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

Clinical Trial Protocol:  HGT-FIR-086 
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 
Product Name: 
Icatibant (Firazyr®) 
Indication: 
Hereditary angioedema 
Investigators: 
Multicenter 
Sponsor: 
Shire Orphan Therapies, Inc. 
Sponsor Contact: 
300 Shire Way  
Lexington, MA  02421 USA 
Medical Monitor: 
 MD,  
 Shire Human Genetic Therapies (HGT), Inc. 
 
 
Date 
Original Protocol: 
14 June 2011 
Amendment 1 
05 August 2011 
 
Confidentiality Statement 
This document is the proprietary and confidential property of Shire Human Genetic Therapies, 
Inc.   
PPD
PPD
PPD

Icatibant (Firazyr®) 
Clinical Trial Protocol Amendment 1: HGT-FIR-086 
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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) during an acute HAE attack.  
• To evaluate the efficacy of a single SC dose of icatibant in children and 
adolescents with HAE. 
• To evaluate levels of reproductive hormones 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 
repeat exposure.  
• To evaluate reproductive hormone levels in pubertal/postpubertal children after 
repeat exposure.  
• To evaluate the efficacy of icatibant in pubertal/postpubertal children after repeat 
exposure. 
Study Endpoints:  
The primary endpoints of this study are: 
• The PK profile of icatibant after a single SC injection in pediatric subjects treated 
for acute attacks of HAE. 
 

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• The tolerability and safety of SC icatibant as assessed by injection site reactions, 
adverse events (AEs), 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). 
The secondary endpoints of this study are: 
• For all subjects (2 to 17 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 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 a 20% improvement is seen in the 
post-treatment score. 
• For subjects <4 years of age only:  investigator assessment of HAE-related pain 
using the Faces, Legs, Activity, Cry, and Consolability (FLACC) scale.  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 incidence of rescue medication use. 
• The proportion of subjects with worsened intensity of clinical HAE 
symptoms between 2 and 4 hours after treatment with SC icatibant using 
investigator-rated symptom scores. 
Study Population:  
The study will enroll approximately 36 pediatric subjects from 2 through 17 years of age 
who present with cutaneous, abdominal, or laryngeal attacks of acute HAE after a 
qualifying screening period.   
Subject enrollment will be stratified into 2 groups based on Tanner staging:  a prepubertal 
group (defined as Tanner stage I) and a pubertal/postpubertal group (defined as Tanner 
stages II to V).  A subject’s classification as prepubertal or pubertal/postpubertal will be 
determined at the time of the subject’s first attack. 
Study Design: 
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, 
and safety, including reproductive hormone assessments, of a single SC administration of 
icatibant in up to approximately 36 pediatric subjects with HAE during an initial acute 
attack.  The study is planned to enroll up to approximately 16 prepubertal and 
20 pubertal/postpubertal subjects who are from 2 through 17 years of age and who present 
with an acute cutaneous, abdominal, or laryngeal HAE attack.  

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After treatment for an initial attack, further open-label treatment with icatibant will be 
offered to pubertal/postpubertal subjects contingent upon having been treated previously 
and presenting with a subsequent acute cutaneous, abdominal, or laryngeal attack of HAE 
at least 7 days after initial treatment.  Open-label treatment will continue until at least 
15 pubertal/postpubertal subjects have been treated with icatibant for a total of 3 attacks 
each.  Tolerability and safety evaluations, including reproductive hormone assessments, 
will be performed at each subsequent icatibant-treated attack as for the initial treated 
attack. 
Study Duration: 
Once subject eligibility is established at screening, the minimal planned duration of 
participation for subjects who present with an initial attack of acute HAE will be 
approximately 90 days and will consist of treatment with a single SC administration of 
icatibant on Day 1 and a 90-day follow-up period after treatment.  
Subjects will be closely monitored in the hospital/study center for at least 8 hours after 
administration.  Follow-up to assess the subject’s condition at 24 hours and 48 hours after 
treatment will be conducted by a telephone call from study personnel (or in person at the 
investigator’s discretion). 
After receiving treatment for an initial attack, at least 15 pubertal/postpubertal subjects 
who present with subsequent attacks of acute HAE may continue to receive treatment with 
icatibant for a total of 3 attacks each.   
Once the sixteenth prepubertal subject and the twentieth pubertal/postpubertal subject 
have completed the Day 90 follow-up after treatment for an initial attack, and the fifteenth 
pubertal/postpubertal subject has completed the Day 90 follow-up after the third and final 
treatment, the study will be closed.   
Study Inclusion and Exclusion Criteria: 
Subjects must meet all of the following criteria to be considered eligible for enrollment: 
1. Two through 17 years of age, inclusive (ie, from the second birthday through the day 
prior to the eighteenth birthday) at the time of the subject’s first attack. 
2. Documented diagnosis of HAE type I or II.  Diagnosis must be confirmed by 
documented immunogenic (below the lower limit of normal) and/or functional (<50% 
of normal levels) C1-INH deficiency.  Diagnosis may be on the basis of historic data 
or by diagnostic testing conducted at the time of screening. 
3. Informed consent (and subject assent as appropriate) signed by the subject’s parent(s) 
or legal guardian(s). 
 
Subjects will be excluded from the study if there is evidence of any of the following 
criteria at screening or at any time prior to the time of the first attack: 
1. Diagnosis of angioedema other than HAE. 
2. Participation in another clinical study during the 30 days prior to treatment.  
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. 
 

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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. The subject is pregnant or breastfeeding.   
 
Pharmacokinetic Variables: 
PK 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.   
PK parameter estimates will include, where appropriate:  actual icatibant and metabolite 
concentrations at each sampling time, 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 AEs.  Local tolerability will be 
assessed by evaluation of reactions at the site of study drug administration (injection site).  
Levels of reproductive hormones will be assessed in 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 below 
4 years of age will have symptoms assessed by the investigator only; including an 
assessment of HAE-related pain using the FLACC scale.  The time of initial symptom 
relief as assessed by the investigator will be recorded for all subjects. 
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 Initial Non-laryngeal Treatment Population will consist of those subjects who 
were treated with icatibant for their initial attack and whose primary symptom was 
either cutaneous or abdominal.  

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• The Second Non-laryngeal Treatment Population will consist of those subjects 
who had a second icatibant-treated attack for which the primary symptom was 
either cutaneous or abdominal, regardless of the primary symptom for the initial 
attack. 
• The Third Non-laryngeal Treatment Population will consist of those subjects who 
had a third icatibant-treated attack, for which the primary symptom was either 
cutaneous or abdominal, regardless of the primary symptom for the initial attack. 
• The Laryngeal Population will consist of those subjects who were treated with 
icatibant for any attack for which the primary symptom was laryngeal.  
• The PK Population will consist of those subjects who were treated with icatibant 
for their initial attack and who had at least 1 post-treatment icatibant concentration 
recorded.   
• The Initial Treatment Population will consist of those subjects who were treated 
with icatibant for the initial attack.  Safety and tolerability analyses will use this 
population. 
• The Additional Treatment Population will consist of those pubertal/post-pubertal 
subjects who were treated with icatibant for more than 1 attack.  Safety and 
tolerability analyses will use this population.  
Subject disposition, demographic and baseline characteristics, medical history, and use of 
concomitant medications will be summarized for each analysis population.   
Efficacy endpoints, including change from baseline when appropriate, will be summarized 
descriptively for the Initial, Second, and Third Non-laryngeal Treatment Populations.  The 
primary efficacy endpoint is the time to onset of symptom relief measured using the 
investigator-rated symptom score.  Time 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 efficacy data 
associated with the laryngeal attacks will be provided in data listings for the Laryngeal 
Population. 
Plasma concentrations of icatibant by time point and the PK parameters will be 
summarized descriptively. 
The assessment of safety will be based mainly on the frequency of AEs.  AEs will be 
summarized by presenting the number and percentage of subjects having any AE, having 
an AE in each body system, and having each individual AE using the Medical Dictionary 
for Regulatory Activity (MedDRA).  AEs 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 AEs.  Local tolerability will be tabulated and 
summarized according to the type and severity of attack. 
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. 

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Date of Amended Protocol:  05 August 2011 

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TABLE OF CONTENTS 
SYNOPSIS.................................................................................................................................2 
TABLE OF CONTENTS...........................................................................................................8 
LIST OF IN-TEXT TABLES..................................................................................................11 
LIST OF APPENDICES..........................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................12 
1 
INTRODUCTION ...........................................................................................................14 
1.1 
Disease Background...............................................................................................14 
1.2 
Previous Clinical Studies.......................................................................................15 
1.2.1 
Pharmacokinetics of Icatibant......................................................................15 
1.2.2 
Phase III Investigation of SC Icatibant........................................................15 
1.2.3 
Investigations of Potential Effects of Bradykinin Inhibition on Reproductive 
Function .......................................................................................................16 
1.3 
Rationale for Dose Selection .................................................................................17 
2 
STUDY OBJECTIVES....................................................................................................19 
2.1 
Objectives ..............................................................................................................19 
2.2 
Other Objectives ....................................................................................................19 
3 
STUDY ENDPOINTS.....................................................................................................20 
3.1 
Primary Endpoint(s)...............................................................................................20 
3.2 
Secondary Endpoint(s)...........................................................................................20 
4 
INVESTIGATIONAL PLAN..........................................................................................21 
4.1 
Overall Study Design and Plan..............................................................................21 
4.2 
Rationale for Study Design....................................................................................23 
4.3 
Study Duration.......................................................................................................23 
5 
STUDY POPULATION SELECTION ...........................................................................25 
5.1 
Study Population....................................................................................................25 
5.2 
Inclusion Criteria ...................................................................................................25 
5.3 
Exclusion Criteria ..................................................................................................25 
6 
STUDY TREATMENT(S)..............................................................................................26 
6.1 
Description of Treatment(s)...................................................................................26 
6.1.1 
Investigational Product ................................................................................26 
6.1.2 
Comparator ..................................................................................................26 
6.2 
Treatment(s) Administered....................................................................................26 
6.3 
Selection and Timing of Dose for Each Subject....................................................26 
6.4 
Method of Assigning Subjects to Treatment Groups.............................................26 
6.5 
Blinding..................................................................................................................26 
6.6 
Concomitant Medication Usage.............................................................................27 
6.7 
Rescue Therapy......................................................................................................27 

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6.8 
Restrictions ............................................................................................................28 
6.8.1 
Fluid and Food Intake..................................................................................28 
6.8.2 
Subject Activity Restrictions .......................................................................28 
6.9 
Treatment Compliance...........................................................................................28 
6.10 
Packaging and Labeling.........................................................................................28 
6.11 
Storage and Accountability....................................................................................28 
6.12 
Investigational Product Retention at Study Site ....................................................29 
7 
STUDY PROCEDURES .................................................................................................30 
7.1 
Informed Consent...................................................................................................30 
7.2 
Study Entrance Criteria..........................................................................................30 
7.3 
Confirmation of Study Eligibility..........................................................................30 
7.4 
Demographics ........................................................................................................30 
7.5 
Medical History .....................................................................................................30 
7.6 
Height and Weight.................................................................................................31 
7.7 
Tanner Staging.......................................................................................................31 
7.8 
Investigational Product Administration.................................................................31 
7.9 
Pharmacokinetic Assessments ...............................................................................31 
7.9.1 
Pharmacokinetic Variables ..........................................................................31 
7.9.2 
Pharmacokinetic Sampling ..........................................................................31 
7.9.3 
Bioanalytical Method...................................................................................32 
7.10 
Efficacy Assessments.............................................................................................32 
7.10.1 
Investigator Symptom Score........................................................................32 
7.10.2 
Subject Self-assessment of Pain...................................................................32 
7.10.3 
Investigator Assessment of Pain..................................................................33 
7.10.4 
Initial Symptom Relief.................................................................................33 
7.11 
Reproductive Hormone Assessments ....................................................................33 
7.12 
Safety Assessments................................................................................................33 
7.12.1 
Physical Examination...................................................................................33 
7.12.2 
Vital Signs....................................................................................................33 
7.12.3 
Electrocardiography.....................................................................................33 
7.12.4 
Clinical Laboratory Tests.............................................................................33 
7.12.5 
Local Tolerability.........................................................................................34 
7.12.6 
Immunogenicity...........................................................................................34 
7.12.7 
Pregnancy Testing........................................................................................35 
7.13 
Sample Collection, Storage, and Shipping ............................................................35 
7.14 
Recording of Concomitant Medications................................................................35 
7.15 
Adverse Events Assessments.................................................................................35 
7.15.1 
Definitions of Adverse Events and Serious Adverse Events.......................35 

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7.15.2 
Classification of Adverse Events and Serious Adverse Events...................37 
7.15.3 
Relatedness of Adverse Events and Serious Adverse Events......................37 
7.15.4 
Procedures for Recording and Reporting Adverse Events ..........................38 
7.16 
Pregnancy...............................................................................................................39 
7.17 
Abuse, Overdose, and Medication Error................................................................40 
7.18 
Removal of Subjects from the Trial or Investigational Product ............................40 
7.18.1 
Safety-Related Study Stopping Rules..........................................................41 
7.19 
Appropriateness of Measurements.........................................................................41 
8 
STUDY ACTIVITIES .....................................................................................................43 
8.1 
Screening Period (Day of Informed Consent to Pretreatment on Day 1 of the 
Initial Attack).........................................................................................................43 
8.2 
Pretreatment (Baseline) Assessments (Day 1, Initial and Subsequent Attacks)....43 
8.3 
Initial Attack ..........................................................................................................44 
8.3.1 
Treatment Period (Day 1 to Day 8)..............................................................44 
8.3.2 
Follow-up Visit (Day 90 ±7 days) ...............................................................44 
8.4 
Subsequent Attacks (Pubertal/postpubertal Subjects Only) ..................................45 
8.4.1 
Treatment Period (Day 1 to Day 8)..............................................................45 
8.4.2 
Follow-up Visit (Day 90 ±7 days) ...............................................................45 
9 
QUALITY CONTROL AND ASSURANCE .................................................................46 
10 PLANNED STATISTICAL METHODS ........................................................................47 
10.1 
General Considerations..........................................................................................47 
10.2 
Determination of Sample Size ...............................................................................47 
10.3 
Analysis Populations..............................................................................................47 
10.4 
Demographics and Baseline Characteristics..........................................................48 
10.5 
Pharmacokinetic Analysis......................................................................................48 
10.5.1 
Estimation of PK Parameters.......................................................................48 
10.6 
Safety and Tolerability Analysis............................................................................49 
10.7 
Efficacy Analysis...................................................................................................50 
10.8 
Other Analyses.......................................................................................................51 
10.9 
Data Monitoring and Interim Analysis ..................................................................51 
10.10 Handling of Missing Data......................................................................................51 
11 ADMINISTRATIVE CONSIDERATIONS....................................................................52 
11.1 
Investigators and Study Administrative Structure.................................................52 
11.2 
Institutional Review Board or Independent Ethics Committee Approval .............52 
11.3 
Ethical Conduct of the Study.................................................................................52 
11.4 
Subject Information and Consent/Assent...............................................................52 
11.5 
Subject Confidentiality ..........................................................................................53 
11.6 
Study Monitoring...................................................................................................54 

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11.7 
Case Report Forms and Study Records .................................................................54 
11.7.1 
Critical Documents ......................................................................................54 
11.8 
Data and Safety Monitoring Board........................................................................55 
11.9 
Protocol Violations/Deviations..............................................................................55 
11.10 Premature Closure of the Study.............................................................................56 
11.11 Access to Source Documentation ..........................................................................56 
11.12 Data Generation and Analysis ...............................................................................56 
11.13 Retention of Data...................................................................................................57 
11.14 Financial Disclosure...............................................................................................57 
11.15 Publication and Disclosure Policy .........................................................................57 
12 LIST OF REFERENCES.................................................................................................58 
 
LIST OF IN-TEXT TABLES 
Table 4-1  
Study Periods ...............................................................................................21 
Table 7-1  
List of Laboratory Tests...............................................................................34 
Table 7-2  
Adverse Event Severity................................................................................37 
Table 7-3  
Adverse Event Relatedness..........................................................................37 
 
LIST OF APPENDICES 
Appendix 1 
Study Schedule of Events (Initial Icatibant-treated Attack) ..............59 
Appendix 2 
Study Schedule of Events (Subsequent Icatibant-treated Attacks)....62 
Appendix 3 
Tanner Stages of Puberty...................................................................64 
Appendix 4 
Faces Pain Scale-Revised (FPS-R)....................................................65 
Appendix 5 
Faces, Legs, Activity, Cry, and Consolability Scale (FLACC).........66 
Appendix 6 
Protocol Signature Page.....................................................................67 
Appendix 7 
Summary of Changes for Amendment 1 ...........................................68 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
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 
HAE 
Hereditary Angioedema 
hCG 
Human chorionic gonadotropin 
HGT 
Human Genetic Therapies 
hr 
Hour(s) 

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ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
kg 
Kilogram(s) 
L 
Liter(s) 
LBW 
Lean body weight 
LH 
Luteinizing hormone 
LOCF 
Last observation carried forward 
MCB 
Master Cell Bank 
MedDRA 
Medical Dictionary for Regulatory Activity  
mg 
Milligram 
min 
Minute(s) 
mL 
Milliliter(s) 
mm 
Millimeters 
MRT 
Mean residual time 
n 
Number 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ng 
Nanogram(s) 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic(s) 
SAE 
Serious adverse event 
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 
 

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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   
The disease is generally caused by either a quantitative (Type I) or qualitative (Type II) 
deficiency of C1 inhibitor.  The functions of C1 inhibitor include the prevention 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, the principal mediator of the increased vascular permeability characteristic 
of HAE, by its cleavage from high molecular weight kininogen by dysregulated, activated 
kallikrein.  There is a third, more rare type of HAE (Type III) which is of unknown etiology and 
pathophysiology and thus will not be considered further here. 
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 accelerated 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 adult subjects 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 mean age at disease onset 
ranges from approximately 4 to 11 years.  Subcutaneous edema of the extremities, face, neck, 
torso and genitals is the most common, and usually the earliest, manifestation of HAE seen in 
children.  Analyses of the time of onset of disease symptoms have indicated an increase in the 
frequency and severity of manifestations between 3 and 6 years of age, as well as at around 
puberty, most likely related to the many physiological (endocrine, mental, and somatic) changes 
occurring during these periods of development.  In the gastrointestinal tract, submucosal edema 
may be associated with colicky abdominal pain, nausea, vomiting, and diarrhea.  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.6  

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Prompt control of attacks, short-term prophylaxis, and intermittent 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.  Antifibrinolytics are generally preferred (eg, tranexamic acid) for 
long-term prophylaxis because of their comparatively favorable safety profile relative to 
attenuated androgens; though their efficacy may be limited.  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 Clinical Study Report) 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. 
1.2.2 
Phase III Investigation of SC Icatibant 
Despite the rarity of HAE, a comprehensive data set supports the efficacy and safety of SC 
icatibant.   

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In Phase I, II, and III clinical studies, SC icatibant 30 mg has been administered to 129 healthy 
adult subjects and to 236 adult subjects with HAE.  A total of 999 acute attacks of HAE have 
been treated with icatibant administered by a health care provider, and an additional 56 attacks 
have been treated with icatibant when self administered by patients (Integrated Summary of 
Safety 11 January 2011).  
In integrated analyses of pooled data from 3 controlled Phase III studies (HGT-FIR-054, 
JE049-2102, and JE049-2103), icatibant significantly decreased the time to onset of symptom 
relief for cutaneous and abdominal attacks relative to comparator agents (placebo, tranexamic 
acid) as demonstrated by the primary and key secondary endpoint analyses in subjects with 
non-laryngeal symptoms randomized to double-blind treatment.  Moreover, the median time to 
onset of symptom relief after icatibant treatment was consistent across all of the controlled 
Phase III studies and across the 2 endpoints, ranging from 1.5 to 2.3 hours.  Likewise, icatibant 
showed effectiveness in the treatment of laryngeal attacks.   
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; therefore, dose adjustments for adult males or females are not considered necessary.  
Beyond exposure in clinical studies, it is estimated that over 8000 patient exposures to Firazyr® 
have occurred cumulatively in the postmarketing setting from the time of European Union 
regulatory approval in July 2008 through January 2011. 
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of icatibant. 
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.  Potential effects of icatibant on sexual organs and sexual 
maturation are being investigated further in studies in juvenile rats.  These are a SC 
administration local tolerance study, and a 7-week toxicity study with assessment of fertility.  
The local tolerance study in juvenile rats established the doses for the 7-week toxicity study.  
Briefly, in the 7-week toxicity study juvenile males and females were dosed with icatibant at 3, 
9, 25 mg/kg/day during a 7-week maturation period.  In males, slightly but statistically 
significant delayed physical maturation and lowered prostate and testes weight were seen at the 
mid and high doses.  Small testes and epididymis were occasionally seen at the highest dose.  
Microscopically, tubular cell vacuolation and germ cell degeneration were seen in males in the 
testes at all doses.  Statistically significantly decreased sperm motility, velocity, and counts at 
recovery were observed at the highest dose.   

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Decreased fertility was observed in untreated females paired with treated males at the highest 
dose.  All microscopic and organ weight findings were either completely or partially reversible.  
The complete results will be reported in the final study reports.  
A retrospective analysis, prompted by nonclinical observations, of serum levels of gonadotrophic 
hormone levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) in male and 
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 
basal and GnRH-stimulated concentrations of reproductive hormones (estradiol, progesterone, 
prolactin, DHEA, DHEA-S, 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.  The complete results will be reported in the final clinical 
study report.   
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.   

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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 
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 during an acute HAE attack 
• To evaluate the efficacy of a single SC dose of icatibant in children and adolescents with 
HAE 
• To evaluate levels of reproductive hormones 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 repeat 
exposure  
• To evaluate reproductive hormone levels in pubertal/postpubertal children after repeat 
exposure  
• To evaluate the efficacy of icatibant in pubertal/postpubertal children after repeat exposure 
 

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3 
STUDY ENDPOINTS 
3.1 
Primary Endpoint(s)  
The primary endpoints of this study are: 
• The PK profile of icatibant after a single SC injection in pediatric subjects treated for acute 
attacks of HAE. 
• The tolerability and safety of SC icatibant as assessed by injection site reactions, AEs, 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 Endpoint(s)  
The secondary endpoints of this study are: 
• For all subjects (2 to 17 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 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 a 20% improvement is seen in the post-treatment score. 
• For subjects <4 years of age only:  investigator assessment of HAE-related pain using the 
Faces, Legs, Activity, Cry, and Consolability (FLACC) scale.  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 incidence of rescue medication use. 
• The proportion of subjects with worsened intensity of clinical HAE symptoms between 2 and 
4 hours after treatment with SC icatibant using investigator-rated symptom scores. 
 

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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, and 
safety, including reproductive hormone assessments, of a single SC administration of icatibant in 
approximately 36 pediatric subjects with hereditary angioedema (HAE) during an initial acute 
attack.  The study is planned to enroll approximately 16 prepubertal and 20 pubertal/postpubertal 
subjects who are from 2 through 17 years of age and who present with a cutaneous, abdominal, 
or laryngeal attack of acute HAE.  
After treatment for an initial attack, further open-label treatment with icatibant will be offered to 
pubertal/postpubertal subjects contingent upon having been treated previously and presenting 
with a subsequent acute cutaneous, abdominal, or laryngeal attack of HAE at least 7 days 
after initial treatment.  Open-label treatment will continue until at least 15 pubertal/postpubertal 
subjects have been treated with icatibant for a total of 3 attacks each.  Tolerability and safety 
evaluations, including reproductive hormone assessments, will be performed at each subsequent 
icatibant-treated attack as for the initial treated attack. 
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 of the initial 
attack 
Initial icatibant-treated attack (All subjects) 
    Treatment  
Day 1 
    Post-treatment 
Day 1 through Day 8 
    Follow-up 
Day 9 through Day 90 (±7 days) 
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 
    Follow-up 
Day 9 through Day 90 (±7 days) 
 
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 immunogenic 
and/or functional C1-INH deficiency (<50% of normal levels) indicative of HAE Type I or II.  

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Diagnosis may be supported by family history, characteristic attack manifestations, and 
recurrence of attacks.  Assessments performed at screening will include demography, medical 
history, history of HAE, concomitant medication use, physical examination (including height and 
weight), vital signs, ECG, urine pregnancy test in female pubertal/postpubertal subjects, and 
blood sample collection for C1-INH testing.  
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 <4 years of age), and adherence to inclusion/exclusion criteria will be re-confirmed.  
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 (with 
Tanner staging), height and weight, vital signs, collection of samples for clinical laboratory tests 
(serum chemistry [including liver function tests], hematology, and urinalysis), urine pregnancy 
test for pubertal/postpubertal females, baseline PK and immunogenicity evaluations, and baseline 
assessment 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 administered as a SC injection 
within 12 hours after the onset of the acute attack.  Subjects will be monitored closely at the 
hospital/study center for at least 8 hours after treatment.  Subjects will be discharged after 
completion of scheduled assessments and when, according to the investigator’s judgment, they 
are deemed medically stable.  Follow-up to assess the subject’s condition at 24 hours (±4 hours) 
and 48 hours (±4 hours) after treatment will be conducted by a telephone call from study 
personnel (or in person at the discretion of the investigator). 
The time of study drug administration on Day 1 will be designated as Time 0.  All post-treatment 
assessments will be calculated from the time of study drug administration.  Blood samples for 
PK evaluation in pubertal/postpubertal subjects will be collected on Day 1 at pretreatment, 
15 (±5) minutes, 30 (±5) minutes, 45 (±5) minutes, 1 (±0.17) hour, 2 (±0.17) 
hours, 4 (±0.5) hours, 6 (±0.5), and 8 (±0.5) hours after treatment with study drug.  In 
prepubertal subjects, blood samples for PK evaluation will be collected on Day 1 at pretreatment, 
15 (±5) minutes, 30 (±5) minutes, 2 (±0.5) hours, 4 (±0.5) hours, and 8 (±0.5) hours.  
Safety and efficacy assessments will be performed on Day 1 through 8 hours after treatment.  
These assessments will include physical examination, vital signs, ECG, clinical laboratory tests 
(serum chemistry [including liver function tests], hematology, and urinalysis), injection site 
reactions, and assessment 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 <4 years of age) on Day 1 at 1, 2, 4, 6, and 8 hours 
after treatment.  Subject who are 4 years of age or older will also complete a self-assessment of 
HAE-related pain at these time points. 

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Rescue medication use will be assessed through 48 hours after treatment, either in person or by 
telephone at the discretion of the investigator. 
Subjects will undergo safety assessments, including physical examination, vital signs, and 
clinical laboratory tests (serum chemistry [including liver function tests], hematology, and 
urinalysis), evaluation of injection site reactions, immunogenicity, and measurement of 
reproductive hormones on Day 8 after treatment. 
Subjects will be followed over a 90-day (±7 days) period after initial treatment.  All subjects will 
provide blood samples for immunogenicity testing and determination of reproductive hormone 
levels at the Day 90 visit and undergo safety assessments including physical examination, vital 
signs, and clinical laboratory tests (serum chemistry, hematology, and urinalysis).  Additionally, 
pubertal/postpubertal females will undergo urine pregnancy testing. 
Further open-label treatments with study drug will be offered to pubertal/postpubertal subjects 
who have been previously treated and who present with an eligible attack at least 7 days 
post-treatment.  Open-label treatment will continue until a total number of at least 15 adolescents 
have been treated with icatibant for a total of 3 eligible acute attacks (ie, after their first 
icatibant-treated attack, pubertal/postpubertal subjects only may receive further treatment with 
icatibant for up to 2 subsequent attacks of acute HAE).  All primary and secondary outcomes, 
including antibodies (except PK), are to be measured after each administration.  Safety, 
reproductive hormone, and other assessments in association with subsequent attacks of acute 
HAE will be performed 90 days (±7 days) after treatment (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.   
All assessments are outlined in full in the Schedule of Events in Appendix 1, Initial 
Icatibant-treated Attack and Appendix 2, 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 being treated for an acute attack of 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, 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 
The approximate overall duration of the study will be 36 months.   
 

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Once subject eligibility is established at screening, the minimal planned duration of participation 
for individual subjects who present with an initial attack of acute HAE will be approximately 
90 days, and will consist of a single SC dose of icatibant on Day 1 and a 90-day follow-up period 
after treatment.   
Pubertal/postpubertal subjects, who may receive treatment for up to 2 additional attacks of acute 
HAE, will have a longer duration of participation.  Due to the unpredictable nature of HAE 
attacks, the actual expected duration of these subjects is unknown.  After receiving treatment for 
an initial attack, pubertal/postpubertal subjects who present with subsequent attacks of acute 
HAE may continue to receive treatment with icatibant up to a total of 3 icatibant-treated attacks. 
Once the sixteenth prepubertal subject and the twentieth pubertal/postpubertal subject has 
completed Day 90 follow-up after treatment for an initial attack, and the fifteenth 
pubertal/postpubertal subject has completed the Day 90 follow-up after the third and final 
treatment, the study will be closed.   

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5 
STUDY POPULATION SELECTION 
5.1 
Study Population 
Pediatric subjects from 2 through 17 years of age who present with cutaneous, abdominal, or 
laryngeal attacks of acute HAE after a qualifying screening period will be eligible for enrollment 
in the study.  Subject enrollment will be stratified into 2 groups, based on Tanner staging,7, 8 to 
consist of a prepubertal group (defined as Tanner stage I) and a pubertal/postpubertal group 
(defined as Tanner stages II to V).   
A subject’s classification as prepubertal or pubertal/postpubertal will be determined at the time 
of the subject’s first attack. 
5.2 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study. 
1. Two through 17 years of age, inclusive (ie, from the second birthday until the day prior to the 
eighteenth birthday) at the time of the subject’s first attack. 
2. Documented diagnosis of HAE Type I or II.  Diagnosis must be confirmed by documented 
immunogenic (below the lower limit of normal) and/or functional (<50% of normal levels) 
C1-INH deficiency.  Diagnosis may be on the basis of historic data or by diagnostic testing 
conducted at the time of screening. 
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 study during the 30 days prior to treatment.  
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 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. The subject is pregnant or breastfeeding. 
 

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6 
STUDY TREATMENT(S) 
6.1 
Description of Treatment(s) 
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(s) Administered 
All subjects will receive treatment with icatibant for an initial acute attack of HAE as a single, 
weight-adjusted dose of 0.4 mg/kg up to a maximum of 30 mg administered as a SC injection. 
Subsequent treatment with icatibant for up to 2 additional attacks of acute HAE will be offered to 
pubertal/postpubertal subjects who present with a new attack at least 7 days after prior treatment.  
The dosing regimen for treatment of subsequent attacks will be the same as that for treatment of 
the initial attack (ie, a single weight-adjusted dose of 0.4 mg/kg up to a maximum of 30 mg per 
attack administered as a SC injection).  Thus, no more than 3 doses of icatibant will be 
administered to any subject during the study. 
6.3 
Selection and Timing of Dose for Each Subject 
Each subject will be administered a single dose of icatibant as a SC injection within 12 hours 
after the onset of an acute HAE attack.  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 who have been previously treated and who present with another attack at least 7 days 
post-treatment with study drug.   
6.4 
Method of Assigning Subjects to Treatment Groups 
Not applicable to this study.  All subjects will be administered study drug at a weight-adjusted 
dose of 0.4 mg/kg SC up to a maximum of 30 mg per treatment.   
6.5 
Blinding 
Not applicable to this open-label study. 

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6.6 
Concomitant Medication Usage 
All prescription and over-the-counter medications which 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 study 
drug. 
• 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 during the study: 
• 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 a single attack is not allowed in this study.   
The determination of the necessity for pain medication or other rescue therapy will be at the 
discretion of the investigator.  If pain medication is required, the investigator may administer 
morphine sulfate at a dose of 0.05 mg/kg or an equivalent low dose narcotic.  Antiemetics may 
also be prescribed as necessary to treat nausea.  Other acceptable rescue therapies include FFP, 
epinephrine, C1-INH if available and intravenous or prescription-strength non-steroidal 
anti-inflammatory drugs (NSAIDs).  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.   

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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/site 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 
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. 

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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 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 Schedule of Events Tables in Appendix 1, Initial Icatibant-treated Attack and Appendix 2, 
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 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 on 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, 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 of the first 
dose will be reported as medical history. 

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7.6 
Height and Weight 
Height and weight will be recorded for all subjects.   
7.7 
Tanner Staging 
The investigator will perform Tanner staging for all subjects to determine pubertal status.  A 
description of the Tanner stages of puberty is provided in Appendix 3. 
7.8 
Investigational Product Administration 
All subjects will receive treatment with icatibant for an initial acute attack of HAE as a single, 
weight-adjusted dose of 0.4 mg/kg administered as a SC injection up to a maximum dose of 
30 mg.  Treatment with icatibant will be administered within 12 hours of onset of an acute HAE 
attack.  Pubertal/postpubertal subjects who present with a subsequent attack at least 7 days 
post-treatment may receive further treatment with icatibant for a total of 3 attacks. 
7.9 
Pharmacokinetic Assessments  
7.9.1 
Pharmacokinetic Variables 
PK 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.  The methods to be used for 
estimation of PK parameter values are described in Section 10.5.1. 
PK parameter estimates will include, where appropriate:  actual icatibant and metabolite 
concentrations at each sampling time, 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). 
7.9.2 
Pharmacokinetic Sampling 
Sampling for PK assessments will be collected according to the Schedule of Events Table in 
Appendix 1, Initial Icatibant-treated Attack.   
The time of study drug administration on Day 1 will be designated as Time 0.  All post-treatment 
assessments will be calculated from the time of study drug 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, 15 (±5) minutes, 30 (±5) minutes, 45 (±5) 
minutes, 1 (±0.17) hour, 2 (±0.17) hours, 4 (±0.5) hours, 6 (±0.5), and 8 (±0.5) hours after 
treatment with study drug.   

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Blood samples for determination of plasma concentrations of icatibant in prepubertal subjects 
will be collected on Day 1 at pretreatment, 15 (±5) minutes 30 (±5) minutes, 2 (±0.5) hours, 
4 (±0.5) hours and 8 (±0.5) hours.  
7.9.3 
Bioanalytical Method 
Plasma samples will be assayed for concentrations of icatibant and its metabolites (M1 and M2) 
using a validated method (see Section 7.19). 
7.10 Efficacy Assessments 
7.10.1 
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 on the CRF. 
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.   
7.10.2 
Subject Self-assessment of Pain  
Subjects who are at least 4 years of age will self-assess HAE-related pain using the Faces Pain 
Scale-Revised (FPS-R).  A copy of the FPS-R is provided in Appendix 4. 
Self-assessment results will be recorded in the e-diary.  The self-assessment diaries will be 
provided to these subjects on Day 1 at pretreatment and at predetermined time points after 
treatment while at the hospital/study center and after their discharge.  Subjects will return the 
e-diary at the next scheduled visit on Day 8.  Subjects will receive detailed instructions on when 
and how to complete the diaries by the investigator and/or clinical site personnel. 

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7.10.3 
Investigator Assessment of Pain 
Subjects who are below 4 years of age will undergo investigator assessment of HAE-related 
symptoms using the Faces, Legs, Activity, Cry, and Consolability (FLACC) comportmental pain 
scale.  A copy of the FLACC scale is provided in Appendix 5. 
7.10.4 
Initial Symptom Relief 
The investigator will be asked to provide the following information on the CRF: 
• To record the date and time when overall subject improvement was first noted and mark the 
date and time accordingly. 
 
7.11 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. 
7.12 Safety Assessments 
7.12.1 
Physical Examination 
Physical examinations will include a review of the subject’s general appearance as well as 
evaluation of the body systems.  Any 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 
 
7.12.2 
Vital Signs 
Vital signs are to be recorded for all subjects and will include pulse, blood pressure, respiration 
rate, and temperature.   
7.12.3 
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. 
7.12.4 
Clinical Laboratory Tests 
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing.  All blood samples will be collected via venipuncture.  Subjects will be in a seated or 
supine position during blood collection. 

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Clinical laboratory tests will include the following (See Table 7-1):  
Table 7-1  List of 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 
 
 
7.12.5 
Local Tolerability 
Injection site reactions (erythema, swelling, burning sensation, itching/pruritis, warm sensation, 
cutaneous pain, or other) will be evaluated by the investigator 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.   
7.12.6 
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 HGT 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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7.12.7 
Pregnancy Testing 
Pubertal and postpubertal female subjects will undergo pregnancy testing at time points specified 
in the Schedule of Events Tables in Appendix 1 and Appendix 2.  All pregnancy testing will be 
conducted using a urine human chorionic gonadotropin (hCG) test.  
7.13 Sample Collection, Storage, and Shipping 
Blood samples will be collected via venipuncture.  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. 
7.14 Recording of Concomitant Medications  
All medications administered to the study subjects from the time of informed consent through the 
Day 90 follow-up visit are regarded as concomitant and will be documented on the CRF.  
7.15 Adverse Events Assessments   
7.15.1 
Definitions of Adverse Events and Serious Adverse Events 
7.15.1.1 
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 
any phase of a clinical study, whether or not considered investigational product-related.  This 
includes an exacerbation of a pre-existing condition.   
AEs include: 
• Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study. 
• Intercurrent illnesses. 
• Drug interactions. 
• Events related to or possibly related to concomitant medications. 
• 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 on the AE 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. 

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In addition, AEs may also include laboratory values that become 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 can be 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 study drug treatment, and 
worsening of a concomitant illness during the study, are to be regarded as AEs 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.  Any 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 
separately from general reports of AEs.  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 detail in the CRF.  They are considered to be 
pre-existing disease and will not be documented as AEs. 
Local tolerability will include symptoms at the site of study drug administration (injection site) 
and will be assessed separately from general reports of AEs.  Injection site reactions will be 
documented in the "local tolerability" page (or form) 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.   
7.15.1.2 
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 AE as it occurred 
(ie, it does not include an AE that, had it occurred in a more severe form, might have caused 
death). 

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7.15.2 
Classification of Adverse Events and Serious Adverse Events 
The severity of AEs will be assessed by the investigator using the National Cancer Institute 
Common Terminology Criteria (NCI CTCAE) Version 4.0 grading scale.  If an AE is not 
described in the NCI CTCAE, the severity should be recorded based on the scale below (see 
Table 7-2).  The severity of all AEs/SAEs should be recorded on the appropriate CRF page as 
Grade 1, 2, 3, 4, or 5 corresponding, respectively, to a severity of mild, moderate, severe, 
life-threatening, or fatal.  
Table 7-2  Adverse Event Severity   
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. 
Grade 4 (Life-threatening) 
Immediate risk of death. 
Grade 5 (Fatal) 
Death 
 
7.15.2.1 
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. 
7.15.3 
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 

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Table 7-3  Adverse Event Relatedness 
Relationship to Product(s) 
Definition 
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. 
 
7.15.4 
Procedures for Recording and Reporting Adverse Events 
7.15.4.1 
Adverse Event Monitoring and Period of Observation 
AEs will be monitored continuously.  For the purposes of this study, the period of observation 
will extend from the time of treatment until the subject’s final evaluation of the study.  For safety 
purposes, the final evaluation will be defined as the follow-up evaluation performed 
approximately 90 days after the last dose for subjects who complete the study. 
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. 
7.15.4.2 
Reporting Serious Adverse Events 
Any SAE, regardless of relationship to investigational product, which occurs in a subject after 
informed consent, should be recorded by the clinical site on an SAE form.  The SAE must be 
completely described on the subject’s CRF, including the judgment of the investigator as to the 
relationship of the SAE to the investigational product.   
The investigator will promptly supply all information identified and requested by the sponsor (or 
contract research organization [CRO]) regarding the SAE.  The investigator must report the SAE 
to the Shire Pharmacovigilance and Risk Management Department AND to the Shire HGT 
Medical Monitor on an SAE form.  This form must be completed and faxed or emailed within 
24 hours of the investigator’s learning of the event to: 
Shire Pharmacovigilance and Risk Management Department: 
FAX: 
(Worldwide) OR 
(North America) 
Email: 
PPD
PPD
PPD

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AND 
Shire HGT Medical Monitor: 
, MD 
  
FAX: 
(USA) 
Any follow-up information must also be completed on an SAE form and faxed or emailed to the 
same numbers listed above. 
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire HGT Medical Monitor by telephone; this is in addition to completing and 
transmitting the SAE form as stated above.  The following provides contact information for the 
Shire HGT Medical Monitor.  
If an SAE is assessed as severe and unexpected, or life-threatening, contact: 
If an SAE is assessed as severe and unexpected, or life-threatening, contact: 
, MD 
Shire Human Genetic Therapies, Inc. 
300 Shire Way 
Lexington, MA 02421 USA 
Telephone: 
 
Fax: 
(USA) 
 
 
The investigator must promptly report all required information to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).  It is the responsibility of the sponsor to ensure that 
each investigator receives a copy of any Council for International Organizations of Medical 
Sciences (CIOMS I)/MedWatch report that has been submitted to the appropriate regulatory 
agencies notifying them of an unexpected related SAE.   
The investigator or sponsor must ensure that the IRB/IEC receives a copy of the report and that a 
copy is also filed within their study files. 
7.16 Pregnancy 
Pregnancy and lactation are exclusion criteria for this study.  The sponsor must be notified in the 
event of a pregnancy occurring during the course of the study and through 90 days after the 
subject’s last dose of investigational product.  Pregnancy is not to be reported as an AE; the 
pregnancy reporting form should be used to report the pregnancy.  The pregnancy will be 
followed up through delivery or final outcome. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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7.17 Abuse, Overdose, and Medication Error 
• Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a 
dose higher than prescribed per protocol (but below the dose defined for overdose) or when 
used for non-medical purpose (eg, altering one’s state of consciousness). 
• Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note:  
this includes a situation where the test article is not used as directed at the dose prescribed by 
the protocol). 
• 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. 
 
All investigational medicinal product provided to pediatric subjects should be supervised by the 
parent(s)/legal guardian(s)/caregiver(s). 
7.18 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 Case Report Form (CRF) describing the reason for 
discontinuation must be completed.  Any AEs experienced up to the point of discontinuation 
must be documented on the AE 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. 

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7.18.1 
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.   
Additional information on safety monitoring can be found in Section 11.8, Data and Safety 
Monitoring Board. 
7.19 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).  PK 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.   
 

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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.9  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.10  
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 
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, consolability) to assess pain in young children.11  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, safety, and efficacy profiles of icatibant in the pediatric population. 

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8 
STUDY ACTIVITIES 
8.1 
Screening Period (Day of Informed Consent to Pretreatment on Day 1 of the 
Initial Attack)   
• Informed Consent/Assent 
• Inclusion/Exclusion Criteria 
• Medical History 
• Confirmation of documented HAE diagnosis 
• Measurement of C1-INH   
• Physical examination 
• Vital signs 
• ECG 
• Height and weight 
• Urine pregnancy test in pubertal/postpubertal females only 
• Recording of concomitant medications 
 
8.2 
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 (at initial attack only) 
• Physical examination 
• Tanner staging 
• Vital signs 
• ECG (at subsequent attacks only) 
• Height and weight 
• Subject self-assessment of HAE-related pain (in subjects ≥4 years of age only) using e-diary 
FPS-R 
• Investigator assessment of HAE symptoms 
• Investigator assessment of HAE-related pain (in subjects <4 years of age only) using FLACC 
• Clinical laboratory tests (serum chemistry, hematology and urinalysis) 
• Urine pregnancy test (in pubertal/postpubertal females only) 
• Assessment of reproductive hormones  
• Pharmacokinetic evaluation (prior to treatment at initial attack only) 
• Immunogenicity evaluation 
• Recording of concomitant medications 
• Assessment of AEs (at subsequent attacks only) 
 

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8.3 
Initial Attack  
8.3.1 
Treatment Period (Day 1 to Day 8) 
• Study drug administration (Day 1, Time 0) 
• Physical examination (Day 1, 8 hours post-dose and Day 8) 
• Vital signs (Day 1, 1 hour and 8 hours post-dose and Day 8) 
• ECG (Day 1, 8 hours post-dose) 
• Subject self-assessment of HAE-related pain (in subjects ≥4 years of age) using e-diary 
FPS-R (Day 1, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose, Day 2 [24 hours], 
Day 3 [48 hours]) 
• Investigator assessment of HAE symptoms (Day 1, 1 hour, 2 hours, 4 hours, 6 hours, and 
8 hours post-dose) 
• Investigator assessment of HAE-related pain (in subjects <4 years of age only) using FLACC 
(Day 1, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose) 
• Clinical laboratory tests (Day 1, 8 hours post-dose and Day 8) 
• Assessment of reproductive hormones (Day 1, 8 hours post-dose and Day 8) 
• Injection site reaction evaluation (Day 1, 1 hour, 6 hours, and 8 hours post-dose, 
Day 2 [24 hours], Day 3 [48 hours], and Day 8) 
• Sampling for PK evaluation in pubertal/post pubertal subjects (Day 1, 15 (±5) minutes, 
30 (±5) minutes, 45 (±5) minutes, 1 (±0.17) hour, 2 (±0.17) hours, 4 (±0.5) hours, 6 (±0.5) 
hours, and 8 (±0.5) hours post-dose at initial attack only) 
• Sampling for PK evaluations in prepubertal subjects (Day 1, 15 (±5) minutes, 30 (±5) 
minutes, 2 (±0.17) hours, 4 (±0.5) hours, and 8 (±0.5) hours post-dose at initial attack only) 
• Immunogenicity evaluation (Day 8) 
• Recording of concomitant medications   
• Assessment of AEs  
 
8.3.2 
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 
• Tanner staging (for those subjects classified as Tanner stage IV or below at baseline) 
• Vital signs 
• Height and weight 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Urine pregnancy test (in pubertal/postpubertal females only) 
• Assessment of reproductive hormones  
• Immunogenicity evaluation  
• Recording of concomitant medications 
• Assessment of AEs 

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8.4 
Subsequent Attacks (Pubertal/postpubertal Subjects Only) 
Pubertal/postpubertal subjects may receive treatment for up to 2 subsequent HAE attacks.  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.    
8.4.1 
Treatment Period (Day 1 to Day 8) 
• Study drug administration (Day 1, Time 0) 
• Physical examination (Day 1, 8 hours post-dose and Day 8)  
• Vital signs (Day 1, 1 hour and 8 hours post-dose and Day 8) 
• ECG (Day 1, 8 hours post-dose) 
• Subject self-assessment of HAE symptoms in subjects ≥4 years of age using e-diary FPS-R 
(Day 1, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose, Day 2 [24 hours], 
Day 3 [48 hours]) 
• Investigator assessment of HAE symptoms (Day 1, 1 hour, 2 hours, 4 hours, 6 hours, and 
8 hours post-dose) 
• Investigator assessment of HAE-related pain (in subjects <4 years of age only) using FLACC 
(Day 1, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose) 
• Clinical laboratory tests (Day 1, 8 hours post-dose and Day 8) 
• Assessment of reproductive hormones (Day 1, 8 hours post-dose and Day 8) 
• Injection site reaction evaluation (Day 1, 1 hour, 6 hours, and 8 hours post-dose, 
Day 2 [24 hours], Day 3 [48 hours], and Day 8) 
• Immunogenicity evaluation (Day 8) 
• Recording of concomitant medications 
• Assessment of AEs  
 
8.4.2 
Follow-up Visit (Day 90 ±7 days) 
• Physical examination 
• Tanner staging (for those subjects classified as Tanner stage IV or below at baseline) 
• Vital signs 
• Height and weight 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Urine pregnancy test (in pubertal/postpubertal females only) 
• Assessment of reproductive hormones  
• Immunogenicity evaluation 
• Recording of concomitant medications 
• Assessment of AEs 
 

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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. 
SAE 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, NC, 
USA).  Data will be summarized with respect to disposition, demographic, pretreatment 
characteristics, PK variables, safety variables, and efficacy variables.  Unless stated otherwise, 
tabular summaries will be presented by the subject’s stratification group at enrollment (ie, 
prepubertal group, pubertal/postpubertal group, and the overall subjects group).  
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 
Enrollment of approximately 16 prepubertal and 20 pubertal/postpubertal subjects, who are from 
2 through 17 years of age and who present with a cutaneous, abdominal, or laryngeal attack of 
acute HAE, is planned.  This sample size is empirically derived and not based on a formal 
sample size calculation.  However, the inclusion of approximately 36 subjects will provide basic 
information for safety, tolerability, PK, and efficacy. 
10.3 Analysis Populations 
The following populations will be used in the analysis: 
• The Initial Non-laryngeal Treatment Population will consist of those subjects who were 
treated with icatibant for their initial attack and whose primary symptom was either 
cutaneous or abdominal.  
• The Second Non-laryngeal Treatment Population will consist of those subjects who had a 
second icatibant-treated attack for which the primary symptom was either cutaneous or 
abdominal, regardless of the primary symptom for the initial attack. 
• The Third Non-laryngeal Treatment Population will consist of those subjects who had a third 
icatibant-treated attack, for which the primary symptom was either cutaneous or abdominal, 
regardless of the primary symptom for the initial attack. 
• The Laryngeal Population will consist of those subjects who were treated with icatibant for 
any attack for which the primary symptom was laryngeal.  
• The PK Population will consist of those subjects who were treated with icatibant for their 
initial attack and who had at least 1 post-treatment icatibant concentration recorded.   
• The Initial Treatment Population will consist of those subjects who were treated with 
icatibant for the initial attack. 
• The Additional Treatment Population will consist of those pubertal/post-pubertal subjects 
who were treated with icatibant for more than 1 attack.   
 

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All efficacy analysis will be performed on the Initial Non-laryngeal Treatment Population, the 
Second Non-laryngeal Treatment Population, and the Third Non-laryngeal Treatment 
Population.  The PK analyses will be based on the PK population.  Safety and tolerability 
analyses will be based on the Initial Treatment Population and the Additional Treatment 
Population.  The Laryngeal Population will be used to explore the efficacy of icatibant for the 
treatment of laryngeal attacks.  All analyses conducted with this population will be limited to 
data corresponding to the subject’s first laryngeal attack. 
10.4 Demographics and Baseline Characteristics 
Demographic data and pretreatment characteristics will be summarized for each analysis 
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 treated for acute attacks of HAE.  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).  PK 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 
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. 
PK 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, clearance (CL/F), 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). 
 

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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 
considered the primary statistical analysis.  A p-value of 0.05 will be considered statistically 
significant for all analyses. 
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 Analysis 
Another primary objective of the study is to investigate the safety and tolerability of a single SC 
dose of icatibant in pediatric subjects with HAE during an acute HAE attack.  The corresponding 
analyses will be based on the Initial Treatment 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. 
AEs will be categorized using MedDRA Version 8.1 or higher.  The assessment of safety will be 
based mainly on the frequency of treatment emergent AEs.  AEs 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 subject stratification group and for the overall subject group.  AEs 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 study drug will be 
identified for the analysis by relationship.  SAEs will be provided in a data listing. 

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Laboratory data will be listed by subject and stratification group.  Subjects with newly occurring 
abnormalities outside the normal range will be flagged and listed separately.  Actual values and 
mean change from pretreatment values will be summarized by the stratification group.  Shift 
tables will also be tabulated by stratification group and time point. 
Vital signs data will be listed by subject and stratification group.  Furthermore, actual values and 
mean changes from baseline will be summarized for each stratification group as well as the 
overall subject group.  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 attack. 
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. 
The assessment of safety and tolerability after repeated treatment with icatibant is also of 
interest.  The analyses described above will be repeated using the Additional Treatment 
Population.  The summary tables and listings will be presented by attack number (ie, Attack 1, 
Attack 2, and Attack 3). 
10.7 Efficacy Analysis 
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, 6, and 8 hours post-treatment.  Eight symptoms will be assessed for 
abdominal and cutaneous attacks, and 13 symptoms will be assessed for laryngeal attacks.  Time 
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 overall subjects group.  An alternative analysis of time to onset of 
symptom relief will focus on the time to minimal symptoms.  In this case, symptom relief is 
defined as the earliest time post-treatment when all symptoms are either absent or mild.  
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.  

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Two subsets of subjects, those 4 years of age or older and those below 4 years of age, will assess 
pain using the FPS-R and FLACC instruments, respectively.  Time to onset of symptom relief 
will be computed in a manner similar to that for the average investigator-reported symptom 
scores.  
All efficacy analysis will be performed on the initial treatment population, the second treatment 
population, and the third treatment population.  The efficacy data for subjects with laryngeal 
attacks will be listed.  If there are at least 5 subjects with laryngeal attacks, then the average 
investigator-reported symptom scores and the change from baseline in the average 
investigator-reported symptom score will be summarized.  Additionally, time to symptom relief 
analysis will be performed on the investigator-reported symptom scores. 
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.  Time to first use of rescue 
medication prior to symptom relief will be calculated from the time of study drug administration 
to the first use of rescue medication prior to symptom relief.  The median time and the 
95% confidence interval will be calculated using Kaplan-Meier methodology if there are at least 
5 subjects who used rescue medication prior to attaining symptom relief. 
10.9 Data Monitoring and Interim Analysis 
A Data and Safety Monitoring Board (DSMB) will be set up to review the safety, tolerability, 
PK, and efficacy data on an ongoing basis.  The goal of the DSMB 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.  
Because no formal hypothesis testing is planned, multiplicity concerns regarding repeated 
analyses are not an issue.  
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.  
Similar approach will be followed 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.  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. 
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, 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.  AEs 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. 
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) as appropriate 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: 
• Completed FDA Form 1572 (Statement of Investigator), signed, dated, and accurate. 
• Curricula vitae of investigator and sub-investigator(s) (current, dated and signed within 
12 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; 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 Data and Safety Monitoring Board (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 17 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, and tolerability 
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.  For any 
subject who does not meet the inclusion or exclusion criteria a protocol exemption may be 
requested by the investigator.  This exemption may be approved by the Shire HGT Medical 
Monitor prior to enrollment and the protocol exception must be fully documented in the source 
documents and on the appropriate page of the CRF. 
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 be required 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 contract research organization or an 
electronic data capture technology provider as designated by Shire HGT.  The sponsor or its 
designee will be responsible for performing study data management activities.  
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 8.1 or 
higher.  Concomitant medication will be coded using WHO-Drug Dictionary (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.  
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 HGT, 
provided Shire HGT a copy of the draft document intended for publication, and obtained the 
written consent of Shire HGT for such publication.  All information obtained during the conduct 
of this study will be regarded as confidential.  Shire HGT 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 angioedema: a current state-of-the-art review, 
VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, 
Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol 
2008;100:S30-40. 
2. Davis AE, 3rd. New treatments addressing the pathophysiology of hereditary angioedema. 
Clin Mol Allergy 2008;6:2. 
3. Knolle J, Breipohl G, Henke S, Wirth K, Scholkens B. New and highly potent bradykinin 
antagonists. Agents Actions Suppl 1992;38 ( Pt 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. B J Pharmacol 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. B J Pharmacol 1991;102:774-7. 
6. Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma 
Clin Immunol 2010;6:18. 
7. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Disease 
Childhood 1969;44:291-303. 
8. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch 
Disease Childhood 1970;45:13-23. 
9. Bieri D RRACGDALZJB. 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. 
10. 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. 
11. The FLACC: A Behavioral Scale for Scoring Postoperative Pain in Young Children. Pediatr 
Nurs 1997;23:293-97. 
 
 

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Appendix 4 
Faces Pain Scale-Revised (FPS-R) 

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Appendix 5 
Faces, Legs, Activity, Cry, and Consolability Scale (FLACC) 
 

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Appendix 6 
Protocol Signature Page 
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 
Original Protocol 
Date: 
14 June 2011 
Amendment 1 Date: 
05 August 2011 
I have read the protocol described above.  I agree to comply with all applicable regulations and 
to conduct the study as described in the protocol.   
Signatory: 
 
 
 
 
 
 
 
 
 
 
 
Investigator 
 
 
 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
Printed Name 
 
 
I have read and approve the protocol described above. 
Signatory: 
 
 
 
 
 
 
 
 
 
 
 
Shire HGT 
Medical 
Monitor 
 
 
 
Signature 
Date 
 
 
 
 
 
 
 
 MD 
 
 
Printed Name 
 
 
 
PPD

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Appendix 7 
Summary of Changes for Amendment 1 
1. Amendment Summary and Rationale 
Protocol HGT-FIR-086 has been modified from the original version to align the protocol with 
recommendations made by EMA/PDCO on 15 July 2011 and outlined in the EMA/PDCO 
Modification Summary Report.  In particular, protocol-specified safety assessments were 
amended to include ECG evaluations.  In addition, an investigator assessment utilizing a 
comportmental pain scale (FLACC) was added for the evaluation of abdominal symptoms of 
acute HAE in children below 4 years of age.  A copy of the FLACC scale and a description of 
the Tanner staging system being used to stratify study participants were added to the protocol as 
appendices.  The original version of the appendix displaying the FPS-R scale was edited to 
include only the copy of the scale (ie, superfluous text and a French translation of the document 
were eliminated).  Lastly, several operational clarifications to the text and changes to the study 
schedules of events were implemented to facilitate study conduct.  These are delineated below. 
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 some 
changes for consistency and clarity), and updates to the list of abbreviations and cross-references 
are not reflected in the change summary. 
Bold text indicates new text. Strikethrough text indicates deleted text. 
NEW OR DELETED TEXT 
Change:  Change to Sponsor contact 
Section impacted by this change:  Cover page 
Revised Text:  
Shire Human Genetic Orphan Therapies, Inc.  
700 Main St. 300 Shire Way 
Cambridge, MA 02139 Lexington, MA 02421 
Other sections impacted by this change:  Synopsis 
 
Change:  Updated information concerning results of nonclinical and clinical studies of icatibant 
Section impacted by this change: 1.2.3 Investigations of Potential Effects of Bradykinin Inhibition on 
Reproductive Function 
Revised Text:  
Updated text describing the results of nonclinical and clinical investigations of icatibant effects on 
reproductive function were included in the introduction. 
Other sections impacted by this change: None 
 
Change:  Delineation of secondary objectives removed 
Section impacted by this change: Section 2.1 Objectives 
Revised Text:  

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Study Objectives 
Primary Objectives 
The primary 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 during an acute HAE attack 
Secondary Objectives 
The secondary objectives of this study are: 
• 
To evaluate the efficacy of a single SC dose of icatibant in children and adolescents with HAE 
• 
To evaluate levels of reproductive hormones after a single SC dose of icatibant in children 
and adolescents with HAE 
Other sections impacted by this change: Synopsis 
 
Change:  Changes to study endpoint definitions 
Section impacted by this change:  3 Study Endpoints 
Revised text: 
The primary endpoints of this study are: 
• 
The PK profile of icatibant after a single SC injection in pediatric subjects treated for acute attacks of 
HAE. 
• 
The tolerability and safety of SC icatibant as assessed by injection site reactions, AEs, 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).  
The secondary endpoints of this study are: 
• 
For all subjects (2 to 17 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 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 a 20% improvement is seen in the post-treatment score. 
• 
For subjects <4 years of age only:  investigator assessment of HAE-related pain using the Faces, 
Legs, Activity, Cry, and Consolability (FLACC) scale.  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 onset of relief of symptoms, measured using investigator reported and subject reported 
outcomes, defined as the earliest time at which a 20% improvement is seen in the average post
treatment score with no worsening of any single component score. 
• 
For all subjects (2 to 17 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 only:  subject self assessment of HAE related pain using the Faces Pain 
Scale Revised (FPS R). 
• 
The time to minimal symptoms, defined as all symptoms mild or absent based on the investigator rated 
symptom score. 
• 
The incidence of rescue medication use. 
• 
The proportion of subjects with worsened intensity of clinical HAE symptoms between 2 and 4 hours 
after treatment with SC icatibant using investigator-rated symptom scores. 
• 
The levels of reproductive hormones (FSH, LH, estradiol, progesterone in females and FSH, LH, and 

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testosterone in males). 
Other sections impacted by this change: Synopsis, 10.6 Safety and Tolerability Analysis, 10.7 Efficacy 
Analysis, 10.10 Handling of Missing Data 
 
Change:  Addition of ECG 
Section impacted by this change:  4.1 Overall Study Design and Plan 
Revised Text:  
Diagnosis may be supported by family history, characteristic attack manifestations, and recurrence of 
attacks.  Assessments performed at screening will include demography, medical history, history of HAE, 
concomitant medication use, physical examination (including height and weight), vital signs, ECG, urine 
pregnancy test in female pubertal/postpubertal subjects, and blood sample collection for C1-INH testing. 
Other sections impacted by this change: Synopsis, 8 Study Activities, Appendix 1 Study Schedule of Events 
(Initial Icatibant-Treated Attack), Appendix 2 Study Schedule of Events (Subsequent Icatibant-Treated 
Attacks) 
 
Change:  Changes to study activities  
Section impacted by this change:  4.1 Overall Study Design and Plan 
Revised Text:  
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 <4 years of age), and adherence to 
inclusion/exclusion criteria will be re confirmed.   
 
On Day 1, subjects will be administered a single dose of icatibant administered as a SC injection within 12 
hours after the onset of the acute attack.  Subjects will be monitored closely at the hospital/study center for 
approximately 6 hours (prepubertal subjects) or at least 8 hours (pubertal/postpubertal subjects) after 
treatment.  Subjects will be discharged after completion of scheduled assessments and when, according to 
the investigator’s judgment, they are deemed medically stable.  Follow-up to assess the subject’s condition 
at 24 hours (±4 hours) and 48 hours (±4 hours) after discharge treatment will be conducted in person or via a 
by a telephone call from study personnel (or in person at the discretion of the investigator). 
 
Safety and efficacy assessments will be performed on Day 1 through 6 8 hours after treatment.  These 
assessments will include physical examination, vital signs, ECG, clinical laboratory tests (serum chemistry 
[including liver function tests], hematology, and urinalysis), injection site reactions, and assessment of 
reproductive hormones (FSH, LH, estradiol, and progesterone in females and FSH, LH, and testosterone in 
males) in all subjects.  Injection site reactions will be evaluated on Day 1 at 1 hour and at 6 hours after 
treatment 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 <4 years of age) on Day 1 at 
1, 2, 4, 6, and 8 hours after treatment.  Subject who are 4 years of age or older will also complete a self-
assessment of HAE-related pain at these time points. 
Other sections impacted by this change: Synopsis, 8 Study Activities, Appendix 1 Study Schedule of Events 
(Initial Icatibant-Treated Attack), Appendix 2 Study Schedule of Events (Subsequent Icatibant-Treated 
Attacks) 
 
Change:  Clarifications to treatment of subsequent attacks 
Section impacted by this change:  4.1 Overall Study Design and Plan 
Revised Text:  
Further open-label treatments with study drug will be offered to pubertal/postpubertal subjects who 
have been previously treated and who present with an eligible attack at least 7 days post-treatment. 

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Open-label treatment will continue until a total number of at least 15 adolescents have been treated 
with icatibant for a total of 3 eligible acute attacks (ie, after their first icatibant-treated attack, 
pubertal/postpubertal subjects only may receive further treatment with icatibant for up to 2 subsequent 
attacks of acute HAE).  All primary and secondary outcomes, including antibodies (except PK), are to 
be measured after each administration.  Safety, reproductive hormone, and other assessments in 
association with subsequent attacks of acute HAE will be performed 90 days (±7 days) after treatment (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.   
Other sections impacted by this change:  None 
 
Change:  Clarification to inclusion criterion 
Section impacted by this change:  5.2 Inclusion Criteria 
Revised Text:  
2.  Documented diagnosis of HAE Type I or II.  Diagnosis must be confirmed by documented immunogenic 
(below the lower limit of normal) and/or functional (<50% of normal levels) C1-INH deficiency and/or 
functional C1 INH deficiency results (<50% of normal levels). Diagnosis may be on the basis of historic 
data or by diagnostic testing conducted at the time of screening. 
Other sections impacted by this change:  Synopsis 
 
Change:  Clarification to concomitant medication usage 
Section impacted by this change:  6.6 Concomitant Medication Usage 
New Text:  
All prescription and over-the-counter medications which 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. 
Other sections impacted by this change:  None 
 
Change:  Clarification to medical history 
Section impacted by this change: 7.5 Medical History 
Revised Text:  
Medical history will be recorded on 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, and concomitant medication 
and illnesses will be recorded at other visits on the appropriate CRF pages.   
Other sections impacted by this change:  None 
 
Change:  Addition of Tanner Staging information 
Section impacted by this change: 7.7 Tanner Staging 
Revised Text:  
The investigator will perform Tanner staging for all subjects to determine pubertal status.  A description of 
the Tanner stages of puberty is provided in Appendix 3. 
Other sections impacted by this change:  Appendix 3 Tanner Stages of Puberty, Appendix 1 Study Schedule 
of Events (Initial Icatibant-Treated Attack), Appendix 2 Study Schedule of Events (Subsequent Icatibant-
Treated Attacks) 
 
Change:  Addition of investigator assessment of pain 
Section impacted by this change:  7.10.3 Investigator Assessment of Pain 

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New Text:  
Subjects who are below 4 years of age will undergo investigator assessment of HAE-related symptoms 
using the Faces, Legs, Activity, Cry, and Consolability (FLACC) comportmental pain scale.  A copy of 
the FLACC scale is provided in Appendix 5. 
Other sections impacted by this change:  Appendix 5  Faces, Legs, Activity, Cry, and Consolability Scale 
(FLACC), Appendix 1 Study Schedule of Events (Initial Icatibant-Treated Attack), Appendix 2 Study 
Schedule of Events (Subsequent Icatibant-Treated Attacks) 
 
Change:  Addition of ECGs 
Section impacted by this change:  7.12.3 Electrocardiography 
New Text:  
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. 
Other sections impacted by this change:  Appendix 1 Study Schedule of Events (Initial Icatibant-Treated 
Attack), Appendix 2 Study Schedule of Events (Subsequent Icatibant-Treated Attacks) 
 
Change:  Deleted instruction for focusing on AEs with a temporal association with study treatment 
Section impacted by this change: Section 7.15.1, Adverse Events 
Revised Text:  
Though AEs will be collected throughout the study, due to the acute nature of HAE attacks and the half life 
of icatibant, it is particularly important to focus on AEs which have a temporal association with treatment.  
Treatment emergent AEs will be collected over a 48 hour window after the time of study drug 
administration. 
Other sections impacted by this change: None 
 
Change:  Clarification to concomitant illnesses 
Section impacted by this change:  7.15.1.1 Adverse Event 
Revised Text:  
Additional illnesses present at the time when informed consent is given are regarded as concomitant 
illnesses and will be documented on the appropriate pages of the CRF.  Illnesses first occurring or detected 
during the study, and worsening of a concomitant illness during the study, are to be regarded as AEs and 
must be documented as such in the CRF. 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 study drug 
treatment, and worsening of a concomitant illness during the study, are to be regarded as AEs and 
must be documented as such in the CRF. 
Other sections impacted by this change:  None 
 
Change:  Clarification to adverse event monitoring 
Section impacted by this change:  7.15.4.1 Adverse Event Monitoring and Period of Observation 
Revised Text:  
AEs will be monitored continuously throughout the study.  For the purposes of this study, the period of 
observation will extend from the time of informed consent treatment until the subject’s final evaluation of 
the study.  For safety purposes, the final evaluation will be defined as the follow-up evaluation performed 
approximately 90 days after the last dose for subjects who complete the study. 
Other sections impacted by this change:  None 
 
Change:  Clarification to SAE reporting 
Section impacted by this change:  7.15.4.2 Reporting Serious Adverse Events 

Icatibant (Firazyr®) 
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Revised Text:  
This form must be completed and faxed or emailed within 24 hours of the investigator’s learning of the 
event to: 
Shire Pharmacovigilance and Risk Management Department: 
FAX:  
(UK Worldwide) OR
(United States North America) 
Email:  
Any follow-up information must also be completed on an SAE form and faxed or emailed to the same 
numbers listed above. 
Other sections impacted by this change:  None 
 
Change:  Alignment of study stopping rules with DSMB charter language 
Section impacted by this change:  7.18.1 Study Stopping Rules 
Revised Text:  
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. 
This study will be stopped and safety data reviewed if any subject experiences a life threatening (Grade 4) 
AE or a death occurs, if either is considered possibly, probably or definitely related to the investigational 
product.  
Other sections impacted by this change:  None 
 
Change:  Description of FLACC Scale  
Section impacted by this change:  7.19 Appropriateness of  Measures 
New Text:  
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 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, consolability) to 
assess pain in young children. 11 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, 
safety, and efficacy profiles of icatibant in the pediatric population. 
Other sections impacted by this change:  None 
 
Change:  Clarification to statistical analysis 
Section impacted by this change:  10.8 Other Analyses 
Revised Text:  
The median time and the 95% confidence interval will be calculated using Kaplan-Meier methodology 
methodology if there are at least 5 subjects who used rescue medication prior to attaining symptom 
relief. 
Other sections impacted by this change:  None 
 
Change:  Clarification to Tanner Staging 
Section impacted by this change:  8.3.2 Follow-up Visit (Day 90 ±7 days) 
New Text:  
• 
Tanner staging (for those subjects classified as Tanner stage IV or below at baseline) 
Other sections impacted by this change:  8.4.2 Follow-up Visit (Day 90 ±7 days)Appendix 1 Study Schedule 
of Events (Initial Icatibant-Treated Attack), Appendix 2 Study Schedule of Events (Subsequent Icatibant-
Treated Attacks) 
 
PPD
PPD
PPD

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Change:  Added in reference citation for FLACC scale 
Section impacted by this change: Section 12, List of References 
Revised Text:  
11. The FLACC: A Behavioral Scale for Scoring Postoperative Pain in Young Children. Pediatr Nurs 
1997;23:293-97. 
Other sections impacted by this change: None