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

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

Icatibant (Firazyr®)
Clinical Trial Protocol Amendment 2: HGT-FIR-086
06 March 2012
Shire
Confidential
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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 the effects on reproductive hormone levels after a single SC dose of 
icatibant in children and adolescents with HAE.
Other objectives of this study are:

To evaluate the continued safety of icatibant in pubertal/postpubertal children after 
repeated exposures.

To evaluate the effects on reproductive hormone levels in pubertal/postpubertal 
children after repeated exposures.

To evaluate the efficacy of icatibant in the treatment of acute HAE attacks in 
pubertal/postpubertal children after repeated exposures.
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.

Icatibant (Firazyr®)
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
The tolerability and safety of SC icatibant as assessed by injection site reactions, 
adverse events, vital signs, electrocardiogram (ECG) recordings, physical 
examination, clinical laboratory parameters (serum chemistry [including liver 
function tests], hematology, urinalysis), reproductive hormone levels, and 
immunogenicity (anti-icatibant antibodies).
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 
(cutaneous, abdominal, and laryngeal) 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 Design:
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, 
and safety, including effect on reproductive hormones, of a single SC administration of 
icatibant in pediatric subjects with HAE during an initial acute attack. 
The study will enroll children and adolescents from 2 to 17 years of age who present with 
cutaneous, abdominal, or laryngeal symptoms of an acute HAE attack after a qualifying 
screening period. Subject enrollment will be stratified into 2 groups based on pubertal 
status: (i) a prepubertal group (defined as Tanner stage I) and (ii) 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 first icatibant-treated HAE 
attack. Subjects classified as pubertal/postpubertal at screening will not require further 
evaluation of pubertal status during the study, whereas subjects classified as prepubertal at 
screening will have their pubertal status reassessed at the time of their first icatibant-
treated HAE attack visit.

Icatibant (Firazyr®)
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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 PK, safety, tolerability and efficacy data will be reviewed by 
an independent Data and Safety Monitoring Board (DSMB). The DSMB review of the 
first 4 subjects shall be completed prior to continuing enrollment of additional 
pubertal/postpubertal subjects, icatibant treatment of second and third HAE attacks in 
pubertal/postpubertal subjects, and initiating enrollment of subjects in the prepubertal 
group.
Subjects will receive treatment with a single SC administration of icatibant on Day 1. 
Subjects will be monitored closely in the hospital/study center for at least 6 to 8 hours 
after treatment and will undergo PK, safety, and efficacy assessments. Subjects will also 
have serum reproductive hormone measurements. A subject may be discharged after 
completion of all assessments at 6 hours post treatment, if deemed medically stable in the 
investigator’s clinical judgment and the subject’s HAE symptoms have resolved (the 
subject’s investigator-rated symptom score must be zero, denoting the absence of 
symptoms). If HAE symptoms have not completely resolved at 6 hours (ie, the
investigator-rated symptom score is >0), the subject shall remain in the hospital/study 
center for at least 8 hours after icatibant administration for further evaluation.
Safety follow-up to assess the subject’s condition must be conducted at 24 and 48 hours 
after icatibant injection, and will occur either by telephone call from study personnel or in 
person at the investigator’s discretion. Subjects will return to the hospital/study center for 
scheduled assessments on Day 8 and for a follow-up visit on Day 90.
Pubertal/postpubertal subjects may be offered further open-label treatment with icatibant 
contingent upon having been treated for an initial attack and presenting with a subsequent 
acute cutaneous, abdominal, or laryngeal attack of HAE at least 7 days after prior 
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 assessments, including reproductive hormone measurements, will be performed at 
each subsequent icatibant-treated attack as for the initial treated attack.
The investigator will schedule a telephone contact approximately 6 months after Day 1 of 
each icatibant-treated attack to obtain specific updates concerning pubertal 
changes/milestones.
Study Population: 
The study will enroll a sufficient number of children and adolescents to ensure study 
completion of 36 evaluable subjects. The study population will consist of subjects from 
2 through 17 years of age who present with an acute cutaneous, abdominal, or laryngeal 
HAE attack, at least 16 of whom were prepubertal at the time of their first icatibant treated 
HAE attack and 20 of whom were pubertal/postpubertal at the time of their first icatibant 
treated HAE attack.
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 HAE attack treated 
with icatibant as part of this study.

Icatibant (Firazyr®)
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2. Documented diagnosis of HAE type I or II. Diagnosis must be confirmed by 
documented C1-INH deficiency (C1-INH protein level below the lower limit of 
normal and/or functional level <50% of normal). Diagnosis may be on the basis of 
historic data or by diagnostic testing conducted at the time of screening. Inclusion will 
be permitted initially based on medical history only if a clear diagnosis has been made 
based on all of the following criteria:
-
Family history
-
Characteristic attack manifestations, recurrent attacks
-
Historical C1-INH deficiency as demonstrated by immunologic or functional test 
results
-
Exclusion of other forms of angioedema
-
Subsequent confirmation of the diagnosis to be made on the basis of C1-INH level 
or function (all subjects)
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 trial that involves use of any investigational product 
(drug or device) within 30 days prior to study enrollment or at any time during the 
study.
3. Any known factor/disease that might interfere with the treatment compliance, study 
conduct, or result interpretation.
4. Congenital or acquired cardiac anomalies that interfere significantly with cardiac 
function.
5. Treatment with angiotensin converting enzyme (ACE) inhibitors within 7 days prior to 
treatment.
6. Use of hormonal contraception within the 90 days prior to treatment.
7. Androgen use (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone
within the 90 days prior to treatment).
8. Pregnancy or breastfeeding. 
9. A physical condition that interferes with pubertal status determination.
Study Duration:
Once eligibility is established at screening, the subject will be enrolled but will enter a 
period of inactive participation of variable duration until such time as the subject 
experiences an acute attack of HAE and is offered treatment. At that time, the subject will 
enter a 90-day period of active participation which will consist of treatment with a single 
SC administration of icatibant on Day 1 through follow-up at Day 90. After receiving 
treatment for an initial attack of acute HAE, at least 15 pubertal/postpubertal subjects who 
present with subsequent attacks of acute HAE will continue to receive treatment with 
icatibant for a total of 3 attacks each. 
Thus, the period of active participation in the study for prepubertal subjects will be 
approximately 90 days, while that for pubertal/postpubertal subjects will be a maximum of 
approximately 270 days (3 separate active periods of approximately 90 days), with each 

Icatibant (Firazyr®)
Clinical Trial Protocol Amendment 2: HGT-FIR-086
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active period separated by periods of inactive participation of variable duration.  The 
period of active participation may be shorter if pubertal/postpubertal subjects have 
recurrent HAE attacks in between the Day 8 and Day 90 visits for a prior icatibant-treated 
HAE attack.  Telephone follow-up will occur approximately 6 months after each icatibant-
treated attack.
Once the sixteenth prepubertal subject and the twentieth pubertal/postpubertal subject 
have completed the 6-month follow-up after treatment for an initial attack, and the 
fifteenth pubertal/postpubertal subject has completed the 6-month follow-up after his or 
her third and final treatment, the study will be closed. 
The approximate overall duration of the study is expected to be 3 years.  
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 adverse events.  Local 
tolerability will be assessed by evaluation of reactions at the site of icatibant
administration (injection site).  Levels of reproductive hormones will be assessed in 
female (follicle stimulating hormone [FSH], luteinizing hormone [LH], estradiol, 
progesterone) and male (FSH, LH, testosterone) subjects.
Efficacy Assessments:  
Efficacy will be assessed using both investigator- and subject-reported outcomes, 
depending on the subject’s age. Investigators will assess and score symptoms of acute 
cutaneous, abdominal, and laryngeal attacks of HAE for all subjects using an 
investigator-rated symptom score. Subjects who are 4 years of age or older will perform a 
self-assessment of HAE-related pain using the FPS-R instrument. Subjects who are
younger than 4 years of age will have symptoms assessed by the investigator only; 
including an assessment of HAE-related pain (cutaneous, abdominal, and laryngeal) using 
the FLACC scale. The time of initial symptom relief as assessed by the investigator will 
be recorded for all subjects.
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 

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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.

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 adverse events.  
Adverse events will be summarized by presenting the number and percentage of subjects 
having any adverse event, having an adverse event in each body system, and having each 
individual adverse event using the Medical Dictionary for Regulatory Activity 
(MedDRA).  Adverse events also will be tabulated by severity and relationship to 

Icatibant (Firazyr®)
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treatment.
Local tolerability will include symptoms at the injection site and will be assessed 
separately from general reports of adverse events.  Local tolerability will be tabulated and 
summarized according to the type and severity of 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.
Date of Amended Protocol:  06 March 2012

Icatibant (Firazyr®)
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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................2
TABLE OF CONTENTS...........................................................................................................9
LIST OF IN-TEXT TABLES ..................................................................................................12
LIST OF APPENDICES..........................................................................................................12
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................13
1
INTRODUCTION ...........................................................................................................15
1.1
Disease Background...............................................................................................15
1.2
Previous Clinical Studies.......................................................................................16
1.2.1
Pharmacokinetics of Icatibant......................................................................16
1.2.2
Phase III Investigation of SC Icatibant ........................................................17
1.2.3
Investigations of Potential Effects of Bradykinin Inhibition on Reproductive 
Function .......................................................................................................17
1.3
Rationale for Dose Selection .................................................................................19
2
STUDY OBJECTIVES....................................................................................................20
2.1
Objectives ..............................................................................................................20
2.2
Other Objectives ....................................................................................................20
3
STUDY ENDPOINTS.....................................................................................................21
3.1
Primary Endpoint(s)...............................................................................................21
3.2
Secondary Endpoint(s)...........................................................................................21
4
INVESTIGATIONAL PLAN..........................................................................................22
4.1
Overall Study Design and Plan..............................................................................22
4.1.1
Study Design................................................................................................22
4.1.2
Study Assessments.......................................................................................23
4.2
Rationale for Study Design....................................................................................25
4.3
Study Duration.......................................................................................................25
5
STUDY POPULATION SELECTION ...........................................................................27
5.1
Study Population....................................................................................................27
5.2
Inclusion Criteria ...................................................................................................27
5.3
Exclusion Criteria ..................................................................................................27
6
STUDY TREATMENT(S)..............................................................................................29
6.1
Description of Treatment(s)...................................................................................29
6.1.1
Investigational Product ................................................................................29
6.1.2
Comparator ..................................................................................................29
6.2
Treatments Administered.......................................................................................29
6.3
Selection and Timing of Dose for Each Subject....................................................29
6.4
Method of Assigning Subjects to Treatment Groups.............................................29
6.5
Blinding..................................................................................................................29

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6.6
Concomitant Medication Usage.............................................................................30
6.7
Rescue Therapy......................................................................................................30
6.8
Restrictions ............................................................................................................31
6.8.1
Fluid and Food Intake..................................................................................31
6.8.2
Subject Activity Restrictions .......................................................................31
6.9
Treatment Compliance...........................................................................................31
6.10
Packaging and Labeling.........................................................................................31
6.11
Storage and Accountability....................................................................................32
6.12
Investigational Product Retention at Study Site ....................................................32
7
STUDY PROCEDURES .................................................................................................33
7.1
Informed Consent...................................................................................................33
7.2
Study Entrance Criteria..........................................................................................33
7.3
Confirmation of Study Eligibility..........................................................................33
7.4
Demographics ........................................................................................................33
7.5
Medical History .....................................................................................................33
7.6
Menstrual Cycle History........................................................................................34
7.7
Height and Weight .................................................................................................34
7.8
Pubertal Status Determination ...............................................................................34
7.9
Investigational Product Administration.................................................................34
7.10
Pharmacokinetic Assessments ...............................................................................35
7.10.1
Pharmacokinetic Variables ..........................................................................35
7.10.2
Pharmacokinetic Sampling ..........................................................................35
7.10.3
Bioanalytical Method...................................................................................35
7.11
Efficacy Assessments.............................................................................................35
7.11.1
Investigator Symptom Score........................................................................35
7.11.2
Subject Self-assessment of Pain...................................................................36
7.11.3
Investigator Assessment of Pain..................................................................36
7.11.4
Initial Symptom Relief.................................................................................36
7.12
Reproductive Hormone Assessments ....................................................................36
7.13
Safety Assessments................................................................................................37
7.13.1
Physical Examination...................................................................................37
7.13.2
Vital Signs....................................................................................................37
7.13.3
Electrocardiography.....................................................................................37
7.13.4
Clinical Laboratory Tests.............................................................................37
7.13.5
Local Tolerability.........................................................................................38
7.13.6
Immunogenicity...........................................................................................38
7.13.7
Pregnancy Testing........................................................................................39
7.14
Sample Collection, Storage, and Shipping ............................................................39

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7.15
Recording of Concomitant Medications................................................................39
7.16
Recording of Adverse Events ................................................................................39
7.17
Adverse Events Assessments.................................................................................39
7.17.1
Definitions of Adverse Events and Serious Adverse Events.......................39
7.17.2
Classification of Adverse Events and Serious Adverse Events...................41
7.17.3
Relatedness of Adverse Events and Serious Adverse Events......................42
7.17.4
Procedures for Recording and Reporting Adverse Events ..........................42
7.18
Pregnancy...............................................................................................................44
7.19
Abuse, Overdose, and Medication Error................................................................44
7.20
Removal of Subjects from the Trial or Investigational Product ............................45
7.20.1
Safety-Related Study Stopping Rules..........................................................45
7.21
Appropriateness of Measurements.........................................................................46
8
STUDY ACTIVITIES .....................................................................................................48
8.1
Screening (Day of Informed Consent to Pretreatment on Day 1 of the Initial 
Attack)....................................................................................................................48
8.2
Pretreatment (Baseline) Assessments (Day 1, Initial and Subsequent Attacks)....48
8.3
Initial Attack ..........................................................................................................49
8.3.1
Treatment Period (Day 1 to Day 8 [± 1 Day]).............................................49
8.3.2
Follow-up Visit (Day 90 ±7 days) ...............................................................50
8.3.3
Telephone Contact (Month 6 ±7 days) ........................................................50
8.4
Subsequent Attacks (Pubertal/postpubertal Subjects Only) ..................................51
8.4.1
Treatment Period (Day 1 to Day 8 [± 1 Day]).............................................51
8.4.2
Follow-up Visit (Day 90 ±7 days) ...............................................................52
8.4.3
Telephone Contact (Month 6 ±7 days) ........................................................52
9
QUALITY CONTROL AND ASSURANCE .................................................................53
10
PLANNED STATISTICAL METHODS ........................................................................54
10.1
General Considerations..........................................................................................54
10.2
Determination of Sample Size ...............................................................................54
10.3
Analysis Populations..............................................................................................54
10.4
Demographics and Baseline Characteristics..........................................................55
10.5
Pharmacokinetic Analysis......................................................................................55
10.5.1
Estimation of PK Parameters.......................................................................55
10.6
Safety and Tolerability Analysis............................................................................56
10.7
Efficacy Analysis...................................................................................................57
10.8
Other Analyses.......................................................................................................58
10.9
Data Monitoring and Interim Analysis ..................................................................58
10.10 Handling of Missing Data......................................................................................58
11
ADMINISTRATIVE CONSIDERATIONS....................................................................59

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11.1
Investigators and Study Administrative Structure.................................................59
11.2
Institutional Review Board or Independent Ethics Committee Approval .............59
11.3
Ethical Conduct of the Study.................................................................................59
11.4
Subject Information and Consent/Assent...............................................................59
11.5
Subject Confidentiality ..........................................................................................60
11.6
Study Monitoring...................................................................................................61
11.7
Case Report Forms and Study Records .................................................................61
11.7.1
Critical Documents ......................................................................................61
11.8
Data and Safety Monitoring Board........................................................................62
11.9
Protocol Violations/Deviations..............................................................................62
11.10 Premature Closure of the Study.............................................................................63
11.11 Access to Source Documentation ..........................................................................63
11.12 Data Generation and Analysis ...............................................................................63
11.13 Retention of Data...................................................................................................64
11.14 Financial Disclosure...............................................................................................64
11.15 Publication and Disclosure Policy .........................................................................64
12
LIST OF REFERENCES.................................................................................................65
LIST OF IN-TEXT TABLES
Table 4-1
Study Periods ...............................................................................................23
Table 7-1
List of Clinical Laboratory Tests .................................................................38
Table 7-2
Adverse Event Severity................................................................................41
Table 7-3
Adverse Event Relatedness..........................................................................42
LIST OF APPENDICES
Appendix 1
Study Schedule of Events (Initial Icatibant-treated Attack) ..............66
Appendix 2
Study Schedule of Events (Subsequent Icatibant-treated Attacks)....71
Appendix 3
Modified Sexual Maturation Scale ....................................................74
Appendix 4
Faces Pain Scale-Revised (FPS-R)....................................................75
Appendix 5
Faces, Legs, Activity, Cry, and Consolability Scale (FLACC).........76
Appendix 6
Protocol Signature Page.....................................................................77
Appendix 7
Summary of Changes for Amendment 2 ...........................................78

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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
GnRH
Gonadotrophin releasing hormone
HAE
Hereditary Angioedema
hCG
Human chorionic gonadotropin
HGT
Human Genetic Therapies

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hr
Hour(s)
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
MedDRA
Medical Dictionary for Regulatory Activity 
mg
Milligram
min
Minute(s)
mL
Milliliter(s)
mm
Millimeters
MRT
Mean residual time
n
Number
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
HAE is usually caused by either a quantitative (Type I) or qualitative (Type II) deficiency of C1 
inhibitor. C1 inhibitor functions in several biochemical pathways, including inhibition of C1 
complement auto-activation (its originally identified function which led to its name), inactivation 
of coagulation factors XIIa, XIIf, XIa, and inhibition of activated kallikrein. After a triggering 
event, the deficiency in C1 inhibitor results in accelerated release of bradykinin by its cleavage 
from high molecular weight kininogen by dysregulated, activated kallikrein.  Bradykinin is the 
principal mediator of the increased vascular permeability characteristic of HAE. Type III HAE 
is much more rare, is not related to C1-INH protein function, and has unknown etiology; thus its
pathophysiology 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 adults experiencing an acute HAE 
attack, icatibant also produces a rapid and safe treatment response.
The management of HAE in pediatric patients is complex. The age at onset, the frequency and 
duration of symptoms, as well as the severity of attacks all exhibit substantial inter-individual 
variation. Although acute episodes of HAE may occur at any age, the median age at first 
symptomatic HAE attack is estimated to range between 4 to 11 years (reviewed by Farkas6). 
Subcutaneous edema of the extremities, face, neck, torso, and genitals is the most common, and 
usually the earliest, manifestation of HAE seen in children.  Two peaks of increased frequency 
and severity of HAE symptoms were reported in a large pediatric cohort, one peak between 
3 and 6 years of age and the second at around puberty. These peaks are attributed to 
physiological changes which occur in these periods of development.6  In the gastrointestinal 
tract, submucosal edema may be associated with colicky abdominal pain, nausea, vomiting, and 
diarrhea. 

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

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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.  
In Phase I, II, and III clinical studies, SC icatibant 30 mg was administered to 129 healthy adult 
subjects and to 236 adult subjects with HAE.  A total of 999 acute attacks of HAE were treated 
with icatibant administered by a health care provider, and an additional 56 attacks were 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 13,000 patient exposures to Firazyr®
occurred cumulatively in the postmarketing setting from the time of European Union regulatory 
approval in July 2008 through July 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 

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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.  
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 16 male 
and 16 female healthy volunteers in an Phase I study (JE049-1103) showed no clinically 
important changes from baseline in levels of FSH and LH after administration of 3 SC doses 
(30 mg each) of icatibant 6 hours apart on Day 1 followed by single SC doses (30 mg) on Day 8 
and Day 15. 
Phase 1 study (HGT-FIR-062) was a double-blind, randomized, placebo-controlled, single center 
study to assess the effect of icatibant on serum reproductive hormone levels in male and 
premenopausal female healthy adult subjects and seminal fluid analysis in healthy male adult 
subjects.  This study was intended to definitively determine the effect of repeated administration 
of 3 SC doses of icatibant 30 mg on reproductive hormone levels in adults prior to any 
investigational use in pediatric subjects per the recommendation of the European Medicines 
Agency (EMA).  Subjects were randomized to receive icatibant or placebo as a single SC 
injection at 6 hour intervals 3 times daily on Days 1, 4, and 7 of the treatment week (total 
9 doses/week) with an approximately 8 week follow-up phase. 
Thirty-nine adult subjects (16 females and 23 males) were enrolled and treated in Study 
HGT-FIR-062; 32 subjects completed the study in its entirety (7 subjects did not return for
follow-up visits).  No negative trends were seen with regard to the results of basal or 
gonadotrophin releasing hormone (GnRH)-stimulated reproductive hormone assessments in 
female and male subjects treated with icatibant or placebo.  Though the number of subjects 
participating was small, and the study was not powered for statistical significance, a suppressive 
effect of icatibant on GnRH-stimulated reproductive hormone concentrations was not generally 
observed in either sex. Overall, there were no clinically significant changes from baseline in 
basal and GnRH-stimulated concentrations of reproductive hormones (estradiol, progesterone, 
prolactin, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), sex 
hormone binding globulin (SHBG), FSH, and LH in females and testosterone, DHEA, DHEA-S, 
SHBG, FSH, LH, and Inhibin-B in males) in response to treatment with icatibant.  Additionally, 
there were no significant effects of icatibant on the concentration of luteal phase progesterone, an 
indicator of ovulation status and luteal function, or on menstrual cycle length in females, and 
there were no significant effects of icatibant on semen parameters in males.  
Adrenal cortex function in male and female subjects, as assessed by serum cortisol 
concentrations, was unaffected by treatment with icatibant.

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1.3
Rationale for Dose Selection
Icatibant has not been evaluated in clinical trial subjects below the age of 18 years.  The 
proposed study will be the first in which icatibant is administered to pediatric subjects for 
treatment of acute HAE attacks.  All subjects in the proposed study will receive a single, 
weight-adjusted dose of 0.4 mg/kg per attack as a SC injection up to a maximum dose of 30 mg.  
This dose regimen was selected to target an exposure (Cmax and area under the curve [AUC]) 
comparable to that observed in adults treated with icatibant. Only 1 dose of icatibant will be 
permitted for treatment of a single attack.  
The 0.4 mg/kg dose was derived from pharmacokinetic/pharmacodynamic (PK/PD) modeling of 
data from a study (JE049-1001), which investigated the inhibitory potential of icatibant at 
various IV infusion doses and regimens after bradykinin challenge in healthy male subjects.  The 
PK and PD data sets were used to model the PK/PD relationship of icatibant using a sigmoidal 
Emax model.  A high degree of concordance of half maximal effective concentration (EC50)
values was obtained for each of the PD parameters studied (heart rate, blood pressure, and 
cutaneous blood flow) with the majority of values being between 8.54 and 9.77 ng/mL.  Thus, a 
mean EC50 value of 9.5 ng/mL (7.3 nM) was used for subsequent PK/PD simulation.  Based on 
the PK/PD modeling, IV icatibant doses of 0.4 mg/kg and 0.8 mg/kg were predicted to provide 
duration of therapeutic effect of as much as 9 or 13 hours, respectively, when infused over 0.5 to 
1 hour.  These results supported a minimum effective dose of 0.4 mg/kg to treat acute attacks of 
HAE.  This corresponds to a dose of 30 mg of icatibant in a 75 kg subject.  
A subsequent Phase II (JE049-2101) dose-ranging proof of concept efficacy study in HAE 
subjects was then conducted that examined the efficacy of doses ranging from 0.4 to 0.8 mg/kg 
IV (ie, 30 to 60 mg in a 75 kg person) and 30 to 45 mg SC. The results of this study indicated
that SC administration of icatibant 30 mg produced a rapid onset of symptom relief and that 
45 mg SC showed no improvement in efficacy over 30 mg SC. 
As a result of clinical exploration of the efficacy, safety and exposure-response relationship of 
icatibant, a single SC administration of 30 mg icatibant (10 mg/mL formulation) was selected 
and consistently employed in the Phase III studies in adult HAE subjects.  The totality of 
available efficacy information obtained from the Phase III clinical studies demonstrates that a 
single SC 30 mg dose of icatibant provides a sufficient magnitude and duration of effect to 
clinically manage the majority of acute attacks in adult HAE subjects across a wide range of 
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 the effects on reproductive hormone levels after a single SC dose of icatibant in 
children and adolescents with HAE.
2.2
Other Objectives 
Other objectives of this study are:
•
To evaluate the continued safety of icatibant in pubertal/postpubertal children after repeated 
exposures.
•
To evaluate the effects on reproductive hormone levels in pubertal/postpubertal children after 
repeated exposures.
•
To evaluate the efficacy of icatibant in the treatment of acute HAE attacks in 
pubertal/postpubertal children after repeated exposures.

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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, adverse 
events, vital signs, ECG recordings, physical examination, clinical laboratory parameters 
(serum chemistry [including liver function tests], hematology, urinalysis), reproductive 
hormone levels, and immunogenicity (presence of anti-icatibant antibodies).
3.2
Secondary 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 (cutaneous, 
abdominal, and laryngeal) 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
4.1.1
Study Design
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, and 
safety, including effects on reproductive hormones, of a single SC administration of icatibant in 
pediatric subjects with HAE during an initial acute attack. 
The study will enroll children and adolescents from 2 to 17 years of age who present with 
cutaneous, abdominal, or laryngeal manifestations of an acute HAE attack after a qualifying 
screening period. Subject enrollment will be stratified into 2 groups based on pubertal status: (i) 
a prepubertal group (defined as Tanner stage I) and (ii) 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 first icatibant-treated HAE attack.  Subjects classified as 
pubertal/postpubertal at screening will not require further evaluation of pubertal status during the 
study, whereas subjects classified as prepubertal at screening will have their pubertal status 
reassessed at the time of their first icatibant-treated HAE attack visit.
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 
PK, safety, tolerability, and efficacy data will be reviewed by an independent Data and Safety 
Monitoring Board (DSMB). The DSMB review of the first 4 subjects shall be completed prior to
continuing enrollment of additional pubertal/postpubertal subjects, icatibant treatment of second 
and third HAE attacks in pubertal/postpubertal subjects, and initiating enrollment of subjects in 
the prepubertal group.
Subjects will receive treatment with a single SC administration of icatibant on Day 1.  Subjects 
will be monitored closely in the hospital/study center for at least 6 to 8 hours after treatment and 
will undergo PK, safety, and efficacy assessments. Subjects will also have serum reproductive 
hormone measurements.  A subject may be discharged after completion of all assessments at 
6 hours post treatment, if deemed medically stable in the investigator’s clinical judgment and the 
subject’s HAE symptoms have resolved (the subject’s investigator-rated symptom score must be 
zero, denoting the absence of symptoms).  If HAE symptoms have not completely resolved at 
6 hours (ie, the investigator-rated symptom score is >0), the subject shall remain in the 
hospital/study center for at least 8 hours after icatibant administration for further evaluation.
Safety follow-up to assess the subject’s condition must be conducted at 24 and 48 hours after 
icatibant injection, and will occur either by a telephone call from study personnel or in person at 
the investigator’s discretion. Subjects will return to the hospital/study center for scheduled 
assessments on Day 8 and for a follow-up visit on Day 90.  
Pubertal/postpubertal subjects may be offered further open-label treatment with icatibant, 
contingent upon having been treated for an initial attack and presenting with a subsequent acute 
cutaneous, abdominal, or laryngeal attack of HAE at least 7 days after prior treatment. Open-
label treatment will continue until at least 15 pubertal/postpubertal subjects have been treated 

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with icatibant for a total of 3 attacks each.  Tolerability and safety assessments, including 
reproductive hormone measurements, will be performed at each subsequent icatibant-treated 
attack as for the initial treated attack.  Subjects who reach their 18th birthday during the course of 
follow-up are allowed to remain in the study and receive subsequent treatments with icatibant 
according to the protocol. 
The investigator will schedule a telephone contact approximately 6 months after Day 1 of each 
icatibant-treated attack to obtain specific updates concerning pubertal changes/milestones.
4.1.2
Study Assessments
The study will consist of the following periods (Table 4-1).
Table 4-1 Study Periods
Study Periods
Screening 
Day of informed consent through pretreatment on Day 1 of the initial 
attack
Initial icatibant-treated attack (All subjects)
    Treatment 
Day 1
    Post Treatment
Day 1 through Day 8 (± 1 day)
    Follow-up
Day 9 through Day 90 (±7 days)
    Telephone Contact
Month 6 (± 7 days) from Day 1 of the attack
Two additional icatibant-treated attacks for a total of 3 icatibant-treated attacks 
(Pubertal/postpubertal subjects only)
    Treatment 
Day 1
    Post Treatment
Day 1 through Day 8 (±1 day)
    Follow-up
Day 9 through Day 90 (±7 days)
    Telephone Contact
Month 6 (± 7 days) from Day 1 of the attack
The study will include a screening period to determine subject eligibility. Eligibility will be 
evaluated after the subjects’ parent(s)/legal guardian(s) and the subject (if applicable) provide 
informed consent/assent. 
Study activities at screening will include confirmation of diagnosis of HAE type I or II by review 
of the subject’s medical history and documentation of C1-INH deficiency (C1-INH protein level
below the lower limit of normal and/or functional level <50% of normal) indicative of HAE 
Type I or II. Diagnosis may be supported by family history, characteristic attack manifestations, 
and recurrence of attacks. Other assessments performed at screening will include demography, 

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medical history and history of HAE, concomitant medication use, physical examination 
(including height and weight), pubertal status determination, 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 younger than 4 years of age), and adherence to inclusion/exclusion criteria will be 
reconfirmed. Subjects who are 4 years of age or older will perform a self-assessment of 
HAE-related pain. Other baseline assessments performed at pretreatment will include physical 
examination, pubertal status determination (only for those subjects classified as prepubertal at 
screening), height and weight, vital signs, collection of samples for clinical laboratory tests 
(serum chemistry [including liver function tests], hematology, urinalysis), urine pregnancy test 
for pubertal/postpubertal females, baseline PK and immunogenicity assessments, and baseline 
measurement of reproductive hormones (FSH, LH, estradiol, and progesterone in females and 
FSH, LH, and testosterone in males). 
On Day 1, subjects will be administered a single dose of icatibant as an abdominal SC injection 
within 12 hours after the onset of the acute attack. The time of investigational product
administration on Day 1 will be designated as Time 0. All post-treatment assessments will be 
calculated from the time of investigational product administration. PK, safety, and efficacy 
assessments will be performed on Day 1 after treatment at the time points indicated in the study 
schedules of events (Appendix 1 and Appendix 2). These assessments will consist of physical 
examination, vital signs, ECG, clinical laboratory tests (serum chemistry [including liver 
function tests], hematology, urinalysis), injection site reactions, and measurement of 
reproductive hormones (FSH, LH, estradiol, and progesterone in females and FSH, LH, and 
testosterone in males) in all subjects. The investigator will complete assessments of symptoms 
of the acute attack of HAE for all subjects (including a separate assessment of HAE-related pain 
in subjects younger than 4 years of age). Subject who are 4 years of age or older will also 
complete a self-assessment of HAE-related pain.
A safety follow-up contact must occur at 24 (±4) hours and 48 (±4) hours after treatment, and
will be conducted either by a telephone call from study personnel or in person at the discretion of 
the investigator.
Rescue medication use will be assessed through 48 (±4) hours after treatment either in person or 
by telephone at the discretion of the investigator.
Subjects will return to the hospital/study center to undergo safety assessments, including 
physical examination, vital signs, and clinical laboratory tests (serum chemistry [including liver 
function tests], hematology, urinalysis), evaluation of injection site reactions, immunogenicity, 
and measurement of reproductive hormones on Day 8 (±1 day) after treatment.
Subjects will be followed over a 90-day period after initial treatment. All subjects will provide 
blood samples for immunogenicity testing and measurement of reproductive hormone levels at 

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the Day 90 (±7 days) visit and undergo safety assessments including physical examination, vital 
signs, and clinical laboratory tests (serum chemistry, hematology, and urinalysis). Additionally, 
females of childbearing potential will undergo urine pregnancy testing.
Subsequent open-label treatments with icatibant may be offered to pubertal/postpubertal subjects 
who have been treated for an initial attack and who present with a subsequent attack at least 
7 days after prior treatment.  In the event that a subsequent attack occurs at least 7 days after 
prior treatment, but within the window (±1 day) allowed for performance of Day 8 assessments 
associated with a prior attack, the Day 8 assessments may also serve as the pretreatment 
(baseline) assessments for the subsequent attack.  Open-label treatment will continue until a total 
number of at least 15 adolescents have been treated with icatibant for a total of 3 acute attacks 
(ie, after the first icatibant-treated attack, only pubertal/postpubertal subjects may receive further 
treatment with icatibant for up to 2 subsequent attacks of acute HAE). Except for PK 
determinations, all primary and secondary outcomes, including immunogenicity, are to be 
measured after each administration. Safety, reproductive hormones, and other assessments in 
association with subsequent attacks of acute HAE will be performed on Day 90 (±7 days) after 
treatment (each treatment for a subsequent attack will require its own Day 90 follow up visit; 
however, if a subsequent attack occurs within 7 days of the Day 90 follow-up visit for the 
previous attack, the assessments on Day 8 and Day 90 may be combined). 
The investigator will schedule a telephone contact approximately 6 months after Day 1 of each
icatibant-treated attack to obtain updates concerning pubertal changes/milestones.  If this 
prescheduled telephone contact date should occur within the 90-day follow-up period (ie, Day 1 
through Day 90) of a subsequent attack, this prescheduled contact may be omitted.
All assessments are outlined in full in the study schedules 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 
and adolescents, particularly with respect to potential effects on reproductive development, and 
to demonstrate the effectiveness of icatibant in relieving the symptoms of acute HAE attacks.  
Therefore, this study will help determine whether icatibant can address an unmet medical need 
for a safe and effective treatment for acute attacks of HAE in pediatric patients. 
4.3
Study Duration
Once eligibility is established at screening, the subject will be enrolled but will enter a period of 
inactive participation of variable duration until such time as the subject experiences an acute 
attack of HAE and is offered treatment.  At that time, the subject will enter a 90-day period of 

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active participation which will consist of treatment with a single SC administration of icatibant
on Day 1 through follow-up at Day 90.  
After receiving treatment for an initial attack of acute HAE, at least 15 pubertal/postpubertal 
subjects who present with subsequent attacks of acute HAE will continue to receive treatment 
with icatibant for a total of 3 attacks each.  Thus, the period of active participation in the study 
for prepubertal subjects will be approximately 90 days, while that for pubertal/postpubertal 
subjects will be a maximum of approximately 270 days (3 separate active periods of 
approximately 90 days), with each active period separated by periods of inactive participation of 
variable duration. The period of active participation may be shorter if pubertal/postpubertal 
subjects have recurrent HAE attacks in between the Day 8 and Day 90 visits for a prior icatibant-
treated HAE attack.  Telephone follow-up will occur approximately 6 months after each 
icatibant-treated attack.
Once the sixteenth prepubertal subject and the twentieth pubertal/postpubertal subject have 
completed the 6-month follow-up after treatment for an initial attack, and the fifteenth 
pubertal/postpubertal subject has completed the 6-month follow-up after his or her third and final 
treatment, the study will be closed.  
The approximate overall duration of the study is expected to be 3 years.  

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5
STUDY POPULATION SELECTION
5.1
Study Population
The study will enroll a sufficient number of children and adolescents to ensure study completion 
of 36 evaluable subjects.  The study population will consist of subjects from 2 through 17 years 
of age who present with an acute cutaneous, abdominal, or laryngeal HAE attack, at least 16 of 
whom were prepubertal at the time of their first icatibant treated HAE attack and 20 of whom 
were pubertal/postpubertal at the time of their first icatibant treated HAE attack.
5.2
Inclusion 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 until the day prior to the 
eighteenth birthday) at the time of the subject’s first HAE attack treated with icatibant as part 
of this study. 
2. Documented diagnosis of HAE type I or II. Diagnosis must be confirmed by C1-INH 
deficiency (C1-INH protein level below the lower limit of normal and/or functional level 
<50% of normal). Diagnosis may be on the basis of historic data or by diagnostic testing 
conducted at the time of screening. Inclusion will be permitted initially based on medical 
history only if a clear diagnosis has been made based on all of the following criteria:
-
Family history
-
Characteristic attack manifestations, recurrent attacks
-
Historical C1-INH deficiency as demonstrated by immunologic or functional test results
-
Exclusion of other forms of angioedema
-
Subsequent confirmation of the diagnosis to be made on the basis of C1-INH level or 
function (all subjects)
3. Informed consent (and subject assent as appropriate) signed by the subject’s parent(s) or 
legal guardian(s).
5.3
Exclusion Criteria
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 trial that involves use of any investigational product (drug or 
device) within 30 days prior to study enrollment or at any time during the study.
3. Any known factor/disease that might interfere with the treatment compliance, study conduct, 
or result interpretation.
4. Congenital or acquired cardiac anomalies that interfere significantly with cardiac function.
5. Treatment with angiotensin converting enzyme (ACE) inhibitors within 7 days prior to 
treatment.
6. Use of hormonal contraception within the 90 days prior to treatment.
7. Androgen use (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) within 
the 90 days prior to treatment.

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8. Pregnancy or breastfeeding.
9. A physical condition that interferes with pubertal status determination.

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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
Treatments 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 in the abdominal 
region as a SC injection.
The dosing regimen for treatment of subsequent attacks in pubertal/postpubertal subjects 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 contingent upon having been treated 
for an initial attack and presenting with a subsequent acute attack at least 7 days after prior 
treatment (see Section 4.1.2).  
6.4
Method of Assigning Subjects to Treatment Groups
Not applicable to this study.  All subjects will be administered icatibant at a weight-adjusted dose 
of 0.4 mg/kg SC up to a maximum of 30 mg per treatment.  
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 that are being taken by subjects during the 
study are regarded as concomitant medications and must be documented on the case report form 
(CRF) following informed consent.
Use of the following concomitant medications is allowed during the study:
•
All chronically administered medications, except for treatments of HAE, are allowed, but the 
dose and regimen must have been stable for at least 1 month before the first dose of icatibant 
in this study.
•
Prophylactic therapies for HAE (eg, anti-fibrinolytics or C1-INH) other than attenuated 
androgens will be allowed, but therapies known to attenuate an acute HAE attack (eg, 
C1-INH concentrate, fresh-frozen plasma [FFP]) must not be used during the attack being 
treated with icatibant unless these are required as rescue medications (see Section 6.7).  An 
exception is that fibrinolysis inhibitors may be given in a subject’s usual, stable prophylactic 
regimen. 
Use of the following concomitant medications is forbidden within 90 days prior to treatment, and 
for 90 days after receiving treatment with icatibant:
•
ACE inhibitors.
•
Androgens or attenuated androgens (eg, stanozolol, danazol, oxandrolone,
methyltestosterone, testosterone).
•
Hormonal contraceptives (acceptable contraception during the study for sexually active 
females will consist of abstinence or a double barrier method such as condom plus 
diaphragm, condom or diaphragm plus spermicide, condom or diaphragm plus intrauterine 
device).
6.7
Rescue Therapy
For the purposes of this protocol, rescue therapy is any medication used after the administration 
of icatibant which, in the opinion of the investigator, is immediately necessary to alleviate acute 
symptoms which are judged by the investigator as resultant from the current HAE attack. 
Repeat administration of icatibant for treatment of a single attack is not allowed in this study.  
The determination of the necessity for rescue therapy will be at the discretion of the investigator.  
Rescue therapies will include agents to control the HAE attack, such as C1-INH inhibitor 
concentrates. C1-INH therapy has been used safely for the treatment of acute attacks in the 
pediatric setting.6  If C1-INH concentrates are unavailable, FFP may be used.7  A kallikrein 
inhibitor, ecallantide, approved only in the United States, is indicated for use in patients 16 years 
of age and older. 

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

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

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7
STUDY PROCEDURES
Detailed descriptions of subject evaluations required for this protocol are described in this 
section. These evaluations will be performed during the indicated days and weeks of the study 
(see the study schedules of events in Appendix 1, 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 in the CRF. Details of prior HAE attacks (eg, typical 
frequency, symptom duration, onset of relief, and type and frequency of medical interventions 
required) will be obtained at screening through pretreatment on Day 1.  Other important medical 
events, menstrual cycle history in females (see Section 7.6), and concomitant medication and 
illnesses will be recorded at other visits on the appropriate CRF pages. Any existing medical 
condition present prior to the time of the first dose will be reported as medical history.

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7.6
Menstrual Cycle History
A menstrual cycle history will be determined historically for female subjects and will be 
recorded in the CRF. The timing of the blood sampling with respect to the menstrual cycle must 
be known to inform the interpretation of any potential changes in reproductive hormones in 
adolescent females, because of the normal cyclical rise and fall of reproductive hormones of the 
menstrual cycle.
Instructions for investigators:
To assist in this determination, investigators should obtain the following information and 
document in the CRF.
•
Age of menarche.
•
Normal duration of menstrual flow.
•
Normal interval in between menstrual periods.
•
Date of last onset of bleeding.
•
Prospectively ask female subjects to write down subsequent dates of onset of bleeding and 
cessation of bleeding between Day 1 and Day 90.
•
Date of ovulation (sometimes called ovulation pain, mid-cycle pain or mittelschmerz) may 
also be documented if subjects can identify this feeling.
7.7
Height and Weight
Height and weight will be recorded for all subjects.  
7.8
Pubertal Status Determination
The investigator will perform an examination for all subjects to determine whether they are 
prepubertal or pubertal/postpubertal. A description of the sexual maturation scale described by 
Marshall and Tanner8, 9is provided in Appendix 3.
7.9
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 an abdominal 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 that present with a subsequent attack at least 
7 days after prior treatment (see Section 4.1.2) may receive further treatment with icatibant for a 
total of 3 attacks.

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7.10
Pharmacokinetic Assessments
7.10.1
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).
7.10.2
Pharmacokinetic Sampling
Sampling for PK assessments will be collected according to the schedule of events provided in 
Appendix 1, Initial Icatibant-treated Attack.  
The time of investigational product administration on Day 1 will be designated as Time 0.  All 
post-treatment assessments will be calculated from the time of investigational product
administration.  Detailed sample collection, processing, and shipping instructions will be 
provided in the study Operations Manual.
Blood samples for determination of plasma concentrations of icatibant in pubertal/postpubertal 
subjects will be collected on Day 1 at pretreatment, and at 15 (±5) minutes, 30 (±5) minutes, 
45 (±5) minutes, 1 hour (±10) minutes, 2 hours (±10) minutes, 4 (±0.5) hours, and 6 (±0.5) after 
treatment.
Blood samples for determination of plasma concentrations of icatibant in prepubertal subjects 
will be collected on Day 1 at pretreatment, and at 15 (±5) minutes, 30 (±5) minutes, 2 hours 
(±10) minutes, 4 (±0.5) hours, and 6 (±0.5) hours after treatment.
7.10.3
Bioanalytical Method
Plasma samples will be assayed for concentrations of icatibant and its metabolites (M1 and M2)
using a validated method (see Section 7.21).
7.11
Efficacy Assessments
7.11.1
Investigator Symptom Score 
The investigator will use a symptom score to assess the severities of symptoms of acute 
cutaneous, abdominal, and laryngeal attacks of HAE using the following 5-point scale.  
Symptom scores will be recorded on Day 1 at pretreatment and at predetermined time points 
after treatment. Results will be recorded in the CRF.

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

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

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Table 7-1 List of Clinical Laboratory Tests
Hematology:
-
Hematocrit 
-
Hemoglobin 
-
Mean corpuscular hemoglobin 
-
Mean corpuscular hemoglobin 
concentration 
-
Mean corpuscular volume 
-
Platelet count
-
Red blood cell count 
-
White blood cell  count with 
differential 
Urinalysis: 
-
Appearance
-
Bilirubin
-
Color
-
Glucose
-
Ketones
-
Nitrite 
-
Occult blood
-
pH
-
Protein
-
Specific gravity
Serum Chemistry:
-
Albumin 
-
Alkaline phosphatase 
-
Alanine aminotransferase
-
Aspartate aminotransferase 
-
Calcium 
-
Carbon dioxide 
-
Chloride 
-
Creatinine
-
Creatine kinase 
-
Gamma-glutamyl transferase 
-
Glucose
-
Lactate dehydrogenase 
-
Phosphorus
-
Potassium 
-
Sodium 
-
Total bilirubin
7.13.5
Local Tolerability
Injection site reactions (erythema, swelling, burning sensation, itching/pruritis, warm sensation, 
cutaneous pain, or other) will be evaluated by the investigator or other medically qualified 
personnel when the subject is at the hospital/study center, and the diameter of any erythema or 
swelling will be measured.  
After discharge, the subject (or the subject’s parent/legal guardian on behalf of the subject as 
appropriate) will be interviewed about injection site reactions, either in person or by telephone 
contact.  
7.13.6
Immunogenicity
The immunogenicity of icatibant will be assessed.  Serum samples for immunogenicity testing 
will be collected for determination of anti-icatibant antibodies.  Serum samples will be analyzed 
for anti-icatibant antibodies at Shire 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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7.13.7
Pregnancy Testing
Female subjects of childbearing potential (ie, those who have experienced menarche) will 
undergo pregnancy testing at time points specified in the study schedule of events in Appendix 1
and Appendix 2. All pregnancy testing will be conducted using a urine human chorionic 
gonadotropin (hCG) test kit. The test will be performed and interpreted by the study personnel at 
the hospital/study center at the time of the visit.
7.14
Sample Collection, Storage, and Shipping
Blood samples will be collected via venipuncture. Use of an indwelling catheter is encouraged 
for collection of serial blood samples for PK assessments when feasible. Use of a topical local 
anesthetic (such as EMLA or LMX) is acceptable to make the procedure more tolerable for 
children, provided that the timing of this application does not interfere with blood sample 
collection.  Subjects will be in a seated or supine position during blood collection.
All samples will be stored and secured in a way that assures that unauthorized access is 
prohibited and the samples are not lost, allowed to deteriorate, or are accidentally or illegally 
destroyed.  Detailed sample collection, processing, and shipping instructions will be provided in 
the study Operations Manual.
7.15
Recording of Concomitant Medications 
All medications administered to the study subjects from the time of informed consent through the 
follow-up visit 90 (±7) days after investigational product administration are regarded as 
concomitant and will be documented in the CRF. Concomitant medications are defined in 
Section 6.6.  
7.16
Recording of Adverse Events
Adverse events will be collected over an observation period from the time of treatment until the 
follow-up visit 90 (±7) days after investigational product administration (or until the event has 
resolved/stabilized or an outcome is reached, whichever comes first).  Adverse event monitoring 
and the period of observation defined for this study are described in Section 7.17.4.1.  
7.17
Adverse Events Assessments  
7.17.1
Definitions of Adverse Events and Serious Adverse Events
7.17.1.1
Adverse Event
An adverse event is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
a clinical study, whether or not considered investigational product related.  This includes an 
exacerbation of a pre-existing condition.  However, anyexacerbation or worsening of symptoms 
of an acute HAE attack treated with icatibant is considered a result of the underlying disease and 
will not be considered an adverse event (unless meeting the criteria for a serious adverse event, 
see Section 7.17.1.2).

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

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7.17.1.2
Serious Adverse Event
A serious adverse event (SAE) is any adverse event 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 a serious adverse event 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 adverse event is defined 
as an adverse event that placed the subject, in the view of the initial reporter, at immediate risk of 
death from the adverse event as it occurred (ie, it does not include an adverse event that, had it 
occurred in a more severe form, might have caused death).
7.17.2
Classification of Adverse Events and Serious Adverse Events
The severity of adverse events will be assessed by the investigator as mild, moderate, or severe 
based on the scale in Table 7-2.  The severity of adverse events and serious adverse events
should be recorded on the appropriate CRF page as Grade 1, 2, or 3, corresponding, respectively, 
to a severity of mild, moderate, or severe.
Table 7-2 Adverse Event Severity
Grade
Severity
Definition
Grade 1 
Mild
No limitation of usual activities.
Grade 2 
Moderate
Some limitation of usual activities.
Grade 3 
Severe
Inability to carry out usual activities.
7.17.2.1
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (eg, severe headache).  This is not the same as “serious,” which is based on 
the outcome or action criteria usually associated with events that pose a threat to life or 
functioning.  Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.

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

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

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

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

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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.
7.21
Appropriateness of Measurements
The safety assessments used in this study are standard and will provide a detailed measure of the 
safety of icatibant in the pediatric population. 
The measures of serum reproductive hormone concentration are accepted measures for assessing 
the function of reproductive organs.  
Plasma samples will be assayed for concentrations of icatibant and its 2 major metabolites 
(M1 and M2) using a validated high-performance liquid chromatography/tandem mass 
spectrometry (LC-MS/MS) method with a lower limit of quantification of 1 ng/mL and a range 
from 1 to 1000 ng/mL (Analytical Report SHR10-002).  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.  
In all pediatric subjects in the present study, irrespective of age, the investigator-rated symptom 
score will provide an appropriate means to measure the severity of primary symptoms (eg, 
cutaneous and/or abdominal pain, cutaneous swelling, or laryngeal symptoms) of acute attacks of 
HAE at pretreatment and the change in symptom severity, if any, after treatment with icatibant.
Though subject-reported outcomes such as the symptom score and visual analog scale (VAS) 
have been employed successfully as efficacy measures in clinical studies of icatibant in adults, 
the use of these subject-reported outcomes in children poses special challenges. The Faces Pain 
Scale is a validated, self-reported measure used to assess the intensity of children's pain in a wide 
variety of clinical contexts.10  The Faces Pain Scale-Revised (FPS-R) was adapted from the
original FPS in order to make it possible to score pain on a widely accepted 0-to-10 metric.11
The scales are suitable for use in assessment of the intensity of children's acute pain from age 
4 onward, are simple to administer, and require no specialized equipment other than the
standardized images of faces. Use of the FPS-R is planned for this study, and will provide an 
appropriate means to measure pain associated with acute attacks of HAE in pediatric subjects 
who are at least 4 years of age.

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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 preverbal children or children with limited verbal 
capability.12, 13 Each category is scored on a 0-to-2 scale which results in a total score from 0 to 
10.
Collectively, the measures employed in this study are expected to allow for assessment of the PK
profile, tolerability, and safety, and efficacy of icatibant in the pediatric population.

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8
STUDY ACTIVITIES
8.1
Screening (Day of Informed Consent to Pretreatment on Day 1 of the Initial 
Attack) 
•
Informed Consent/Assent
•
Inclusion/Exclusion Criteria
•
Medical History
•
Confirmation of documented HAE diagnosis
•
Measurement of C1-INH 
•
Pubertal status determination
•
Physical examination
•
Vital signs
•
ECG
•
Height and weight
•
Urine pregnancy test (in females of childbearing potential)
•
Recording of concomitant medications
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 
•
Pubertal status determination (only if the subject was classified as prepubertal at the time of 
the screening visit)
•
Menstrual cycle history (in pubertal/postpubertal females only)
•
Physical examination
•
Vital signs
•
ECG (at subsequent attacks only)
•
Height and weight
•
Subject self-assessment of HAE-related pain (in subjects 4 years of age and older) using 
e-diary FPS-R
•
Investigator assessment of HAE symptoms
•
Investigator assessment of HAE-related pain (in subjects younger than 4 years of age only) 
using FLACC
•
Clinical laboratory tests (serum chemistry, hematology and urinalysis)
•
Urine pregnancy test (in females of childbearing potential)
•
Reproductive hormone assessments
•
Pharmacokinetic assessment (at pretreatment for initial attack only)
•
Immunogenicity assessment

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•
Recording of concomitant medications
•
Assessment of adverse events (at pretreatment for subsequent attacks only)
8.3
Initial Attack
8.3.1
Treatment Period (Day 1 to Day 8 [± 1 Day])
•
Investigational product administration (Day 1, Time 0)
•
Physical examination (Day 1, 6 (±0.5) hours) [or 8 (±0.5) hours) if the subject is not 
discharged***] post dose and Day 8 (±1 day))
•
Vital signs (Day 1, 1 hour (±10 minutes), 6 (±0.5) hours) [or 8 (±0.5) hours if the subject is 
not discharged***] post dose and Day 8 (±1 day))
•
ECG (Day 1, 6 (±0.5) hours [or 8 (±0.5) hours if the subject is not discharged***] post dose)
•
Subject self-assessment of HAE-related pain (in subjects 4 years of age and older) using 
e-diary FPS-R (Day 1, 1 hour (± 10 minutes), 2 hours (± 10 minutes), 4 (±0.5) hours, 6 (±0.5)
hours and 8* (±0.5) hours post dose, Day 2 (24 (± 4) hours), Day 3 (48 (±4) hours)
•
Investigator assessment of HAE symptoms (Day 1, 1 hour (±10 minutes), 2 hours 
(± 10 minutes), 4 (±0.5) hours, 6 (±0.50) hours [and 8 (±0.5) hours if the subject is not 
discharged**] post dose)
•
Investigator assessment of HAE-related pain (in subjects younger than 4 of age only) using 
FLACC (Day 1, 1 hour (±10 minutes), 2 hours (±10 minutes), 4 (±0.5) hours, 6 (±0.5) hours 
[and 8 (±0.5) hours if the subject is not discharged**] post dose)
•
Clinical laboratory tests (Day 1, 6 (±0.5) hours post dose and Day 8 (±1 day))
•
Reproductive hormone assessments (Day 1, 6 (±0.5) hours post dose and Day 8 (±1 day))
•
Injection site reaction assessment (Day 1, 1 hour (±10 minutes), 6 (±0.5) hours [and 8 (±0.5) 
hours if the subject is not discharged**] post dose, Day 2 (24 (±4) hours), Day 3 (48 (±4)
hours), and Day 8 (±1 day))
•
Sampling for PK assessments in pubertal/post pubertal subjects (Day 1, 15 minutes (±5 min),
30 minutes (±5 min), 45 minutes (±5 min), 1 hour (± 10 minutes), 2 hours (±10 minutes), 
4 (±0.5) hours, 6 (±0.5) hours post dose at initial attack only)
•
Sampling for PK assessments in prepubertal subjects (Day 1, 15 (± 5) minutes, 30 (± 5) 
minutes, 2 hours (±10 minutes), 4 (±0.5) hours, 6 (±0.5) hours post dose at initial attack only)
•
Safety follow-up contact (Day 2 (24 (±4) hours), Day 3 (48 (±4) hours)) either by telephone 
or in person at the investigator’s discretion
•
Immunogenicity assessment (Day 8 (±1 day))
•
Menstrual cycle history (Day 8 (±1 day) (in pubertal/postpubertal females)
•
Recording of concomitant medications 
•
Assessment of adverse events
*A subject may be discharged after completion of all assessments at 6 hours post treatment, if 
deemed medically stable in the investigator’s clinical judgment and the subject’s HAE symptoms 
have resolved (the subject’s investigator-rated symptom score = zero, denoting the absence of 
symptoms).  

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If this is the case, the assessments scheduled for 8 hours post treatment will be omitted with the 
exception of subject self-assessment of HAE-related pain using the e-diary FPS-R. 
**If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s 
investigator-rated symptom score ≠ zero) and the subject is not to be discharged after completion 
of assessments at the 6-hour time point, the assessments indicated will be performed at both 
6 AND 8 hours post treatment.
***If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s 
investigator-rated symptom score ≠ zero) and the subject is not to be discharged after completion 
of assessments at the 6-hour time point, the assessments indicated will be performed at either 
6 OR 8 hours post treatment.
8.3.2
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
•
Vital signs
•
Height and weight
•
Clinical laboratory tests (serum chemistry, hematology, and urinalysis)
•
Urine pregnancy test (in females of childbearing potential)
•
Reproductive hormone assessments
•
Immunogenicity assessment 
•
Menstrual cycle history (in pubertal/postpubertal females)
•
Recording of concomitant medications
•
Assessment of adverse events
•
Documentation of HAE attack(s) not treated with icatibant
8.3.3
Telephone Contact (Month 6 ±7 days) 
The scheduled telephone contact will document pubertal changes/milestones, if any.
•
Pubarche
•
Menarche (females only)
•
Changes in menstrual cycle (females only)
•
Pregnancy (females and male partner)

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8.4
Subsequent Attacks (Pubertal/postpubertal Subjects Only)
Pubertal/postpubertal subjects may receive treatment for up to 2 subsequent HAE attacks, 
contingent upon having been treated for an initial attack and presenting with a subsequent acute 
attack of at least 7 days after prior treatment (see Section 4.1.2).  
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 [± 1 Day])
•
Investigational product administration (Day 1, Time 0)
•
Physical examination (Day 1, 6 (±0.5) hours [or 8 (±0.5) hours if the subject is not 
discharged***] post dose and Day 8 (±1 day))
•
Vital signs (Day 1, 1 hour (±10 minutes), 6 (±0.5) hours [or 8 (±0.5) hours if the subject is 
not discharged***] post dose and Day 8 (±1 day))
•
ECG (Day 1, 6 (±0.5) hours [or 8 (±0.5) hours if the subject is not discharged***] post dose)
•
Subject self-assessment of HAE symptoms in subjects 4 years of age and older using e-diary 
FPS-R (Day 1, 1 hour (±10 minutes), 2 hours (±10 minutes), 4 (±0.5) hours, 6 (±0.5) hours 
and 8* (±0.5) hours post dose, Day 2 (24 (±4) hours), Day 3 (48 (±4) hours))
•
Investigator assessment of HAE symptoms (Day 1, 1 hour (±10 minutes), 2 hours (±10 
minutes), 4 (±0.5) hours, 6 (±0.5) hours [and 8 (±0.5) hours if the subject is not discharged**] 
post dose)
•
Investigator assessment of HAE-related pain (in subjects younger than 4 years of age only) 
using FLACC (Day 1, 1 hour (±10 minutes), 2 hours (±10 minutes), 4 (±0.5) hours, 6 (±0.5) 
hours [and 8 (±0.5) hours if the subject is not discharged**] post dose)
•
Clinical laboratory tests (Day 1, 6 (±0.5) hours post dose and Day 8 (±1 day))
•
Reproductive hormone assessments (Day 1, 6 (±0.5) hours post dose and Day 8 (±1 day))
•
Injection site reaction assessment (Day 1, 1 hour (±10 minutes), 6 (±0.5) hours [and 8 (±0.50) 
hours if the subject is not discharged**] post dose, Day 2 (24 (± 4) hours), Day 3 (48 (± 4) 
hours), and Day 8 (±1 day))
•
Safety follow-up contact (Day 2 (24 (±4) hours], Day 3 (48 (±4) hours)) either by telephone 
or in person at the investigator’s discretion
•
Immunogenicity assessment (Day 8 (±1 day))
•
Menstrual cycle history (Day 8 (± 1 day) (in pubertal/postpubertal females)
•
Recording of concomitant medications
•
Assessment of adverse events 
*A subject may be discharged after completion of all assessments at 6 hours post treatment, if 
deemed medically stable in the investigator’s clinical judgment and the subject’s HAE symptoms 
have resolved (the subject’s investigator-rated symptom score = zero, denoting the absence of 
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If this is the case, the assessments scheduled for 8 hours post treatment will be omitted with the 
exception of subject self-assessment of HAE-related pain using the e-diary FPS-R. 
**If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s 
investigator-rated symptom score ≠ zero) and the subject is not to be discharged after completion 
of assessments at the 6-hour time point, the assessments indicated will be performed at both 
6 AND 8 hours post treatment.
***If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s 
investigator-rated symptom score ≠ zero) and the subject is not to be discharged after completion 
of assessments at the 6-hour time point, the assessments indicated will be performed at either 
6 OR 8 hours post treatment.
8.4.2
Follow-up Visit (Day 90 ±7 days)
•
Physical examination
•
Vital signs
•
Height and weight
•
Clinical laboratory tests (serum chemistry, hematology, and urinalysis)
•
Urine pregnancy test (in females of childbearing potential)
•
Reproductive hormone assessments
•
Immunogenicity assessment
•
Menstrual cycle history (in pubertal/postpubertal females)
•
Recording of concomitant medications
•
Assessment of adverse events
•
Documentation of HAE attack(s) not treated with icatibant
8.4.3
Telephone Contact (Month 6 ±7 days) 
The scheduled telephone contact will document pubertal changes/milestones, if any.
•
Pubarche
•
Menarche (females only)
•
Changes in menstrual cycle (females only)
•
Pregnancy (females and male partner)

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

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10 PLANNED STATISTICAL METHODS
10.1
General Considerations
All statistical analyses will be performed using SAS® statistical software (SAS Institute, North 
Carolina, USA).  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
The study will enroll a sufficient number of children and adolescents to ensure study completion 
of 36 evaluable subjects. The study population is planned to consist of at least 16 prepubertal 
and 20 pubertal/postpubertal subjects from 2 through 17 years of age who present with an acute 
cutaneous, abdominal, or laryngeal HAE attack.  Though empirically derived and not based on a 
formal sample size calculation, this sample size will provide basic information concerning the 
PK, tolerability and safety, and efficacy of icatibant in children and adolescents with HAE.
10.3
Analysis Populations
The following populations will be used in the analysis:
•
The 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 adverse events, vital signs, ECG, local tolerability 
at the injection site, reproductive hormone levels, immunogenicity, and standard hematology, 
serum chemistry, and urinalysis.
Adverse events will be categorized using MedDRA Version 8.1 or higher. The assessment of 
safety will be based mainly on the frequency of treatment emergent adverse events. Adverse 
events will be summarized by system organ class (SOC) and preferred term. The number and 
proportion of subjects experiencing an adverse event will be tabulated by the subject 
stratification group and for the overall subject group. Adverse events by SOC and preferred term 
also will be tabulated by severity and by relationship to treatment. In the case of multiple 
occurrences of the same adverse events (at the preferred term level) in an individual subject, the 
adverse event that is classified as the most severe (ie, maximum severity) will be identified for 
the analysis by severity and the adverse event that has the highest relationship to investigational 
product will be identified for the analysis by relationship. Serious adverse events will be 
provided in a data listing.

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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, and 6 hours post treatment, and at 8 hours post treatment for subjects 
who had not shown complete resolution of HAE symptoms at 6 hours. Eight symptoms will be 
assessed for abdominal and cutaneous attacks, and 13 symptoms will be assessed for laryngeal 
attacks. Time 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 investigational product
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 DSMB is described in Section 11.8; its goal will 
be to assess the risk/benefit of icatibant treatment in this pediatric population.  An analysis of the 
data for DSMB review is planned after the first 4 subjects in the pubertal/postpubertal group 
have been treated, and is planned to follow quarterly enrollment milestones (ie, 25%, 50%, and 
75%) thereafter. 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. 
A similar approach will be followed in case of missing or partial adverse event 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
24 months of study initiation).
•
Copy of investigator(s) and sub-investigator(s) current medical license (indicating license 
number and expiration date).
•
Signed and dated agreement of the final protocol.
•
Signed and dated agreement of any amendment(s), if applicable.
•
Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed by 
name, number and date of approval or re approval:  protocol, any amendments, Subject 
Information/Informed Consent Form, and any other written information to be provided 
regarding subjects recruitment procedures.
•
Copy of IRB/IEC approved Subject Information/Informed Consent Form/any other written 
information/advertisement (with IRB approval stamp and date of approval).
•
Current list of IRB/IEC Committee members/constitution (dated within 12 months prior to 
study initiation).
•
Financial Disclosure Form signed by investigator(s) and sub-investigator(s).
•
Current laboratory reference ranges (if applicable).
•
Certification/QA scheme/other documentation (if applicable).

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Regulatory approval and notification as required must also be available; 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, tolerability,
and efficacy data will be reviewed and assessed by the DSMB. This review must be completed 
prior to initiating enrollment of subjects in the prepubertal group. As the outcome of its review, 
the DSMB may make a recommendation to continue enrolling subjects in the 
pubertal/postpubertal group, to initiate dosing of subjects in the prepubertal group, or to 
administer a different dose, or to terminate the study. 
11.9
Protocol Violations/Deviations
The investigator will conduct the study in compliance with the protocol. The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to subjects.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC. The sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.
A record of subjects screened, but not entered into the study, is also to be maintained.  No 
protocol waivers or exemptions will be considered by the sponsor during the study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the investigator will contact the sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.  

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Any departures from the protocol must be fully documented as a protocol deviation.  Protocol 
deviations will need to be reviewed by the medical monitor and may also need to be submitted to 
the IRB/IEC.
Protocol modifications will only be initiated by the sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.10 Premature Closure of the Study
If the sponsor, investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable risk to 
subjects, the study may be terminated after appropriate consultation between the sponsor and the 
investigator.  In addition, a decision on the part of the sponsor to suspend or discontinue 
development of the investigational product may be made at any time.  Conditions that may 
warrant termination of the study or site include, but are not limited to:
•
The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled in 
the study.
•
Failure of the investigator to comply with pertinent global regulations.
•
Submission of knowingly false information from the study site to the sponsor or other 
pertinent regulatory authorities.
•
Insufficient adherence by the Investigator to protocol requirements.
11.11 Access to Source Documentation
Regulatory authorities, the IRB/IEC, or the sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, cross-checking with 
source documents, and clarification of administrative matters may be performed.
11.12 Data Generation and Analysis
The clinical database will be developed and maintained by a 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. 
Adverse events 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 angiodema: a current state-of-the-art review, 
VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, 
Therapy, and Management of Hereditary Angioedema. Annals of Allergy Asthma 
Immunology 2008;100:S30-40.
2. Davis AE, 3rd. New treatments addressing the pathophysiology of hereditary angioedema. 
Clinical and Molecular Allergy 2008;6:2.
3. Knolle J, Breipohl G, Henke S, Wirth K, Scholkens B. New and highly potent bradykinin 
antagonists. Agents and Actions Supplement 1992;38 ( Part 1):559-64.
4. Hock FJ, Wirth K, Albus U, et al. Hoe 140 a new potent and long acting 
bradykinin-antagonist: in vitro studies. British Journal of Pharmacology 1991;102:769-73.
5. Wirth K, Hock FJ, Albus U, et al. HOE 140 a new potent and long acting 
bradykinin-antagonist: in vivo studies. British Journal of Pharmacology 1991;102:774-7.
6. Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy, Asthma 
and Clinical Immunology 2010;6:18.
7. Zuraw BL. Clinical practice. Hereditary angioedema. New England Journal of Medicine 
2008;359:1027-36.
8. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of 
Disease in Childhood 1969;44:291-303.
9. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of 
Disease in Childhood 1970;45:13-23.
10. Bieri D, Reeve RA, Champion GD, Addicoat L, Ziegler JB. The Faces Pain Scale for the 
self-assessment of the severity of pain experienced by children: development, initial 
validation, and preliminary investigation for ratio scale properties. Pain 1990;41:139-50.
11. Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain 
Scale-Revised: toward a common metric in pediatric pain measurement. Pain 
2001;93:173-83.
12. Manworren RC, Hynan LS. Clinical validation of FLACC: preverbal patient pain scale. 
Pediatric Nursing 2003;29:140-6.
13. Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for 
scoring postoperative pain in young children. Pediatric Nursing 1997;23:293-7.

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

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

Ic ati b a nt ( Fir az yr ® )
Cli nic al Tri al Pr ot oc ol A m e n d me nt 2 : H G T- FI R-0 8 6
0 6 M arc h 2 0 1 2
S hire
C o nfi de nti al
7 7
A p pe n di x 6
Pr ot oc ol Si g n at ure P a ge
St u d y Title:
A M ultice nter, O pe n -La bel, N o n -Ra n d o mize d St u d y  t o Assess 
t he P har mac o ki netics, T olera bilit y, a n d Safety of a Si n gle 
S u bc uta ne o us A d mi nistrati o n of Icati ba nt i n C hil dre n a n d 
A d olesce nts wit h Here ditar y  A n gi oe de ma
St u d y N u m ber:
H G T -FI R- 0 8 6
Ori gi n al Pr ot oc o l 
D ate:
1 4 J u ne 2 0 1 1
A m e n d me nt 1 D ate:
0 5 A u g ust 2 0 1 1
A m e n d me nt 2 D ate:
0 6 Marc h 2 0 1 2
I ha ve rea d t he pr ot oc ol descri be d a b o ve.  I a gree t o c o m pl y wit h all a p plica ble re g ulati o ns a n d 
t o c o n d uct t he st u d y as descri be d i n t he pr ot oc ol.  
Si g n at or y:
I n vesti g at or
Si g n at ure
D ate
Pri nte d N a me
I ha ve rea d a n d a p pr o ve t he pr ot oc ol descri be d a b o ve.
Si g n at or y:
S hire H G T 
Me dic al 
M o nit or
Si g n at ure
D ate
 M D, P h D
Pri nte d N a me
P P D

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Appendix 7
Summary of Changes for Amendment 2
1. Amendment Summary and Rationale
Protocol HGT-FIR-086 has been amended to incorporate feedback from investigators and 
institutional ethics committees.  Operational clarifications to the text and changes to the study 
schedules of events were implemented to facilitate study conduct.  
Noteworthy changes are as follows:
•
Determination of Tanner stage was eliminated in favor of simply stratifying subjects by 
pubertal status (prepubertal [Tanner stage I] or pubertal/postpubertal [Tanner stages II to V]
as defined by PDCO).  An assessment of pubertal status was added at Screening to ensure 
that, as required by the DSMB, the first 4 subjects enrolled will be pubertal/postpubertal.  It 
was also specified that subjects classified as pubertal/postpubertal at Screening would not 
require further evaluations or pubertal status during the study.  Finally, the pubertal status 
assessment scheduled on Day 90 in previous versions of the protocol lacks a clear rationale 
and has been eliminated in this amended version.
•
The duration of time over which blood samples for pharmacokinetic and other assessments
are to be collected on the day of dosing was reduced from 8 to 6 hours to reduce the burden 
of study participation on subjects.  Text was also added to encourage the use of an 
intravenous cannula for pharmacokinetic blood draws and to allow for the use of a topical 
anesthetic, as appropriate.
•
Clarifications were made to inclusion criterion #2 pertaining to the definition of C1-INH 
deficiency and to ensure that the text is clear that though all subjects will have confirmatory 
C1-INH testing, the results are not predetermining for inclusion (due to the approximate 
1-month turnaround time for test results) unless the patient does not have a previously 
documented diagnosis of HAE.  
•
Clarification to exclusion criterion #2 was made to ensure that the text clearly prohibits 
patients from participating in another concurrent interventional clinical study.  Additonally, 
new exclusion criterion #9 was added to exclude subjects with a physical condition that 
interferes with pubertal status determination.
•
The text was modified to reflect a change in the sponsor’s medical monitor and contact 
information.
•
A collection window was added around the Day 8 (±1 day) visit, and it was specified that 
existing windows for pharmacokinetic assessments should be applied to other assessments 
performed at those time points.
•
Collection of menstrual cycle history on Day 1, Day 8, and Day 90 was added to the study 
schedule of events to inform interpretation of the results of female reproductive hormone 
assessments.
•
A telephone-based contact 6 months after treatment of each attack was added to document
pubertal changes/milestones, if any.
•
Documentation of HAE attacks not treated with icatibant was added to the schedule of events 
on Day 90.

Ic ati b a nt ( Fir az yr ® )
Cli nic al Tri al Pr ot oc ol A m e n d me nt 2 : H G T- FI R-0 8 6
0 6 M arc h 2 0 1 2
S hire
C o nfi de nti al
7 9
2. Det aile d S u m m ar y of C h a n ges f or t he A me n d me nt
T his is a secti o n t hat has bee n u p date d t o descri be t he c ha n ges fr o m t he pre vi o us pr ot oc ol 
versi o n. Si g nifica nt c ha n ges a n d a d diti o ns t o t he pr ot oc ol te xt are ca pt ure d bel o w. 
C ha n ges i n gra m mar, s pelli n g, p u nct uati o n, f or mat, mi n or e dit orial c ha n ges (i ncl u di n g 
re- orderi n g of te xt or ot her e dits f or c o nsiste nc y a n d clarit y), a n d u p dates t o t he list of 
a b bre viati o ns a n d cr oss -refere nces are n ot reflecte d i n t he c ha n ge s u m mar y.
B ol d te xt i n dicates ne w te xt. Stri ket hr o u g h te xt i n dicates delete d te xt.
C H A N G E S T O T E X T
C ha n ge:  A d diti o n of a ne w me dical m o nit or
Secti o n i m pacte d b y c ha n ge:  C o ver pa ge
C ha n ge:  
M D, P h D
S hire H u ma n Ge netic T hera pies ( H G T), I nc.
M o bile:
Ot her secti o ns i m pacte d b y c ha n ge:  7. 1 7. 4. 2 Re p orti n g Seri o us A d verse E ve nts
C ha n ge:  Clarificati o n c o ncer ni n g o nset of s y m pt o ms
Se cti o n i m pacte d b y c ha n ge:  1. 1 Disease Bac k gr o u n d
Alt h o u g h ac ute e pis o des of H A E ma y occ ur at a n y a ge, t he mea n me di a n a ge at first s y m pt o matic H A E 
att ac k is esti mate d t o ra n ge bet wee n 4 t o 1 1 years (re vie we d by F ar k as 6).  S u bc uta ne o us e de ma of t he 
e xtre mities, face, nec k, t ors o, a n d ge nitals is t he m ost c o m m o n, a n d us uall y t he earliest, ma nifestati o n of 
H A E see n i n c hil dre n.  T w o pe a ks of i ncre ase d fre q ue nc y a n d se verit y of H A E s y m pt o ms were 
re p orte d i n a l ar ge pe di atric c o h ort, o ne pe a k bet wee n 3 a n d 6 ye ars of a ge a n d t he sec o n d at ar o u n d 
p u bert y.  T hese pe a ks are attri b ute d t o p h ysi ol o gic al c h a n ges w hic h occ ur i n t hese peri o ds of 
de vel o p me nt. 6  
Ot her secti o ns i m pacte d b y c ha n ge:  N o ne
C ha n ge:  Clarificati o n c o ncer ni n g H A E ma na ge me nt
Secti o n i m pacte d b y c ha n ge:  1. 1 Disease Bac k gr o u n d
Pr o m pt c o ntr ol of attac ks, s h ort -ter m pr o p h yla xis, "i nter mitte nt " pr o p h yl a xis, l o n g -ter m pr o p h yl a xis 
a n d e mer ge nc y t her a p y are rec o m me n de d f or t he ma na ge me nt of pe diatric H A E. 6 Treat me nt o pti o ns f or 
c hil dre n wit h H A E acc or di n g t o c urre nt g ui deli nes i ncl u de a ntifi bri n ol ytics, atte n uate d a n dr o ge ns, a n d C 1 
i n hi bit or ( C 1-I N H) re place me nt t hera p y.  C urre nt g ui deli nes f a v or a ntifi bri n ol y tics f or l o n g ter m 
pr o p h yl a xis bec a use of t heir s afet y pr ofile rel ati ve t o atte n u ate d a n dr o ge ns.  T he preferre d 
a ntifi br ol ytic a ge nt, w here a p pr o ve d f or use, is tr a ne x a mic aci d, t h o u g h -a m i n oc a pr oic aci d is 
s o meti mes als o use d f or t his p ur p ose.  
Ot her s ecti o ns i m pacte d b y c ha n ge:  N o ne
C ha n ge:  Clarificati o n c o ncer ni n g p u bertal stat us assess me nt
Secti o n i m pacte d b y c ha n ge:  4. 1. 1 St u d y Desi g n
A s u bject’s classificati o n as pre p u bertal or p u bertal/ p ost p u bert al will be deter mi ne d at t he ti me of t he first 
icati ba nt-treate d H A E attac k.  S u bjects cl assifie d as p u bert al/ p ost p u bert al at scree ni n g will n ot re q uire 
f urt her e v al u ati o n of p u bert al st at us d uri n g t he st u d y, w here as s u bjects cl assifie d as pre p u bert al at 
scree ni n g will h a ve t heir p u bert al st at us re assesse d at t he ti m e of t heir first ic ati b a nt -tre ate d H A E 
att ac k visit .
P P D
P P D

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Other sections impacted by change:  Synopsis, Appendix 1 Study Schedule of Events (Initial Icatibant-
treated Attack), Appendix 2 Study Schedule of Events (Subsequent Icatibant-treated Attacks)  
Change:  Clarification concerning enrollment of first 4 subjects
Section impacted by change:  4.1.1 Study Design
Change:  
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 
PK, safety, tolerability, and efficacy data will be reviewed by an independent Data and Safety 
Monitoring Board (DSMB).  The DSMB review of the first 4 subjects shall be completed prior to 
continuing enrollment of additional pubertal/postpubertal subjects, icatibant treatment of second and 
third HAE attacks in pubertal/postpubertal subjects, and initiating enrollment of subjects in the 
prepubertal group.
Other sections impacted by change:  Synopsis
Change:  Clarification concerning duration of time for monitoring and assessment 
Section impacted by change:  4.1.1 Study Design
Change:  
Subjects will be monitored closely in the hospital/study center for at least 6 to 8 8 hours after treatment.  A 
subject may be discharged after completion of all assessments at 6 hours post treatment, if deemed 
medically stable in the investigator’s clinical judgment and the subject’s HAE symptoms have 
resolved (the subject’s investigator-rated symptom score must be zero, denoting the absence of 
symptoms).  If HAE symptoms have not completely resolved at 6 hours (ie, the investigator-rated 
symptom score is >0), the subject shall remain in the hospital/study center for at least 8 hours after 
icatibant administration for further evaluation.
Other sections impacted by change:  Synopsis
Change:  Clarification concerning subject participation
Section impacted by change:  4.1.1 Study Design
Change:  
Subjects who reach their 18th birthday during the course of follow-up are allowed to remain in the 
study and receive subsequent treatments with icatibant according to the protocol.
Other sections impacted by change:  None
Change:  Addition of telephone follow-up every 6 months
Section impacted by change:  4.1.1 Study Design
Change:  
The investigator will schedule a telephone contact approximately 6 months after Day 1 of each 
icatibant-treated attack to obtain specific updates concerning pubertal changes/milestones.
Other sections impacted by change:  Synopsis, 4.1.2 Study Assessments (and Table 4-1)
Change:  Allowance for a window for performance of assessments schedules on Day 8
Section impacted by change:  4.1.2 Study Assessments
Change:  
    Post-treatment Day 1 through Day 8 (± 1 day)
Other sections impacted by change:  Synopsis, 4.1.2 Study Assessments (and Table 4-1)

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Change:  Clarification concerning timing of treatment of subsequent attacks
Section impacted by change:  4.1.2 Study Assessments
Change:  
In the event that a subsequent attack occurs at least 7 days after prior treatment, but within the 
window (±1 day) allowed for performance of Day 8 assessments associated with a prior attack, the 
Day 8 assessments may also serve as the pretreatment (baseline) assessments for the subsequent 
attack.  
Other sections impacted by change:  Synopsis
Change:  Detail concerning 6-month telephone contacts
Section impacted by change:  4.1.2 Study Assessments
Change:  
The investigator will schedule a telephone contact approximately 6 months after Day 1 of each 
icatibant-treated attack to obtain updates concerning pubertal changes/milestones.  If this 
prescheduled telephone contact date should occur within the 90-day follow-up period (ie, Day 1 
through Day 90) of a subsequent attack, this prescheduled contact may be omitted.
Other sections impacted by change:  Synopsis, Table 4-1 Study Periods
Change:  Clarification concerning duration of subject participation
Section impacted by change:  4.3 Study Duration
Change:  
Once eligibility is established at screening, the subject will be enrolled but will enter a period of 
inactive participation of variable duration until such time as the subject experiences an acute attack 
of HAE and is offered treatment.  At that time, the subject will enter a 90-day period of active 
participation which will consist of treatment with a single SC administration of icatibant on Day 1 
through follow-up at Day 90.  After receiving treatment for an initial attack of acute HAE, at least 15 
pubertal/postpubertal subjects who present with subsequent attacks of acute HAE will continue to 
receive treatment with icatibant for a total of 3 attacks each.  Thus, the period of active participation 
in the study for prepubertal subjects will be approximately 90 days, while that for 
pubertal/postpubertal subjects will be a maximum of approximately 270 days (3 separate active of 
approximately 90 days), with each active period separated by periods of inactive participation of 
variable duration The period of active participation may be shorter if pubertal/postpubertal subjects 
have recurrent HAE attacks in between the Day 8 and Day 90 visits for a prior icatibant treated HAE 
attack.  Telephone follow-up will occur approximately 6 months after each icatibant-treated attack.
Once the sixteenth prepubertal subject and the twentieth pubertal/postpubertal subject have completed the 
Day 90 6-month follow-up after treatment for an initial attack, and the fifteenth pubertal/postpubertal 
subject has completed the Day 90 6-month follow-up after his or her third and final treatment, the study will 
be closed.  
Other sections impacted by change:  Synopsis
Change:  Clarification concerning study population
Section impacted by change:  5.1 Study Population
Change:  
The study will enroll a sufficient number of children and adolescents to ensure study completion of 36 
evaluable subjects.  The study population will consist of subjects from 2 through 17 years of age who 
present with an acute cutaneous, abdominal, or laryngeal HAE attack, at least 16 of whom were 
prepubertal at the time of their first icatibant treated HAE attack and 20 of whom were 
pubertal/postpubertal at the time of their first icatibant treated HAE attack.
Other sections impacted by change:  Synopsis

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Change:  Clarifications to inclusion criteria
Section impacted by change:  5.2 Inclusion criteria
Change:  
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 HAE attack treated with icatibant as part of this 
study.
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 C1-INH deficiency (C1-INH protein level below the lower limit of normal and/or 
functional level <50% of normal).  Diagnosis may be on the basis of historic data or by diagnostic testing 
conducted at the time of screening.  Inclusion will be permitted initially based on medical history only if 
a clear diagnosis has been made based on all of the following criteria:
-
Family history
-
Characteristic attack manifestations, recurrent attacks
-
Historical C1-INH deficiency as demonstrated by immunologic or functional test results
-
Exclusion of other forms of angioedema
-
Subsequent confirmation of the diagnosis to be made on the basis of C1-INH level or function (all 
subjects)
Other sections impacted by change:  Synopsis
Change:  Clarifications to exclusion criteria
Section impacted by change:  5.2 Inclusion criteria
Change:  
2. Participation in another clinical study during the 30 days prior to treatment trial that involves use of 
any investigational product (drug or device) within 30 days prior to study enrollment or at any time 
during the study.
9.
A physical condition that interferes with pubertal status determination.
Other sections impacted by change:  Synopsis
Change:  Clarification to subcutaneous injection 
Section impacted by change:  6.2 Treatments Administered
Change:  
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 in the abdominal region as a SC 
injection.
Other sections impacted by change:  Synopsis, 4.1.2 Study Assessments
Change:  Clarification to concomitant medication use
Section impacted by change: 6.6 Concomitant Medication Usage
Change:  
Use of the following concomitant medications is forbidden within 90 days prior to treatment, and for 90 
days after receiving treatment with icatibant:
Other sections impacted by change:  None
Change:  Clarification to rescue medications
Section impacted by change: 6.7 Rescue Therapy 

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Change:  
Rescue therapies will include agents to control the HAE attack, such as C1-INH inhibitor 
concentrates.  C1-INH therapy has been used safely for the treatment of acute attacks in the pediatric 
setting.6  If C1-INH concentrates are unavailable, FFP may be used.7  A kallikrein inhibitor, 
ecallantide, approved only in the United States, is indicated for use in patients 16 years of age and 
older.  
Other acceptable rescue therapies for acute attacks include palliative medications that are intended to 
ameliorate the symptoms (eg, pain, nausea) of angioedema rather than to control the HAE attack 
itself.  If pain medication is required, the investigator may administer intravenous or prescription-
strength non-steroidal anti inflammatory drugs (NSAIDs) for mild to moderate pain and administer 
morphine sulfate (or opiate equivalent) intravenously or intramuscularly at a dose of 0.05 mg/kg (or 
an equivalent dose if another opiate medication is used).  Antiemetics may also be prescribed as 
necessary to treat nausea.  Acceptable rescue therapies may also include epinephrine, intravenous 
fluids, or other medicinal products at the discretion of the investigator. 
Other sections impacted by change:  None
Change:  Collection of menstrual cycle history
Section impacted by change:  7.6 Menstrual Cycle History
Change:  
7.6 Menstrual Cycle History
A menstrual cycle history will be determined historically for female subjects and will be recorded in 
the CRF.  The timing of the blood sampling with respect to the menstrual cycle must be known to 
inform the interpretation of any potential changes in reproductive hormones in adolescent females, 
because of the normal cyclical rise and fall of reproductive hormones of the menstrual cycle.
Instructions for investigators:
To assist in this determination, investigators should obtain the following information and document in 
the CRF.
•
Age of menarche.
•
Normal duration of menstrual flow. 
•
Normal interval in between menstrual periods. 
•
Date of last onset of bleeding. 
•
Prospectively ask female subjects to write down subsequent dates of onset of bleeding and 
cessation of bleeding between Day 1 and Day 90.
•
Date of ovulation (sometimes called ovulation pain, mid-cycle pain or mittelschmerz) may also be 
documented if subjects can identify this feeling.
Other sections impacted by change:  Synopsis
Change:  Clarification to PK sampling times
Section impacted by change:  7.10.2 Pharmacokinetic Sampling
Change:  
Blood samples for determination of plasma concentrations of icatibant in pubertal/postpubertal 
subjects will be collected on Day 1 at pretreatment, and at 15 (±5) minutes, 30 (±5) minutes, 45 (±5) 
minutes, 1 hour (±10) minutes, 2 hours (±10) minutes, 4 (±0.5) hours, and 6 (±0.5) and 8 (±0.5) after 
treatment.
Blood samples for determination of plasma concentrations of icatibant in prepubertal subjects will be 
collected on Day 1 at pretreatment, and at 15 (±5) minutes, 30 (±5) minutes, 2 hours (±10) minutes, 4 
(±0.5) hours, and 6 (±0.5) hours and 8 (±0.5) after treatment.
Other sections impacted by change:  Synopsis, Appendix 1 Study Schedule of Events (Initial Icatibant-
treated Attack) 

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Change:  Investigator assessment of pain in children younger than 4 years of age
Section impacted by change: 7.11.3 Investigator Assessment of Pain
Change:  
Subjects who are below 4 years of age will undergo investigator assessment of HAE-related pain 
(cutaneous, abdominal, and laryngeal) using the Faces, Legs, Activity, Cry, and Consolability (FLACC) 
comportmental pain scale.  
Other sections impacted by change:  Synopsis, 3.2 Secondary Endpoints
Change:  Clarification to evaluation of injection site reactions 
Section impacted by change:  7.13.5 Local Tolerability
Change:  
Injection site reactions (erythema, swelling, burning sensation, itching/pruritis, warm sensation, cutaneous 
pain, or other) will be evaluated by the investigator or other medically qualified personnel when the 
subject is at the hospital/study center, and the diameter of any erythema or swelling will be measured.  
Other sections impacted by change:  None
Change:  Clarification to pregnancy testing
Section impacted by change:  7.13.7 Pregnancy Testing
Change:  
Female subjects of childbearing potential (ie, those who have experienced menarche) will undergo 
pregnancy testing at time points specified in the study schedule of events in Appendix 1 and Appendix 2.  
All pregnancy testing will be conducted using a urine human chorionic gonadotropin (hCG) test kit.  The 
test will be performed and interpreted by the study personnel at the hospital/study center at the time 
of the visit.
Other sections impacted by change:  None
Change:  Clarification concerning blood sample collection
Section impacted by change:  7.14 Sample Collection, Storage, and Shipping
Change:  
Use of an indwelling catheter is encouraged for collection of serial blood samples for PK assessments 
when feasible.  Use of a topical local anesthetic (such as EMLA or LMX) is acceptable to make the 
procedure more tolerable for children, provided that the timing of this application does not interfere 
with blood sample collection.  Subjects will be in a seated or supine position during blood collection.
Other sections impacted by change:  None
Change:  Clarification to adverse event recording 
Section impacted by change:  7.16 Recording of Adverse Events
Change:  
7.16 
Recording of Adverse Events
Adverse events will be collected over an observation period from the time of treatment until the 
follow-up visit 90 (±7) days after investigational product administration (or until the event has 
resolved/stabilized or an outcome is reached, whichever comes first).  Adverse event monitoring and 
the period of observation defined for this study are described in Section 7.17.4.1.  
Other sections impacted by change: 7.17.4.1 Adverse Event Monitoring and Period of Observation
Change:  Clarification to adverse event definition
Section impacted by change: 7.17.1.1 Adverse Event  
Change:  

Ic ati b a nt ( Fir az yr ® )
Cli nic al Tri al Pr ot oc ol A m e n d me nt 2 : H G T- FI R-0 8 6
0 6 M arc h 2 0 1 2
S hire
C o nfi de nti al
8 5
A n y e x acer b ati o n or w orse ni n g of s y m pt o ms of a n ac ute H A E att ac k tre ate d wit h ic ati b a nt is 
c o nsi dere d a res ult of t he u n derl yi n g dise ase a n d will n ot be c o nsi dere d a n a d verse e ve nt ( u nless 
meeti n g t he criteri a f or a
seri o us a d verse e ve nt, see Secti o n 7. 1 7. 1. 2) …
T he treate d H A E attac k is defi ne d as a n y s y m pt o ms occ urri n g i n treate d s u bjects w it hi n 4 8 h o urs of t he 
o nset of s y m pt o ms.   Cli nicall y rele va nt w orse ni n g of t he si g ns a n d s y m pt o ms of a treate d attac k is 
c o nsi d ere d t o be relate d t o t he u n derl yi n g disease of H A E a n d will be c ollecte d i n t he a p pr o pri ate C R F
se paratel y fr o m ge neral re p orts of a d verse e ve nts u nless me eti n g t he criteri a of a seri o us a d verse e ve nt .  
S y m pt o ms re occ urri n g m ore t ha n 4 8 h o urs after a n i ni tial attac k will be c o nsi dere d a ne w attac k, a n d will 
als o n ot be re p orte d as a d verse e ve nts.  Att ac ks n ot tre ate d wit h ic ati b a nt will be d oc u me nte d i n t he 
a p pr o pri ate C R F at t he D a y 9 0 visit; t he y are c o nsi dere d t o be pre e xisti n g disease a n d will n ot be 
d oc u me nte d as a d verse e ve nts.
Ot her secti o ns i m pacte d b y c ha n ge:  N o ne 
C ha n ge:  Clarificati o n t o a d verse e ve nt se verit y classificati o n
Secti o n i m pacte d b y c ha n ge:  7. 1 7. 2 Classificati o n of A d verse E ve nts a n d Seri o us A d verse E ve nts
C ha n ge:  
T he se verit y of a d verse e ve nts will be assesse d b y t he i n vesti g at or as m il d, m o der ate, or se vere b ase d 
o n t he sc ale i n T a ble 7 - 2  T he se verit y of a d verse e ve nts a n d seri o us a d verse e ve nts s h o ul d be rec or de d 
o n t he a p pr o p ri ate C R F p a ge as Gr a de 1, 2, or 3, c orres p o n di n g, res pecti vel y, t o a se verit y of m il d, 
m o der ate, or se vere. 
T a ble 7 -2 A d verse E ve nt Se verit y
Gr a de
Se verit y
Defi niti o n
Gr a de 1 
Mil d
N o li mit ati o n of us u al acti vities.
Gr a de 2 
M o der ate
S o m e li mit ati o n o f us u al acti vities.
Gr a de 3 
Se vere
I n a bilit y t o c arr y o ut us u al acti vities.
Ot her secti o ns i m pacte d b y c ha n ge:  N o ne
C ha n ge:  Clarificati o n c o ncer ni n g a d verse e ve nt c ollecti o n
Secti o n i m pacte d b y c ha n ge:  7. 1 7. 4. 1 A d verse E ve nt M o nit ori n g a n d Peri o d of O bser vati o n
C ha n ge: 
A d verse e ve nts will be m o nit ore d c o nti n u o usl y.  F or t he p ur p oses of t his st u d y, t he s afet y o bser v ati o n 
peri o d will e xte n d fr o m  t he ti me of tre at me nt of t he s u bject’s ac ute H A E att ac k u ntil t he s u bject’s 
fi n al e v al u ati o n after tre at me nt.  F or s u bjects w h o c o mplete t he st u d y, t he fi n al e v al u ati o n of a d verse 
e ve nts will occ ur at t he f oll o w -u p visit perf or m e d 9 0 ( ± 7) d a ys after tre at m e nt wit h i n vesti g ati o n al 
pr o d uct. .  
Ot her secti o ns i m pa cte d b y c ha n ge: 7. 1 6 Rec or di n g of A d verse E ve nts
C ha n ge:  A d diti o n of ne w me dical m o nit or c o ntact i nf or mati o n 
Secti o n i m pacte d b y c ha n ge:  7. 1 7. 4. 2 Re p orti n g Ser i o us A d verse E ve nts
C ha n ge:  
S hire P har mac o vi gila nce a n d Ris k Ma na ge me nt De part me nt:
F A X: 
( W orl d wi de) O R
 ( N ort h A merica)
E m ail: 
A N D
S hire H G T Me dical M o nit or: 
 M D, P h D
F A X: 
( U S A)
P P D
P P D
P P D
P P D
P P D
P P D

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•
Safety follow-up contact (Day 2 (24 (±4) hours), Day 3 (48 (±4) hours)) either by telephone or in 
person at the investigator’s discretion
•
Menstrual cycle history (Day 8 (± 1 day)) (in pubertal/postpubertal females)
It is indicated in the list of study activities that the windows allowed for collection of PK samples 
should also be applied to collection of other assessments being performed at those time points. 
It is further stated that a subject may be discharged after completion of all assessments at 6 hours 
post treatment, if deemed medically stable in the investigator’s clinical judgment and the subject’s 
HAE symptoms have resolved (the subject’s investigator-rated symptom score = zero, denoting the 
absence of symptoms).  If this is the case, the assessments (*) scheduled for 8 hours post treatment will 
be omitted with the exception of subject self-assessment of HAE-related pain using the e-diary FPS-R. 
If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s 
investigator-rated symptom score ≠ zero) and the subject is not to be discharged after completion of 
assessments at the 6-hour time point, the assessments indicated (**) will be performed at both 6 AND 
8 hours post treatment.
If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s 
investigator-rated symptom score ≠ zero) and the subject is not to be discharged after completion of 
assessments at the 6-hour time point, the assessments indicated (***) will be performed at either 6 OR 
8 hours post treatment.
8.3.2
Follow-up Visit (Day 90 ±7 days)
•
Tanner staging (for those subjects classified as Tanner stage IV or below at baseline)
•
Urine pregnancy test (in females of childbearing potential)
•
Menstrual cycle history (in pubertal/postpubertal females)
•
Documentation of HAE attack(s) not treated with icatibant
8.3.3
Telephone Contact (Month 6 ±7 days) .
The scheduled telephone contact will document pubertal changes/milestones, if any.
•
Pubarche
•
Menarche (females only)
•
Changes in menstrual cycle (females only)
•
Pregnancy (females and male partner)
8.4 Subsequent Attacks (Pubertal/postpubertal Subjects Only)
8.4.1
Treatment Period (Day 1 to Day 8 [±1 day])
•
Clinical laboratory tests (Day 1, 8 6 (±0.5) hours post dose and Day 8 (±1 day))
•
Reproductive hormone assessments (Day 1, 8 6 (±0.5) hours post dose and Day 8 (±1 day))
•
Safety follow-up contact (Day 2 (24 (±4) hours], Day 3 (48 (±4) hours)) either by telephone or in 
person at the investigator’s discretion
•
Menstrual cycle history (Day 8 (± 1 day)) (in pubertal/postpubertal females)
It is indicated in the list of study activities that the windows allowed for collection of PK samples 
should also be applied to collection of other assessments being performed at those time points. 
It is further stated that a subject may be discharged after completion of all assessments at 6 hours 
post treatment, if deemed medically stable in the investigator’s clinical judgment and the subject’s 
HAE symptoms have resolved (the subject’s investigator-rated symptom score = zero, denoting the 
absence of symptoms).  If this is the case, the assessments (*) scheduled for 8 hours post treatment will 
be omitted with the exception of subject self-assessment of HAE-related pain using the e-diary FPS-R. 
If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s 
investigator-rated symptom score ≠ zero) and the subject is not to be discharged after completion of 
assessments at the 6-hour time point, the assessments indicated (**) will be performed at both 6 AND 
8 hours post treatment.
If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s 
investigator-rated symptom score ≠ zero) and the subject is not to be discharged after completion of 
assessments at the 6-hour time point, the assessments indicated (***) will be performed at either 6 OR 
8 hours post treatment.

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8.4.2
Follow-up Visit (Day 90 ±7 days)
•
Tanner staging (for those subjects classified as Tanner stage IV or below at baseline)
•
Urine pregnancy test (in females of childbearing potential)
•
Menstrual cycle history (in pubertal/postpubertal females)
•
Documentation of HAE attack(s) not treated with icatibant
8.4.3
Telephone Contact (Month 6 ±7 days) 
The scheduled telephone contact will document pubertal changes/milestones, if any.
•
Pubarche
•
Menarche (females only)
•
Changes in menstrual cycle (females only)
•
Pregnancy (females and male partner)
Other sections impacted by change:  4.1.2 Study Assessments, Appendix 1 Study Schedule of Events (Initial 
Icatibant-treated Attack), Appendix 2 Study Schedule of Events (Subsequent Icatibant-treated Attacks)  
Change:  Clarification to efficacy analysis
Section impacted by change:  10.7 Efficacy Analysis
Change:  
The investigator will report symptom scores at pretreatment and 1, 2, 4, and 6 hours and 8 hours post 
treatment, and at 8 hours post treatment for subjects who had not shown complete resolution of HAE 
symptoms at 6 hours.  
Other sections impacted by change:  None
Change:  Clarification concerning DSMB role
Section impacted by change: 10.9 Data Monitoring and Interim Analysis
Change:  
An analysis of the data for DSMB review is planned after the first 4 subjects in the pubertal/postpubertal 
group have been treated, and is planned to follow quarterly enrollment milestones (ie, 25%, 50%, and 
75%) thereafter.  
Other sections impacted by change:  None
Change:  Clarification concerning curricula vitae
Section impacted by change:  11.7.1 Critical Documents
Change:  
•
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed within 12 24 months of 
study initiation).
Other sections impacted by change:  None
Change:  Clarification concerning waivers
Section impacted by change: 11.9Protocol Violations/Deviations
Change:  
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.  No protocol waivers or exemptions will be 
considered by the sponsor during the study.
Other sections impacted by change:  None

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Change:  Clarification to female pubic hair stage
Section impacted by change:  Appendix 3 Modified Sexual Maturation Scale
Change:  
Sparse growth of long, slightly pigmented downy hair, straight or only slightly curled, appearing chiefly 
along the labia on the pubis.  Do not consider hair on the labia.
a
Pubic hair development reflects adrenal function, not hypothalamic/gonadal function.  The 
descriptions used in this table are intended to provide guidance for the investigators and may not 
align with descriptions of pubic hair and pubertal stage in other sources.
Other sections impacted by change:  None