit or
Secti o n i mpacte d b y c ha n ge: C o ver pa ge
Re vise d Te xt :  
 M D, P h D
S hire H u ma n Ge netic T hera pies ( H G T), I nc.
M o bile: 
Ot her secti o ns i m pacte d b y c ha n ge: Secti o n 7. 1 7. 4. 2 Re p orti n g Seri o us A d verse E ve nts
C ha n ge: C ha n ge t o st u d y o bjecti ves
Secti o n i m pacte d b y c ha n ge: Secti o n 2. 1 O bjecti ves
Re vise d Te xt :  
•
T o i n vesti gate t he p har mac o ki netics ( P K), t olera bilit y, a n d safet y of a si n gle s u bc uta ne o us ( S C) d ose of 
icati ba nt i n c hil dre n a n d a d olesce nts wit h here ditar y a n gi oe de ma ( H A E) d uri n g a n ac ute H A E attac k
Ot her secti o ns i m pacte d b y c ha n ge: S y n o psis, Secti o n 1 0 Pla n ne d S tatistical Met h o ds
C ha n ge: C ha n ge t o st u d y e n d p oi nts
Secti o n i m pacte d b y c ha n ge: Se cti o n 3 E n d p oi nts
Re vise d Te xt :  
3. 1 Pri mar y E n d p oi nt s
Pri mar y e n d p oi nts:
•
T he P K pr ofile of icati ba nt after a si n gle S C i njecti o n i n pe diatric s u bjects (i n pre p u bert al c hil dre n wit h a n 
ac ute att ac k of H A E a n d p u bert al/ p ost p u bert al c hil dre n wit h or wit h o ut a n ac ute att ac k of H A E) .
•
T he t olera bilit y a n d safet y of S C icati ba nt as assesse d b y i njecti o n site reacti o ns, a d verse e ve nts, vital si g ns, 
E C G rec or di n gs, p h ysical e xa mi nati o n, cli nical la b orat or y para meters (ser u m c he mistr y [i ncl u di n g li ver f u ncti o n 
tests], he mat ol o g y, uri nal ysis), re pr o d ucti ve h or m o ne le vels, a n d i m m u n o ge nicit y ( prese nce of a nti-icati ba nt 
a nti b o dies). 
3. 2 Sec o n dar y E n d p oi nt s
Sec o n dar y e n d p oi nts ( o nl y f or s u bjects tre ate d wit h ic ati b a nt d uri n g a H A E att ac k):
Ti me t o o nset of relief of s y m pt o ms a n d ti me t o mi ni m al s y m pt o ms, as me as ure d b y i n vesti g at or - a n d s u bject -
re p orte d o utc o mes
•
F or all s u bjects ( 2 t o < 1 8 1 7 years of a ge):  i n vesti gat or assess me nt a n d sc ori n g of c uta ne o us, a b d o mi nal, a n d 
lar y n geal s y m pt o ms of ac ute H A E attac ks b y a n i n vesti gat or-rate d s y m pt o m sc ore.  
-
T he ti me t o o nset of relief of s y m pt o ms, defi ne d as t he earliest ti me at w hic h a t le ast a 2 0 % i m pr o ve me nt is 
see n i n t he a vera ge p ost-treat me nt sc ore wit h n o worse ni n g of a n y si n gle c o m p o ne nt sc ore.
-
T he ti me t o mi ni mal s y m pt o ms, defi ne d as t he earliest ti me p ost treat me nt w he n all s y m pt o ms are eit her mil d or 
a bse nt base d o n t he i n ve sti gat or-rate d s y m pt o m sc ore.
•
F or s u bjects ≥4 years of a ge o nl y: s u bject self -assess me nt of H A E -relate d pai n usi n g t he Faces Pai n Scale-
Re vise d ( F P S -R).  
-
T he ti me t o o nset of relief of s y m pt o ms , defi ne d as t he e arliest ti me at w hic h t he p ost -tre at me nt sc ore 
i mpr o ves b y at le ast o n e le vel.
-
T he ti me t o mi ni m al s y m pt o ms, defi ne d as t he e arliest ti me at w hic h t he p ost -tre at me nt sc ore i m pr o ves t o 
zer o ( or n o p ai n) .
•
F or s u bjects < 4 years of a ge o nl y:  i n vesti gat or assess me nt of H A E -relate d pai n (c uta ne o us, a b d o mi nal, a n d 
lar y n geal) usi n g a v ali d ate d p ai n sc ale ( Faces, Le gs, Acti vit y, Cr y, a n d C o ns ola bilit y [ F L A C C].
-
T he ti me t o o nset of relief of s y m pt o ms , defi ne d as t he earliest ti me at w hic h a 2 0 % i m pr o ve me nt is see n i n t he 
t otal p ost treat me nt sc ore.
-
T he ti me t o mi ni m al s y m pt o ms , defi ne d as t he e arliest ti me at w hic h t he t ot al p ost-tre at me nt sc ore 
i mpr o ves t o zer o.
T he I nci de nce of resc ue me dicati o n use.
T he Pr o p orti o n of s u bjects wit h w orse ne d i nte nsit y of cli nical H A E s y m pt o ms bet wee n 2 a n d 4 h o urs after treat me nt 
wit h S C icatiba nt usi n g i n vesti gat or rate d s y m pt o m sc ores.
P P D
P P D

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Other sections impacted by change: Synopsis, Section 10 Planned Statistical Methods
Change: Change to study design
Section impacted by change: Section 4.1.1 Study Design
Revised Text:  
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, and safety, including 
effects on reproductive hormones, of a single SC administration of icatibant in pediatric subjects with HAE during 
an initial acute attack.
The study will enroll children and adolescents from 2 to less than 18 17 years of age, divided into 2 groups: 
prepubertal (Tanner stage I) and pubertal/postpubertal (Tanner stages II to V).  
At least 10 prepubertal children and at least 20 adolescents (including 10 treated during a HAE attack) must 
be enrolled in the study.
Other sections impacted by change: Synopsis
Change: Change to study design
Section impacted by change: Section 4.1.2 Study Methodology
Revised Text:  
A subject’s classification as prepubertal or pubertal/postpubertal will be determined at screening and, if 
appropriate, at the time of the first icatibant-treated HAE attack.  Subjects classified as pubertal/postpubertal at 
screening will not require further evaluation of pubertal status during the study, whereas subjects classified as 
prepubertal at screening will have their pubertal status reassessed at the time of their first icatibant-treated attack 
visit.
After a qualifying screening period, the PK, safety/tolerability, and efficacy of treatment with SC icatibant will be 
evaluated in at least 20 subjects (10 prepubertal and 10 pubertal/postpubertal subjects) who present with 
cutaneous, abdominal, or laryngeal symptoms of an acute attack of HAE.  Subjects should initiate treatment 
with icatibant within 12 hours of the onset of symptoms; however, there are no prespecified attack severity 
criteria that are required for treatment.  Subjects with attacks considered to be mild, moderate, or severe are 
all potentially eligible to receive treatment with icatibant. 
The PK and safety/tolerability of SC icatibant will be evaluated in at least 10 additional 
pubertal/postpubertal subjects who meet screening criteria, but receive treatment with SC icatibant in the 
absence of a current acute HAE attack.
Initially, enrollment and dosing of pubertal/postpubertal subjects will precede that of prepubertal subjects.  After the 
first 4 subjects in the pubertal/postpubertal group have been treated with icatibant (whether during or in the 
absence of attack), PK, safety/tolerability, and efficacy (as appropriate) will be reviewed by an independent Data 
and Safety Monitoring Board (DSMB). The DSMB review of the first 4 subjects shall be completed prior to 
continuing enrollment of additional pubertal/postpubertal subjects, treatment of second and third HAE attacks in 
pubertal/postpubertal subjects, and initiating enrollment of subjects in the prepubertal group.
Subjects will receive treatment with a single SC administration of icatibant on Day 1 and will be monitored closely 
in the hospital/study center for at least 6 to 8 hours after treatment. Subjects will undergo PK and safety 
assessments; efficacy assessments will be performed if treatment occurs during an acute HAE attack.  All 
subjects will have serum reproductive hormone measurements.  A subject may be discharged after completion of 
assessments at 6 hours post treatment, if deemed medically stable in the investigator’s clinical judgment and, if 
applicable, the subject’s HAE symptoms have resolved (the subject’s investigator-rated symptom score must be 
zero, denoting the absence of symptoms).  If HAE symptoms have not completely resolved at 6 hours (ie, the 
investigator-rated symptom score is >0), the subject shall remain in the hospital/study center for at least 8 hours after 
icatibant administration for further evaluation.
Telephone follow-up will occur at both 24 and 48 hours after treatment. Safety follow up to assess the subject’s 
condition must be conducted at 24 and 48 hours after icatibant injection, and will occur either by a telephone call 
from study personnel or in person at the investigator’s discretion. 
Subjects will return to the hospital/study center for scheduled assessments on Day 8 and for a follow-up visit on Day 
90.
After having received initial treatment with icatibant, either during or in the absence of attack, at least 10 
pubertal/postpubertal subjects who subsequently experience an acute HAE attack may continue to receive treatment 

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with icatibant as a single SC administration per attack for a total of 3 eligible icatibant-treated attacks.  Further 
treatment with icatibant is contingent upon presentation of an acute cutaneous, abdominal, or laryngeal attack of 
HAE at least 7 days after prior treatment.  All primary and secondary outcomes as above (including anti-icatibant 
antibodies and reproductive hormones) will be measured in these pubertal/postpubertal subjects after each 
administration.  Note that for some of the pubertal/postpubertal subjects who receive further treatment, ie, those who 
provided PK and safety/tolerability measurements without an attack, their first icatibant-treated attack will represent 
their second on-study exposure to icatibant for safety analysis purposes.
The investigator will schedule a telephone contact approximately 6 months after Day 1 of each icatibant-treated 
attack to obtain specific updates concerning pubertal changes/milestones.
Other sections impacted by change: Synopsis
Change: Change to Study Design
Section impacted by change: Section 4.1.3 Study Assessments
Revised Text:  
Table 4-1 Study Periods
Study Periods
Screening 
Day of informed consent through pretreatment on Day 1 
No attack (Pubertal/postpubertal subjects only)
    Treatment 
Day 1
    Post Treatment
Day 1 through Day 8 (± 1 day)
    Follow-up
Day 9 through Day 90 (±7 days)
    Telephone Contact
Month 6 (± 7 days) from Day 1 
Other sections impacted by change: Section 8 Study Activities, Appendix 1 Schedule of Events (No Attack)
Change: Change to Study Design
Section impacted by change: Section 4.1.3 Study Assessments
Revised Text:  
Study activities at screening will include confirmation of diagnosis of HAE type I or II by review of the subject’s 
medical history and documentation of C1-INH deficiency (C1 INH protein level below the lower limit of normal 
and/or functional level <50% of normal) indicative of HAE Type I or II.  Diagnosis may be supported by family 
history, characteristic attack manifestations, and recurrence of attacks.  A blood sample will be collected for C1-
INH testing.  Other assessments performed at screening will include demography, medical history and history of 
HAE, concomitant medication use, physical examination (including height and weight), pubertal status 
determination, vital signs, ECG, and a urine pregnancy test in female pubertal/postpubertal subjects, and blood 
sample collection for C1 INH testing.
4.1.3.1
Initial Treatment
Eligible pubertal/postpubertal subjects who undergo treatment with icatibant in the absence of an acute HAE 
attack will receive single dose of icatibant as an abdominal SC injection on Day 1 and undergo PK and safety 
assessments as for subjects who receive treatment with icatibant during an attack.  (Efficacy assessments will 
not be performed for those pubertal/postpubertal subjects treated with icatibant in the absence of an HAE 
attack.)
A safety follow-up contact to assess the subject’s condition will occur by telephone at 24 (±4) hours and 48 (±4) 
hours after treatment with icatibant (for a subject who remains hospitalized, this safety follow-up will be 
conducted in person).
Rescue medication use will be assessed through 48 (±4) hours after treatment either in person or by telephone at the 
discretion of the investigator.  With exception of icatibant, any medicinal product may be used as rescue 

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medication, at the discretion of the treating physician.
4.1.3.2
Subsequent Treatment
Subsequent treatment with icatibant may be offered to pubertal/postpubertal subjects who have received initial 
treatment and who present subsequently with an attack at least 7 days after prior treatment.  In the event that a 
subsequent attack occurs at least 7 days after prior treatment, but within the window (±1 day) allowed for 
performance of Day 8 assessments associated with a prior attack, the Day 8 assessments may also serve as the 
pretreatment (baseline) assessments for the subsequent attack.  Subjects will be eligible for treatment with 
icatibant until a total number of at least 10 15 adolescents have been treated with icatibant for a total of 3 acute 
attacks (ie, after the first icatibant treated attack, only pubertal/postpubertal subjects may receive further treatment 
with icatibant for up to 2 subsequent attacks of acute HAE). Except for PK determinations, all primary and 
secondary outcomes, including immunogenicity, are to be measured after each administration. Safety, reproductive 
hormones, and other assessments in association with subsequent attacks of acute HAE will be performed on Day 90 
(±7 days) after treatment (each treatment for a subsequent attack will require its own Day 90 follow up visit; 
however, if a subsequent attack occurs within 7 days of the Day 90 follow-up visit for the previous attack, the 
assessments on Day 8 and Day 90 may be combined). Note that for some of the pubertal/postpubertal subjects 
who receive further treatment, ie, those who provide PK and safety/tolerability measurements without 
experiencing a current attack, their first icatibant-treated attack will represent their second on-study 
exposure to icatibant for safety analysis purposes.
The investigator will schedule a telephone contact approximately 6 months after Day 1 of each icatibant-treated 
attack to obtain updates concerning pubertal changes/milestones.  If this prescheduled telephone contact date should 
occur within the 90-day follow-up period (ie, Day 1 through Day 90) of a subsequent attack, this prescheduled 
contact may be omitted.
In addition, for all subjects who remain enrolled in the study for longer than 6 months, a telephone contact 
will be scheduled every 6 months to collect information concerning HAE attacks not treated with icatibant in 
the study.
All assessments are outlined in full in the study schedules of events in Appendix 1, No Attack, Appendix 2, Initial 
Icatibant treated Attack, and Appendix 3, Subsequent Icatibant-treated Attacks.    
Other sections impacted by change: Synopsis, Appendix 1 Schedule of Events (No Attack), Appendix 2, Initial 
Icatibant treated Attack, and Appendix 3, Subsequent Icatibant-treated Attacks    
Change: Change to Study Design
Section impacted by change: Section 4.3 Study Duration  
Revised Text:  
At minimum, the duration of a subject’s active participation in the study will consist of single day dosing with 
90-day follow-up.  
Once eligibility is established at screening, the subject will be enrolled into the study but will enter a period of 
inactive participation of variable duration until such time as the subject experiences an acute attack of HAE and is
offered treatment.  For those pubertal/postpubertal subjects who will be treated without an attack, eligibility 
will be established at screening and the subject will be immediately enrolled and treated with icatibant.  At 
the time of enrollment into the study, the subject will enter a 90-day period of active participation which will consist 
of treatment with a single SC administration of icatibant on Day 1 through follow-up at Day 90.  
After receiving the first treatment for an initial attack of HAE with icatibant with or without an attack (N=20), at 
least 10 15 pubertal/postpubertal subjects who present with subsequent attacks of acute HAE will continue to 
receive treatment with icatibant for a total of 3 attacks each.  Thus, the period of active participation in the study for 
prepubertal subjects will be approximately 90 days, while that for pubertal/postpubertal subjects could be a 
maximum of approximately 270 or 360 days (3 separate active periods of approximately 90 days for those treated 
with icatibant during an attack; 4 separate active periods for those treated without an attack), with each active 
period separated by periods of inactive participation of variable duration.  The period of active participation may be 
shorter if pubertal/postpubertal subjects have recurrent HAE attacks in between the Day 8 and Day 90 visits for a 
prior icatibant-treated HAE attack.  Telephone follow-up will occur approximately 6 months after each icatibant-
treated attack.
Once the tenth sixteenth prepubertal subject and the twentieth pubertal/postpubertal subject have completed the 6-
month follow-up after the initial treatment, and the tenth pubertal/postpubertal subject has completed the 6-month 
follow-up after his or her third and final treatment for an attack, the study will be closed.

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The approximate overall duration of the study is expected to be 3 years.  
Other sections impacted by change: Synopsis
Change: Change to study design
Section impacted by change: Section 5.1 Study Population
Revised Text:  
The study will enroll a sufficient number of children and adolescents with HAE to ensure study completion of 30 36 
evaluable subjects.  The study population to provide efficacy, PK, and safety/tolerability measurements will 
consist of at least 20 subjects from 2 to less than 18 17 years of age, at least 10 16 of whom are prepubertal and at 
least 10 20 of whom are pubertal/postpubertal at the time of their first icatibant-treated acute cutaneous, abdominal, 
or laryngeal attack of HAE.  An additional 10 subjects who are pubertal/postpubertal at the time of enrollment, 
but who are not experiencing a current HAE attack, will provide PK and safety/tolerability measurements 
only.
Other sections impacted by change: Synopsis
Change: Change to study design
Section impacted by change: Section 5.2 Inclusion Criteria
Revised Text:  
1.
Two through <18 17 years of age (ie, from the second birthday until the day prior to the eighteenth birthday) at 
the time of the subject’s first HAE attack treated with icatibant as part of this study.
-
Prepubertal and pubertal/postpubertal subjects experiencing an acute cutaneous, abdominal, or 
laryngeal HAE attack treated with icatibant as part of this study. 
-
Pubertal/postpubertal subjects with HAE who are treated with icatibant as part of this study, but not 
during an attack. 
2.
Documented diagnosis of HAE type I or II.  Diagnosis may be on the basis of historical data: family history, 
characteristic attack manifestations, recurrent attacks, historical C1-INH deficiency, and exclusion of other 
forms of angioedema.  Inclusion will be permitted initially based on medical history only if a clear diagnosis has 
been made based on all of the preceding criteria.  However, the diagnosis must be confirmed prior to treatment
by documented immunogenic and/or functional C1-INH deficiency (C1-INH protein level below the lower limit of 
normal and/or functional level <50% of normal) as performed by the Sponsor’s central laboratory.
Other sections impacted by change: Synopsis
Change: Change to study design
Section impacted by change: Section 6.2 Treatments Administered
Revised Text:  
Pubertal/postpubertal subjects are potentially eligible to receive treatment with icatibant in the absence of an 
attack, and to receive treatment with icatibant for a total of 3 attacks of acute HAE. Thus, a maximum of 4
doses of icatibant may be administered to a pubertal/postpubertal subject in the study, while all prepubertal 
subjects will receive a single dose of icatibant.
Other sections impacted by change: 
Change: Change to study design
Section impacted by change: Section 6.3 Selection and Timing of Dose for Each Subject
Revised Text:  
All subjects, whether treated during or in the absence of an acute attack of HAE, will be administered a single
SC injection of icatibant.
Subjects treated for an acute attack of HAE should receive icatibant within 12 hours after the onset of the 
attack.  There are no prespecified attack severity criteria that are required for treatment.  Subjects with 
attacks considered to be mild, moderate, or severe are all potentially eligible to receive treatment with 
icatibant.   

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Other sections impacted by change: Synopsis
Change: Clarification to rescue therapy
Section impacted by change: Section 6.7 Rescue Therapy
Revised Text:  
The determination of the necessity for rescue therapy will be at the discretion of the investigator.  With the 
exception of icatibant, any medicinal product may be used as rescue medication at the discretion of the 
treating physician.
Other sections impacted by change: Synopsis
Change:  Clarification to PK variables
Section impacted by change:  Section 7.10.1 Pharmacokinetic Variables
Revised Text:  
Individual patient PK variables for icatibant and major metabolites will be determined from the respective 
plasma concentration time profiles where appropriate, using noncompartmental methods. 
A population PK model will be derived to evaluate the correlation of key covariates (ie age, body weight, 
gender) on the pharmacokinetic profile of icatibant.
Other sections impacted by change: Synopsis
Change: Clarification concerning AE classification
Section impacted by change: Section 7.17.2 Classification of Adverse Events and Serious Adverse Events
Revised Text:  
The severity of adverse events will be assessed by the investigator as mild, moderate, or severe based on the scale
definitions shown in Table 7-2.  The severity of adverse events and serious adverse events should be recorded on 
the appropriate CRF page as Grade 1, 2, or 3, corresponding, respectively, to a severity of mild, moderate, or severe.
Table 7-2 Adverse Event Severity
Grade
Severity
Definition
Grade 1 
Mild
No limitation of usual activities.
Grade 2 
Moderate
Some limitation of usual activities.
Grade 3 
Severe
Inability to carry out usual activities.
Other sections impacted by change: None
Change: Clarification concerning AE recording
Section impacted by change: Section 7.17.4.1 Adverse Event Monitoring and Period of Observation
Revised Text:  
Adverse events will be monitored continuously.  For the purposes of this study, the safety observation period will 
extend from the time of treatment with investigational product of the subject’s acute HAE attack until the subject’s 
final evaluation after treatment.  
Other sections impacted by change: None
Change: Change to SAE reporting
Section impacted by change: Section 7.17.4.2 Reporting Serious Adverse Events
Revised Text:  
If an SAE is assessed as severe and unexpected, or life-threatening, contact:

Ic ati b a nt ( Fir az yr ® )
Cli nic al Tri al Pr ot oc ol A m e n d me nt 3: H G T - FI R-0 8 6
1 9 J u ne 2 0 1 3
S hire
C o nfi de nti al
9 4
 M D, P h D
S hire H u ma n Ge netic T hera pies, I nc.
3 0 0 S hire Wa y
Le xi n gt o n, M A 0 2 4 2 1 U S A
Tele p h o ne: 
M o bile: 
Fa x: 
( U S A)
Ot her secti o ns i m pacte d b y c ha n ge: C o ver pa ge
C ha n ge: Clarificati o n c o ncer ni n g i n vesti gati o nal pr o d uct
Secti o n i m pacte d b y c ha n ge: Secti o n 7. 1 9 A b use, O ver d ose, a n d Me dicati o n Err or
Re vise d Te xt :  
•
Mis use – I nte nti o nal or u ni nte nti o nal use of i n vesti gati o nal me dici nal pr o d uct ot her t ha n as directe d or i n dicate d 
at a n y d ose, w hic h is at or bel o w t he d ose defi ne d f or o ver d ose ( N ote:  t his i ncl u des a sit uati o n w here t he pr o d uct
test article is n ot use d as directe d at t he d ose prescri be d b y t he pr ot oc ol).
All i n vesti gati o nal me dici nal pr o d uct pr o vi de d t o pe diatric s u bjects s h o ul d be s u per vise d b y t he pare nt(s)/le gal 
g uar dia n(s)/care gi ver(s).
Ot her secti o ns i m pacte d b y c ha n ge: N o ne
C ha n ge: C ha n ge t o st u d y assess me nts
Secti o n i m pacte d b y c ha n ge: Secti o n 8. 1 Scree ni n g ( Da y of I nf or me d C o nse nt t o Pretreat me nt o n Da y 1)
Re vise d Te xt :  
•
D oc u me nt ati o n of H A E att ac k(s) n ot tre at e d wit h ic ati b a nt *
•
C o nfir mati o n of d oc u me nte d H A E dia g n osis ( vi a t he s p o ns or’s ce ntr al l a b or at or y)
* F or all s u bjects w h o re m ai n e nr olle d i n t he st u d y f or l o n ger t h a n 6 m o nt hs, a tele p h o ne c o nt act will be 
sc he d ule d e ver y 6 mo nt hs t o c ollect i nf or m ati o n c o ncer ni n g H A E att ac ks n ot tre ate d wit h ic ati b a nt i n t he 
st u d y.
Ot her secti o ns i m pacte d b y c ha n ge: A p pe n di x 1 Sc he d ule of E ve nts ( N o Attac k), A p pe n di x 2 , I nitial Icatiba nt -
treate d Attac k, A p pe n di x 3 , S u bse q ue nt Icati ba nt-treate d Attac ks
C ha n ge: C ha n ge t o st u d y assess me nts
Secti o n i m pacte d b y c ha n ge: Secti o n 8. 2 Pretreat me nt ( Ba seli ne) Assess me nts ( Da y 1, N o Attac k)
Re vise d Te xt :  
T he f oll o wi n g assess me nts will be perf or me d f or s u bjects w h o will be tre ate d wit h ic ati b a nt i n t he a bse nce of 
a c urre nt H A E att ac k.  All e v al u ati o ns a n d s a m ple c ollecti o ns m ust be perf or m e d pri or t o tre at me nt.
•
Me dic al hist or y 
•
C o nfir m  i ncl usi o n/e xcl usi o n criteri a 
•
P u bert al st at us deter mi n ati o n ( o nl y if t he s u bject w as cl assifie d as pre p u bert al at t he ti m e of t he
       scree ni n g visit)
•
Me nstr u al c ycle hist or y (i n p u bert al/ p ost p u bert al fe m ales o nl y)
•
P h ysic al e x a mi n ati o n
•
Vit al si g ns
•
Hei g ht a n d wei g ht
•
Cli nic al l a b or at or y tests (ser u m c he mistr y, he m at ol o g y a n d uri n al ysis)
•
Uri ne pre g n a nc y test (i n fe m ales of c hil d be ari n g p ote nti al)
•
Re pr o d ucti ve h or m o ne assess me nts
•
P h ar m ac o ki netic asses s me nt
•
I m m u n o ge nicit y assess me nt
•
Rec or di n g of c o nc o m it a nt me dic ati o ns
P P D
P P D
P P D
P P D
P P D
P P D

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Other sections impacted by change: Appendix 1 Schedule of Events (No Attack)
Change: Change to study assessments
Section impacted by change: Section 8.4 No Attack
Revised Text:  
8.4 No Attack
8.4.1 Treatment Period (Day 1 to Day 8 [± 1 Day])
•
Investigational product administration (Day 1, Time 0)
•
Physical examination (Day 1, 6 [±0.5] hours) (or 8 [±0.5] hours if the subject is not discharged***)
       post dose and Day 8 [±1 day])
•
Vital signs (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours) (or 8 [±0.5] hours if the subject is not
      discharged***) post dose and Day 8 [±1 day])
•
ECG (Day 1, 6 [±0.5] hours (or 8 [±0.5] hours if the subject is not discharged***) post dose) 
•
Clinical laboratory tests (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])
•
Reproductive hormone assessments (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])
•
Injection site reaction assessment (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours) (and 8 [±0.5] hours
       if the subject is not discharged**) post dose, Day 2 (24 [±4] hours), Day 3 (48 [±4] hours), and
        Day 8 [±1 day])
•
Sampling for PK assessments in pubertal/post pubertal subjects (Day 1, 15 [±5] minutes, 30 [±5]
       minutes, 45 [±5 minutes], 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] hours, 6 [±0.5]
       hours post dose)
•
Safety follow-up contact (Day 2 (24 [±4] hours), Day 3 (48 [±4] hours) by telephone (If a subject
       remains hospitalized, this safety follow-up will be conducted in person.)
•
Immunogenicity assessment (Day 8 [±1 day])
•
Menstrual cycle history (Day 8 [±1 day] in pubertal/postpubertal females)
•
Recording of concomitant medications  
•
Assessment of adverse events 
*A subject may be discharged after completion of all assessments at 6 hours post treatment, if deemed 
medically stable in the investigator’s clinical judgment.   If this is the case, the assessments scheduled for 8 
hours post treatment will be omitted.
Other sections impacted by change: Appendix 1 Schedule of Events (No Attack)
Change: Clarification to study assessments
Section impacted by change: Section 8.6.1 Treatment Period (Day 1 to Day 8 [± 1 Day])
Revised Text:  
•
Investigator assessment of HAE related pain (in subjects younger than 4 years of age only) using FLACC (Day 
1, 1 hour (±10 minutes), 2 hours (±10 minutes), 4 (±0.5)] hours, 6 (±0.5) hours [and 8 (±0.5) hours if the subject is 
not discharged**] post dose) (If a subject remains hospitalized, this safety follow-up will be conducted in 
person.)
Other sections impacted by change: Section 8.4.1 Treatment Period (Day 1 to Day 8 [± 1 Day]), Section 8.5.1
Treatment Period (Day 1 to Day 8 [± 1 Day]), Appendix 1 Schedule of Events (No Attack), Appendix 2, Initial 
Icatibant treated Attack, and Appendix 3, Subsequent Icatibant-treated Attacks     
Change: Clarification to study assessments
Section impacted by change: Section 8.6.1 Treatment Period (Day 1 to Day 8 [± 1 Day])  
Revised Text:  
•
Safety follow-up contact (Day 2 (24 [±4] hours), Day 3 (48 [±4] hours) either by telephone or in person at the 
investigator’s discretion)
Other sections impacted by change: Appendix 1 Schedule of Events (No Attack), Appendix 2, Initial Icatibant
treated Attack, and Appendix 3, Subsequent Icatibant-treated Attacks     

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Change: Change to planned statistical methods
Section impacted by change: Section 10.1 General Considerations
Revised Text:  
All statistical analyses will be performed using SAS® statistical software (SAS Institute, North Carolina, USA) 
except for the population PK modeling which will be performed with
nonlinear mixed effect modeling software (eg, Phoenix NLME module, Pharsight Corp.).  A
separate analytic plan will be developed to support the analysis of PK data.  The analysis
methods for all other study data (disposition, demographic and pretreatment characteristics, efficacy 
variables, and safety variables) will be detailed in the statistical analysis plan (SAP).
Other sections impacted by change: None
Change: Change to planned statistical methods
Section impacted by change:  Section 10.2 Determination of Sample Size
Revised Text:  
The study will enroll a sufficient number of children and adolescents to ensure study completion of 30 36 evaluable
subjects.  The study population is planned to consist of at least 10 16 prepubertal and 20 pubertal/postpubertal 
subjects from 2 to less than 18 17 years of age.  Though empirically derived and not based on a formal sample size 
calculation, this sample size will provide basic information concerning the PK, tolerability and safety, and efficacy 
of icatibant in children and adolescents with HAE.
Other sections impacted by change: Synopsis
Change: Change to planned statistical methods
Section impacted by change: Section 10.3 Analysis Populations
Revised Text:  
The following populations will be used in the analysis:
•
The Efficacy Population will consist of those subjects who were treated with icatibant for their first and 
any additional attacks.
•
The PK Population will consist of those subjects who were treated with icatibant and had sufficient 
icatibant plasma concentration time measurements to derive primary PK parameters. 
•
The Safety Population will consist of those subjects who were treated with icatibant at least once
All efficacy analyses will be performed on the Efficacy Population.  The corresponding tabular summaries 
and listings will be presented by the subject stratification group at enrollment (ie, prepubertal group or 
pubertal/postpubertal group) and icatibant-treated attack number. 
The PK analyses will be based on the PK Population.  
Safety and tolerability analyses will be based on the Safety Population.  All tabular summaries and listings 
within this population will be presented by the subject stratification group and icatibant exposure number.
Other sections impacted by change: Synopsis
Change: Change to planned statistical methods
Section impacted by change: Section 10.4 Demographics and Baseline Characteristics
Revised Text:  
Demographic data and pretreatment characteristics will be summarized separately for the Safety Population and 
the Efficacy Population.
Other sections impacted by change: Synopsis
Change: Change to planned statistical methods
Section impacted by change: Section 10.6 Safety and Tolerability Analyses  
Revised Text:  
Another key objective of the study is to investigate the safety and tolerability of a single SC dose of icatibant in 
pediatric subjects treated with icatibant for the first time or treated with icatibant more than once.  The 

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corresponding analyses will be based on the Safety Population.
The safety and tolerability parameters include adverse events, vital signs, ECG, local tolerability at the injection site, 
reproductive hormone levels, immunogenicity, and standard hematology, serum chemistry, and urinalysis.
Adverse events will be categorized using MedDRA Version 8.1.  The assessment of safety will be based mainly on 
the frequency of treatment emergent adverse events.  Adverse events will be summarized by system organ class 
(SOC) and preferred term.  The number and proportion of subjects experiencing an adverse event will be tabulated 
by the stratification group and icatibant exposure number.  
Laboratory data will be listed by subject, stratification group and icatibant exposure number.  Subjects with newly 
occurring abnormalities outside the normal range will be flagged and listed separately.  Observed values and 
changes from pretreatment values will be summarized by the stratification group and icatibant exposure number.  
Shift tables will also be tabulated by stratification group, icatibant exposure number, and study time point.
Vital signs data will be listed by subject, stratification group, and icatibant exposure number. Furthermore, 
observed values and changes from baseline will be summarized by stratification group and icatibant exposure 
number.  Shift tables may be presented, utilizing reference ranges. Subjects with notably abnormal values will be 
identified and listed separately along with their values.
Local tolerability will be tabulated and summarized according to the type and severity of the injection site reaction.
Other sections impacted by change: Synopsis
Change: Change to planned statistical methods
Section impacted by change: Section 10.7 Efficacy Analyses
Revised Text:  
Efficacy analyses will be performed on the Efficacy Population.  The primary efficacy endpoint is the time to 
onset of symptom relief measured using the investigator-reported symptom score. The investigator will report 
symptom scores at pretreatment and 1, 2, 4, and 6 hours post treatment, and at 8 hours post treatment for subjects 
who had not shown complete resolution of HAE symptoms at 6 hours.  Eight symptoms will be assessed for 
abdominal and cutaneous attacks, and 13 symptoms will be assessed for laryngeal attacks.  Time to onset of 
symptom relief is defined as the earliest time post treatment at which there is a 20% improvement in the average 
post-treatment symptom score with no worsening of any single component score. The median time and the 95% 
confidence interval will be calculated using the Kaplan-Meier methodology.
A tabular summary of the average investigator-reported symptom score and the change from baseline in the average 
investigator-reported symptom score will be presented by the stratification group and the icatibant treated attack 
number.  An alternative analysis will focus on the time to minimal symptoms and is defined as the time from 
study drug administration to the earliest time post treatment when all symptoms are either absent or mild.  
The median time and 95% confidence interval will be calculated using Kaplan-Meier methodology.
For individual investigator-reported symptom scores, a shift table from baseline will be presented for each post-
treatment time point.  The analysis will be repeated to assess shift in the individual symptom scores from the 2 hour 
time-point.  Also, for individual symptoms that are moderate or worse at pretreatment, the median and 95% 
confidence interval will be presented for the time to the symptom being mild or absent. 
Two subsets of subjects, those 4 years of age or older and those below 4 years of age, will have assessment of 
pain using the FPS-R and FLACC instruments, respectively.  For subjects  ≥4 years of age, the time to onset 
of symptom relief is defined as the earliest time at which the post-treatment score improves by at least one 
level.  The time to onset of symptom relief for subjects <4 years of age is defined as the earliest time at which 
a 20% improvement is seen in the total post-treatment score.  Additionally, time to minimal symptoms 
defined as the earliest time at which the post-treatment score (or total post-treatment score for FLACC) 
improves to zero, will be analyzed.  The time to onset of symptom relief and time to minimal symptoms will 
be analyzed using the same methods as the primary efficacy endpoint.
Other sections impacted by change: Synopsis
Change: Change to planned statistical methods
Section impacted by change: Section 10.8 Other Analyses
Revised Text:  
The number and percentage of subjects who received rescue medications before the onset of symptom relief will be 
summarized by the stratification group and icatibant-treated attack number.  Time to first use of rescue medication 

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prior to symptom relief will be calculated from the time of investigational product administration to the first use of 
rescue medication prior to the onset of symptom relief.  The median time and the 95% confidence interval will be 
calculated using Kaplan-Meier methodology if there are at least 5 subjects for a given attack who used rescue 
medication prior to attaining symptom relief.
Other sections impacted by change: None
Change: Change to planned statistical methods
Section impacted by change: Section 10.9 Data Monitoring and Interim Analysis
Revised Text:  
An analysis of the data for DSMB review is planned after the first 4 subjects in the pubertal/postpubertal group have 
been treated, and will be repeated at subsequent time points as specified in the DSMB charter.  Because no 
formal hypothesis testing is planned, multiplicity concerns regarding repeated analyses are not an issue.
Based on the anticipated sequence of data being generated in the study, an initial interim analysis of the data 
from pubertal/postpubertal patients (N=20) is planned.  It is expected that this will be followed by an interim 
analysis of data from prepubertal patients (N=10), and then by a final analysis to include the data of patients 
treated for subsequent attacks.  This sequence is based on the anticipated sequence of data being generated 
during the study and may be modified to fit the actual study conduct.
Other sections impacted by change: None
Change: Change to planned statistical methods
Section impacted by change: 10.10 Handling of Missing Data
Revised Text:  
Individual pretreatment symptom scores, FPS-R scores, and FLACC scores will be assigned a value of zero. For 
missing post-treatment scores, imputation will be employed using the Last Observation Carried Forward (LOCF) 
approach. The pretreatment values may also be used in the imputation.  For missing or partial rescue medication 
dates, the imputation will be performed such that the earliest possible time post treatment will be assigned to the 
rescue medication use.  A similar approach will be followed to determine treatment emergent adverse events in
case of missing or partial adverse event dates.
Other sections impacted by change: None
Change: Change to administrative considerations
Section impacted by change: Section 11.1 Investigators and Study Administrative Structure
Revised Text:  
Before initiation of the study, the investigator must provide the sponsor with a completed Form FDA 1572 or 
Investigator Agreement.  Investigational product may be administered only under the supervision of the 
investigator listed on this form.  Curriculum vitae must be provided for the investigator and sub investigators listed 
on Form FDA 1572 or the Investigator Agreement.
Other sections impacted by change: None
Change: Change to administrative considerations
Section impacted by change: Section 11.2 Institutional Review Board or Independent Ethics Committee Approval
Revised Text:  
Status reports must be submitted to the IRB/IEC at least once per year.  The IRB/IEC must be notified of completion 
of the study.  Within 3 months of study completion or termination (or as required), a final report must be provided 
to the IRB/IEC.  A copy of these reports will be sent to the study clinical monitor.  The investigators must maintain 
an accurate and complete record of all submissions made to the IRB/IEC, including a list of all reports and 
documents submitted.  Serious drug-related adverse events which are reported to the US Food and Drug 
Administration (FDA) or other Regulatory agencies (Investigational New Drug [IND] Safety Reports) must be 
submitted promptly to the IRB/IEC.
Other sections impacted by change: None

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Change: Change to administrative considerations
Section impacted by change: Section 11.7.1 Critical Documents
Revised Text:  
•
Completed FDA Applicable local regulatory documentation (eg, completed Form FDA 1572
      [Statement of Investigator], signed, dated, and accurate.
Regulatory approval and notification as required must also be available.  The protocol will not be initiated until 
regulatory approval and notification are obtained; these are the responsibility of the sponsor.
Other sections impacted by change: None
Change: Change to administrative considerations
Section impacted by change: Section 11.14 Financial Disclosure
Revised Text:  
Changes in status concerning financial interests during the study and after its completion will be disclosed by 
the Investigator in accordance 21 CFR Part 54.   
Other sections impacted by change: None
Change: Clarification to study schedule of events
Section impacted by change: Appendix 2, Initial Icatibant treated Attack
Revised Text:  
Time Post Treatment (hours) 0.45 0.75  (±5) min
Other sections impacted by change: None
Change: New study schedule of events
Section impacted by change:  see Appendix 1, No Attack
Other sections impacted by change: Section 8 Study Activities