Clinical trial NCT01386658
Conditions: Hereditary Angioedema (HAE)
Keywords: Efficacy Hereditary angioedema HAE Pediatric Children Pharmacokinetics Safety Firazyr icatibant
Sponsor: Shire
Start date: 2012-01-27; Completion date: 2018-03-12
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
HGT-FIR-086 is a multicenter, open-label, non-randomized, single-arm study to evaluate the Pharmacokinetics, tolerability,safety, and efficacy on reproductive hormones, of a single subcutaneous (SC) administration of icatibant in approximately 30 pediatric subjects with Hereditary Angioedema (HAE) during an initial acute attack.

Detailed description:
Study HGT-FIR-086 will enroll 30 subjects from 2 to less than 18 years of age, divided into 2 groups: prepubertal and pubertal/postpubertal. At least 10 prepubertal children and at least 20 adolescents (including 10 treated during a HAE attack) must be enrolled in the study.

After a qualifying screening period, the PK, safety/tolerability, and efficacy of treatment with SC icatibant will be evaluated in at least 20 subjects (10 prepubertal and 10 pubertal/postpubertal subjects) who present with cutaneous, abdominal, or laryngeal symptoms of an acute attack of HAE. The PK and safety/tolerability of SC icatibant will be evaluated in at least 10 additional pubertal/postpubertal subjects who meet screening criteria and receive treatment with SC icatibant in the absence of a current acute HAE attack.

The planned duration of active participation for subjects who present with an initial attack of acute HAE will consist of treatment with a single subcutaneous injection of icatibant on Day 1 through follow up at day 90.

After having received initial treatment with icatibant, either during or in the absence of an attack, at least 10 pubertal/postpubertal subjects who subsequently experience an acute HAE attack may continue to receive treatment with icatibant as a single SC administration per attack for a total of 3 eligible icatibant-treated attacks.

The period of active participation in the study for prepubertal subjects will be approximately 90 days, while that for pubertal/postpubertal subjects could be a maximum of approximately 270 or 360 days (3 separate active periods of approximately 90 days for those treated with icatibant during an attack; 4 separate active periods for those treated without an attack), with each active period separated by periods of inactive participation of variable duration.

Arms: arm 1: Single dose of icatibant 0.4 mg/kg subcutaneous(SC) up to a maximal dose of 30 mg
Interventions: intervention 1: icatibant
Intervention descriptions: intervention 1: Single dose of icatibant 0.4 mg/kg subcutaneous(SC) up to a maximal dose of 30 mg

Protocol documents:
Prot_003.pdf: 
Cli nic al Tr i al Prot oc ol:  H G T- FI R-0 8 6
St u d y Title:
A M ultice nter, O pe n -La bel, N o n -Ra n d o mize d St u d y  t o Assess t he 
P har mac o ki netics, T olera bilit y , a n d Safety of a Si n gle S u bc uta ne o us 
A d mi nistrati o n of Icati ba nt i n C hil dre n a n d A d olesce nts wit h 
Here ditar y  A n gi oe de ma
St u d y N u m ber:
H G T -FI R- 0 8 6
St u d y P h ase:
III
Pr o d uct N a me:
Icati ba nt ( Firazyr ® )
I n dic ati o n:
Here ditar y  a n gi oe de ma
I n vesti g at ors:
M ultice nter
S p o ns or:
S hire Or p ha n T hera pies, I nc.
S p o ns or C o nt act:
3 0 0 S hire Wa y  
Le xi n gt o n, M A  0 2 4 2 1 U S A
Me dic al M o nit or:
 M D, P h D
S hire H u ma n Ge netic T hera pies ( H G T), I nc.
M o bile:  
 
Date
Ori gi n al Pr ot oc ol:
1 4 J u ne 2 0 1 1
A m e n d me nt 1
0 5 A u g ust 2 0 1 1
A m e n d me nt 2
0 6 Marc h 2 0 1 2
A m e n d me nt 3
1 9 J u ne 2 0 1 3 
C o nfi de nti alit y St ate me nt
T his d oc u me nt is t he pr o prietar y  a n d c o nfi de ntial pr o perty of 
S hire H u ma n Ge netic T hera pies, I nc.  
P P D
P P D
P P D


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


























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


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


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




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


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


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


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


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


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


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


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


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


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


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


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


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

Prot_002.pdf: 
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 
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Here ditar y  A n gi oe de ma
St u d y N u m ber:
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Icati ba nt ( Firazyr ® )
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M ultice nter
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S hire Or p ha n T hera pies , I nc.
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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.


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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.


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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.


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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 


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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 


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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


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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 
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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 
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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 
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.
8.4.2
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

Prot_004.pdf: 
Cli nic al Tr i al Prot oc ol:  H G T- FI R-0 8 6
St u d y Title:
A M ultice nter, O pe n -la bel, N o n -ra n d o mize d St u d y t o Assess t he 
P har mac o ki netics, T olera bilit y , a n d Safety of a Si n gle S u bc uta ne o us 
A d mi nistrati o n of Icati ba nt i n C hil dre n a n d A d olesce nts wit h 
Here ditar y  A n gi oe de ma
St u d y N u m ber:
H G T -FI R- 0 8 6
St u d y P h ase:
III
Pr o d uct N a me:
Icati ba nt (F I R A Z Y R®)
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 L L C
S p o ns or C o nt act:
3 0 0 S hire Wa y  
Le xi n gt o n, M A  0 2 4 2 1 U S A
Me dic al M o nit or:
, M D, M P H
M o bile: 
 
Date
Ori gi n al Pr ot oc ol:
1 4 J u ne 2 0 1 1
A m e n d me nt 1
0 5 A u g ust 2 0 1 1
A m e n d me nt 2
0 6 Marc h 2 0 1 2
A m e n d me nt 3
1 9 J u ne 2 0 1 3 
A m e n d me nt 4
1 8 Marc h 2 0 1 6
C o nfi de nti alit y St ate me nt
T h is d oc u me nt is t he pr o prietar y a n d c o nfi de ntial pr o perty of 
S hire Or p ha n T hera pies L L C.  
P P D
P P D
P P D


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


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adverse events, vital signs, electrocardiogram (ECG) recordings, physical 
examination, clinical laboratory parameters (serum chemistry [including liver 
function tests], hematology, urinalysis), reproductive hormone levels, and 
immunogenicity (anti-icatibant antibodies).
Secondary endpoints (only for subjects treated with icatibant during a HAE attack):

Time to onset of relief of symptoms and time to minimal symptoms, as measured 
by investigator- and subject-reported outcomes.
o
For subjects 2 to less than 18 years of age: investigator assessment and scoring 
of cutaneous, abdominal, and laryngeal symptoms of acute HAE attacks by an 
investigator-rated symptom score.
o
For subjects 4 years of age and older: subject self-assessment of HAE related 
pain using the Faces Pain Scale-Revised (FPS-R).
o
For subjects less than 4 years of age: investigator assessment of HAE-related 
pain (cutaneous, abdominal, and laryngeal) using a validated pain scale (Faces, 
Legs, Activity, Cry, and Consolability [FLACC].

Incidence of rescue medication use.

Proportion of subjects with worsened intensity of clinical HAE symptoms between 
2 and 4 hours after treatment with icatibant.
Study Design:
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, 
and safety, including effect on reproductive hormones, of a single SC administration of 
icatibant in pediatric subjects with HAE.
The study will enroll children and adolescents from 2 to less than 18 years of age, divided 
into 2 groups: prepubertal (Tanner stage I) and pubertal/postpubertal (Tanner stages II to 
V). 
At least 10 prepubertal children and at least 20 adolescents (including 10 treated during a 
HAE attack) must be enrolled in the study.
Study Methodology:
A subject’s classification as prepubertal or pubertal/postpubertal will be determined at 
screening and, if classified as prepubertal at screening will have their pubertal status 
reassessed at the time of their first icatibant-treated 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 with icatibant (whether during or in the absence of attack), PK, 
safety/tolerability, and efficacy (as appropriate) will be reviewed by an independent Data 
and Safety Monitoring Board (DSMB).  The DSMB review of the first 4 subjects shall be 
completed prior to continuing enrollment of additional pubertal/postpubertal subjects, 
treatment of second and third HAE attacks in pubertal/postpubertal subjects, and initiating 
enrollment of subjects in the prepubertal group.


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Initial Icatibant Treatment
After a qualifying screening period, the PK, safety/tolerability, and efficacy of treatment 
with SC icatibant will be evaluated in at least 20 subjects (10 prepubertal and 10 
pubertal/postpubertal subjects) who present with cutaneous, abdominal, or laryngeal 
symptoms of an acute attack of HAE.  Subjects should initiate treatment with icatibant 
within 12 hours of the onset of symptoms; however, there are no prespecified attack 
severity criteria that are required for treatment.  Subjects with attacks considered to be 
mild, moderate, or severe are all potentially eligible to receive treatment with icatibant.  
The PK and safety/tolerability of SC icatibant will be evaluated in at least 10 additional 
pubertal/postpubertal subjects who meet screening criteria, but receive treatment with SC 
icatibant in the absence of a current acute HAE attack.
Subjects will receive treatment with a single SC administration of icatibant on Day 1 and 
will be monitored closely in the hospital/study center for at least 6 to 8 hours after 
treatment.  Subjects will undergo PK and safety assessments; efficacy assessments will be 
performed if treatment occurs during an acute HAE attack.  All subjects will have serum 
reproductive hormone measurements.  
A subject may be discharged after completion of assessments at 6 hours post treatment, if 
deemed medically stable in the investigator’s clinical judgment and, if applicable, the 
subject’s HAE symptoms have resolved (the subject’s investigator-rated symptom score 
must be zero, denoting the absence of symptoms).  If HAE symptoms have not completely 
resolved at 6 hours (ie, the investigator-rated symptom score is >0), the subject shall 
remain in the hospital/study center for at least 8 hours after icatibant administration for 
further evaluation.
Telephone follow-up will occur at both 24 and 48 hours after treatment.  
Subjects will return to the hospital/study center for scheduled assessments on Day 8 and 
for a follow-up visit on Day 90.  
The investigator will schedule a telephone contact approximately 6 months after Day 1 of 
initial icatibant-treatment to obtain specific updates concerning pubertal 
changes/milestones.
Subsequent Icatibant-treated Attack
After having received initial treatment with icatibant, either during or in the absence of an 
attack, at least 10 pubertal/postpubertal subjects who subsequently experience an acute 
HAE attack may continue to receive treatment with icatibant as a single SC administration 
per attack for a total of 3 icatibant treatments.  Further treatment with icatibant is 
contingent upon presentation of an acute cutaneous, abdominal, or laryngeal attack of 
HAE at least 3 days after prior treatment.  
For subsequent attacks, study drug may be administered by study site personnel at the 
hospital/study center or by qualified home healthcare personnel at the subject’s home.  
Alternatively, a parent/legal guardian/caregiver will be allowed to administer or the 
subject (under the supervision of a parent/legal guardian/caregiver) will be allowed to 
self-administer the investigational product after having received appropriate training.  For 
all subsequent laryngeal attacks, subjects should be advised to seek medical attention in an 


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appropriate healthcare facility immediately following treatment with icatibant.  
Except for PK determinations, all primary and secondary endpoints as above will be 
measured in these pubertal/postpubertal subjects after each administration. Note that for 
some of the pubertal/postpubertal subjects who receive further treatment, ie, those who 
provided PK and safety/tolerability measurements without an attack, their first icatibant-
treated attack will represent their second on-study exposure to icatibant for safety analysis 
purposes.
In addition, for all subjects who remain enrolled in the study, a safety telephone contact 
will be scheduled every month to collect information concerning AEs, weight, eligibility, 
and HAE attacks not treated within the study.  
Study Population: 
The study will enroll a sufficient number of children and adolescents with HAE to ensure 
study completion of 30 subjects.  The study population to provide efficacy, PK, and 
safety/tolerability measurements will consist of at least 20 subjects from 2 to less than 
18 years of age at least 10 of whom are prepubertal and at least 10 of whom are 
pubertal/postpubertal at the time of their first icatibant-treated acute cutaneous, 
abdominal, or laryngeal attack of HAE.  An additional 10 subjects who are 
pubertal/postpubertal at the time of enrollment, but who are not experiencing a current 
HAE attack, will provide PK and safety/tolerability measurements only.
Study Inclusion and Exclusion Criteria:
Subjects must meet all of the following criteria to be considered eligible for enrollment:
1. Two to <18 years of age (ie, from the second birthday through the day prior to the 
eighteenth birthday) at the time of enrollment and treatment with icatibant.
-
Prepubertal and pubertal/postpubertal subjects experiencing an acute cutaneous, 
abdominal, or laryngeal HAE attack treated with icatibant as part of this study. 
-
Pubertal/postpubertal subjects with HAE who are treated with icatibant as part of 
this study, but not during an attack. 
2. Documented diagnosis of HAE type I or II.  Diagnosis may be on the basis of 
historical data: family history, characteristic attack manifestations, recurrent attacks, 
historical C1-INH deficiency, and exclusion of other forms of angioedema.  Inclusion 
will be permitted initially based on medical history only if a clear diagnosis has been 
made based on all of the preceding criteria.  However, the diagnosis must be 
confirmed prior to treatment by documented immunogenic and/or functional C1-INH 
deficiency (C1-INH protein level below the lower limit of normal and/or functional 
level <50% of normal) as performed by the Sponsor’s central laboratory.
3. Informed consent (and subject assent as appropriate) signed by the subject’s parent(s) 
or legal guardian(s).
Subjects who meet any of the following criteria will be excluded from the study:
1. Diagnosis of angioedema other than HAE.
2. Participation in another clinical trial that involves use of any investigational product 
(drug or device) within 30 days prior to study enrollment or at any time during the 
study. 


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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:
At minimum, the duration of a subject’s active participation in the study will consist of 
single day dosing with 90-day follow-up.  
Once eligibility is established at screening, the subject will be enrolled into the study but 
will enter a period of inactive participation of variable duration until such time as the 
subject experiences an acute attack of HAE and is offered treatment.  For those 
pubertal/postpubertal subjects who will be treated without an attack, eligibility will be 
established at screening and the subject will be immediately enrolled and treated with 
icatibant.  At the time of enrollment, the subject will enter a 90-day period of active 
participation which will consist of treatment with a single SC administration of icatibant 
on Day 1 through follow-up at Day 90.  
After receiving the first treatment with icatibant with or without an attack (N=20), at least 
10 pubertal/postpubertal subjects who present with subsequent attacks of acute HAE will 
continue to receive treatment with icatibant for a total of 3 icatibant administrations each.  
Thus, the period of active participation in the study for prepubertal subjects will be 
approximately 90 days, while that for pubertal/postpubertal subjects could be a maximum 
of approximately 270 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 initial 
icatibant-treated attack.
Once the tenth prepubertal subject and the twentieth pubertal/postpubertal subject have 
completed the 6-month follow-up after the initial treatment, and the tenth 
pubertal/postpubertal subject has completed the Day 90 follow-up after his or her third 
and final treatment for an attack, the study will be closed. 
Pharmacokinetic Variables:
Individual patient PK variables for icatibant and major metabolites will be determined 
from the respective plasma concentration time profiles where appropriate, using 
noncompartmental methods. 
A population PK model will be derived to evaluate the correlation of key covariates (ie 
age, body weight, gender) on the pharmacokinetic profile of icatibant.
Primary and secondary pharmacokinetic parameter estimates will be reported and include 


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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, qualified home healthcare personnel, or 
parent/legal guardian/caregiver will assess and score symptoms of acute cutaneous, 
abdominal, and laryngeal attacks of HAE for all subjects using a 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, qualified home healthcare personnel, or 
parent/legal guardian/caregiver will be recorded for all subjects.
(Efficacy assessments will not be performed for those pubertal/postpubertal subjects 
treated with icatibant in the absence of an HAE attack).
Statistical Methods: 
Summary statistics for continuous variables will include the number of subjects, the mean, 
median, standard deviation, and range.  For PK parameters, the coefficient of variation 
and geometric mean also will be provided.  
For categorical data, summaries will include counts and percentages.  For time-to-event 
data, the median time to event and other summary statistics will be estimated using 
Kaplan-Meier methodology.
The following populations will be used in the analysis:

The Efficacy Population will consist of those subjects who were treated with 
icatibant for their first and any additional attacks.

The PK Population will consist of those subjects who were treated with icatibant 
and had sufficient icatibant plasma concentration time measurements to derive 
primary PK parameters. 

The Safety Population will consist of those subjects who were treated with 
icatibant at least once.
Subject disposition, demographic and baseline characteristics, and medical history will be 


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summarized separately for the Efficacy Population and the Safety Population.  
Efficacy analyses will be based on the Efficacy Population.  Efficacy endpoints, including 
change from baseline when appropriate, will be summarized descriptively.  The primary 
efficacy endpoint is the time to onset of symptom relief measured using the investigator-
rated symptom score.  The time to onset of symptom relief is defined as the earliest time 
post treatment at which there is a 20% improvement in the average post-treatment 
symptom score with no worsening of any single component score. 
Plasma concentrations of icatibant by time point and the PK parameters will be 
summarized descriptively.
Safety and tolerability analyses will be based on the Safety Population.  The assessment of 
safety will be based mainly on the frequency of treatment-emergent 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)
Version 16.0.  Adverse events also will be tabulated by severity and relationship to 
treatment.
Local tolerability will include symptoms at the injection site and will be assessed 
separately from general reports of adverse events.  Local tolerability will be tabulated and 
summarized according to the type and severity of the injection site reaction.
The change from baseline in the secretion of reproductive hormones and the change from 
baseline in HAE symptoms (as reported by the investigator or subject) will be summarized 
descriptively.
Date of Amended Protocol: 18 March 2016


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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................2
TABLE OF CONTENTS...........................................................................................................9
LIST OF IN-TEXT TABLES ..................................................................................................13
LIST OF APPENDICES..........................................................................................................13
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................14
1
INTRODUCTION..........................................................................................................16
1.1
Disease Background...............................................................................................16
1.2
Previous Clinical Studies.......................................................................................17
1.2.1
Pharmacokinetics of Icatibant......................................................................17
1.2.2
Overview of the Safety and Efficacy of Subcutaneous Icatibant in Clinical 
Studies..........................................................................................................18
1.2.3
Investigations of Potential Effects of Bradykinin Inhibition on 
Reproductive Function.................................................................................19
1.3
Rationale for Dose Selection .................................................................................20
2
STUDY OBJECTIVES....................................................................................................22
2.1
Objectives ..............................................................................................................22
2.2
Other Objectives ....................................................................................................22
3
STUDY ENDPOINTS.....................................................................................................23
3.1
Primary Endpoints .................................................................................................23
3.2
Secondary Endpoints .............................................................................................23
4
INVESTIGATIONAL PLAN..........................................................................................24
4.1
Overall Study Design and Plan..............................................................................24
4.1.1
Study Design................................................................................................24
4.1.2
Study Methodology......................................................................................24
4.1.3
Study Assessments.......................................................................................26
4.1.3.1
Initial Treatment.................................................................................27
4.1.3.2
Subsequent Icatibant-Treated Attacks ...............................................28
4.2
Rationale for Study Design....................................................................................29
4.3
Study Duration.......................................................................................................29
5
STUDY POPULATION SELECTION ...........................................................................31
5.1
Study Population....................................................................................................31
5.2
Inclusion Criteria ...................................................................................................31
5.3
Exclusion Criteria ..................................................................................................31
6
STUDY TREATMENT...................................................................................................32
6.1
Description of Treatment .......................................................................................32
6.1.1
Investigational Product ................................................................................32
6.1.2
Comparator ..................................................................................................32


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6.2
Treatment Administered ........................................................................................32
6.3
Selection and Timing of Dose for Each Subject....................................................32
6.4
Method of Assigning Subjects to Treatment Groups.............................................33
6.5
Blinding..................................................................................................................33
6.6
Concomitant Medication Usage.............................................................................33
6.7
Rescue Therapy......................................................................................................33
6.8
Restrictions ............................................................................................................34
6.8.1
Fluid and Food Intake..................................................................................34
6.8.2
Subject Activity Restrictions .......................................................................34
6.9
Treatment Compliance...........................................................................................35
6.10
Packaging and Labeling.........................................................................................35
6.11
Storage and Accountability....................................................................................35
6.12
Investigational Product Retention at Study Site ....................................................36
7
STUDY PROCEDURES .................................................................................................37
7.1
Informed Consent...................................................................................................37
7.2
Study Entrance Criteria..........................................................................................37
7.3
Confirmation of Study Eligibility..........................................................................37
7.4
Demographics ........................................................................................................37
7.5
Medical History .....................................................................................................37
7.6
Menstrual Cycle History........................................................................................38
7.7
Height and Weight .................................................................................................38
7.8
Pubertal Status Determination ...............................................................................38
7.9
Investigational Product Administration.................................................................38
7.10
Pharmacokinetic Assessments ...............................................................................39
7.10.1
Pharmacokinetic Variables ..........................................................................39
7.10.2
Pharmacokinetic Sampling ..........................................................................39
7.10.3
Bioanalytical Method...................................................................................40
7.11
Efficacy Assessments.............................................................................................40
7.11.1
Symptom Score............................................................................................40
7.11.1.1
Investigator Symptom Score..............................................................40
7.11.1.2
Home Healthcare Provider or Parent/Legal Guardian/Caregiver 
Symptom Score..................................................................................40
7.11.2
Subject Self-assessment of Pain ..................................................................41
7.11.3
Investigator Assessment of Pain..................................................................41
7.11.4
Initial Symptom Relief.................................................................................41
7.11.4.1
Investigator-assessed Initial Symptom Relief....................................41
7.11.4.2
Home Healthcare Provider and Parent/Legal Guardian/Caregiver 
Initial Symptom Relief.......................................................................41
7.12
Reproductive Hormone Assessments ....................................................................41


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7.13
Safety Assessments................................................................................................41
7.13.1
Physical Examination ..................................................................................41
7.13.2
Vital Signs....................................................................................................42
7.13.3
Electrocardiography.....................................................................................42
7.13.4
Clinical Laboratory Tests.............................................................................42
7.13.5
Local Tolerability ........................................................................................43
7.13.6
Immunogenicity...........................................................................................43
7.13.7
Pregnancy Testing........................................................................................43
7.14
Sample Collection, Storage, and Shipping ............................................................43
7.15
Recording of Concomitant Medications................................................................43
7.16
Recording of Adverse Events ................................................................................44
7.17
Adverse Events Assessments.................................................................................44
7.17.1
Definitions of Adverse Events and Serious Adverse Events.......................44
7.17.1.1
Adverse Event....................................................................................44
7.17.1.2
Serious Adverse Event.......................................................................45
7.17.2
Classification of Adverse Events and Serious Adverse Events...................45
7.17.2.1
Clarification between Serious and Severe .........................................46
7.17.3
Relatedness of Adverse Events and Serious Adverse Events......................46
7.17.4
Procedures for Recording and Reporting Adverse Events ..........................47
7.17.4.1
Adverse Event Monitoring and Period of Observation......................47
7.17.4.2
Reporting Serious Adverse Events ....................................................47
7.18
Pregnancy...............................................................................................................48
7.19
Abuse, Overdose, and Medication Error................................................................48
7.20
Removal of Subjects from the Trial or Investigational Product ............................49
7.20.1
Safety-Related Study Stopping Rules..........................................................49
7.21
Appropriateness of Measurements.........................................................................49
8
STUDY ACTIVITIES .....................................................................................................52
8.1
Screening (Day of Informed Consent to Pretreatment on Day 1)..........................52
8.2
No Attack...............................................................................................................52
8.2.1
Pretreatment (Baseline) Assessments (Day 1).............................................52
8.2.2
Treatment Period (Day 1 to Day 8 [± 1 Day]).............................................53
8.3
Initial Icatibant-treated Attack...............................................................................53
8.3.1
Pretreatment (Baseline) Assessments (Day 1).............................................53
8.3.2
Treatment Period (Day 1 to Day 8 [± 1 Day]).............................................54
8.3.3
Follow-up Visit (Day 90 ±7 days) ...............................................................55
8.3.4
Telephone Contact (Month 6 ±7 days) ........................................................55
8.4
Subsequent Icatibant-treated Attacks (Pubertal/Postpubertal Subjects Only).......56
8.4.1
Subsequent Icatibant-treated Attack Baseline Assessments........................56


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8.4.2
Treatment Period (Day 1 to Day 8 [± 1 Day]).............................................57
8.4.2.1
Day of Subsequent Attack (Day 1) ....................................................57
8.4.2.2
Day 2(24 [± 4] hours).........................................................................59
8.4.3
Follow-up Visits ..........................................................................................59
8.4.3.1
Day 8 (±1 day) ...................................................................................59
8.4.3.2
Day 90 (±7 days)................................................................................59
9
QUALITY CONTROL AND ASSURANCE .................................................................61
10
PLANNED STATISTICAL METHODS ........................................................................62
10.1
General Considerations..........................................................................................62
10.2
Determination of Sample Size ...............................................................................62
10.3
Analysis Populations..............................................................................................62
10.4
Demographics and Baseline Characteristics..........................................................63
10.5
Pharmacokinetic Analysis......................................................................................63
10.5.1
Estimation of PK Parameters.......................................................................63
10.5.1.1
Noncompartmental Modeling ............................................................63
10.5.1.2
Compartmental Modeling Using Population Methods ......................64
10.6
Safety and Tolerability Analyses...........................................................................64
10.7
Efficacy Analyses ..................................................................................................65
10.8
Other Analyses.......................................................................................................66
10.9
Data Monitoring and Interim Analysis ..................................................................66
10.10 Handling of Missing Data......................................................................................66
11
ADMINISTRATIVE CONSIDERATIONS....................................................................67
11.1
Investigators and Study Administrative Structure.................................................67
11.2
Institutional Review Board or Independent Ethics Committee Approval .............67
11.3
Ethical Conduct of the Study.................................................................................67
11.4
Subject Information and Consent/Assent...............................................................67
11.5
Subject Confidentiality ..........................................................................................68
11.6
Study Monitoring...................................................................................................69
11.7
Case Report Forms and Study Records .................................................................69
11.7.1
Critical Documents ......................................................................................69
11.8
Data and Safety Monitoring Board........................................................................70
11.9
Protocol Violations/Deviations..............................................................................70
11.10 Premature Closure of the Study.............................................................................71
11.11 Access to Source Documentation ..........................................................................71
11.12 Data Generation and Analysis ...............................................................................71
11.13 Retention of Data...................................................................................................71
11.14 Financial Disclosure...............................................................................................72
11.15 Publication and Disclosure Policy .........................................................................72


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12
LIST OF REFERENCES.................................................................................................73
LIST OF IN-TEXT TABLES
Table 4-1
Study Periods..............................................................................................26
Table 7-1
List of Clinical Laboratory Tests................................................................42
Table 7-2
Adverse Event Severity..............................................................................46
Table 7-3
Adverse Event Relatedness ........................................................................46
LIST OF APPENDICES
Appendix 1
Study Schedule of Events (No Attack).......................................................74
Appendix 2
Study Schedule of Events (Initial Icatibant-treated Attack).......................78
Appendix 3
Study Schedule of Events (Subsequent Icatibant-treated Attacks) ............83
Appendix 4
Modified Sexual Maturation Scale.............................................................85
Appendix 5
Faces Pain Scale-Revised (FPS-R).............................................................86
Appendix 6
Faces, Legs, Activity, Cry, and Consolability Scale (FLACC) .................87
Appendix 7
Protocol Signature Page .............................................................................88
Appendix 8
Summary of Changes for Amendment 4....................................................89


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ACE
angiotensin converting enzyme
AE
adverse event
AUC
area under the curve
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
EMA
European Medicines Agency
FDA
Food and Drug Administration
FFP
fresh frozen plasma
FLACC
Faces, Legs, Activity, Cry, and Consolability
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
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
IV
intravenous(ly)


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Abbreviation
Definition
kg
kilogram(s)
LBW
lean body weight
LC-MS
liquid chromatography/tandem mass spectrometry
LH
luteinizing hormone
LOCF
last observation carried forward
LOQ
limit of quantification
MedDRA
Medical Dictionary for Regulatory Activity 
mg
milligram(s)
mL
milliliter(s)
mm
millimeters
MRT
mean residual time
ng
nanogram(s)
NSAID
non-steroidal anti-inflammatory drug
PD
pharmacodynamic
PK
pharmacokinetic(s)
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System®
SBS
solid bleached sulfate
SC
subcutaneous(ly)
SHBG
sex hormone binding globulin
SOC
system organ class
t1/2
terminal elimination half-life
TBW
total body weight
Tmax
time to maximum concentration
TOSR
time to onset of symptom relief
US(A)
United States (of America)
VAS
visual analog scale
Vss
volume of distribution at steady state
WHO-DD
World Health Organization Drug Dictionary


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1
INTRODUCTION
1.1
Disease Background
Bradykinin is responsible for the clinical symptoms of hereditary angioedema (HAE), causing 
increased vascular permeability, vasodilation, and contraction of visceral smooth muscle.  HAE 
is a rare autosomal dominant disorder characterized clinically by recurrent and self-limiting 
attacks of edema of the skin, gastrointestinal tract, and larynx.  Its prevalence is estimated at 
1:10,000 to 1:50,000 (Bowen et al. 2008).
HAE is caused by either a quantitative (Type I) or qualitative (Type II) deficiency of C1 
inhibitor.  C1 inhibitor functions in several biochemical pathways, including inhibition of C1 
complement auto-activation, inactivation of coagulation factors XIIa, XIIf, XIa, and inhibition of 
activated kallikrein.  After a triggering event, the deficiency in C1 inhibitor results in accelerated 
release of bradykinin by its cleavage from high molecular weight kininogen by activated 
kallikrein.  Bradykinin is the principal mediator of the increased vascular permeability 
characteristic of HAE.  
Icatibant is a synthetic decapeptide with a structure similar to bradykinin that acts as an 
antagonist of the bradykinin B2 receptor (Davis 2008; Knolle et al. 1992). 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 (Hock et al. 
1991; Wirth et al. 1991). Inhibition of bradykinin action through use of a B2 receptor antagonist 
is a therapeutic strategy for treatment of clinical symptoms of HAE, and represents the rationale 
for use of icatibant in treatment of acute attacks of angioedema in HAE patients.  In adults, SC 
icatibant 30 mg has been shown to produce a rapid and durable response in the treatment of 
cutaneous, abdominal, and laryngeal attacks of acute HAE.  A single SC injection is generally 
sufficient for rapid relief of symptoms of acute HAE attacks irrespective of edema location.  
Repeated use of icatibant over time for treatment of multiple acute HAE attacks in adults 
produces a consistent response at each attack, with no diminution of efficacy.  When self-
administered by adults experiencing an acute HAE attack, icatibant also produces a rapid and 
safe treatment response.
The management of HAE in pediatric patients is complex.  The age at onset, the frequency and 
duration of symptoms, as well as the severity of attacks all exhibit substantial inter-individual 
variation.  Although acute episodes of HAE may occur at any age, the median age at first 
symptomatic HAE attack is estimated to range between 4 to 11 years (reviewed by Farkas 2010).   
Subcutaneous edema of the extremities, face, neck, torso, and genitals is the most common, and 
usually the earliest, manifestation of HAE seen in children.  In the gastrointestinal tract, 
submucosal edema may be associated with colicky abdominal pain, nausea, vomiting, and 
diarrhea.  In a large pediatric cohort, increased frequency and severity of HAE symptoms were 
reported at between 3 and 6 years of age and at around puberty, and were attributed to 
physiological changes which occur during these periods of development (Farkas 2010).  
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 


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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
(Farkas 2010). Treatment options for children with HAE according to current guidelines include 
antifibrinolytics, attenuated androgens, and C1 esterase inhibitor (human) (C1-INH) replacement 
therapy.  Current guidelines favor antifibrinolytics for long-term prophylaxis because of their 
safety profile relative to attenuated androgens.  The preferred antifibrinolytic 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 observed plasma concentration (Cmax) of 974 ± 280 
ng/mL was observed after approximately 0.75 hours.  The mean area under the concentration-
time curve (AUC0-∞) after a single 30 mg dose was 2165 ± 568 ng•hr/mL, with no evidence of 
accumulation of icatibant after three 30 mg doses administered 6 hours apart.  
Plasma clearance after SC administration of icatibant was 245 ± 58 mL/min with a mean 
elimination half-life of 1.4 ± 0.4 hours and volume of distribution at steady state (Vss) of 
29.0 ± 8.7 L.  The information obtained from Phase III clinical studies clearly demonstrated that 
SC icatibant 30 mg is a clinically safe and effective treatment for attacks of acute angioedema 
across a wide range of subject demographics, including age, sex, and body weight. 
Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are 
primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug.  
Icatibant is not degraded by oxidative metabolic pathways, and is not an inhibitor of major 
cytochrome P450 (CYP) isoenzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 
3A4) and is not an inducer of CYP 1A2 and 3A4.
Clinical PK studies demonstrate that for mild to moderate impairment of renal or hepatic 
function no dose adjustment is necessary.  In 10 subjects with hepatorenal syndrome (glomerular 
filtration rate (GFR) 30 to 60 mL/min), clearance of icatibant was not dependent on renal 
function.  Icatibant clearance in subjects with a wide range of hepatic impairment (Child-Pugh 
score ≥7 and ≤15) was similar to that in healthy subjects.


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1.2.2
Overview of the Safety and Efficacy of Subcutaneous Icatibant in Clinical 
Studies
Despite the rarity of HAE, a robust clinical dataset supports the safety of icatibant.  
In registrational clinical studies, a total of 1,411 HAE attacks have been treated with 30 mg 
icatibant administered SC by a healthcare professional.  In Phase I-III studies, icatibant has been 
administered by a healthcare professional to 177 healthy subjects and to 269 subjects with HAE.  
In completed Phase III studies, the maximum number of icatibant-treated attacks in a single 
subject was 142 (over approximately 3 years) in JE049-2102, 22 (over approximately 1.5 years) 
in JE049-2103, and 34 (over approximately 3 years) in HGT-FIR-054.  
Icatibant has been well tolerated in all clinical studies. Nonserious reactions (erythema, swelling, 
burning sensation, itching, warmth, and cutaneous pain) at the injection site were the most 
commonly reported adverse effects in clinical studies, and occurred transiently in almost all 
subjects after SC injection of icatibant. These reactions were self-resolving and typically mild to 
moderate in severity. Icatibant was generally non-immunogenic. Over repeated treatment for 
multiple attacks in the 3 controlled Phase III studies, transient positivity in test results for the 
presence of anti-icatibant antibodies was observed in rare cases. No hypersensitivity or 
anaphylactic reactions were reported with use of icatibant. 
Collectively, across the 3 controlled Phase III studies, subjects on icatibant had a faster median 
time to onset of symptom relief (2.0, 2.5, and 2.0 hours, respectively) compared to tranexamic 
acid (12.0 hours) and placebo (4.6 and 19.8 hours).  The treatment effect of icatibant was 
confirmed by secondary efficacy endpoints.  In subgroup analyses of data pooled across these 
3 controlled Phase III studies, the time to onset of symptom relief and time to onset of primary 
symptom relief were similar regardless of age group, sex, race, weight or whether or not the 
subject used androgens or antifibrinolytic agents.  A consistent treatment response was observed 
across repeated attacks in studies HGT-FIR-054, JE049-2102, and JE049-2103, during which a 
total of 237 subjects were treated with 1, 383 doses of SC icatibant for 1278 acute attacks of 
HAE.  
The initial treatment component of the current study is complete.  Sites will remain open to 
complete the subsequent icatibant-treated attack portion of the study.  The results from a single 
administration of icatibant in this study found:

Systemic exposure to icatibant in pediatric subjects was demonstrated.

Icatibant provided rapid resolution of symptoms in pediatric HAE subjects. Overall, the 
median time to onset of symptom relief was 1.0 hour (95% CI: 1.0, 1.1). The median time 
to onset of symptom relief was similar between the prepubertal subjects (median: 1.0 
hour; 95% CI: 1.0, 2.0) and the pubertal/postpubertal subjects (median: 1.0 hour; 95% CI: 
1.0, 2.0). Overall, the median time to minimal symptoms was 1.1 hours (95% CI: 1.0, 
2.0). The median time to minimal symptoms was similar for the prepubertal subjects 
(median: 1.9 hours; 95% CI: 1.0, 2.0) and the pubertal/postpubertal subjects 
(median: 1.0 hour; 95% CI: 1.0, 2.0).

Icatibant was generally well tolerated by pediatric subjects with HAE.  The safety profile 
was favorable and consistent with the disease as well as previous experience with 
icatibant in adult HAE subjects.  No new safety signals were identified.


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Thus, the clinical data supports the favorable benefit-risk profile of icatibant as a treatment for 
acute attacks of HAE. 
The recommended dose of icatibant in adults is 1 SC injection of 3 mL (30 mg) administered in 
the abdominal area for the treatment of acute attacks of HAE.  In case of insufficient relief or 
recurrence of symptoms, a second injection of icatibant can be administered after 6 hours.  No 
more than 3 injections of icatibant should be administered in a 24-hour period.  In clinical trials, 
a single SC injection of icatibant was generally sufficient to treat an acute HAE attack.  No 
differences in the efficacy or safety of icatibant in clinical trials have been observed between 
sexes; no dose adjustments for adult males or females are necessary. 
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of icatibant.
1.2.3
Investigations of Potential Effects of Bradykinin Inhibition on Reproductive 
Function
In nonclinical studies performed in rat and dog, high repeated doses of icatibant have been 
associated with effects on sexual organs and sexual maturation.  These findings are consistent 
with published data showing a role of bradykinin action through B2 receptors in the control of 
reproductive hormone release. 
Completed juvenile toxicology study in sexually immature rats involving fertility assessment 
over the course of 7-weeks of administration of icatibant (3.0, 9.0, or 25 mg/kg/day) elicited 
effects on reproductive organs and impaired fertility. These findings on reproductive tissues in 
males to be largely expected due to the known effects of antagonizing the bradykinin B2 receptor 
and were seen to be partially or fully reversible during the dose-free recovery period. 
Nonclinical evaluation of icatibant in rats demonstrated icatibant-related effects on hormone 
levels with secondary effects observed on reproductive organs in a 26-week rat toxicity study 
(JE049-0163) at dose levels of 3.0 and 9.0 mg/kg/day.  However, these findings did not result in 
a functional deficit in terms of the mating performance and fertility of the male rat at doses lower 
than 9.0 mg/kg.  Additionally, the dose regimen utilized in this study represents an exaggeration 
of the clinical use of icatibant, thereby minimizing the impact of the findings to what would 
potentially be observed in a clinical setting.
A retrospective analysis, prompted by nonclinical observations, of serum levels of gonadotrophic 
hormone levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) in 16 male 
and 16 female healthy volunteers in an Phase I study (JE049-1103) showed no clinically 
important changes from baseline in levels of FSH and LH after administration of 3 SC doses 
(30 mg each) of icatibant 6 hours apart on Day 1 followed by single SC doses (30 mg) on Day 8 
and Day 15. 
Phase 1 study (HGT-FIR-062) was a double-blind, randomized, placebo-controlled, single center 
study to assess the effect of icatibant on serum reproductive hormone levels in male and 
premenopausal female healthy adult subjects and seminal fluid analysis in healthy male adult 
subjects.  This study was intended to definitively determine the effect of repeated administration 
of 3 SC doses of icatibant 30 mg on reproductive hormone levels in adults prior to any 


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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. 
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 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.  


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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.

To evaluate the efficacy of a single SC dose of icatibant in children and adolescents with 
HAE.

To evaluate the effect on reproductive hormone levels after a single SC dose of icatibant 
in children and adolescents with HAE. 
2.2
Other Objectives 
Other objectives of this study are:

To evaluate the continued safety of icatibant in pubertal/postpubertal children after 
repeated exposures.

To evaluate the efficacy of icatibant in the treatment of acute HAE attacks in 
pubertal/postpubertal children after repeated exposures.

To evaluate the effect on reproductive hormone levels in pubertal/postpubertal children 
after repeated exposures.


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


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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
4.1.1
Study Design
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, and 
safety, including effects on reproductive hormones, of a single SC administration of icatibant in 
pediatric subjects with HAE.
The study will enroll children and adolescents from 2 to less than 18 years of age, divided into 
2 groups: prepubertal (Tanner stage I) and pubertal/postpubertal (Tanner stages II to V). 
At least 10 prepubertal children and at least 20 adolescents (including 10 treated during a HAE 
attack) must be enrolled in the study.
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. Subjects 
will continue to receive icatibant as a single, weight-adjusted dose of 0.4 mg/kg up to a 
maximum of 30 mg administered as an SC injection.
4.1.2
Study Methodology
A subject’s classification as prepubertal or pubertal/postpubertal will be determined at screening 
and, if classified as prepubertal at screening will have their pubertal status reassessed at the time 
of their first icatibant-treated 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 with 
icatibant (whether during or in the absence of attack), PK, safety/tolerability, and efficacy (as 
appropriate) will be reviewed by an independent Data and Safety Monitoring Board (DSMB). 
The DSMB review of the first 4 subjects shall be completed prior to continuing enrollment of 
additional pubertal/postpubertal subjects, treatment of second and third HAE attacks in 
pubertal/postpubertal subjects, and initiating enrollment of subjects in the prepubertal group.
Initial Icatibant Treatment
After a qualifying screening period, the PK, safety/tolerability, and efficacy of treatment with SC 
icatibant will be evaluated in at least 20 subjects (10 prepubertal and 10 pubertal/postpubertal 
subjects) who present with cutaneous, abdominal, or laryngeal symptoms of an acute attack of 
HAE.  Subjects should initiate treatment with icatibant within 12 hours of the onset of 
symptoms; however, there are no prespecified attack severity criteria that are required for 
treatment.  Subjects with attacks considered to be mild, moderate, or severe are all potentially 
eligible to receive treatment with icatibant.  
The PK and safety/tolerability of SC icatibant will be evaluated in at least 10 additional 
pubertal/postpubertal subjects who meet screening criteria, but receive treatment with SC 
icatibant in the absence of a current acute HAE attack.


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Subjects will receive treatment with a single SC administration of icatibant on Day 1 and will be 
monitored closely in the hospital/study center for at least 6 to 8 hours after treatment.  Subjects 
will undergo PK and safety assessments; efficacy assessments will be performed if treatment 
occurs during an acute HAE attack.  All subjects will have serum reproductive hormone 
measurements.  
A subject may be discharged after completion of assessments at 6 hours post treatment, if 
deemed medically stable in the investigator’s clinical judgment and, if applicable, the subject’s 
HAE symptoms have resolved (the subject’s investigator-rated symptom score must be zero, 
denoting the absence of symptoms).  If HAE symptoms have not completely resolved at 6 hours 
(ie, the investigator-rated symptom score is >0), the subject shall remain in the hospital/study 
center for at least 8 hours after icatibant administration for further evaluation.
Telephone follow-up will occur at both 24 and 48 hours after treatment.  
Subjects will return to the hospital/study center for scheduled assessments on Day 8 and for a 
follow-up visit on Day 90.
The investigator will schedule a telephone contact approximately 6 months after Day 1 of initial 
icatibant-treatment to obtain specific updates concerning pubertal changes/milestones.
Subsequent Icatibant-treated Attacks
After having received initial treatment with icatibant, either during or in the absence of an attack, 
at least 10 pubertal/postpubertal subjects who subsequently experience an acute HAE attack may 
continue to receive treatment with icatibant as a single SC administration per attack for a total of 
3 eligible icatibant treatments.  Further treatment with icatibant is contingent upon presentation 
of an acute cutaneous, abdominal, or laryngeal attack of HAE at least 3 days after prior 
treatment.  
For subsequent attacks, study drug may be administered by study site personnel at the 
hospital/study center or by qualified home healthcare personnel at the subject’s home.  
Alternatively, a parent/legal guardian/caregiver will be allowed to administer or the subject 
(under the supervision of a parent/legal guardian/caregiver) will be allowed to self-administer the 
investigational product after having received appropriate training.  For all subsequent laryngeal 
attacks, subjects should be advised to seek medical attention in an appropriate healthcare facility 
immediately following treatment with icatibant.  
Except for PK determinations, all primary and secondary endpoints as above will be measured in 
these pubertal/postpubertal subjects after each administration. Note that for some of the 
pubertal/postpubertal subjects who receive further treatment, ie, those who provided PK and 
safety/tolerability measurements without an attack, their first icatibant-treated attack will 
represent their second on-study exposure to icatibant for safety analysis purposes.
In addition, for all subjects who remain enrolled in the study, a safety telephone contact will be 
scheduled every month to collect information concerning AEs, weight, eligibility, and HAE 
attacks not treated within the study.


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4.1.3
Study Assessments
The study will consist of the following periods (Table 4-1).  All assessments are outlined in full 
in the study schedules of events in Appendix 1, No Attack, Appendix 2, Initial Icatibant-treated 
Attack, and Appendix 3, Subsequent Icatibant-treated Attacks.
Table 4-1
Study Periods
Study Periods
Screening 
Day of informed consent through pretreatment 
on Day 1 
No attack (Pubertal/postpubertal subjects only)
    Treatment 
Day 1
    Post Treatment
Day 1 through Day 8 (± 1 day)
    Follow-up
Day 9 through Day 90 (±7 days)
    Telephone Contact
Month 6 (± 7 days) from Day 1 
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-treatments 
(Pubertal/postpubertal subjects only)
    Subsequent Icatibant-treated Attack 
    Baseline Assessments
Every 6 months
    Treatment 
Day 1
    Post Treatment
Day 1 through Day 8 (±1 day)
    Follow-up
Day 9 through Day 90 (±7 days)
The study will include a screening period to determine subject eligibility.  Eligibility will be 
evaluated after the subjects’ parent(s)/legal guardian(s) and the subject (if applicable) provide 
informed consent/assent.  
Study activities at screening will include confirmation of diagnosis of HAE type I or II by review 
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Type I or II.  A blood sample will be collected for C1-INH testing.  Other assessments performed 
at screening will include concomitant medication use, physical examination (including height 
and weight), pubertal status determination, vital signs, ECG, and a urine pregnancy test in female 
pubertal/postpubertal subjects.
4.1.3.1
Initial Treatment
In previously screened, eligible subjects who present with an attack of acute HAE, baseline 
clinical assessments for PK, safety, and efficacy will be performed on Day 1 at pretreatment.  
The initial severity and type of attack (ie, cutaneous, abdominal, or laryngeal) will be determined 
by the investigator.  The investigator will complete baseline assessments at pretreatment of the 
symptoms of the acute HAE attack (including a separate assessment of HAE-related pain in 
subjects younger than 4 years of age), and adherence to inclusion/exclusion criteria will be 
reconfirmed.  Subjects who are 4 years of age or older will perform a self-assessment of 
HAE-related pain.  Other baseline assessments performed at pretreatment will include physical 
examination, pubertal status determination (only for those subjects classified as prepubertal at 
screening), height and weight, vital signs, collection of samples for clinical laboratory tests 
(serum chemistry [including liver function tests], hematology, urinalysis), urine pregnancy test 
for pubertal/postpubertal females, baseline PK and immunogenicity assessments, and baseline 
measurement of reproductive hormones (FSH, LH, estradiol, and progesterone in females and 
FSH, LH, and testosterone in males). 
On Day 1, subjects will be administered a single dose of icatibant as an abdominal SC injection 
within 12 hours after the onset of the acute attack.  The time of investigational product 
administration on Day 1 will be designated as Time 0.  All post-treatment assessments will be 
calculated from the time of investigational product administration.  PK, safety, and efficacy 
assessments will be performed on Day 1 after treatment at the time points indicated in the study 
schedules of events (Appendix 1, Appendix 2).  These assessments will consist of physical 
examination, vital signs, ECG, clinical laboratory tests (serum chemistry [including liver 
function tests], hematology, urinalysis), injection site reactions, and measurement of 
reproductive hormones (FSH, LH, estradiol, and progesterone in females and FSH, LH, and 
testosterone in males) in all subjects.  The investigator will complete assessments of symptoms 
of the acute attack of HAE for all subjects (including a separate assessment of HAE-related pain 
in subjects younger than 4 years of age).  Subject who are 4 years of age or older will also 
complete a self-assessment of HAE-related pain.
Eligible pubertal/postpubertal subjects who undergo treatment with icatibant in the absence of an 
acute HAE attack will receive single dose of icatibant as an abdominal SC injection on Day 1 
and undergo PK and safety assessments as for subjects who receive treatment with icatibant 
during an attack.  (Efficacy assessments will not be performed for those pubertal/postpubertal 
subjects treated with icatibant in the absence of an HAE attack.)
A safety follow-up contact to assess the subject’s condition will occur by telephone at 24 (±4) 
hours and 48 (±4) hours after treatment with icatibant (for a subject who remains hospitalized, 
this safety follow-up will be conducted in person).


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Rescue medication use will be assessed through 48 (±4) hours after treatment.  With exception of 
icatibant, any medicinal product may be used as rescue medication, at the discretion of the 
treating physician.
Subjects will return to the hospital/study center to undergo safety assessments, including 
physical examination, vital signs, and clinical laboratory tests (serum chemistry [including liver 
function tests], hematology, urinalysis), evaluation of injection site reactions, immunogenicity, 
and measurement of reproductive hormones on Day 8 (±1 day) after treatment.
Subjects will be followed over a 90-day period after initial treatment.  All subjects will provide 
blood samples for immunogenicity testing and measurement of reproductive hormone levels at 
the Day 90 (±7 days) visit and undergo safety assessments including physical examination, vital 
signs, and clinical laboratory tests (serum chemistry, hematology, and urinalysis).  Additionally, 
females of childbearing potential will undergo urine pregnancy testing.
4.1.3.2
Subsequent Icatibant-Treated Attacks 
Subsequent treatment with icatibant may be offered to pubertal/postpubertal subjects who have 
received initial treatment and who present subsequently with an attack at least 3 days after prior 
treatment. Subjects will be eligible for treatment with icatibant until a total number of at least 
10 adolescents have been treated 3 times with icatibant.
For all subjects who remain enrolled in the study for longer than 6 months, a study visit will be 
scheduled every 6 months to collect baseline information and to conduct training for 
parents/legal guardian/caretakers for subjects who have expressed an interest in receiving 
icatibant at home.  In addition, for all subjects who remain enrolled in the study a safety 
telephone contact will be scheduled every month to collect information concerning AEs, weight, 
eligibility, and HAE attacks not treated within the study.  
When a pubertal/postpubertal subject experiences an acute HAE attack, subjects (parent/legal 
guardian/caregiver) will contact the hospital/study center (or their home healthcare professional 
in the event the investigator is not available) to confirm the HAE attack diagnosis.  
The investigator (or the home healthcare professional in the event the investigator is not 
available), in consultation with the subject's preference, will determine whether the subject will 
be treated at the hospital/study center, at home by a qualified home healthcare personnel, or at 
home by the trained parent/legal guardian/caregiver.  The qualified home healthcare person will 
be contacted, if applicable.
For subsequent attacks, study drug may be administered by study site personnel at the 
hospital/study center or by qualified home healthcare personnel at the subject’s home.  
Alternatively, a parent/legal guardian/caregiver will be allowed to administer or the subject 
(under the supervision of a parent/legal guardian/caregiver) will be allowed to self-administer the 
investigational product after having received appropriate training.  For all subsequent laryngeal 
attacks, subjects should be advised to seek medical attention in an appropriate healthcare facility 
immediately following treatment with icatibant.  
Except for PK determinations, all primary and secondary endpoints are to be measured after each 
administration. Safety, reproductive hormones, and other assessments in association with 


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subsequent attacks of acute HAE will be performed on Day 90 (±7 days) after treatment (each 
treatment for a subsequent attack will require its own Day 90 follow up visit; however, if a 
subsequent attack occurs within 7 days of the Day 90 follow-up visit for the previous attack, the 
assessments on Day 8 and Day 90 may be combined). 
Note that for some of the pubertal/postpubertal subjects who receive further treatment, ie, those 
who provide PK and safety/tolerability measurements without experiencing a current attack, their 
first icatibant-treated attack will represent their second on-study exposure to icatibant for safety 
analysis purposes.
Each treatment for a subsequent attack will require a Day 8 and a Day 90 follow up visit.  If a 
subsequent attack occurs within 3 days of the Day 8 follow-up visit for the previous attack, the 
visits for Day 1 (of the subsequent icatibant-treated attack) and Day 8 (of the prior icatibant-
treated attack) may be combined.  If a subsequent attack occurs within 7 days of the Day 90 
follow-up visit for the previous attack, the visits for Day 8 (of the subsequent icatibant-treated 
attack) and Day 90 (of the prior icatibant-treated attack) will be combined.
4.2
Rationale for Study Design
This study has an open-label, single arm design.  
The study is intended to determine the PK profile of SC icatibant when administered to children 
and adolescents with HAE and to identify an optimal pediatric dosing regimen.  
In addition, the study is intended to establish the tolerability and safety of icatibant in children 
and adolescents, particularly with respect to potential effects on reproductive development, and 
to demonstrate the effectiveness of icatibant in relieving the symptoms of acute HAE attacks.  
Therefore, this study will help determine whether icatibant can address an unmet medical need 
for a safe and effective treatment for acute attacks of HAE in pediatric patients. 
4.3
Study Duration
At minimum, the duration of a subject’s active participation in the study will consist of single 
day dosing with 90-day follow-up.  
Once eligibility is established at screening, the subject will be enrolled into the study but will 
enter a period of inactive participation of variable duration until such time as the subject 
experiences an acute attack of HAE and is offered treatment.  For those pubertal/postpubertal 
subjects who will be treated without an attack, eligibility will be established at screening and the 
subject will be immediately enrolled and treated with icatibant.  At the time of enrollment, the 
subject will enter a 90-day period of active participation which will consist of treatment with a 
single SC administration of icatibant on Day 1 through follow-up at Day 90.  
After receiving the first treatment with icatibant with or without an attack (N=20), at least 
10 pubertal/postpubertal subjects who present with subsequent attacks of acute HAE will 
continue to receive treatment with icatibant for a total of 3 attacks each. Thus, the period of 
active participation in the study for prepubertal subjects could be approximately 90 days, while 
that for pubertal/postpubertal subjects could be a maximum of approximately 270 (3 separate 


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active periods of approximately 90 days for those treated with icatibant during an attack), with 
each active period separated by periods of inactive participation of variable duration. The period 
of active participation may be shorter if pubertal/postpubertal subjects have recurrent HAE 
attacks in between the Day 8 and Day 90 visits for a prior icatibant-treated HAE attack. 
Telephone follow-up will occur approximately 6 months after each initial icatibant-treated 
attack.
Once the tenth prepubertal subject and the twentieth pubertal/postpubertal subject have 
completed the 6-month follow-up after the initial treatment, and the tenth pubertal/postpubertal 
subject has completed the Day 90 follow-up after his or her third and final treatment for an 
attack, the study will be closed. 


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


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


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For all subsequent laryngeal attacks, subjects should be advised to seek medical attention in an 
appropriate healthcare facility immediately following treatment with icatibant. 
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.
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, antifibrinolytics 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. 

The use of ACE inhibitors within 7 days prior to treatment is forbidden.
Use of the following concomitant medications is forbidden within 90 days prior to treatment, and 
for 90 days after receiving treatment with icatibant:

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.  For 
subjects treated at home for a subsequent attack, subjects must contact the hospital/study center 
(or their home healthcare professional in the event the investigator is not available) if symptom 


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improvement is not seen after the administration of icatibant and they believe they need 
additional treatment to alleviate acute symptoms.
Repeat administration of icatibant for treatment of a single attack is not allowed in this study.  
The determination of the necessity for rescue therapy will be at the discretion of the investigator.  
With the exception of icatibant, any medicinal product may be used as rescue medication at the 
discretion of the treating physician.
Rescue therapies will include agents to control the HAE attack, such as C1-INH inhibitor 
concentrates.  C1-INH therapy has been used safely for the treatment of acute attacks in the 
pediatric setting (Farkas 2010).  If C1-INH concentrates are unavailable, FFP may be used 
(Zuraw 2008).  A kallikrein inhibitor, ecallantide, approved only in the United States of America 
(USA), is indicated for use in patients 16 years of age and older. 
Other acceptable rescue therapies for acute attacks include palliative medications that are 
intended to ameliorate the symptoms (eg, pain, nausea) of angioedema rather than to control the 
HAE attack itself.  If pain medication is required, the investigator may administer IV 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, IV fluids, or other medicinal products.
Medications provided for rescue therapy will be denoted as rescue medications on the 
appropriate CRF.  Antihistamines (diphenhydramine, loratadine, cetirizine, etc.) and 
glucocorticoids are considered ineffective for the alleviation of an acute HAE attack.  If 
administered during an acute attack that occurs during the study, they should be recorded as 
concomitant medications but will not be considered as rescue medications.  
If rescue medication is provided, the investigator will document the drug name, amount, time, 
route of administration, frequency, and duration administered.  
6.8
Restrictions
Subjects are not to receive treatment with any investigational product(s) other than icatibant or 
any investigational device(s) at any point during this study.
6.8.1
Fluid and Food Intake 
No specific restrictions on fluid or food intake apply for this study.
6.8.2
Subject Activity Restrictions
No specific restrictions on subject activity apply for this study.


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6.9
Treatment Compliance
During this study, the investigational product will be administered by study site personnel, a 
qualified home health professional, the subject, or a parent/guardian; 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. For countries outside the US, secondary packaging consists of 1 icatibant syringe, 
labeled in a tray with a 25-guage needle placed inside a plain white carton, also labeled. In the 
US, the secondary packaging consists of one solid bleached sulfate (SBS) insert/sleeve 
containing one pre-filled syringe with attached plunger rod and backstop with one needle 
(25-guage, 16 mm) packed separately.  The insert/sleeve is contained in a SBS outer carton, 
which protects the formulation from light.  A fluid-dispensing adaptor will be used to secure a 
1-mL or 3-mL syringe to the glass syringe for withdrawal of icatibant.
See the Pharmacy Manual for additional details.
6.11
Storage and Accountability
The following information should be considered when storing and using the investigational 
product.
The investigational product will be shipped at 2° to 8°C.  Icatibant 10 mg/mL formulated for SC 
administration should be stored at or below 25°C.  The syringes must not be frozen.
The disposition of all investigational product delivered to a principal investigator must be 
recorded on a subject-by-subject basis by completing the clinical trial material accountability 
log.  The date and time of administration of the investigational product must be documented on 
the appropriate CRF.
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. 
Subjects who were issued study drug for administration at home will be required to return any 
used or unused IP to their site for destruction.


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6.12
Investigational Product Retention at Study Site
The process for destruction of investigational product must be determined and documented 
during the study start-up phase.  
If the investigational product is to be destroyed by the study sites, sites must follow their own 
process/policy that describes such activities.  All drug destruction processes will be documented 
and the sites must retain copies of these documents within the site regulatory binder.  The sites 
must ensure that the clinical trial material accountability and destruction log is complete, 
accurate, and ready for review and/or audit at each monitoring visit.  
All manifests documenting shipments of investigational product must be retained as well copies 
of any investigational product return forms.  
See the Pharmacy Manual for additional details.


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


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7.6
Menstrual Cycle History
A menstrual cycle history will be determined historically for female subjects and will be 
recorded in the CRF.  The timing of the blood sampling with respect to the menstrual cycle must 
be known to inform the interpretation of any potential changes in reproductive hormones in 
adolescent females, because of the normal cyclical rise and fall of reproductive hormones of the 
menstrual cycle.
Instructions for investigators:
To assist in this determination, investigators should obtain the following information and 
document in the CRF.

Age of menarche

Normal duration of menstrual flow 

Normal interval in between menstrual periods 

Date of last onset of bleeding 

Prospectively ask female subjects to write down subsequent dates of onset of bleeding 
and cessation of bleeding between Day 1 and Day 90

Date of ovulation (sometimes called ovulation pain, mid-cycle pain or mittelschmerz) 
may also be documented if subjects can identify this feeling
7.7
Height and Weight
Height and weight will be recorded for all subjects.  
7.8
Pubertal Status Determination
The investigator will perform an examination for all subjects to determine whether they are 
prepubertal or pubertal/postpubertal.  A description of the sexual maturation scale described by 
Marshall and Tanner (1969 and 1970) is provided in Appendix 4.
7.9
Investigational Product Administration
Subjects will receive treatment with icatibant as a single, weight-adjusted dose of 0.4 mg/kg 
administered as an abdominal SC injection up to a maximum dose of 30 mg.  Treatment with 
icatibant should be administered within 12 hours of onset of an acute HAE attack.  
Pubertal/postpubertal subjects that present with a subsequent attack at least 3 days after prior 
treatment (see Section 4.1.3) may receive further treatment with icatibant for a total of 3 icatibant 
treatments.  For subsequent attacks, study drug may be administered by study site personnel at 
the hospital/study center or by qualified home healthcare personnel at the subject’s home.  
Alternatively, a parent/legal guardian/caregiver will be allowed to administer or the subject 
(under the supervision of a parent/legal guardian/caregiver) will be allowed to self-administer the 
investigational product after having received appropriate training.  For all subsequent laryngeal 
attacks, subjects should be advised to seek medical attention in an appropriate healthcare facility 
immediately following treatment with icatibant.  


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See the Pharmacy Manual for additional instructions regarding dose calculation and 
administration.     
7.10
Pharmacokinetic Assessments 
7.10.1
Pharmacokinetic Variables
Individual patient PK variables for icatibant and major metabolites will be determined from the 
respective plasma concentration time profiles where appropriate, using noncompartmental 
methods. 
A population PK model will be derived to evaluate the correlation of key covariates (ie, age, 
body weight, gender) on the PK profile of icatibant.
Pharmacokinetic variables will be determined by full sampling and noncompartmental methods 
where possible, and elsewhere by sparse sampling (at least 4 to 7 time points) and a population
PK approach using nonlinear mixed effects modeling software.  
Primary and secondary pharmacokinetic parameter estimates will be reported and include time to 
peak concentration (Tmax), actual peak (Cmax) and minimum (Cmin) concentrations, total body 
clearance (CL/F), actual AUC0-last and AUC0-inf, mean residence time (MRT), volume of 
distribution at steady state (Vss/F) and terminal elimination half-life (t1/2).
The methods to be used for estimation of PK parameter values are described in Section 10.5.1.
7.10.2
Pharmacokinetic Sampling
Sampling for PK assessments will be collected according to the schedule of events provided in 
Appendix 1 (No Attack) and Appendix 2 (Initial Icatibant-treated Attack).  Pharmacokinetic 
assessments are not conducted during subsequent attacks. 
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 Laboratory 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.


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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
Symptom Score 
7.11.1.1
Investigator Symptom Score
For subjects treated at the hospital/study center, 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.
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.  
7.11.1.2
Home Healthcare Provider or Parent/Legal Guardian/Caregiver Symptom 
Score
The home healthcare provider or parent/legal guardian/caregiver, after having received 
appropriate training, will assess the severities of symptoms of acute cutaneous, abdominal, and 
laryngeal attacks of HAE using the 5-point scale provided in Section 7.11.1.1. Symptom scores 
will be recorded on Day 1 at pretreatment and at predetermined time points after treatment. 
Results will be recorded in the CRF.
For attacks classified as cutaneous and/or abdominal, the home healthcare provider or 
parent/legal guardian/caregiver-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, the home healthcare provider or parent/legal 
guardian/caregiver-assessed symptom scores will be collected for 13 symptoms:  abdominal 


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tenderness, nausea, vomiting, diarrhea, skin pain, erythema, skin irritation, skin swelling, 
dysphagia, voice change, breathing difficulties, stridor, and asphyxia.
7.11.2
Subject Self-assessment of Pain 
Subjects who are at least 4 years of age will self-assess HAE-related pain using the FPS-R.  A 
copy of the FPS-R is provided in Appendix 5.  
FPS-R self-assessment data will be recorded in a diary. Subjects will record self-assessments on 
Day 1 at pretreatment and at predetermined time points after treatment. Subjects will return the 
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 diary from the investigator 
and/or clinical site personnel.
7.11.3
Investigator Assessment of Pain
Subjects who are below 4 years of age will undergo investigator assessment of HAE-related pain 
(cutaneous, abdominal, and laryngeal) using the FLACC comportmental pain scale.  A copy of 
the FLACC scale is provided in Appendix 6.
7.11.4
Initial Symptom Relief
7.11.4.1
Investigator-assessed Initial Symptom Relief
For subjects treated at the hospital/study center, 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.  
7.11.4.2
Home Healthcare Provider and Parent/Legal Guardian/Caregiver Initial 
Symptom Relief
The home healthcare provider or parent/legal guardian/caregiver, after having received 
appropriate training, will be asked to record the date and time when overall subject improvement 
was first noted and record the date and time.  
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.  
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 AE on the appropriate CRF.  The physical examination will include the following:


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-
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 following treatment.  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. 
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
*Urinalysis will not be conducted for subsequent attacks.


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7.13.5
Local Tolerability
Injection site reactions (erythema, swelling, burning sensation, itching/pruritus, warm sensation, 
cutaneous pain, or other) will be evaluated by the investigator or other medically qualified 
personnel, the home healthcare provider, or the parent/legal guardian/caretaker after having 
received appropriate training, and the diameter of any erythema or swelling will be measured.  
After discharge or in a subject treated at home for a subsequent attack, the subject (or the 
subject’s parent/legal guardian on behalf of the subject as appropriate) will report about injection 
site reactions, either in person or by telephone contact.  
7.13.6
Immunogenicity
The immunogenicity of icatibant will be assessed.  Serum samples for immunogenicity testing 
will be collected for determination of anti-icatibant antibodies.  Serum samples will be analyzed 
for anti-icatibant antibodies at Shire or at a designated laboratory.  Details concerning sample 
collection and preparation will be provided in the study Laboratory 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 Laboratory Manual.
7.13.7
Pregnancy Testing
Female subjects of childbearing potential (ie, those who have experienced menarche) will 
undergo pregnancy testing at time points specified in the study schedule of events (Appendix 1, 
Appendix 2, and Appendix 3).  All pregnancy testing will be conducted using a urine human 
chorionic gonadotropin (hCG) test kit.  The test will be performed and interpreted prior to study 
drug administration.
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 Laboratory Manual.
7.15
Recording of Concomitant Medications 
All medications administered to the study subjects from the time of informed consent through the 
final 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.  


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7.16
Recording of Adverse Events
Adverse events will be collected over an observation period from the time of treatment until the 
final follow-up visit 90 (±7) days after investigational product administration (or until the event 
has resolved/stabilized or an outcome is reached, whichever comes first).  Adverse event 
monitoring and the period of observation defined for this study are described in Section 7.17.4.1.  
7.17
Adverse Events Assessments  
7.17.1
Definitions of Adverse Events and Serious Adverse Events
7.17.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
a clinical study, whether or not considered investigational product related.  This includes an 
exacerbation of a pre-existing condition.  However, anyexacerbation or worsening of symptoms 
of an acute HAE attack treated with icatibant is considered a result of the underlying disease and 
will not be considered an AE (unless meeting the criteria for a serious adverse event (SAE), see 
Section 7.17.1.2).
Adverse events include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset of 
the study (with the exception of HAE).

Intercurrent illnesses.

Drug interactions.

Events related to or possibly related to concomitant medications.

Clinically significant abnormal laboratory values (this includes significant shifts from 
baseline within the range of normal that the investigator considers to be clinically 
important).

Clinically significant abnormalities in physical examination, vital signs, and weight.
The investigator must record all AEs in the CRF, regardless of the severity or relationship to 
investigational product.  The investigator should treat subjects with AEs appropriately and 
observe them at suitable intervals until the events stabilize or resolve.  Adverse events may be 
discovered through observation or examination of the subject, questioning of the subject, 
complaint by the subject, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become clinically significantly out of 
range.  In the event of an out-of-range value, the laboratory test should be repeated until it 
returns to normal or stabilizes, or can be medically explained, and the subject’s safety is not at 
risk.
Additional illnesses present at the time when informed consent is given until the time of
treatment are regarded as concomitant illnesses and will be documented on the medical history 
page of the CRF.  Illnesses first occurring or detected on or after treatment, and worsening of a 


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concomitant illness during the study, are to be regarded as AEs and must be documented as such 
in the CRF.
The treated HAE attack is defined as any symptoms occurring in treated subjects within 48 hours 
of the onset of symptoms.  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 AEs unless meeting the criteria of an 
SAE.  Symptoms reoccurring more than 48 hours after an initial attack will be considered a new 
attack, and will also not be reported as AEs.  Attacks not treated with icatibant will be 
documented in the appropriate CRF at the Day 90 visit; they are considered to be pre-existing 
disease and will not be documented as AEs.
Local tolerability will include symptoms at the site of icatibant administration (injection site) and 
will be assessed separately from general reports of AEs.  Injection site reactions will be 
documented in the “local tolerability” page of the CRF.  Injection site reactions that have been 
reported previously with icatibant included erythema, swelling, burning sensation, itching, 
warmth and pain and were generally, mild to moderate, transient, and resolved without sequelae. 
Injection site reactions that do not meet the criteria of an SAE will not need to be additionally 
reported as AEs.
7.17.1.2
Serious Adverse Event
An SAE is any AE occurring at any dose that results in any of the following outcomes:

Death.

Is life-threatening.

Requires hospitalization.

Requires prolongation of existing hospitalization.

A persistent or significant disability or incapacity. 

A congenital anomaly or birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  A life-threatening AE is defined as an AE that placed the 
subject, in the view of the initial reporter, at immediate risk of death from the AE as it occurred 
(ie, it does not include an AE that, had it occurred in a more severe form, might have caused 
death).
7.17.2
Classification of Adverse Events and Serious Adverse Events
The severity of AEs will be assessed by the investigator as mild, moderate, or severe based on 
the definitions shown in Table 7-2.  The severity of AEs and SAEs should be recorded on the 
appropriate CRF page as mild, moderate, or severe.


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Table 7-2
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.
7.17.2.1
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (eg, severe headache).  This is not the same as “serious,” which is based on 
the outcome or action criteria usually associated with events that pose a threat to life or 
functioning.  Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.
7.17.3
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product is to be determined by the investigator 
based on the following definitions (see Table 7-3).  
Table 7-3
Adverse Event Relatedness
Relationship to Product(s)
Definition
Not Related
Unrelated to investigational product
Possibly Related
A clinical event or laboratory abnormality with a reasonable 
time sequence to administration of investigational product, but 
which could also be explained by concurrent disease or other 
drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable 
time sequence to administration of investigational product, 
unlikely to be attributable to concurrent disease or other drugs 
and chemicals and which follows a clinically reasonable 
response on de-challenge.  The association of the clinical event 
or laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds.
Definitely related
The event follows a reasonable temporal sequence from 
administration of the investigational product, follows a known 
or suspected response pattern to the investigational product, is 
confirmed by improvement upon stopping the investigational 
product (de-challenge), and reappears upon repeated exposure 
(re-challenge).  Note that this is not to be construed as requiring 
re-exposure of the subject to investigational product; however, 
the determination of definitely related can only be used when 
recurrence of event is observed.


Ic ati b a nt (F I R A Z Y R)
Cli nic al Tri al Pr ot oc ol A m e n d me nt 4: H G T - FI R-0 8 6
1 8 M arc h 2 0 1 6
S hire
C o nfi de nti al
4 7
7. 1 7. 4
Pr oce d ures f or Rec or di n g a n d Re p orti n g A d verse E ve nts
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 v ati o n
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 safety 
o bser vati o n peri o d will e xte n d fr o m t he ti me of treat me nt wit h i n vesti gati o nal pr o d uct u ntil t he 
s u bject’s fi nal e val uati o n after treat me nt.  F or s u bjects w h o c o m plete t he st u d y, t he fi nal 
e val uati o n of A Es will occ ur at t he fi nal f oll o w-u p visit perf or me d 9 0 ( ± 7) da y s after treat me nt
wit h i n vesti gati o nal pr o d uct.  
If t he i n vesti gat or c o nsi ders it necessar y t o re p ort a n A E i n a s u bject after t he e n d of t he safety 
o bser vati o n peri o d, he or s he s h o ul d c o ntact t he s p o ns or t o deter mi ne h o w t he A E s h o ul d be 
d oc u me nte d a n d re p orte d.  
7. 1 7. 4. 2
Re p or ti n g Seri o us A d verse E ve nts
A n y  S A E, re gar dless of relati o ns hi p t o i n vesti gati o nal pr o d uct, w hic h occ urs i n a s u bject after 
i nf or me d c o nse nt, s h o ul d be rec or de d by t he cli nical site o n a n S A E f or m.  T he S A E m ust be 
c o m pletel y descri be d o n t he s u bject’s C R F, i ncl u di n g t he j u d g me nt of t he i n vesti gat or as t o t he 
relati o ns hi p of t he S A E t o t he i n vesti gati o nal pr o d uct.  
T he i n vesti gat or will pr o m ptl y  s u p ply all i nf or mati o n i de ntifie d a n d re q ueste d b y t he s p o ns or ( or 
c o ntract researc h or ga nizati o n [ C R O]) re gar di n g t he S A E.  T he i n vesti gat or m ust re p ort t he S A E
t o t he S hire P har mac o vi gila nce a n d Ris k Ma na ge me nt De part me nt A N D t o t he S hire Me dical 
M o nit or o n a n S A E f or m.  T his f or m m ust be c o m plete d a n d fa xe d or e maile d wit hi n 2 4 h o urs of 
t he i n vesti gat or’s lear ni n g of t he e ve nt t o:
S hire P h ar m ac o vi gil a nce a n d Ris k M a n a ge me nt De p art me nt:
F A X:  
 ( W orl d wi de) O R 
( N ort h A meric a)
E m ail:  
A N D
S hire Me dic al M o nit or: 
 M D, M P H
F A X: 
( U S A)
A n y  f oll o w-u p i nf or mati o n m ust als o be c o m plete d o n a n S A E f or m a n d fa xe d or e maile d t o t he 
sa me n u m bers liste d a b o ve. 
I n t he e ve nt of a se vere a n d u ne x pecte d, fatal, or life-t hreate ni n g S A E, t he cli nical site m ust 
c o ntact t he S hire Me dical M o nit or b y tele p h o ne; t his is i n a d diti o n t o c o m pleti n g a n d 
tra ns mitti n g t he S A E f or m as state d a b o ve.  T he f oll o wi n g pr o vi des c o ntact i nf or mati o n f or t he 
S hire Me dical M o nit or. 
If a n S A E is assesse d as se vere a n d u ne x pecte d, or life-t hreate ni n g, c o ntact:  
P P D
P P D
P P D
P P D
P P D
P P D


Ic ati b a nt (F I R A Z Y R) 
Cli nic al Tri al Pr ot oc ol  A me n d me nt 4: H G T -FI R -0 8 6  
1 8 M arc h 2 0 1 6  
S hire  
C o nfi de nti al  
4 8  
 
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, M P H  
 
S hire Or p h a n T her a pies L L C  
3 0 0 S hire W a y   
Le xi n gt o n, M A 0 2 4 2 1 U S A 
Tele p h o ne: 
 
M o bile:  
F a x:  
( U S A) 
 
 
T he i n vesti gat or m ust pr o m ptl y re p ort all re q uire d i nf or mati o n t o t he I nstit uti o nal Re vie w B oar d 
(I R B)/I n d e pe n d e 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 p y of a n y C o u n cil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces ( CI O M S)/ 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 ul at or y 
a ge ncies n otif yi n g t he m of a n u ne x pecte d relate d S A E.   
T he i n vesti gat or or s p o ns or m ust e ns ure t hat t he I R B/I E C recei ves a c o p y of t he re p ort a n d t hat a 
c o p y is als o file d wit hi n t heir st u d y files.  
7. 1 8  
Pre g n a nc y  
Pre g n a nc y a n d lactati o n are e x cl usi o n criteria f or t his st u d y.  T h e s p o ns or m ust be n otifie d i n t he 
e ve nt of a pre g na n c y occ urri n g d uri n g t he c o urs e of t he st u d y a n d t hr o u g h t he fi nal f oll o w- u p 
visit after t he s u bject’s last d ose of i n vesti gati o nal p r o d uct.  Pre g na n c y is n ot t o be re p orte d as a n 
A E; t he pre g na n c y re p orti n g f or m s h o ul d be us e d t o re p ort t he pre g na nc y.  T he pre g n a nc y will 
be f oll o we d u p t hr o u g h d eli ver y or fi nal o utc o m e. 
7. 1 9  
A b use, O ver d ose, a n d Me dic ati o n Err or  
A b use  – Persiste nt or s p ora dic i nte nti o nal i nta ke of i n vesti gati o nal me dici nal pr o d uct at a d os e 
hi g her t h a n pres cri be d p er pr ot oc ol ( b ut bel o w t he d ose defi ne d f or o ver d ose) or w h e n use d f or 
n o n- me dical p ur p ose (e g, alteri n g o n e’s state of c o nsci o us ness).  
Mis use  – I nt e 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 her e t he pr o d uct is n ot use d as directe d at t he d ose prescri be d b y t he 
pr ot oc ol). 
O ver d ose  – N o cli nical i nf or mati o n o n o ver d ose is a vaila ble.  A d ose of 3. 2 m g/ k g 
(a p pr o xi matel y 8 ti mes t he t hera p e utic d ose) ca us e d tra nsie nt er yt h e ma, itc hi n g or h y p ote nsi o n 
i n healt h y s u bjects.  N o t hera pe utic i nter ve nti o n w as necess ar y. 
M e dic ati o n Err or  – A mista ke ma de i n prescri bi n g, dis pe nsi n g, a d mi nistrati o n a n d/ or use of t h e 
i n vesti gati o nal me dici nal pr o d uct. 
P P D
 
P P D
P P D
P P D
P P D
P P D


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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 AE.

The study is terminated by the sponsor.

The study is closed prior to the subject’s first eligible attack.
The subject, the subject’s parent(s), or the subject’s legal guardian(s) acting on behalf of the 
subject is free to withdraw consent and discontinue participation in the study at any time without 
prejudice to further treatment.
If a subject or the subject’s parent(s) or the subject’s legal guardian(s) acting on behalf of the 
subject, discontinues participation in the study, or the subject is discontinued by the investigator, 
the subject completion/discontinuation CRF describing the reason for discontinuation must be 
completed.  Any AEs experienced up to the point of discontinuation must be documented in the 
CRF.  If AEs are present when the subject withdraws from the study, the subject will be re-
evaluated within 30 days of withdrawal.  All ongoing SAEs at the time of withdrawal will be 
followed until resolution.
7.20.1 Safety-Related Study Stopping Rules  
The Data and Safety Monitoring Board (see Section 11.8 for a description of the DSMB and its 
role) may recommend to suspend the study until the DSMB can review any death that is drug or 
disease-related or unexplained, or if there is an unexpected drug-related severe AE.
Following the review of safety data, the study will be either:

Resumed unchanged

Resumed with modifications to the protocol 

Terminated
Subject safety will be monitored on a continuous basis during this study until the last subject 
completes his or her last scheduled study visit/assessment.  
Additional information on safety monitoring can be found in Section 11.8.
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. 


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The measures of serum reproductive hormone concentration are accepted measures for assessing 
the function of reproductive organs.  
Plasma samples will be assayed for concentrations of icatibant and its 2 major metabolites 
(M1 and M2) using a validated high-performance liquid chromatography/tandem mass 
spectrometry (LC-MS/MS) method with a lower limit of quantification of 1 ng/mL and a range 
from 1 to 1000 ng/mL (Analytical Report SHR10-002).  Pharmacokinetic variables will be 
determined by full sampling and noncompartmental methods where possible, and elsewhere by 
sparse sampling (at least 4 to 7 time points) and a population PK approach using non-linear 
mixed effects modeling software.
The symptom score used in efficacy assessments in this study is an investigator-rated measure of 
symptom severity based on a standard 5-point scoring system (0-absence of symptoms, 1-mild, 
2-moderate, 3-severe, 4-very severe)  capturing symptoms of acute attacks of HAE that have 
been identified and validated to assess efficacy in adults.  For attacks classified as abdominal or 
cutaneous, investigator-rated symptom scores are collected for 8 symptoms:  abdominal 
tenderness, nausea, vomiting, diarrhea, skin pain, erythema, skin irritation, and skin swelling.  
For attacks classified as laryngeal, investigator-assessed symptom scores are collected for 
13 symptoms:  abdominal tenderness, nausea, vomiting, diarrhea, skin pain, erythema, skin 
irritation, skin swelling, dysphagia, voice change, breathing difficulties, stridor, and asphyxia.  
In all pediatric subjects in the present study, irrespective of age, the investigator-rated symptom 
score will provide an appropriate means to measure the severity of primary symptoms (eg, 
cutaneous and/or abdominal pain, cutaneous swelling, or laryngeal symptoms) of acute attacks of 
HAE at pretreatment and the change in symptom severity, if any, after treatment with icatibant.
Though subject-reported outcomes such as the symptom score and visual analog scale (VAS) 
have been employed successfully as efficacy measures in clinical studies of icatibant in adults, 
the use of these subject-reported outcomes in children poses special challenges.  The Faces Pain 
Scale is a validated, self-reported measure used to assess the intensity of children's pain in a wide 
variety of clinical contexts (Bieri et al. 1990).  The 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 (Hicks et al. 2001).  
The scales are suitable for use in assessment of the intensity of children's acute pain from age 
4 onward, are simple to administer, and require no specialized equipment other than the 
standardized images of faces.  Use of the FPS-R is planned for this study, and will provide an 
appropriate means to measure pain associated with acute attacks of HAE in pediatric subjects 
who are at least 4 years of age.
Young children (ie, those below the age of 4 years) frequently lack the verbal and cognitive 
skills necessary to report physical discomfort and pain intensity.  Behavioral cues are the primary 
indicators of pain in children who are unable to report pain or follow instructions in the use of 
assessment tools.  The FLACC instrument comprises 5 categories of behavior (face, legs, 
activity, cry, and consolability) to assess pain in preverbal children or children with limited 
verbal capability (Manworren and Hynan 2003; Merkel et al. 1997). Each category is scored on 
a 0-to-2 scale which results in a total score from 0 to 10.


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Collectively, the measures employed in this study are expected to allow for assessment of the PK 
profile, tolerability, safety, and efficacy of icatibant in the pediatric population.


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8
STUDY ACTIVITIES
8.1
Screening (Day of Informed Consent to Pretreatment on Day 1)  

Informed Consent/Assent

Inclusion/Exclusion Criteria

Medical history

Documentation of HAE attack(s) not treated with icatibant*

Confirmation of documented HAE diagnosis (via the sponsor’s central laboratory)

Measurement of C1-INH 

Pubertal status determination

Physical examination

Vital signs

ECG

Height and weight

Urine pregnancy test (in females of childbearing potential)

Recording of concomitant medications
*For all subjects who remain enrolled in the study for longer than 6 months, a telephone contact 
will be scheduled every 6 months to collect information concerning HAE attacks not treated with 
icatibant in the study.
8.2
No Attack
8.2.1
Pretreatment (Baseline) Assessments (Day 1)
The following assessments will be performed for subjects who will be treated with icatibant in 
the absence of a current HAE attack.  All evaluations and sample collections must be performed 
prior to treatment.

Medical history 

Confirm inclusion/exclusion criteria 

Pubertal status determination (only if the subject was classified as prepubertal at the time 
of the screening visit)

Menstrual cycle history (in pubertal/postpubertal females only)

Physical examination

Vital signs

Height and weight

Clinical laboratory tests (serum chemistry, hematology and urinalysis)

Urine pregnancy test (in females of childbearing potential)

Reproductive hormone assessments

Pharmacokinetic sampling

Immunogenicity evaluation

Recording of concomitant medications


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8.2.2
Treatment Period (Day 1 to Day 8 [± 1 Day])

Investigational product administration (Day 1, Time 0)

Physical examination (Day 1, 6 [±0.5] hours) (or 8 [±0.5] hours if the subject is not 
discharged***) post dose and Day 8 [±1 day])

Vital signs (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours) (or 8 [±0.5] hours if the subject 
is not discharged***) post dose and Day 8 [±1 day])

ECG (Day 1, 6 [±0.5] hours (or 8 [±0.5] hours if the subject is not discharged***) post 
dose) 

Clinical laboratory tests (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])

Reproductive hormone assessments (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])

Injection site reaction evaluation (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours) (and 8 
[±0.5] hours if the subject is not discharged**) post dose, Day 2 (24 [±4] hours), Day 3 
(48 [±4] hours), and Day 8 [±1 day])

Sampling for PK assessments in pubertal/post pubertal subjects (Day 1, 15 [±5] minutes, 
30 [±5] minutes, 45 [±5 minutes], 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] 
hours, 6 [±0.5] hours post dose)

Safety follow-up contact (Day 2 (24 [±4] hours), Day 3 (48 [±4] hours) by telephone (If a 
subject remains hospitalized, this safety follow-up will be conducted in person.)

Immunogenicity evaluation (Day 8 [±1 day])

Menstrual cycle history (Day 8 [±1 day] in pubertal/postpubertal females)

Recording of concomitant medications 

Assessment of AEs
*A subject may be discharged after completion of all assessments at 6 hours post treatment, if 
deemed medically stable in the investigator’s clinical judgment.   If this is the case, the 
assessments scheduled for 8 hours post treatment will be omitted.
8.3
Initial Icatibant-treated Attack 
8.3.1
Pretreatment (Baseline) Assessments (Day 1)
The following assessments will be performed at the initial icatibant-treated attack.  All 
evaluations and sample collections must be performed prior to treatment.  

Medical history 

Confirm inclusion/exclusion criteria 

Pubertal status determination (only if the subject was classified as prepubertal at the time 
of the screening visit)

Menstrual cycle history (in pubertal/postpubertal females only)

Physical examination

Vital signs

Height and weight

Subject self-assessment of HAE-related pain (in subjects 4 years of age and older) using 
diary FPS-R

Investigator assessment of HAE symptoms


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
Investigator assessment of HAE-related pain (in subjects younger than 4 years of age 
only) using FLACC

Clinical laboratory tests (serum chemistry, hematology and urinalysis)

Urine pregnancy test (in females of childbearing potential)

Reproductive hormone assessments

Pharmacokinetic sampling 

Immunogenicity evaluation

Recording of concomitant medications
8.3.2
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 
diary FPS-R (Day 1, 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] hours, 6 
[±0.5] hours and 8* [±0.5] hours post dose, Day 2 (24 [±4] hours), Day 3 (48 [±4] hours)

Investigator assessment of HAE symptoms (Day 1, 1 hour [±10 minutes], 2 hours 
[±10 minutes], 4 [±0.5] hours, 6 [±0.50] hours (and 8 [±0.5] hours if the subject is not 
discharged**) post dose)

Investigator assessment of HAE-related pain (in subjects younger than 4 of age only) 
using FLACC (Day 1, 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] hours, 6 
[±0.5] hours (and 8 [±0.5] hours if the subject is not discharged**) post dose)

Clinical laboratory tests (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])

Reproductive hormone assessments (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])

Injection site reaction evaluation (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours (and 8 
[±0.5] hours if the subject is not discharged**) post dose, Day 2 (24 [±4] hours), Day 3 
(48 [±4] hours), and Day 8 [±1 day])

Sampling for PK assessments in pubertal/post pubertal subjects (Day 1, 15 minutes [±5 
minutes], 30 minutes [±5 minutes], 45 minutes [±5 minutes], 1 hour [±10 minutes], 2 
hours [±10 minutes], 4 [±0.5] hours, 6 [±0.5] hours post dose at initial attack only)

Sampling for PK assessments in prepubertal subjects (Day 1, 15 minutes [±5 minutes], 
30 minutes [±5 minutes], 2 hours [±10 minutes], 4 [±0.5] hours, 6 [±0.5] hours post dose 
at initial attack only)

Safety follow-up contact (Day 2 (24 [±4] hours), Day 3 (48 [±4] hours) by telephone (If a 
subject remains hospitalized, this safety follow-up will be conducted in person.)

Immunogenicity evaluation (Day 8 [±1 day])

Recording of concomitant medications 

Assessment of AEs


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*A subject may be discharged after completion of all assessments at 6 hours post treatment, if 
deemed medically stable in the investigator’s clinical judgment and the subject’s HAE symptoms 
have resolved (the subject’s investigator-rated symptom score = zero, denoting the absence of 
symptoms).  
If this is the case, the assessments scheduled for 8 hours post treatment will be omitted with the 
exception of subject self-assessment of HAE-related pain using the 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.
8.3.3
Follow-up Visit (Day 90 ±7 days)
In the event that a subject has a subsequent HAE attack within the 90 day follow-up period for 
the first treatment, the date of the Day 90 follow-up visit for the first treatment remains the same.  
Each subsequent treatment will have a corresponding Day 90 follow-up visit.

Physical examination

Vital signs

Height and weight

Clinical laboratory tests (serum chemistry, hematology, and urinalysis)

Urine pregnancy test (in females of childbearing potential)

Reproductive hormone assessments

Immunogenicity evaluation 

Menstrual cycle history (in pubertal/postpubertal females)

Recording of concomitant medications

Assessment of AEs

Documentation of HAE attack(s) not treated with icatibant
8.3.4
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 Icatibant-treated Attacks (Pubertal/Postpubertal Subjects Only)
Pubertal/postpubertal subjects may receive treatment for up to 2 subsequent HAE attacks, 
contingent upon having received an initial icatibant treatment and presenting with a subsequent 
acute attack of at least 3 days after prior treatment (see Section 4.1.3).
For subsequent attacks, study drug may be administered by study site personnel at the 
hospital/study center or by qualified home healthcare personnel at the subject’s home.  
Alternatively, a parent/legal guardian/caregiver will be allowed to administer or the subject 
(under the supervision of a parent/legal guardian/caregiver) will be allowed to self-administer the 
investigational product after having received appropriate training.  For all subsequent laryngeal 
attacks, subjects should be advised to seek medical attention in an appropriate healthcare facility 
immediately following treatment with icatibant.    
8.4.1
Subsequent Icatibant-treated Attack Baseline Assessments
All evaluations and sample collections must be performed at the hospital/study center within 
6 months prior to treatment:

Confirm inclusion/exclusion criteria 

Menstrual cycle history (in pubertal/postpubertal females only)

Documentation of HAE attack(s) not treated with icatibant

Physical examination

Vital signs

Height and weight

Clinical laboratory tests (serum chemistry and hematology)

Urine pregnancy test (in females of childbearing potential)

Reproductive hormone assessments

Immunogenicity evaluation

Recording of concomitant medications 

Assessment of AEs

Training for parent/legal guardian/caregiver on how to assess HAE symptoms using the 
5-point rating scale, time to initial symptom relief, and injection site reactions (for 
subjects who have expressed interest in self-administering or having a parent/legal 
guardian/caregiver administer icatibant in the home)

Training on icatibant administration (for subjects who have expressed interest in self-
administration or having a parent/legal guardian/caregiver administer icatibant in the 
home)

Dispense 1 syringe of study drug (for subjects who have expressed interest in being 
treated at home by a home healthcare provider, parent/legal guardian/caregiver, or self-
administration)

Instruct the subject (parent/legal guardian/caregiver) to record a weight measurement 
every month and to contact the hospital/study center to confirm dosing (for subjects who 
have expressed interest in being treated at home by a home healthcare provider,
parent/legal guardian/caregiver, or self-administration)


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
Instruct the subject (parent/legal guardian/caregiver) to contact the hospital/study center 
(or their home healthcare professional in the event the investigator is not available) at the 
time of a subsequent attack to confirm the HAE attack diagnosis.  
8.4.2
Treatment Period (Day 1 to Day 8 [± 1 Day])
8.4.2.1
Day of Subsequent Attack (Day 1)
When a pubertal/postpubertal subject experiences an acute HAE attack, subjects (parent/legal 
guardian/caregiver) will contact the hospital/study center (or their home healthcare professional 
in the event the investigator is not available) to confirm the HAE attack diagnosis.  
The investigator (or the home healthcare professional in the event the investigator is not 
available), in consultation with the subject's preference, will determine whether the subject will 
be treated at the hospital/study center, at home by a qualified home healthcare personnel, at 
home by the trained parent/legal guardian/caregiver, or by self-administration.  The qualified 
home healthcare person will be contacted, if applicable.
The following will occur prior to study drug administration:
Subject Treated at 
Study Site
Subject Treated at 
Home
Call hospital/study center (or their home 
healthcare professional in the event the 
investigator is not available) to confirm the 
HAE attack diagnosis
X
X
Investigator Symptom Score
X
Home Healthcare Provide or Parent/Legal 
Guardian/Caregiver Symptom Score
X
X
Subject Self-Assessment of Pain
X
X
Urine pregnancy test
X
X
Concomitant Medications
X
X
Adverse Events
X
X

Assessment of HAE symptoms
o
The investigator will assess HAE symptoms using the Investigator Symptom 
Score if the subject is treated at the hospital/study center
o
The home healthcare provider will assess HAE symptoms using the Home 
Healthcare Provider or Parent/Legal Guardian/Caregiver Symptom Score if the 
subject is treated at home
o
The parent/legal guardian/caregiver will assess HAE symptoms using the Home 
Healthcare Provider or Parent/Legal Guardian/Caregiver Symptom Score if the 
subject is treated at either the hospital/study site or at home

Subject will self-assess HAE-related pain using diary FPS-R

Urine pregnancy test for females of child-bearing potential

Concomitant medications will be recorded

Adverse events will be recorded


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Once the pretreatment assessments are completed, icatibant will be administered 
(Day 1, Time 0).

Study drug may be administered by study site personnel at the hospital/study center or by 
qualified home healthcare personnel at the subject’s home.  Alternatively, a parent/legal 
guardian/caregiver will be allowed to administer or the subject (under the supervision of 
a parent/legal guardian/caregiver) will be allowed to self-administer the investigational 
product after having received appropriate training.  

For all subsequent laryngeal attacks, subjects should be advised to seek medical attention 
in an appropriate healthcare facility immediately following treatment with icatibant.
The subject will be observed by the investigator, the home healthcare provider or the 
parent/guardian/caregiver for a minimum of 2 hours after icatibant administration.  
The following will occur after icatibant administration: 
Subject Treated at 
Study Site
Subject Treated at 
Home
Icatibant Administration
X
X
Investigator Symptom Score
X
Home Healthcare Provide or Parent/Legal 
Guardian/Caregiver Symptom Score
X
X
Subject Self-Assessment of Pain
X
X
Injection site reaction evaluation
X
X
Concomitant Medications
X
X
Adverse Events
X
X
Contact site 6 to 8 hours after attack
X
X

HAE symptoms will be assessed at Day 1, 1 hour [±10 minutes] post dose and 2 hours 
[±10 minutes] post dose AND every 2 hours [±10 minutes] until the subject’s symptoms 
are absent or mild [if the subject’s symptoms are not absent or mild at 2 hours post dose])  
o
The investigator will assess HAE symptoms using the Investigator Symptom 
Score and record the time of initial symptom relief if the subject is treated at the 
hospital/study center
o
The home healthcare provider will assess HAE symptoms using the Home 
Healthcare Provider or Parent/Legal Guardian/Caregiver Symptom Score and 
record the time of initial symptom relief if the subject is treated at home
o
The parent/legal guardian/caregiver will assess HAE symptoms using the Home 
Healthcare Provider or Parent/Legal Guardian/Caregiver Symptom Score if the 
subject is treated at either the hospital/study site or at home

The subject will self-assess pain using diary FPS-R (1 hour [±10 minutes] post dose and 
2 hours [±10 minutes] post dose, and every 2 hours [±10 minutes] until pain is absent 
[if the subject’s pain is not absent at 2 hours post dose]);


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
Injection site reaction will be recorded (1 hour [±10 minutes] post dose and 
2 [±0.5] hours post dose, and every 2 [±0.5] hours until injection site reaction is mild or 
absent [if the subject’s injection site reaction is not mild or absent at 2 hours post dose]); 

Concomitant medications will be recorded

Adverse events will be recorded

Subjects (parent/legal guardian/caregiver) will contact the hospital/study center 6 to 
8 hours after icatibant administration to update the investigator of the subject’s condition
8.4.2.2
Day 2(24 [± 4] hours)
On Day 2 (24 [± 4] hours):

The subject will self-assess HAE pain using diary FPS-R

Injection site reaction will be recorded

Concomitant medications will be recorded

Adverse events will be recorded
8.4.3
Follow-up Visits 
Each treatment for a subsequent attack will require a Day 8 and a Day 90 follow up visit.  If a 
subsequent attack occurs within 3 days of the Day 8 follow-up visit for the previous attack, the 
visits for Day 1 (of the subsequent icatibant-treated attack) and Day 8 (of the prior icatibant-
treated attack) will be combined.  If a subsequent attack occurs within 7 days of the Day 90 
follow-up visit for the previous attack, the visits for Day 8 (of the subsequent icatibant-treated 
attack) and Day 90 (of the prior icatibant-treated attack) will be combined.
8.4.3.1
Day 8 (±1 day)
The subject will return to the hospital/study on Day 8 (±1 day).  The following evaluations and 
sample collections will be performed on Day 8:

Vital signs

Reproductive hormone assessments

Immunogenicity evaluation 

Injection site reaction evaluation

Concomitant medications will be recorded

Adverse events will be recorded
8.4.3.2
Day 90 (±7 days)

Physical examination

Vital signs

Height and weight

Clinical laboratory tests (serum chemistry, hematology)

Urine pregnancy test (in females of childbearing potential)

Reproductive hormone assessments

Immunogenicity evaluation

Menstrual cycle history (in pubertal/postpubertal females)


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
Recording of concomitant medications

Assessment of AEs

Documentation of HAE attack(s) not treated with icatibant


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


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10.4
Demographics and Baseline Characteristics
Demographic data and pretreatment characteristics will be summarized separately for the Safety 
Population and the Efficacy Population. 
10.5
Pharmacokinetic Analysis
A primary objective of the study is to investigate the PK of a single SC injection of icatibant in 
pediatric subjects.  All PK analyses will use the PK population.
Plasma concentrations of icatibant and metabolites (ie, M1 and M2) and actual blood sampling 
times will be listed by subject and sampling time.  Plasma concentrations will be summarized 
using descriptive statistics (number, mean and standard deviation).  Pharmacokinetic parameters 
for icatibant and metabolites will be listed by subject and will be summarized using descriptive 
statistics (number, mean, standard deviation, coefficient of variation, geometric mean, minimum, 
median, maximum).  Individual and mean plasma concentrations of icatibant and metabolites 
versus time will be displayed on linear and semi-logarithmic axes.
10.5.1
Estimation of PK Parameters
10.5.1.1
Noncompartmental Modeling
For subjects in whom the number of samples is sufficient to permit noncompartmental modeling, 
individual and mean PK parameters will be computed for icatibant and metabolites (M1 and M2) 
using standard noncompartmental methods, where possible, using the WinNonLin software 
package (Pharsight Corp., Mountain View, CA).  For descriptive statistical tabulation of mean 
plasma concentrations and graphical displays, nominal collection times will be used, while all 
PK analysis and parameter calculations will use actual collection times.  Plasma concentrations
<limit of quantification (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 predose to the first concentration ≥LOQ will be treated 
as 0 and those that occur thereafter will be treated as missing.
Pharmacokinetic parameter estimates will include, where appropriate:  icatibant and metabolite 
concentrations at each sampling time, Tmax, actual peak (Cmax) and minimum (Cmin) 
concentrations, CL/F, AUC0-last and AUC0-inf, MRT, volume of distribution at steady state (Vss/F) 
and t1/2.
The distribution of continuous data will be evaluated using parametric tests.  A transformation, 
such as logs, will be used where appropriate.  Multiple regression analysis, with an appropriate 
transformation on the dependent variable, will be used to assess the contribution of potential PK 
covariates while controlling for demographic covariates (eg, subject’s age and gender) to the
inter-subject variability of icatibant PK parameters.  The multivariable analysis will be 
considered the primary statistical analysis.  A p-value of 0.05 will be considered statistically 
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10.5.1.2
Compartmental Modeling Using Population Methods 
Nonlinear mixed effects modeling will be used to define individual subject profiles and if 
possible, parameter estimates.  The structural PK model will be developed and validated using 
PK information obtained from adult subjects and will enable delineation of the impact of age-
dependent changes on icatibant disposition.  Development of this model will allow for 
characterization and better prediction of the dose-concentration-exposure relationship for 
icatibant in pediatric subjects.  Population PK modeling will be performed with nonlinear mixed 
effect modeling software (eg, NONMEM, Globomax LLC or WinNonMix, Pharsight Corp.).  
The program will estimate the inter- and intra-individual variability of PK parameter estimates.  
Both weight-normalization and allometric scaling principles will be evaluated.  For selecting 
preliminary meaningful covariates the general additive model (GAM) analysis will be used.  
Variables to be considered will include (but are not limited to):  age, sex, ethnicity, total and lean 
bodyweight (TBW, LBW), body mass index (BMI), and body surface area (BSA).
Monte Carlo simulation experiments based on the model(s) developed above may be performed 
by a validated simulation software program (eg, Trial Simulator, Pharsight Corp.) to assess the 
response patterns for various dosage regimens of icatibant treatments in the pediatric population.
10.6
Safety and Tolerability Analyses
Another key objective of the study is to investigate the safety and tolerability of a single SC dose 
of icatibant in pediatric subjects treated with icatibant for the first time or treated with icatibant 
more than once.  The corresponding analyses will be based on the Safety Population.
The safety and tolerability parameters include AEs, vital signs, ECG, local tolerability at the 
injection site, reproductive hormone levels, immunogenicity, and standard hematology, serum 
chemistry, and urinalysis.
Adverse events will be categorized using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 16.0. The assessment of safety will be based mainly on the frequency of 
treatment emergent AEs. Adverse events will be summarized by system organ class (SOC) and 
preferred term. The number and proportion of subjects experiencing an AE will be tabulated by 
the stratification group and icatibant exposure number. Adverse events by SOC and preferred 
term also will be tabulated by severity and by relationship to treatment. In the case of multiple 
occurrences of the same AEs (at the preferred term level) in an individual subject, the AE that is 
classified as the most severe (ie, maximum severity) will be identified for the analysis by 
severity and the AE that has the highest relationship to investigational product will be identified 
for the analysis by relationship. Serious adverse events will be provided in a data listing.
Laboratory data will be listed by subject, stratification group and icatibant exposure number.  
Subjects with newly occurring abnormalities outside the normal range will be flagged and listed 
separately.  Observed values and changes from pretreatment values will be summarized by the 
stratification group and icatibant exposure number.  Shift tables will also be tabulated by 
stratification group, icatibant exposure number, and study time point.
Vital signs data will be listed by subject, stratification group, and icatibant exposure number. 
Furthermore, observed values and changes from baseline will be summarized by stratification 


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group and icatibant exposure number.  Shift tables may be presented, utilizing reference ranges. 
Subjects with notably abnormal values will be identified and listed separately along with their 
values.
Local tolerability will be tabulated and summarized according to the type and severity of the 
injection site reaction.
The impact of icatibant on the reproductive hormone levels will be assessed by presenting 
tabular summaries for FSH, LH, estradiol, and progesterone for females, and FSH, LH, and 
testosterone for males.  The change from baseline values will also be summarized.  Subjects with 
newly occurring abnormalities outside the normal range will be flagged and listed separately.
Data from other tests (eg, immunogenicity, ECG) will be listed and summarized as appropriate.
10.7
Efficacy Analyses
Efficacy analyses will be performed on the Efficacy Population.  The primary efficacy endpoint 
is the time to onset of symptom relief measured using the investigator-reported symptom score. 
For the initial icatibant-treated attack, 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.  For subsequent icatibant-treated 
attacks, the investigator will report symptom scores at pretreatment and 1 and 2 hours post 
treatment, and every 2 hours afterwards until discharge.  Eight symptoms will be assessed for 
abdominal and cutaneous attacks, and 13 symptoms will be assessed for laryngeal attacks.  Time 
to onset of symptom relief is defined as the earliest time post treatment at which there is a 20% 
improvement in the average post-treatment symptom score with no worsening of any single 
component score. The median time and the 95% confidence interval will be calculated using the 
Kaplan-Meier methodology.
A tabular summary of the average investigator-reported symptom score and the change from 
baseline in the average investigator-reported symptom score will be presented by the 
stratification group and the icatibant exposure number.  An alternative analysis will focus on the 
time to minimal symptoms and is defined as the time from study drug administration to the 
earliest time post treatment when all symptoms are either absent or mild.  The median time and 
95% confidence interval will be calculated using Kaplan-Meier methodology. 
For individual investigator-reported symptom scores, a shift table from baseline will be 
presented for each post-treatment time point.  The analysis will be repeated to assess shift in the 
individual symptom scores from the 2 hour time-point. Also, for individual symptoms that are 
moderate or worse at pretreatment, the median and 95% confidence interval will be presented for 
the time to the symptom being mild or absent. 
Two subsets of subjects, those 4 years of age or older and those below 4 years of age, will have 
assessment of pain using the FPS-R and FLACC instruments, respectively.  For subjects ≥4 years 
of age, the time to onset of symptom relief is defined as the earliest time at which the post-
treatment score improves by at least one level.  The time to onset of symptom relief for subjects 
<4 years of age is defined as the earliest time at which a 20% improvement is seen in the total 
post-treatment score.  Additionally, time to minimal symptoms defined as the earliest time at 


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which the post-treatment score (or total post-treatment score for FLACC) improves to zero, will 
be analyzed.  The time to onset of symptom relief and time to minimal symptoms will be 
analyzed using the same methods as the primary efficacy endpoint. 
Home healthcare provider or parent/legal guardian/caregiver symptom scores (referred to as 
caregiver-reported symptom scores hereafter) will be measured for all subjects’ subsequent 
icatibant-treated attacks. A tabular summary of the average caregiver-reported symptom scores 
and the change from baseline in the average caregiver-reported symptom scores will be 
presented by the stratification group and the subsequent icatibant treated attack number.  For 
individual caregiver-reported symptom scores, a shift table from baseline will be presented for 
each post-treatment time point.
10.8
Other Analyses
The number and percentage of subjects who received rescue medications before the onset of 
symptom relief will be summarized by the stratification group and icatibant exposure number.  
Time to first use of rescue medication prior to symptom relief will be calculated from the time of 
investigational product administration to the first use of rescue medication prior to the onset of 
symptom relief.  The median time and the 95% confidence interval will be calculated using 
Kaplan-Meier methodology if there are at least 5 subjects for a given attack who used rescue 
medication prior to attaining symptom relief.
10.9
Data Monitoring and Interim Analysis
A DSMB will be set up to review the safety, tolerability, PK, and efficacy data on an ongoing 
basis.  The DSMB is described in Section 11.8; its goal will be to assess the risk/benefit of 
icatibant treatment in this pediatric population.  
An analysis of the data for DSMB review is planned after the first 4 subjects in the 
pubertal/postpubertal group have been treated, and will be repeated at subsequent time points as 
specified in the DSMB charter.  Because no formal hypothesis testing is planned, multiplicity 
concerns regarding repeated analyses are not an issue.
Based on the anticipated sequence of data being generated in the study, an initial interim analysis 
of the data from the initial attack (N=30) is planned.  It is expected that this will be followed by a 
final analysis to include the data of patients treated for subsequent attacks.  This sequence is 
based on the anticipated sequence of data being generated during the study and may be modified 
to fit the actual study conduct.
10.10 Handling of Missing Data
Individual pretreatment symptom scores, FPS-R scores, and FLACC scores will be assigned a 
value of zero. For missing post-treatment scores, imputation will be employed using the Last 
Observation Carried Forward (LOCF) approach. The pretreatment values may also be used in the 
imputation.  For missing or partial rescue medication dates, the imputation will be performed 
such that the earliest possible time post treatment will be assigned to the rescue medication use.  
A similar approach will be followed to determine treatment emergent AEs in case of missing or 
partial AE dates. 


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


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


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


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


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Any departures from the protocol must be fully documented as a protocol deviation.  Protocol 
deviations will need to be reviewed by the medical monitor and may also need to be submitted to 
the IRB/IEC.
Protocol modifications will only be initiated by the sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.10 Premature Closure of the Study
If the sponsor, investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable risk to 
subjects, the study may be terminated after appropriate consultation between the sponsor and the 
investigator.  In addition, a decision on the part of the sponsor to suspend or discontinue 
development of the investigational product may be made at any time.  Conditions that may 
warrant termination of the study or site include, but are not limited to:
The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled in the 
study
Failure of the investigator to comply with pertinent global regulations
Submission of knowingly false information from the study site to the sponsor or other pertinent 
regulatory authorities
Insufficient adherence by the Investigator to protocol requirements
11.11 Access to Source Documentation
Regulatory authorities, the IRB/IEC, or the sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, cross-checking with 
source documents, and clarification of administrative matters may be performed.
11.12 Data Generation and Analysis
The clinical database will be developed and maintained by a CRO or an electronic data capture 
technology provider as designated by Shire.  The sponsor or its designee will be responsible for 
performing study data management activities. 
Adverse events will be coded using MedDRA Version 8.1 or higher.  Concomitant medication 
will be coded using the World Health Organization Drug Dictionary (WHO-DD) (December 
2011). Centralized laboratories will be employed as described in the study manual to aid in 
consistent measurement of efficacy and safety parameters.
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 


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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.
Changes in status concerning financial interests during the study and for 1 year after its 
completion must be disclosed by the Investigator in accordance with 21 CFR Part 54. 
11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the sponsor and not 
previously published are considered confidential and will remain the sole property of the 
sponsor.  The investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies.  In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the sponsor with complete test results and all data developed 
in the study in a timely manner.
The investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire, 
provided Shire a copy of the draft document intended for publication, and obtained the written 
consent of Shire for such publication.  All information obtained during the conduct of this study 
will be regarded as confidential.  Shire will use the information for registration purposes and for 
the general development of the drug.


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12
LIST OF REFERENCES
Bieri, D., Reeve, R. A., Champion, G. D., Addicoat, L. & Ziegler, J. B. 1990. 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, 41, 139-50.
Bowen, T., Cicardi, M., Bork, K., Zuraw, B., Frank, M., Ritchie, B., Farkas, H., Varga, L., 
Zingale, L. C., Binkley, K., Wagner, E., Adomaitis, P., Brosz, K., Burnham, J., 
Warrington, R., Kalicinsky, C., Mace, S., Mccusker, C., Schellenberg, R., Celeste, L., 
Hebert, J., Valentine, K., Poon, M. C., Serushago, B., Neurath, D., Yang, W., Lacuesta, 
G., Issekutz, A., Hamed, A., Kamra, P., Dean, J., Kanani, A., Stark, D., Rivard, G. E., 
Leith, E., Tsai, E., Waserman, S., Keith, P. K., Page, D., Marchesin, S., Longhurst, H. J., 
Kreuz, W., Rusicke, E., Martinez-Saguer, I., Aygoren-Pursun, E., Harmat, G., Fust, G., 
Li, H., Bouillet, L., Caballero, T., Moldovan, D., Spath, P. J., Smith-Foltz, S., Nagy, I., 
Nielsen, E. W., Bucher, C., Nordenfelt, P. & Xiang, Z. Y. 2008. 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. Ann 
Allergy Asthma Immunol, 100, S30-40.
Davis, A. E., 3rd 2008. New treatments addressing the pathophysiology of hereditary 
angioedema. Clin Mol Allergy, 6, 2.
Farkas, H. 2010. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma 
Clin Immunol, 6, 18.
Hicks, C. L., Von Baeyer, C. L., Spafford, P. A., Van Korlaar, I. & Goodenough, B. 2001. The 
Faces Pain Scale-Revised: toward a common metric in pediatric pain measurement. Pain,
93, 173-83.
Hock, F. J., Wirth, K., Albus, U., Linz, W., Gerhards, H. J., Wiemer, G., Henke, S., Breipohl, G., 
Konig, W. & Knolle, J. 1991. Hoe 140 a new potent and long acting bradykinin-
antagonist: in vitro studies. British journal of pharmacology, 102, 769-73.
Knolle, J., Breipohl, G., Henke, S., Wirth, K. & Scholkens, B. 1992. New and highly potent 
bradykinin antagonists. Agents Actions Suppl, 38 ( Pt 1), 559-64.
Manworren, R. C. & Hynan, L. S. 2003. Clinical validation of FLACC: preverbal patient pain 
scale. Pediatric nursing, 29, 140-6.
Marshall, W. A. & Tanner, J. M. 1969. Variations in pattern of pubertal changes in girls. 
Archives of disease in childhood, 44, 291-303.
Marshall, W. A. & Tanner, J. M. 1970. Variations in the pattern of pubertal changes in boys. 
Archives of disease in childhood, 45, 13-23.
Merkel, S. I., Voepel-Lewis, T., Shayevitz, J. R. & Malviya, S. 1997. The FLACC: a behavioral 
scale for scoring postoperative pain in young children. Pediatric nursing, 23, 293-7.
Wirth, K., Hock, F. J., Albus, U., Linz, W., Alpermann, H. G., Anagnostopoulos, H., Henk, S., 
Breipohl, G., Konig, W. & Knolle, J. 1991. HOE 140 a new potent and long acting 
bradykinin-antagonist: in vivo studies. British journal of pharmacology, 102, 774-7.
Zuraw, B. L. 2008. Clinical practice. Hereditary angioedema. N Engl J Med, 359, 1027-36.


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Appendix 1
Study Schedule of Events (No Attack)
(Pubertal/postpubertal 
subjects only)
Screening
Period
Pre-
treatment
(Baseline) 
Treatment
Post Treatment
Follow-up
Month 6 
(±7 days) 
Telephone 
Contact
Study Day
Day 1
Day 1
Day 1
Day 
2
Day 
3
Day 
8 
(±1)
Day 
90 
(±7)
Time Post Treatment (hours) 
0
0.25 0.5 0.75 
1
2
4 
6 
8
24 
48 
Window (hours or minutes) 
(±5) 
min
(±5) 
min
(±5) 
min
(±10) 
min
(±10) 
min
(±0.5) 
hr
(±0.5) 
hr
(±0.5) 
hr
(±4) 
hr
(±4) 
hr
Assessments
Informed Consent/Assent
X
Medical History 
X
X
Documentation of HAE 
Attack(s) Not Treated with 
icatibant
Xf
X
Documentation of Pubertal 
Changes/Milestones
X
Confirm Documented HAE 
Diagnosis (via Sponsor’s central 
lab)
X
C1-INH Assessment
X
Inclusion/Exclusion Assessment
X
Xa
Physical Examination 
X
X
X
Xe
X
X 
Pubertal Status Determinationb
X
X


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(Pubertal/postpubertal 
subjects only)
Screening
Period
Pre-
treatment
(Baseline) 
Treatment
Post Treatment
Follow-up
Month 6 
(±7 days) 
Telephone 
Contact
Study Day
Day 1
Day 1
Day 1
Day 
2
Day 
3
Day 
8 
(±1)
Day 
90 
(±7)
Time Post Treatment (hours) 
0
0.25 0.5 0.75 
1
2
4 
6 
8
24 
48 
Window (hours or minutes) 
(±5) 
min
(±5) 
min
(±5) 
min
(±10) 
min
(±10) 
min
(±0.5) 
hr
(±0.5) 
hr
(±0.5) 
hr
(±4) 
hr
(±4) 
hr
Assessments
Menstrual Cycle History (in 
pubertal/postpubertal females)
X
X
Vital Signs
X
X
X
X
Xe
X
X 
ECG
X
X
Xe
Height and Weight
X
X
X
Clinical Laboratory Tests
(serum chemistry, hematology, 
urinalysis)
X
X
X
X 
Urine Pregnancy Test
(in females of childbearing 
potential)
X
X
X
Reproductive Hormone 
Assessments 
(FSH, LH, estradiol, 
progesterone in females; FSH, 
LH, testosterone in males)
X
X
X
X


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(Pubertal/postpubertal 
subjects only)
Screening
Period
Pre-
treatment
(Baseline) 
Treatment
Post Treatment
Follow-up
Month 6 
(±7 days) 
Telephone 
Contact
Study Day
Day 1
Day 1
Day 1
Day 
2
Day 
3
Day 
8 
(±1)
Day 
90 
(±7)
Time Post Treatment (hours) 
0
0.25 0.5 0.75 
1
2
4 
6 
8
24 
48 
Window (hours or minutes) 
(±5) 
min
(±5) 
min
(±5) 
min
(±10) 
min
(±10) 
min
(±0.5) 
hr
(±0.5) 
hr
(±0.5) 
hr
(±4) 
hr
(±4) 
hr
Assessments
Investigational Product 
Administration (single SC dose)
X
Safety Follow-up Contact 
Xc
Xc
Injection Site Reaction 
Evaluation
X
X
Xe
Xc
Xc
X
PK Samplingd
X
X
X
X
X
X
X
X
Immunogenicity Evaluation
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Xe
Xc
Xc
X
X
Adverse Events 
X
X
X
X
X
X
X
X
Xe
Xc
Xc
X
X


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(Pubertal/postpubertal 
subjects only)
Screening
Period
Pre-
treatment
(Baseline) 
Treatment
Post Treatment
Follow-up
Month 6 
(±7 days) 
Telephone 
Contact
Study Day
Day 1
Day 1
Day 1
Day 
2
Day 
3
Day 
8 
(±1)
Day 
90 
(±7)
Time Post Treatment (hours) 
0
0.25 0.5 0.75 
1
2
4 
6 
8
24 
48 
Window (hours or minutes) 
(±5) 
min
(±5) 
min
(±5) 
min
(±10) 
min
(±10) 
min
(±0.5) 
hr
(±0.5) 
hr
(±0.5) 
hr
(±4) 
hr
(±4) 
hr
Assessments
Abbreviations:  FLACC  = Faces, Legs, Activity, Cry, and Consolability (comportmental pain scale); FPS-R = Faces Pain Scale-Revised; FSH =  follicle 
stimulating hormone; HAE = hereditary angioedema; hr = hour; LH = luteinizing hormone min = minute; PK = pharmacokinetic; SC = subcutaneous
a
The inclusion/exclusion criteria will be confirmed at the Pretreatment (Baseline) Visit.
b
A subject’s classification as prepubertal or pubertal/postpubertal will be determined at the Day 1 pretreatment visit.  Note that a subject classified as 
pubertal/postpubertal at screening will not require further evaluation of pubertal status during the study.
c
These assessments may be conducted by telephone contact.
d
The PK sampling times shown are for pubertal/postpubertal subjects.  
e
A subject may be discharged after completion of all assessments at 6 hours post treatment, if deemed medically stable in the investigator’s clinical judgment. 
If this is the case, the assessments scheduled for 8 hours post treatment will be omitted.
f
For all subjects who remain enrolled in the study for longer than 6 months, a telephone contact will be scheduled every 6 months to collect information 
concerning HAE attacks not treated with icatibant in the study.


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Appendix 2
Study Schedule of Events (Initial Icatibant-treated Attack)
Initial Icatibant-treated 
Attack
(All Subjects)
Screening
Period
Pre-
treatment
(Baseline) 
Treatment
Post Treatment
Follow-up
Month 6 
(±7 days) 
Telephone 
Contact
Study Day
Day 1
Day 1
Day 1
Day 
2
Day 
3
Day 
8 
(±1)
Day 
90 
(±7)
Time Post Treatment (hours) 
0
0.25 0.5 0.75 
1
2
4 
6 
8e
24 
48 
Window (hours or minutes) 
(±5) 
min
(±5) 
min
(±5) 
min
(±10) 
min
(±10) 
min
(±0.5) 
hr
(±0.5) 
hr
(±0.5) 
hr
(±4) 
hr
(±4) 
hr
Assessments
Informed Consent/Assent
X
Medical History 
X
X
Documentation of HAE 
Attack(s) Not Treated with 
icatibant
Xh
X
Documentation of Pubertal 
Changes/Milestones
X
Confirm Documented HAE 
Diagnosis (via Sponsor’s 
Central Laboratory)
X
C1-INH Assessment
X
Inclusion/Exclusion 
Assessment
X
Xa
Physical Examination 
X
X
Xg
Xg
X
X 


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Initial Icatibant-treated 
Attack
(All Subjects)
Screening
Period
Pre-
treatment
(Baseline) 
Treatment
Post Treatment
Follow-up
Month 6 
(±7 days) 
Telephone 
Contact
Study Day
Day 1
Day 1
Day 1
Day 
2
Day 
3
Day 
8 
(±1)
Day 
90 
(±7)
Time Post Treatment (hours) 
0
0.25 0.5 0.75 
1
2
4 
6 
8e
24 
48 
Window (hours or minutes) 
(±5) 
min
(±5) 
min
(±5) 
min
(±10) 
min
(±10) 
min
(±0.5) 
hr
(±0.5) 
hr
(±0.5) 
hr
(±4) 
hr
(±4) 
hr
Assessments
Pubertal Status 
Determinationb
X
X
Menstrual Cycle History (in 
pubertal/postpubertal females)
X
X
Vital Signs
X
X
X
Xg
Xg
X
X 
ECG
X
Xg
Xg
Height and Weight
X
X
X
Subject Self-assessment of
HAE-related Pain Using diary 
FPS-R 
(in subjects 4 years of age and 
older, and before blood work, 
if applicable) 
X
X
X
X
Xf
Xe,f
X
X
Investigator Assessment of 
HAE Symptoms
X
X
X
X
Xf
Xf


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Initial Icatibant-treated 
Attack
(All Subjects)
Screening
Period
Pre-
treatment
(Baseline) 
Treatment
Post Treatment
Follow-up
Month 6 
(±7 days) 
Telephone 
Contact
Study Day
Day 1
Day 1
Day 1
Day 
2
Day 
3
Day 
8 
(±1)
Day 
90 
(±7)
Time Post Treatment (hours) 
0
0.25 0.5 0.75 
1
2
4 
6 
8e
24 
48 
Window (hours or minutes) 
(±5) 
min
(±5) 
min
(±5) 
min
(±10) 
min
(±10) 
min
(±0.5) 
hr
(±0.5) 
hr
(±0.5) 
hr
(±4) 
hr
(±4) 
hr
Assessments
Investigator Assessment of 
HAE-related Pain Using 
FLACC 
(in subjects younger than 4 
years of age, and before blood 
work, if applicable)
X
X
X
X
Xf
Xf
Clinical Laboratory Tests
(serum chemistry, 
hematology, urinalysis)
X
X
X
X 
Urine Pregnancy Test
(in females of childbearing 
potential)
X
X
X
Reproductive Hormone 
Assessments 
(FSH, LH, estradiol, 
progesterone in females; FSH, 
LH, testosterone in males)
X
X
X
X


Icatibant (FIRAZYR)
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Initial Icatibant-treated 
Attack
(All Subjects)
Screening
Period
Pre-
treatment
(Baseline) 
Treatment
Post Treatment
Follow-up
Month 6 
(±7 days) 
Telephone 
Contact
Study Day
Day 1
Day 1
Day 1
Day 
2
Day 
3
Day 
8 
(±1)
Day 
90 
(±7)
Time Post Treatment (hours) 
0
0.25 0.5 0.75 
1
2
4 
6 
8e
24 
48 
Window (hours or minutes) 
(±5) 
min
(±5) 
min
(±5) 
min
(±10) 
min
(±10) 
min
(±0.5) 
hr
(±0.5) 
hr
(±0.5) 
hr
(±4) 
hr
(±4) 
hr
Assessments
Investigational Product 
Administration (single SC 
dose)
X
Safety Follow-up Contact 
Xc
Xc
Injection Site Reaction 
Evaluation
X
Xf
Xf
Xc
Xc
X
PK Samplingd
X
X
X
X
X
X
X
X
Immunogenicity Evaluation
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
Xf
Xf
Xc
Xc
X
X
Adverse Events 
X
X
X
X
X
X
X
Xf
Xf
Xc
Xc
X
X


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Initial Icatibant-treated 
Attack
(All Subjects)
Screening
Period
Pre-
treatment
(Baseline) 
Treatment
Post Treatment
Follow-up
Month 6 
(±7 days) 
Telephone 
Contact
Study Day
Day 1
Day 1
Day 1
Day 
2
Day 
3
Day 
8 
(±1)
Day 
90 
(±7)
Time Post Treatment (hours) 
0
0.25 0.5 0.75 
1
2
4 
6 
8e
24 
48 
Window (hours or minutes) 
(±5) 
min
(±5) 
min
(±5) 
min
(±10) 
min
(±10) 
min
(±0.5) 
hr
(±0.5) 
hr
(±0.5) 
hr
(±4) 
hr
(±4) 
hr
Assessments
Abbreviations:  FLACC  = Faces, Legs, Activity, Cry, and Consolability (comportmental pain scale); FPS-R = Faces Pain Scale-Revised; FSH =  follicle 
stimulating hormone; HAE = hereditary angioedema; hr = hour; LH = luteinizing hormone min = minute; PK = pharmacokinetic; SC = subcutaneous
a
The inclusion/exclusion criteria will be confirmed at the Pretreatment (Baseline) Visit.
b
A subject’s classification as prepubertal or pubertal/postpubertal will be determined at the Day 1 pretreatment visit.  Note that a subject classified as 
pubertal/postpubertal at screening will not require further evaluation of pubertal status during the study.
c
These assessments may be conducted by telephone contact.
d
The PK sampling times shown are for pubertal/postpubertal subjects.  Prepubertal subjects will have blood samples drawn on Day 1 prior to dosing and at 15 
(±5) minutes, 30 (±5) minutes, 2 hours (±10 minutes), 4 (±0.5) hours, and 6 (±0.5) hours post dose as indicated in Section 8.3.2.
e
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 diary 
FPS-R. 
f
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.
g
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.
h
For all subjects who remain enrolled in the study for longer than 6 months, a telephone contact will be scheduled every 6 months to collect information 
concerning HAE attacks not treated with icatibant in the study.


Icatibant (FIRAZYR)
Clinical Trial Protocol Amendment: HGT-FIR-086
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Appendix 3
Study Schedule of Events (Subsequent Icatibant-treated Attacks)  
Subsequent 
Icatibant-
Treated Attack 
Baseline a
(Site)
Every 
Month 
after 
Baseline
(Home)b
Treatment
Post Treatment
Day 1
(Site or Home)
Day 2
(Home)
Day 8 
(±1)c
(Site)
Day 90 
(±7)c
(Site)
Time Post Treatment (hours) 
Prior to 
Dosing
0
1 
2 
6-8
24 
Window (hours or minutes) 
(±10) min (±10) min (±4) hr (±4) hr
Assessments
Inclusion/Exclusion Assessment
X
X
Menstrual Cycle History
X
X
Documentation of HAE Attack(s) Not Treated with 
icatibant
X
X
X
Physical Examination 
X
X 
Vital Signs
X
X
X
Height and Weight
X
X
Clinical Laboratory Tests (serum chemistry/hematology)
X
X
Urine Pregnancy Test (in females of childbearing 
potential)
X
X
X
Reproductive Hormone Assessments (FSH, LH, estradiol, 
progesterone in females; FSH, LH, testosterone in males)
X
X
X
Immunogenicity Evaluation
X
X
X
Training on icatibant administration d
X
Training on how to assess HAE symptoms, time to initial 
symptom relief, and injection site reactions d
X
Dispense 1 syringe of icatibant d
X
Contact investigator with weight to confirm dose d
X
Contact investigator in the event of an HAE attack
Xb
Investigational Product Administration (single SC dose)
Xe
Subject Self-assessment of HAE-related Pain Using FPS-R
X
X
Xf
Xf
X
Investigator Assessment of HAE Symptoms
Xg
Xg,h
Xg,h
Xg,h
Home Healthcare Provider or Parent/Legal 
Guardian/Caregiver Assessment of HAE Symptoms
X
Xh
Xh
Xh
Record Injection Site Reactions 
Xb, i
Xb, i
Xb, i
Xe
X
Safety Follow-up Contact
Xb
Concomitant Medications
X
X
Xb
Xb
Xb
Xb
Xb
Xb
X
X
Adverse Events 
X
X
Xb
Xb
Xb
Xb
Xb
Xb
X
X


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Subsequent 
Icatibant-
Treated Attack 
Baseline a
(Site)
Every 
Month 
after 
Baseline
(Home)b
Treatment
Post Treatment
Day 1
(Site or Home)
Day 2
(Home)
Day 8 
(±1)c
(Site)
Day 90 
(±7)c
(Site)
Time Post Treatment (hours) 
Prior to 
Dosing
0
1 
2 
6-8
24 
Window (hours or minutes) 
(±10) min (±10) min (±4) hr (±4) hr
Assessments
Return study drugd
X
Abbreviations: FPS-R=Faces Pain Scale-Revised; FSH=follicle stimulating hormone; HAE=hereditary angioedema; LH=luteinizing hormone; SC = subcutaneous
a
All evaluations and sample collections must be performed at the hospital/study center within 6 months prior to treatment if a repeat attack does not occur 
within 6 months.  If a second “baseline” visit is conducted due to lack of repeat attacks, one of the monthly phone calls may overlap with the onsite visit.  In 
this case, a monthly call would not be necessary.  
b
These assessments may be conducted by telephone contact.
c
If a subsequent attack occurs within 3 days of the Day 8 follow-up visit for the previous attack, the visits for Day 1 (of the subsequent icatibant-treated 
attack) and Day 8 (of the prior icatibant-treated attack) will be combined.  If a subsequent attack occurs within 7 days of the Day 90 follow-up visit for the 
previous attack, the visits for Day 8 (of the subsequent icatibant-treated attack) and Day 90 (of the prior icatibant-treated attack) will be combined.
d
For subjects who have expressed an interest in self-administering or having a parent/legal guardian/caregiver administer icatibant in the home.
e
For subsequent attacks, study drug may be administered by study site personnel at the hospital/study center or by qualified home healthcare personnel at the 
subject’s home.  Alternatively, a parent/legal guardian/caregiver will be allowed to administer or the subject (under the supervision of a parent/legal 
guardian/caregiver) will be allowed to self-administer the investigational product after having received appropriate training.  For all subsequent laryngeal 
attacks, subjects should be advised to seek medical attention in an appropriate healthcare facility immediately following treatment with icatibant.
f
If after the completion of the assessments scheduled for 2 hours post-treatment, the subject’s pain is absent, no further Day 1 assessments are required.  If the 
subject’s pain at 2 hours post-treatment is NOT absent, the subject will be assessed every 2 hours until pain is absent.
g
For subjects treated at the hospital/study center only.
h
The subject will be observed for a minimum of 2 hours after icatibant administration.  If after the completion of the assessments scheduled for 2 hours post-
treatment, the subject’s symptoms are absent or mild, no further Day 1 assessments are required.  If the subject’s symptoms at 2 hours post-treatment are 
moderate, severe, or very severe, the subject will be assessed every 2 hours until the subject’s symptoms are absent or mild.
i
Injection site reaction will be recorded (1 hour [±10 minutes] post dose and 2 [±0.5] hours post dose, and every 2 [±0.5] hours until injection site reaction is 
mild or absent (if the subject’s injection site reaction is not mild or absent at 2 hours post dose)


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


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


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




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Appendix 8
Summary of Changes for Amendment 4 
1. Amendment Summary and Rationale
This amendment modifies the study parameters for HGT-FIR-086 in order to facilitate 
participation in the subsequent HAE attack phase of the study and make the study less 
burdensome for pubertal/postpubertal subjects. 
The revised study design includes the following:

For subsequent attacks, study drug may be administered by study site personnel at the 
hospital/study center or by qualified home healthcare personnel at the subject’s home.  
Alternatively, a parent/legal guardian/caregiver will be allowed to administer or the 
subject (under the supervision of a parent/legal guardian/caregiver) will be allowed to 
self-administer the investigational product after having received appropriate training.  For 
all subsequent laryngeal attacks, subjects should be advised to seek medical attention in 
an appropriate healthcare facility immediately following treatment with icatibant.  

Shortens the monitoring following subsequent attacks to a minimum of 2 hours after 
treatment. 
Shire believes that the proposed study modifications will still allow for the generation of an 
adequate safety and efficacy data for subsequent attacks in pubertal/postpubertal subjects and 
therefore will continue to fulfill the overall objective of the protocol.
2. Detailed Summary of Changes for the Amendment
This is a section that has been updated to describe the changes from the previous protocol 
version.  Significant changes and additions to the protocol text are captured below. 
Changes in grammar, spelling, punctuation, format, minor editorial changes (including 
re-ordering of text or other edits for consistency and clarity), updates to the list of abbreviations 
and cross-references are not reflected in the change summary.
Bold underline text indicates new text.  Italicized text indicates moved text. Strikethrough text 
indicates deleted text.
CHANGES TO TEXT 
Section impacted by change: Cover page
Revised Text:  
Shire Orphan Therapies, Inc.LLC


Ic ati b a nt (F I R A Z Y R)
Cli nic al Tri al Pr ot oc ol A m e n d me nt: H G T- FI R-0 8 6
1 8 M arc h 2 0 1 6
S hire
C o nfi de nti al
9 0
Secti o n i m pacte d b y c ha n ge : C o ver pa ge
Re vise d Te xt:  
, M D, P h D M P H
S hire H u ma n Ge netic T hera pies ( H G T), I nc.
M o bile: 
 
Secti o n i m pacte d b y c ha n ge : S y n o psis
U p date d t o reflect t he c ha n ges t o t he pr ot oc ol.
Sect i o n i m pacte d b y c ha n ge: Secti o n 1. 2. 2 , O ver vie w of t he Safet y a n d Efficac y of S u bc uta ne o us Icati ba nt i n 
Cli nical St u dies
Re vise d Te xt: 
Des pite t he rarit y of H A E, a r o b ust cli nical dataset s u p p orts t he safet y of icati ba nt.  As of 1 8 A pril 2 0 1 3, I n 
re gistr a ti o n al cli nic al st u dies, a t otal of 2 2 1 4 d oses of S C 1, 4 1 1 H A E att ac ks h a ve bee n tre ate d wit h 3 0 m g
icati ba nt ha ve bee n a d mi nistere d i n cli nical trials. S C b y a he alt hc are pr ofessi o n al   I n P hase I-III st u dies, icati ba nt 
has bee n a d mi nistere d b y a healt hcar e pr ofessi o nal t o 1 7 7 healt h y s u bjects a n d t o 2 6 9 s u bjects wit h H A E.  I n 
c o m plete d P hase III st u desst u dies, t he ma xi m u m n u m ber of icati ba nt-treate d attac ks i n a si n gle s u bject was 1 4 2 
( o ver a p pr o xi matel y 3 years) i n J E 0 4 9-2 1 0 2, 2 2 ( o ver a p pr o xi matel y 1. 5 y ears) i n J E 0 4 9 -2 1 0 3, a n d 3 4 ( o ver 
a p pr o xi matel y 3 years) i n H G T -FI R -0 5 4.
N e w  Te xt:
T he i niti al tre at me nt c o m p o ne nt of t he c urre nt st u d y is c o m plete   Sites will re m ai n o pe n t o c o m plete t he 
s u bse q ue nt ic ati b a nt-tre ate d att ac k p orti o n of t he st u d y.  T he results fr o m  a si n gle a d mi nistr ati o n of ic ati b a nt 
i n t his st u d y f o u n d:

S yste mic e x p os ure t o ic ati b a nt i n pe di atric s u bjects w as de m o nstr ate d.

Ic ati b a nt pr o vi de d r a pi d res ol uti o n of s y mpt o ms i n pe di atric H A E s u bjects. O ver all, t he m e di a n ti me 
t o o nset of s y mp t o m relief w as 1 0 h o ur ( 9 5 % CI: 1 0  1 1)  T he me di a n ti me t o o nset of s y m pt o m 
relief w as si mil ar bet wee n t he pre p u bert al s u bjects ( me di a n: 1. 0 h o ur; 9 5 % CI: 1. 0, 2. 0) a n d t he 
p u bert al/ p ost p u bert al s u bjects ( m e di a n: 1 0 h o ur; 9 5 % CI: 1 0  2 0)  O ver all  t he m e di a n ti me t o 
mi ni m a l s y m pt o ms w as 1. 1 h o urs ( 9 5 % CI: 1. 0, 2. 0). T he me di a n ti me t o mi ni mal s y m pt o ms w as 
si mil ar f or t he pre p u bert al s u bjects ( me di a n: 1 9 h o urs; 9 5 % CI: 1 0 2 0) a n d t he 
p u bert al/ p ost p u bert al s u bjects ( m e di a n: 1. 0 h o ur; 9 5 % CI: 1. 0, 2 . 0).

Ic ati b a nt w as ge ner all y well t oler ate d b y pe di atric s u bjects wit h H A E.  T he s afet y pr ofile w as 
f a v or a ble a n d c o nsiste nt wit h t he dise ase as well as pre vi o us e x perie nce wit h ic ati b a nt i n a d ult H A E 
s u bjects.  N o ne w s afet y si g n als were i de ntifie d.
Sec ti o n i m pacte d b y c ha n ge: Secti o n 4. 1. 1 , St u d y Desi g n
A d de d te xt:
S u bjects w h o re ac h t heir 1 8t h birt h d a y d uri n g t he c o urse of f oll o w -u p are all o we d t o re m ai n i n t he st u d y a n d 
recei ve s u bse q ue nt tre at me nts wit h ic ati b a nt acc or di n g t o t he pr ot oc ol   S u bjects will c o nti n ue t o recei ve 
ic ati b a nt as a si n gle, wei g ht-a dj uste d d ose of 0. 4 m g/ k g u p t o a m a xi m u m of 3 0 m g a d mi nistere d as a n S C 
i njecti o n
Secti o n i m pacte d b y c ha n ge : Secti o n 4. 1. 2 , St u d y Met h o d ol o g y
Re vise d te xt:
A s u bject’s classificati o n as pre p u be rtal or p u bertal/ p ost p u bertal will be deter mi ne d at scree ni n g a n d, if a p pr o priate,
P P D
P P D


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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 classified as prepubertal 
at screening will have their pubertal status reassessed at the time of their first icatibant-treated 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 with icatibant (whether during or in the 
absence of attack), PK, safety/tolerability, and efficacy (as appropriate) will be reviewed by an independent Data 
and Safety Monitoring Board (DSMB). The DSMB review of the first 4 subjects shall be completed prior to 
continuing enrollment of additional pubertal/postpubertal subjects, treatment of second and third HAE attacks in 
pubertal/postpubertal subjects, and initiating enrollment of subjects in the prepubertal group.
Initial Icatibant Treatment
After a qualifying screening period, the PK, safety/tolerability, and efficacy of treatment with SC icatibant will be 
evaluated in at least 20 subjects (10 prepubertal and 10 pubertal/postpubertal subjects) who present with cutaneous, 
abdominal, or laryngeal symptoms of an acute attack of HAE.  Subjects should initiate treatment with icatibant 
within 12 hours of the onset of symptoms; however, there are no prespecified attack severity criteria that are 
required for treatment.  Subjects with attacks considered to be mild, moderate, or severe are all potentially eligible to 
receive treatment with icatibant.  
The PK and safety/tolerability of SC icatibant will be evaluated in at least 10 additional pubertal/postpubertal 
subjects who meet screening criteria, but receive treatment with SC icatibant in the absence of a current acute HAE 
attack.
Initially, enrollment and dosing of pubertal/postpubertal subjects will precede that of prepubertal subjects.  After 
the first 4 subjects in the pubertal/postpubertal group have been treated with icatibant (whether during or in the 
absence of attack), PK, safety/tolerability, and efficacy (as appropriate) will be reviewed by an independent Data 
and Safety Monitoring Board (DSMB). The DSMB review of the first 4 subjects shall be completed prior to 
continuing enrollment of additional pubertal/postpubertal subjects, treatment of second and third HAE attacks in 
pubertal/postpubertal subjects, and initiating enrollment of subjects in the prepubertal group.
Subjects will receive treatment with a single SC administration of icatibant on Day 1 and will be monitored closely 
in the hospital/study center for at least 6 to 8 hours after treatment.  Subjects will undergo PK and safety 
assessments; efficacy assessments will be performed if treatment occurs during an acute HAE attack.  All subjects 
will have serum reproductive hormone measurements.  
A subject may be discharged after completion of assessments at 6 hours post treatment, if deemed medically stable 
in the investigator’s clinical judgment and, if applicable, the subject’s HAE symptoms have resolved (the subject’s 
investigator-rated symptom score must be zero, denoting the absence of symptoms).  If HAE symptoms have not 
completely resolved at 6 hours (ie, the investigator-rated symptom score is >0), the subject shall remain in the 
hospital/study center for at least 8 hours after icatibant administration for further evaluation.
Telephone follow-up will occur at both 24 and 48 hours after treatment.  
Subjects will return to the hospital/study center for scheduled assessments on Day 8 and for a follow-up visit on Day 
90.
The investigator will schedule a telephone contact approximately 6 months after Day 1 of initial icatibant-
treatment to obtain specific updates concerning pubertal changes/milestones.
Subsequent Icatibant-Treated Attacks
After having received initial treatment with icatibant, either during or in the absence of attack, at least 10 
pubertal/postpubertal subjects who subsequently experience an acute HAE attack may continue to receive treatment 
with icatibant as a single SC administration per attack for a total of 3 eligible icatibant treated attacksicatibant
treatments.  Further treatment with icatibant is contingent upon presentation of an acute cutaneous, abdominal, or 
laryngeal attack of HAE at least 73 days after prior treatment.  All primary and secondary outcomes
For subsequent attacks, study drug may be administered by study site personnel at the hospital/study center 
or by qualified home healthcare personnel at the subject’s home   Alternatively  a parent/legal 
guardian/caregiver will be allowed to administer or the subject (under the supervision of a parent/legal 
guardian/caregiver) will be allowed to self-administer the investigational product after having received 
appropriate training.  For all subsequent laryngeal attacks, subjects should be advised to seek medical 
attention in an appropriate healthcare facility immediately following treatment with icatibant   
Except for PK determinations, all primary and secondary endpoints as above (including anti icatibant


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antibodies and reproductive hormones) will be measured in these pubertal/postpubertal subjects after each 
administration.  Note that for some of the pubertal/postpubertal subjects who receive further treatment, ie, those who 
provided PK and safety/tolerability measurements without an attack, their first icatibant-treated attack will represent 
their second on-study exposure to icatibant for safety analysis purposes.
In addition  for all subjects who remain enrolled in the study  a safety telephone contact will be scheduled 
every month to collect information concerning AEs, weight, eligibility, and HAE attacks not treated within 
the study
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.
Section impacted by change: Section 4.1.3, Study Assessments
Revised Text:  
The study will consist of the following periods (Table 4-1).  All assessments are outlined in full in the study 
schedules of events in Appendix 1, No Attack, Appendix 2, Initial Icatibant-treated Attack, and Appendix 3, 
Subsequent Icatibant-treated Attacks.
Table 4-1
Study Periods
Study Periods 
Screening 
Day of informed consent through pretreatment on Day 1 
No attack (Pubertal/postpubertal subjects only)
    Treatment 
Day 1
    Post Treatment
Day 1 through Day 8 (± 1 day)
    Follow-up
Day 9 through Day 90 (±7 days)
    Telephone Contact
Month 6 (± 7 days) from Day 1 
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 attackstreatments
(Pubertal/postpubertal subjects only)
    Subsequent Icatibant-treated Attack 
    Baseline Assessments
Every 6 months
    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
Section impacted by change: Section 4.1.3.2, Subsequent Icatibant-Treated Attacks
Revised Text:  
Subsequent treatment with icatibant may be offered to pubertal/postpubertal subjects who have received initial 
treatment and who present subsequently with an attack at least 73 days after prior treatment.  In the event that a 
subsequent attack occurs at least 7 days after prior treatment, but within the window (±1 day) allowed for 
performance of Day 8 assessments associated with a prior attack, the Day 8 assessments may also serve as the 
pretreatment (baseline) assessments for the subsequent attack. Subjects will be eligible for treatment with icatibant 
until a total number of at least 10 adolescents have been treated 3 times with icatibant for a total of 3 acute attacks 


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(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).  .
For all subjects who remain enrolled in the study for longer than 6 months, a study visit will be scheduled every 6 
months to collect baseline information and to conduct training for parents/legal guardian/caretakers for 
subjects who have expressed an interest in receiving icatibant at home   In addition  for all subjects who 
remain enrolled in the study a safety telephone contact will be scheduled every month to collect information 
concerning AEs  weight  eligibility  and HAE attacks not treated within the study
When a pubertal/postpubertal subject experiences an acute HAE attack, subjects (parent/legal 
guardian/caregiver) will contact the hospital/study center (or their home healthcare professional in the event 
the investigator is not available) to confirm the HAE attack diagnosis.  The investigator (or the home 
healthcare professional in the event the investigator is not available)  in consultation with the subject's 
preference, will determine whether the subject will be treated at the hospital/study center, at home by a 
qualified home healthcare personnel  or at home by the trained parent/legal guardian/caregiver   The 
qualified home healthcare person will be contacted, if applicable.
For subsequent attacks, study drug may be administered by study site personnel at the hospital/study center 
or by qualified home healthcare personnel at the subject’s home.  Alternatively, a parent/legal 
guardian/caregiver will be allowed to administer or the subject (under the supervision of a parent/legal 
guardian/caregiver) will be allowed to self-administer the investigational product after having received 
appropriate training   For all subsequent laryngeal attacks  subjects should be advised to seek medical 
attention in an appropriate healthcare facility immediately following treatment with icatibant.  
Except for PK determinations, all primary and secondary outcomes, including immunogenicity,endpoints are to be 
measured after each administration.  Safety, reproductive hormones, and other assessments in association with 
subsequent attacks of acute HAE will be performed on Day 90 (±7 days) after treatment (each treatment for a 
subsequent attack will require its own Day 90 follow up visit; however, if a subsequent attack occurs within 7 days 
of the Day 90 follow-up visit for the previous attack, the assessments on Day 8 and Day 90 may be combined).  
Note that for some of the pubertal/postpubertal subjects who receive further treatment, ie, those who provide PK and 
safety/tolerability measurements without experiencing a current attack, their first icatibant-treated attack will 
represent their second on-study exposure to icatibant for safety analysis purposes.
The investigator will schedule a telephone contact approximately 6 months after Day 1 of each icatibant treated 
attack to obtain updates concerning pubertal changes/milestones.  If this prescheduled telephone contact date should 
occur within the 90 day follow up period (ie, Day 1 through Day 90) of a subsequent attack, this prescheduled 
contact may be omitted.
In addition, for all subjects who remain enrolled in the study for longer than 6 months, a telephone contact will be 
scheduled every 6 months to collect information concerning HAE attacks not treated with icatibant in the study.
Each treatment for a subsequent attack will require a Day 8 and a Day 90 follow up visit   If a subsequent 
attack occurs within 3 days of the Day 8 follow-up visit for the previous attack, the visits for Day 1 (of the 
subsequent icatibant-treated attack) and Day 8 (of the prior icatibant-treated attack) may be combined   If a 
subsequent attack occurs within 7 days of the Day 90 follow-up visit for the previous attack, the visits for Day 
8 (of the subsequent icatibant-treated attack) and Day 90 (of the prior icatibant-treated attack) will be 
combined.
All assessments are outlined in full in the study schedules of events in Appendix 1, No Attack, Appendix 2, Initial 
Icatibant treated Attack, and Appendix 3, Subsequent Icatibant treated Attacks.    
Section impacted by change: Section 4.3, Study Duration
Revised Text:  
Telephone follow-up will occur approximately 6 months after each initial icatibant-treated attack.
Once the tenth prepubertal subject and the twentieth pubertal/postpubertal subject have completed the 6-month 
follow-up after the initial treatment, and the tenth pubertal/postpubertal subject has completed the 6 monthDay 90
follow-up after his or her third and final treatment for an attack, the study will be closed.


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Section impacted by change: Section 6.2, Treatment Administered
Revised Text:  
Pubertal/postpubertal subjects are potentially eligible to receive an initial treatment with icatibant (in the presence 
or the absence of an attack), and to receive 2 additional treatments with icatibant for an total of 3 attacks of acute 
HAE.  Thus, a maximum of 43 doses of icatibant may be administered to a pubertal/postpubertal subject in the 
study, while all prepubertal subjects will receive a single dose of icatibant.
Section impacted by change: Section 6.3, Selection and Timing of Dose for Each Subject
Revised Text:  
Subsequent treatment with icatibant for up to 2 additional attacks of acute HAE, for a total of 3 attacksicatibant 
administrations, will be offered to pubertal/postpubertal subjects contingent upon having been treated for 
anreceived initial attackicatibant treatment and presenting with a subsequent acute attack at least 73 days after 
prior treatment (see Section 4.1.3). For subsequent attacks, study drug may be administered by study site 
personnel at the hospital/study center or by qualified home healthcare personnel at the subject’s home   
Alternatively, a parent/legal guardian/caregiver will be allowed to administer or the subject (under the 
supervision of a parent/legal guardian/caregiver) will be allowed to self-administer the investigational 
product after having received appropriate training.  For all subsequent laryngeal attacks, subjects should be 
advised to seek medical attention in an appropriate healthcare facility immediately following treatment with 
icatibant.  
Section impacted by change: Section 6.6, Concomitant Medication Usage
Revised Text:  

The use of ACE inhibitors within 7 days prior to treatment is forbidden
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.
Section impacted by change: Section 6.7, Rescue Therapy
Added Text:  
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. For subjects treated at home for a subsequent attack  
subjects must contact the hospital/study center (or their home healthcare professional in the event the 
investigator is not available) if symptom improvement is not seen after the administration of icatibant and 
they believe they need additional treatment to alleviate acute symptoms.
Section impacted by change: Section 6.9, Treatment Compliance
Revised Text:  
During this study, the investigational product will be administered at the hospital/study center under controlled 
conditionsby study site personnel, a qualified home health professional, the subject, or a parent/guardian ; 
therefore, full subject compliance with treatment is anticipated.


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Section impacted by change: Section 6.10, Packaging and Labeling
Revised Text:  
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. SecondaryFor countries outside the US, 
secondary packaging consists of 1 icatibant syringe, labeled in a tray with a 25-guage needle placed inside a plain 
white carton, also labeled. In the US, the secondary packaging consists of one solid bleached sulfate (SBS) 
insert/sleeve containing one pre-filled syringe with attached plunger rod and backstop with one needle 
(25-guage, 16 mm) packed separately.  The insert/sleeve is contained in a SBS outer carton, which protects 
the formulation from light   A fluid-dispensing adaptor will be used to secure a 1 -mL or 3-mL syringe to the glass 
syringe for withdrawal of icatibant.
Section impacted by change: Section 6.11, Storage and Accountability
Added Text:  
Subjects who were issued study drug for administration at home will be required to return any used or 
unused IP to their site for destruction.
Section impacted by change: Section 7.9 Investigational Product Administration
Revised Text:  
Pubertal/postpubertal subjects that present with a subsequent attack at least 73 days after prior treatment (see Section 
4.1.3) may receive further treatment with icatibant for a total of 3 attacks.icatibant treatments   For subsequent 
attacks, study drug may be administered by study site personnel at the hospital/study center or by qualified 
home healthcare personnel at the subject’s home.  Alternatively, a parent/legal guardian/caregiver will be 
allowed to administer or the subject (under the supervision of a parent/legal guardian/caregiver) will be 
allowed to self-administer the investigational product after having received appropriate training. For all 
subsequent laryngeal attacks, subjects should be advised to seek medical attention in an appropriate 
healthcare facility immediately following treatment with icatibant.   
See the Pharmacy Manual for additional instructions regarding dose calculation and administration.     
Section impacted by change: Section 7.10.2 Pharmacokinetic Sampling
Revised Text:  
Sampling for PK assessments will be collected according to the schedule of events provided in Appendix 1 (No 
Attack) and Appendix 2 (Initial Icatibant-treated Attack).  Pharmacokinetic assessments are not conducted 
during subsequent attacks.


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Section impacted by change: Section 7.11.1 Symptom Score
Revised Text:  
7.11.1  Symptom Score
7.11.1.1  Investigator Symptom Score
TheFor subjects treated at the hospital/study center, 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.
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.  
7.11.1.2  Home Healthcare Provider or Parent/Legal Guardian/Caregiver Symptom Score
The home healthcare provider or parent/legal guardian/caregiver, after having received appropriate training,
will assess the severities of symptoms of acute cutaneous, abdominal, and laryngeal attacks of HAE using the 
5-point scale provided in Section 7 11 1 1   Symptom scores will be recorded on Day 1 at pretreatment and at 
predetermined time points after treatment.  Results will be recorded in the CRF.
For attacks classified as cutaneous and/or abdominal  the home healthcare provider or parent/legal 
guardian/caregiver-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, the home healthcare provider or parent/legal guardian/caregiver-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   
Section impacted by change: Section 7.11.2 Subject Self-assessment of Pain
Revised Text:  
FPS-R self-assessment data will be recorded in an e a 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.  


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Section impacted by change: Section 7.11.4 Initial Symptom Relief
Revised Text:  
7.11.4.1  Investigator-assessed Initial Symptom Relief
TheFor subjects treated at the hospital/study center  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 11 4 2  Home Healthcare Provider and Parent/Legal Guardian/Caregiver Initial Symptom Relief
The home healthcare provider or parent/legal guardian/caregiver, after having received appropriate training,
will be asked to record the date and time when overall subject improvement was first noted and record the 
date and time accordingly.  
Section impacted by change: Table 7-1, List of Clinical Laboratory Tests
Added Text:  
*Urinalysis will not be conducted for subsequent attacks.
Section impacted by change: Section 7.13.5, Local Tolerability
Revised Text:  
Injection site reactions (erythema, swelling, burning sensation, itching/pruritus, 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 the home healthcare provider  or the parent/legal guardian/caretaker after having 
received appropriate training, and the diameter of any erythema or swelling will be measured.  
After discharge or in a subject treated at home for a subsequent attack, the subject (or the subject’s parent/legal 
guardian on behalf of the subject as appropriate) will be interviewed report about injection site reactions, either in 
person or by telephone contact.  
Section impacted by change: Section 7.13.6, Immunogenicity
Revised Text:  
Details concerning sample collection and preparation will be provided in the study OperationsLaboratory 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 OperationsLaboratory Manual.
Section impacted by change: Section 7.13.7, Pregnancy Testing
Revised Text:  
Female subjects of childbearing potential (ie, those who have experienced menarche) will undergo pregnancy testing 
at time points specified in the study schedule of events (Appendix 1, Appendix 2, and Appendix 3).  All pregnancy 
testing will be conducted using a urine human chorionic gonadotropin (hCG) test kit.  The test will be performed 
and interpreted by the study personnel at the hospital/study center at the time of the visitprior to study drug 
administration.
Section impacted by change: Section 7.14, Sample Collection, Storage, and Shipping
Revised Text:  
Detailed sample collection, processing, and shipping instructions will be provided in the study 
OperationsLaboratory Manual.




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Section impacted by change: Section 8, Study Activities
Revised Text:  
8.1  Screening (Day of Informed Consent to Pretreatment on Day 1)  

• Informed Consent/Assent

• Inclusion/Exclusion Criteria

• Medical history

• Documentation of HAE attack(s) not treated with icatibant*

• Confirmation of documented HAE diagnosis (via the sponsor’s central laboratory)

• Measurement of C1-INH  

• Pubertal status determination

• Physical examination

• Vital signs

• ECG

• Height and weight

• Urine pregnancy test (in females of childbearing potential)

• Recording of concomitant medications
*For all subjects who remain enrolled in the study for longer than 6 months, a telephone contact will be scheduled 
every 6 months to collect information concerning HAE attacks not treated with icatibant in the study.
8 2  No Attack
8.2.1  Pretreatment (Baseline) Assessments (Day 1, No Attack)
The following assessments will be performed for subjects who will be treated with icatibant in the absence of a 
current HAE attack.  All evaluations and sample collections must be performed prior to treatment.

• Medical history 

• Confirm inclusion/exclusion criteria 

• Pubertal status determination (only if the subject was classified as prepubertal at the time of the screening 
visit)

• Menstrual cycle history (in pubertal/postpubertal females only)

• Physical examination

• Vital signs

• Height and weight

• Clinical laboratory tests (serum chemistry, hematology and urinalysis)

• Urine pregnancy test (in females of childbearing potential)

• Reproductive hormone assessments

• Pharmacokinetic sampling

• Immunogenicity evaluation

• Recording of concomitant medications
8.3 Pretreatment (Baseline) Assessments (Day 1, Initial and Subsequent Attacks)
The following assessments will be performed at both initial and subsequent icatibant treated attacks unless otherwise 
indicated.  All evaluations and sample collections must be performed prior to treatment.
•
Medical history (at initial attack only)
•
Confirm inclusion/exclusion criteria 
•
Pubertal status determination (only if the subject was classified as prepubertal at the time of the screening visit)
•
Menstrual cycle history (in pubertal/postpubertal females only)
•
Physical examination
•
Vital signs
•
ECG (at subsequent attacks only)
•
Height and weight
•
Subject self assessment of HAE related pain (in subjects 4 years of age and older) using e diary FPS R
•
Investigator assessment of HAE symptoms
•
Investigator assessment of HAE related pain (in subjects younger than 4 years of age only) using FLACC
•
Clinical laboratory tests (serum chemistry, hematology and urinalysis)


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•
Urine pregnancy test (in females of childbearing potential)
•
Reproductive hormone assessments
•
Pharmacokinetic sampling (at pretreatment for initial attack only)
•
Immunogenicity evaluation
•
Recording of concomitant medications
•
Assessment of adverse events (at pretreatment for subsequent attacks only)
8.4 No Attack
8.4.1 8.2.2 Treatment Period (Day 1 to Day 8 [± 1 Day])

• Investigational product administration (Day 1, Time 0)

• Physical examination (Day 1, 6 [±0.5] hours) (or 8 [±0.5] hours if the subject is not discharged***) post 
dose and Day 8 [±1 day])

• Vital signs (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours) (or 8 [±0.5] hours if the subject is not 
discharged***) post dose and Day 8 [±1 day])

• ECG (Day 1, 6 [±0.5] hours (or 8 [±0.5] hours if the subject is not discharged***) post dose) 

• Clinical laboratory tests (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])

• Reproductive hormone assessments (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])

• Injection site reaction evaluation (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours) (and 8 [±0.5] hours if the 
subject is not discharged**) post dose, Day 2 (24 [±4] hours), Day 3 (48 [±4] hours), and Day 8 [±1 day])

• Sampling for PK assessments in pubertal/post pubertal subjects (Day 1, 15 [±5] minutes, 30 [±5] minutes, 
45 [±5 minutes], 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] hours, 6 [±0.5] hours post dose)

• Safety follow-up contact (Day 2 (24 [±4] hours), Day 3 (48 [±4] hours) by telephone (If a subject remains 
hospitalized, this safety follow-up will be conducted in person.)

• Immunogenicity evaluation (Day 8 [±1 day])

• Menstrual cycle history (Day 8 [±1 day] in pubertal/postpubertal females)

• Recording of concomitant medications  

• Assessment of adverse events 
*A subject may be discharged after completion of all assessments at 6 hours post treatment, if deemed medically 
stable in the investigator’s clinical judgment.   If this is the case, the assessments scheduled for 8 hours post 
treatment will be omitted.
8.5 8.3  Initial Icatibant-treated Attack 
8 3 1  Pretreatment (Baseline) Assessments (Day 1)
The following assessments will be performed at the initial icatibant-treated attack.  All evaluations and sample 
collections must be performed prior to treatment.  

Medical history 

Confirm inclusion/exclusion criteria 

Pubertal status determination (only if the subject was classified as prepubertal at the time of the screening 
visit)

Menstrual cycle history (in pubertal/postpubertal females only)

Physical examination

Vital signs

Height and weight

Subject self-assessment of HAE-related pain (in subjects 4 years of age and older) using diary FPS-R

Investigator assessment of HAE symptoms

Investigator assessment of HAE-related pain (in subjects younger than 4 years of age only) using FLACC

Clinical laboratory tests (serum chemistry, hematology and urinalysis)

Urine pregnancy test (in females of childbearing potential)

Reproductive hormone assessments

Pharmacokinetic sampling 

Immunogenicity evaluation

Recording of concomitant medications
8.5.1 8 3 2  Treatment Period (Day 1 to Day 8 [± 1 Day])


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
• Investigational product administration (Day 1, Time 0)

• Physical examination (Day 1, 6 [±0.5] hours) (or 8 [±0.5] hours if the subject is not discharged***) post 
dose and Day 8 [±1 day])

• Vital signs (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours) (or 8 (±0.5) hours if the subject is not 
discharged***) post dose and Day 8 [±1 day])

• ECG (Day 1, 6 [±0.5] hours (or 8 [±0.5] hours if the subject is not discharged***) post dose)

• Subject self-assessment of HAE-related pain (in subjects 4 years of age and older) using e diary FPS-R 
(Day 1, 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] hours, 6 [±0.5] hours and 8* [±0.5] hours 
post dose, Day 2 (24 [±4] hours), Day 3 (48 [±4] hours)

• Investigator assessment of HAE symptoms (Day 1, 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] 
hours, 6 [±0.50] hours (and 8 [±0.5] hours if the subject is not discharged**) post dose)

• Investigator assessment of HAE-related pain (in subjects younger than 4 of age only) using FLACC (Day 
1, 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] hours, 6 [±0.5] hours (and 8 [±0.5] hours if the 
subject is not discharged**) post dose)

• Clinical laboratory tests (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])

• Reproductive hormone assessments (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])

• Injection site reaction evaluation (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours (and 8 [±0.5] hours if the 
subject is not discharged**) post dose, Day 2 (24 [±4] hours), Day 3 (48 [±4] hours), and Day 8 [±1 day])

• Sampling for PK assessments in pubertal/post pubertal subjects (Day 1, 15 minutes [±5 minutes], 30 
minutes [±5 minutes], 45 minutes [±5 minutes], 1 hour [±10 minutes], 2 hours [±10 minutes], 4 [±0.5] 
hours, 6 [±0.5] hours post dose at initial attack only)

• Sampling for PK assessments in prepubertal subjects (Day 1, 15 minutes [±5 minutes], 30 minutes [±5 
minutes], 2 hours [±10 minutes], 4 [±0.5] hours, 6 [±0.5] hours post dose at initial attack only)

• Safety follow-up contact (Day 2 (24 [±4] hours), Day 3 (48 [±4] hours) by telephone (If a subject remains 
hospitalized, this safety follow-up will be conducted in person.)

• Immunogenicity evaluation (Day 8 [±1 day])
•
Menstrual cycle history (Day 8 [±1 day] in pubertal/postpubertal females)

• Recording of concomitant medications  
•
Assessment of adverse events 
*A subject may be discharged after completion of all assessments at 6 hours post treatment, if deemed medically 
stable in the investigator’s clinical judgment and the subject’s HAE symptoms have resolved (the subject’s 
investigator-rated symptom score = zero, denoting the absence of symptoms).  
If this is the case, the assessments scheduled for 8 hours post treatment will be omitted with the exception of subject 
self-assessment of HAE-related pain using the e diary FPS-R. 
**If the subject’’s HAE symptoms have not resolved at 6 hours post treatment (the subject’’s investigator-rated 
symptom score ≠ zero) and the subject is not to be discharged after completion of assessments at the 6-hour time 
point, the assessments indicated will be performed at both 6 AND 8 hours post treatment.
***If the subject’s HAE symptoms have not resolved at 6 hours post treatment (the subject’s investigator-rated 
symptom score ≠ zero) and the subject is not to be discharged after completion of assessments at the 6-hour time 
point, the assessments indicated will be performed at either 6 OR 8 hours post treatment.
8.5.2 8.3.3  Follow-up Visit (Day 90 ±7 days)
In the event that a subject has a subsequent HAE attack within the 90 day follow-up period for the first treatment, 
the date of the Day 90 follow-up visit for the first treatment remains the same.  Each subsequent treatment will have 
a corresponding Day 90 follow-up visit.  

• Physical examination

• Vital signs

• Height and weight

• Clinical laboratory tests (serum chemistry, hematology, and urinalysis)

• Urine pregnancy test (in females of childbearing potential)

• Reproductive hormone assessments

• Immunogenicity evaluation 

• Menstrual cycle history (in pubertal/postpubertal females)


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
• Recording of concomitant medications

• Assessment of adverse events

• Documentation of HAE attack(s) not treated with icatibant
8.5.3 8.3.4  Telephone Contact (Month 6 ±7 days) 
The scheduled telephone contact will document pubertal changes/milestones, if any.

• Pubarche

• Menarche (females only)

• Changes in menstrual cycle (females only)

• Pregnancy (females and male partner)
8.6 8.4
Subsequent Icatibant-treated Attacks (Pubertal/Postpubertal Subjects Only)
Pubertal/postpubertal subjects may receive treatment for up to 2 subsequent HAE attacks, contingent upon having 
been treated forreceived an initial attackicatibant treatment and presenting with a subsequent acute attack of at 
least 73 days after prior treatment (see Section 4.1.3).  
Each treatment for a subsequent attack will require a Day 90 follow up visit.  If a subsequent attack occurs within 7
days of the Day 90 follow up visit for the previous attack, the assessments on Day 8 and Day 90 will be combined.   
8.6.1
Treatment Period (Day 1 to Day 8 [± 1 Day])
For subsequent attacks, study drug may be administered by study site personnel at the hospital/study center 
or by qualified home healthcare personnel at the subject’s home.  Alternatively, a parent/legal 
guardian/caregiver will be allowed to administer or the subject (under the supervision of a parent/legal 
guardian/caregiver) will be allowed to self-administer the investigational product after having received 
appropriate training   For all subsequent laryngeal attacks  subjects should be advised to seek medical 
attention in an appropriate healthcare facility immediately following treatment with icatibant.    
8.4.1
Subsequent Icatibant-treated Attack Baseline Assessments
All evaluations and sample collections must be performed at the hospital/study center within 6 months prior 
to treatment:

Confirm inclusion/exclusion criteria 

• Investigational product administration (Day 1, Time 0)Menstrual cycle history (in pubertal/postpubertal 
females only)

Documentation of HAE attack(s) not treated with icatibant

• 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)

Height and weight

• Clinical laboratory tests (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day]serum chemistry and 
hematology)

Urine pregnancy test (in females of childbearing potential)

• Reproductive hormone assessments (Day 1, 6 [±0.5] hours post dose and Day 8 [±1 day])
•
Injection site reaction evaluation (Day 1, 1 hour [±10 minutes], 6 [±0.5] hours (and 8 [±0.50] hours if the 
subject is not discharged**) post dose, Day 2 (24 [± 4] hours), Day 3 (48 [±4] hours), and Day 8 [±1 day])
•
Safety follow up contact (Day 2 (24 [±4] hours], Day 3 (48 [±4] hours) by telephone (If a subject remains 
hospitalized, this safety follow up will be conducted in person.)

• Immunogenicity evaluation (Day 8 [±1 day])
•
Menstrual cycle history (Day 8 [±1 day] in pubertal/postpubertal females)

• Recording of concomitant medications 


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
• Assessment of adverse events 

Training for parent/legal guardian/caregiver on how to assess HAE symptoms using the 5-point 
rating scale, time to initial symptom relief, and injection site reactions (for subjects who have 
expressed interest in self- administering or having a parent/legal guardian/caregiver administer 
icatibant in the home).

Training on icatibant administration (for subjects who have expressed interest in self-administration 
or having a parent/legal guardian/caregiver administer icatibant in the home)

Dispense 1 syringe of study drug (for subjects who have expressed interest in being treated at home 
by a home healthcare provider parent/legal guardian caregiver  or self-administration)

Instruct the subject (parent/legal guardian/caregiver) to record a weight measurement every month
and to contact the hospital/study center to confirm dosing (for subjects who have expressed interest 
in being treated at home by a home healthcare provider, parent/legal guardian caregiver, or self-
administration)

Instruct the subject (parent/legal guardian/caregiver) to contact the hospital/study center (or their 
home healthcare professional in the event the investigator is not available at the time of a subsequent 
attack to confirm the HAE attack diagnosis.  
8.4.2  Treatment Period (Day 1 to Day 8 [± 1 Day])
8 4 2 1  Day of Subsequent Attack (Day 1)
When a pubertal/postpubertal subject experiences an acute HAE attack, subjects (parent/legal 
guardian/caregiver) will contact the hospital/study center (or their home healthcare professional in the event
the investigator is not available) to confirm the HAE attack diagnosis.  The investigator (or the home 
healthcare professional in the event the investigator is not available), in consultation with the subject's 
preference, will determine whether the subject will be treated at the hospital/study center, at home by a 
qualified home healthcare personnel  at home by the trained parent/legal guardian/caregiver  or by self-
administration.  The qualified home healthcare person will be contacted, if applicable.
The following will occur prior to study drug administration:
Subject Treated at 
Study Site
Subject Treated at 
Home
Call hospital/study center (or their home 
healthcare professional in the event the 
investigator is not available) to confirm HAE 
attack diagnosis
X
X
Investigator Symptom Score
X
Home Healthcare Provide or Parent/Legal 
Guardian/Caregiver Symptom Score
X
X
Subject Self-Assessment of Pain
X
X
Urine pregnancy test
X
X
Concomitant Medications
X
X
Adverse Events
X
X

Assessment of HAE symptoms
o
The investigator will assess HAE symptoms using the Investigator Symptom Score if the 
subject is treated at the hospital/study center
o
The home healthcare provider will assess HAE symptoms using the Home Healthcare 
Provider or Parent/Legal Guardian/Caregiver Symptom Score if the subject is treated at 
home
o
The parent/legal guardian/caregiver will assess HAE symptoms using the Home Healthcare 
Provider or Parent/Legal Guardian/Caregiver Symptom Score if the subject is treated at 
either the hospital/study site or at home


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
Subject will self-assess HAE-related pain using diary FPS-R

Urine pregnancy test for females of child-bearing potential
*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.

Concomitant medications will be recorded

Adverse events will be recorded
Once the pretreatment assessments are completed  icatibant will be administered (Day 1  Time 0)

Study drug may be administered by study site personnel at the hospital/study center or by qualified 
home healthcare personnel at the subject’s home.  Alternatively, a parent/legal guardian/caregiver 
will be allowed to administer or the subject (under the supervision of a parent/legal 
guardian/caregiver) will be allowed to self-administer the investigational product after having 
received appropriate training.  

For all subsequent laryngeal attacks, subjects should be advised to seek medical attention in an 
appropriate healthcare facility immediately following treatment with icatibant
The subject will be observed by the investigator, the home healthcare provider or the 
parent/guardian/caregiver for a minimum of 2 hours after icatibant administration   
The following will occur after icatibant administration: 
Subject Treated at 
Study Site
Subject Treated at 
Home
Icatibant Administration
X
X
Investigator Symptom Score
X
Home Healthcare Provide or Parent/Legal 
Guardian/Caregiver Symptom Score
X
X
Subject Self-Assessment of Pain
X
X
Injection site reaction evaluation
X
X
Concomitant Medications
X
X
Adverse Events
X
X
Contact site 6 to 8 hours after attack
X
X

HAE symptoms will be assessed at Day 1, 1 hour [±10 minutes] post dose and 2 hours [±10 minutes] 
postdose AND every 2 hours [±10 minutes] until the subject’s symptoms are absent or mild [if the 
subject’s symptoms are not absent or mild at 2 hours post dose])  
o
The investigator will assess HAE symptoms using the Investigator Symptom Score and 
record the time of initial symptom relief if the subject is treated at the hospital/study center
o
The home healthcare provider will assess HAE symptoms using the Home Healthcare 
Provider or Parent/Legal Guardian/Caregiver Symptom Score and record the time of initial 
symptom relief if the subject is treated at home
o
The parent/legal guardian/caregiver will assess HAE symptoms using the Home Healthcare 
Provider or Parent/Legal Guardian/Caregiver Symptom Score if the subject is treated at 


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either the hospital/study site or at home

The subject will self-assess pain using diary FPS-R (1 hour [±10 minutes] post dose and 2 hours [±10 
minutes] post dose, and every 2 hours [±10 minutes] until pain is absent [if the subject’s pain is not 
absent at 2 hours post dose]);

Injection site reaction will be recorded (1 hour [±10 minutes] post dose and 2 [±0.5] hours post dose, 
and every 2 [±0 5] hours until injection site reaction is mild or absent [if the subject’s injection site 
reaction is not mild or absent at 2 hours post dose]); 

Concomitant medications will be recorded

Adverse events will be recorded

Subjects (parent/legal guardian/caregiver) will contact the hospital/study center 6 to 8 hours after 
icatibant administration to update the investigator of the subject’s condition
8.4.2.2  Day 2(24 [± 4] hours)
On Day 2 (24 [± 4] hours):

The subject will self-assess HAE pain using diary FPS-R

Injection site reaction will be recorded

Concomitant medications will be recorded

Adverse events will be recorded
8 4 3  Follow-up Visits 
Each treatment for a subsequent attack will require a Day 8 and a Day 90 follow up visit.  If a subsequent 
attack occurs within 3 days of the Day 8 follow-up visit for the previous attack  the visits for Day 1 (of the 
subsequent icatibant-treated attack) and Day 8 (of the prior icatibant-treated attack) will be combined.  If a 
subsequent attack occurs within 7 days of the Day 90 follow-up visit for the previous attack  the visits for Day 
8 (of the subsequent icatibant-treated attack) and Day 90 (of the prior icatibant-treated attack) will be 
combined
8.4.3.1  Day 8 (±1 day)
The subject will return to the hospital/study on Day 8 (±1 day)   The following evaluations and sample 
collections will be performed on Day 8:

Vital signs

Reproductive hormone assessments

Immunogenicity evaluation 

Injection site reaction evaluation

Concomitant medications will be recorded

Adverse events will be recorded
8.6.2 Follow up Visit 8.4.3.2  Day 90 ±7 days

• Physical examination

• Vital signs

• Height and weight

• Clinical laboratory tests (serum chemistry, hematology, and urinalysis)

• Urine pregnancy test (in females of childbearing potential)

• Reproductive hormone assessments

• Immunogenicity evaluation

• Menstrual cycle history (in pubertal/postpubertal females)

• Recording of concomitant medications

• Assessment of adverse events

• Documentation of HAE attack(s) not treated with icatibant
8.6.3
Telephone Contact (Month 6 ±7 days)
The scheduled telephone contact will document pubertal changes/milestones, if any.
•
Pubarche
•
Menarche (females only)


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•
Changes in menstrual cycle (females only)
•
Pregnancy (females and male partner)
Section impacted by change: Section 10.7, Efficacy Analyses
Revised Text:  
Efficacy analyses will be performed on the Efficacy Population.  The primary efficacy endpoint is the time to onset 
of symptom relief measured using the investigator-reported symptom score.  For the initial icatibant-treated 
attack, 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.  For 
subsequent icatibant-treated attacks  the investigator will report symptom scores at pretreatment and 1 and 2 
hours post treatment, and every 2 hours afterwards until discharge.  Eight symptoms will be assessed for 
abdominal and cutaneous attacks, and 13 symptoms will be assessed for laryngeal attacks.  Time to onset of 
symptom relief is defined as the earliest time post treatment at which there is a 20% improvement in the average 
post-treatment symptom score with no worsening of any single component score. The median time and the 95% 
confidence interval will be calculated using the Kaplan-Meier methodology.
A tabular summary of the average investigator-reported symptom score and the change from baseline in the average 
investigator-reported symptom score will be presented by the stratification group and the icatibant treated attack 
exposure number.  An alternative analysis will focus on the time to minimal symptoms and is defined as the time 
from study drug administration to the earliest time post treatment when all symptoms are either absent or mild.  The 
median time and 95% confidence interval will be calculated using Kaplan-Meier methodology.
Added text:
Home healthcare provider or parent/legal guardian/caregiver symptom scores (referred to as caregiver-
reported symptom scores hereafter) will be measured for all subjects’ subsequent icatibant-treated attacks  A 
tabular summary of the average caregiver-reported symptom scores and the change from baseline in the 
average caregiver-reported symptom scores will be presented by the stratification group and the subsequent 
icatibant treated attack number.  For individual caregiver-reported symptom scores, a shift table from 
baseline will be presented for each post-treatment time point   
Section impacted by change: Section 10.8, Other Analyses
Revised Text:  
The number and percentage of subjects who received rescue medications before the onset of symptom relief will be 
summarized by the stratification group and icatibant treated attack exposure number.  
Section impacted by change: Section 10.9, Data Monitoring and Interim Analysis
Revised Text:  
Based on the anticipated sequence of data being generated in the study, an initial interim analysis of the data from 
pubertal/postpubertal patientsthe initial attack (N=2030) is planned.  It is expected that this will be followed by an 
interim analysis of data from prepubertal patients (N=10), and then by a final analysis to include the data of patients 
treated for subsequent attacks.  This sequence is based on the anticipated sequence of data being generated during 
the study and may be modified to fit the actual study conduct.


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Section impacted by change: Section 11.12, Data Generation and Analysis
Revised Text:  
Concomitant medication will be coded using the World Health Organization Drug Dictionary (WHO-DD) (2004, 
Q4December 2011).  
Section impacted by change: Section 11.14, Financial Disclosure
Revised Text:  
The investigator should disclose any financial interests in the sponsor as described in 21 CFR Part 54 prior to 
beginning this study.  The appropriate form will be provided to the investigator by the sponsor, which will be signed 
and dated by the investigator, prior to the start of the study, at the end of the study, and one year post study (or site) 
closure. . Changes in status concerning financial interests during the study and for 1 year after its completion 
willmust be disclosed by the Investigator in accordance with 21 CFR Part 54.
Section impacted by change: Appendix 1, Appendix 2, and Appendix 3
Updated to reflect the changes to the protocol.
Section impacted by change: Appendix 4
Revised text:
Pubic hair development reflects adrenal function,DO NOT use development of pubertal hair as evidence of 
progression to Tanner stage II because this could reflect increased adrenal gland function (adrenarche) in 
prepubertal subjects and 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.
Section impacted by change: Appendix 7
Updated to reflect the change in Medical Monitor

Prot_001.pdf: 
Clinical Trial Protocol:  HGT-FIR-086 
Study Title: 
A Multicenter, Open-Label, Non-Randomized Study to Assess the 
Pharmacokinetics, Tolerability, and Safety of a Single Subcutaneous 
Administration of Icatibant in Children and Adolescents with Hereditary 
Angioedema 
Study Number: 
HGT-FIR-086 
Study Phase: 
III 
Product Name: 
Icatibant (Firazyr®) 
Indication: 
Hereditary angioedema 
Investigators: 
Multicenter 
Sponsor: 
Shire Orphan Therapies, Inc. 
Sponsor Contact: 
300 Shire Way  
Lexington, MA  02421 USA 
Medical Monitor: 
 MD,  
 Shire Human Genetic Therapies (HGT), Inc. 
 
 
Date 
Original Protocol: 
14 June 2011 
Amendment 1 
05 August 2011 
 
Confidentiality Statement 
This document is the proprietary and confidential property of Shire Human Genetic Therapies, 
Inc.   
PPD
PPD
PPD


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SYNOPSIS 
Sponsor: 
Shire Orphan Therapies, Inc. 
Name of Finished Product: 
Icatibant (Firazyr®) 
Study Title: 
A Multicenter, Open-Label, Non-Randomized Study to Assess the Pharmacokinetics, 
Tolerability, and Safety of a Single Subcutaneous Administration of Icatibant in Children 
and Adolescents with Hereditary Angioedema  
Study Number: 
HGT-FIR-086 
Study Phase:  III 
Investigational Product; Dose; and Mode of Administration:  
Single dose of icatibant 0.4 mg/kg subcutaneous (SC) up to a maximal dose of 30 mg 
Comparator; Dose; and Mode of Administration: 
Not applicable 
Study Objectives:  
The objectives of this study are: 
• To investigate the pharmacokinetics (PK), tolerability, and safety of a single 
subcutaneous (SC) dose of icatibant in children and adolescents with hereditary 
angioedema (HAE) during an acute HAE attack.  
• To evaluate the efficacy of a single SC dose of icatibant in children and 
adolescents with HAE. 
• To evaluate levels of reproductive hormones after a single SC dose of icatibant in 
children and adolescents with HAE.  
Other objectives of this study are: 
• To evaluate the continued safety of icatibant in pubertal/postpubertal children after 
repeat exposure.  
• To evaluate reproductive hormone levels in pubertal/postpubertal children after 
repeat exposure.  
• To evaluate the efficacy of icatibant in pubertal/postpubertal children after repeat 
exposure. 
Study Endpoints:  
The primary endpoints of this study are: 
• The PK profile of icatibant after a single SC injection in pediatric subjects treated 
for acute attacks of HAE. 
 


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• The tolerability and safety of SC icatibant as assessed by injection site reactions, 
adverse events (AEs), vital signs, electrocardiogram (ECG) recordings, physical 
examination, clinical laboratory parameters (serum chemistry [including liver 
function tests], hematology, urinalysis), reproductive hormone levels, and 
immunogenicity (anti-icatibant antibodies). 
The secondary endpoints of this study are: 
• For all subjects (2 to 17 years of age):  investigator assessment and scoring of 
cutaneous, abdominal, and laryngeal symptoms of acute HAE attacks by an 
investigator-rated symptom score.   
- 
The time to onset of relief of symptoms, defined as the earliest time at 
which a 20% improvement is seen in the average post-treatment score with 
no worsening of any single component score. 
- 
The time to minimal symptoms, defined as the earliest time post-treatment 
when all symptoms are either mild or absent based on the investigator-rated 
symptom score. 
• For subjects ≥4 years of age only:  subject self-assessment of HAE-related pain 
using the Faces Pain Scale-Revised (FPS-R).  The time to onset of relief of 
symptoms, defined as the earliest time at which a 20% improvement is seen in the 
post-treatment score. 
• For subjects <4 years of age only:  investigator assessment of HAE-related pain 
using the Faces, Legs, Activity, Cry, and Consolability (FLACC) scale.  The time 
to onset of relief of symptoms, defined as the earliest time at which a 20% 
improvement is seen in the total post-treatment score. 
• The incidence of rescue medication use. 
• The proportion of subjects with worsened intensity of clinical HAE 
symptoms between 2 and 4 hours after treatment with SC icatibant using 
investigator-rated symptom scores. 
Study Population:  
The study will enroll approximately 36 pediatric subjects from 2 through 17 years of age 
who present with cutaneous, abdominal, or laryngeal attacks of acute HAE after a 
qualifying screening period.   
Subject enrollment will be stratified into 2 groups based on Tanner staging:  a prepubertal 
group (defined as Tanner stage I) and a pubertal/postpubertal group (defined as Tanner 
stages II to V).  A subject’s classification as prepubertal or pubertal/postpubertal will be 
determined at the time of the subject’s first attack. 
Study Design: 
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, 
and safety, including reproductive hormone assessments, of a single SC administration of 
icatibant in up to approximately 36 pediatric subjects with HAE during an initial acute 
attack.  The study is planned to enroll up to approximately 16 prepubertal and 
20 pubertal/postpubertal subjects who are from 2 through 17 years of age and who present 
with an acute cutaneous, abdominal, or laryngeal HAE attack.  


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


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5. Treatment with angiotensin converting enzyme (ACE) inhibitors within 7 days prior to 
treatment. 
6. Use of hormonal contraception within the 90 days prior to treatment. 
7. Androgen use (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) 
within the 90 days prior to treatment). 
8. The subject is pregnant or breastfeeding.   
 
Pharmacokinetic Variables: 
PK variables will be determined by full sampling and noncompartmental methods where 
possible, and elsewhere by sparse sampling (at least 4 to 7 time points) and a population 
PK approach using non-linear mixed effects modeling software.   
PK parameter estimates will include, where appropriate:  actual icatibant and metabolite 
concentrations at each sampling time, time to peak concentration (Tmax), actual peak 
(Cmax) and minimum (Cmin) concentrations, clearance (CL/F), actual area under the plasma 
concentration-time curve (AUC0-last and AUC0-inf), mean residence time (MRT), volume of 
distribution at steady state (Vss/F) and elimination half-life (t1/2). 
Safety Assessments: 
Safety will be assessed by standard criteria including physical examination, vital signs, 
ECGs, clinical laboratory evaluations (clinical chemistry [including liver function tests], 
hematology, urinalysis), and immunogenicity (presence of anti-icatibant antibodies), 
recording of concomitant medications, and monitoring of AEs.  Local tolerability will be 
assessed by evaluation of reactions at the site of study drug administration (injection site).  
Levels of reproductive hormones will be assessed in female (follicle stimulating hormone 
[FSH], luteinizing hormone [LH], estradiol, progesterone) and male (FSH, LH, 
testosterone) subjects. 
Efficacy Assessments:   
Efficacy will be assessed using both investigator- and subject-reported outcomes, 
depending on the subject’s age.  Investigators will assess and score symptoms of acute 
cutaneous, abdominal, and laryngeal attacks of HAE for all subjects using an 
investigator-rated symptom score.  Subjects who are 4 years of age or older will perform a 
self-assessment of HAE-related pain using the FPS-R instrument.  Subjects who are below 
4 years of age will have symptoms assessed by the investigator only; including an 
assessment of HAE-related pain using the FLACC scale.  The time of initial symptom 
relief as assessed by the investigator will be recorded for all subjects. 
Statistical Methods:  
Summary statistics for continuous variables will include the number of subjects, the mean, 
median, standard deviation, and range.  For PK parameters, the coefficient of variation 
and geometric mean also will be provided.  For categorical data, summaries will include 
counts and percentages.  For time-to-event data, the median time to event and other 
summary statistics will be estimated using Kaplan-Meier methodology. 
The following populations will be used in the analysis: 
• The Initial Non-laryngeal Treatment Population will consist of those subjects who 
were treated with icatibant for their initial attack and whose primary symptom was 
either cutaneous or abdominal.  


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• The Second Non-laryngeal Treatment Population will consist of those subjects 
who had a second icatibant-treated attack for which the primary symptom was 
either cutaneous or abdominal, regardless of the primary symptom for the initial 
attack. 
• The Third Non-laryngeal Treatment Population will consist of those subjects who 
had a third icatibant-treated attack, for which the primary symptom was either 
cutaneous or abdominal, regardless of the primary symptom for the initial attack. 
• The Laryngeal Population will consist of those subjects who were treated with 
icatibant for any attack for which the primary symptom was laryngeal.  
• The PK Population will consist of those subjects who were treated with icatibant 
for their initial attack and who had at least 1 post-treatment icatibant concentration 
recorded.   
• The Initial Treatment Population will consist of those subjects who were treated 
with icatibant for the initial attack.  Safety and tolerability analyses will use this 
population. 
• The Additional Treatment Population will consist of those pubertal/post-pubertal 
subjects who were treated with icatibant for more than 1 attack.  Safety and 
tolerability analyses will use this population.  
Subject disposition, demographic and baseline characteristics, medical history, and use of 
concomitant medications will be summarized for each analysis population.   
Efficacy endpoints, including change from baseline when appropriate, will be summarized 
descriptively for the Initial, Second, and Third Non-laryngeal Treatment Populations.  The 
primary efficacy endpoint is the time to onset of symptom relief measured using the 
investigator-rated symptom score.  Time of symptom relief is defined as the earliest time 
post-treatment at which there is a 20% improvement in the average post-treatment 
symptom score with no worsening of any single component score.  The efficacy data 
associated with the laryngeal attacks will be provided in data listings for the Laryngeal 
Population. 
Plasma concentrations of icatibant by time point and the PK parameters will be 
summarized descriptively. 
The assessment of safety will be based mainly on the frequency of AEs.  AEs will be 
summarized by presenting the number and percentage of subjects having any AE, having 
an AE in each body system, and having each individual AE using the Medical Dictionary 
for Regulatory Activity (MedDRA).  AEs also will be tabulated by severity and 
relationship to treatment. 
Local tolerability will include symptoms at the injection site and will be assessed 
separately from general reports of AEs.  Local tolerability will be tabulated and 
summarized according to the type and severity of attack. 
The change from baseline in the secretion of reproductive hormones and the change from 
baseline in HAE symptoms (as reported by the investigator or subject) will be summarized 
descriptively. 


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Date of Amended Protocol:  05 August 2011 


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


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


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


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


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
AUC 
Area under the curve extrapolated to zero 
BMI 
Body mass index 
BSA 
Body surface area 
C1-INH 
C1 esterase inhibitor (human) 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CL/F 
Total body clearance  
Cmax 
Maximum observed plasma concentration 
Cmin 
minimum plasma drug concentration 
CRF 
Case report form 
CRO 
Contract research organization 
CYP 
Cytochrome P450 
DHEA 
Dehydroepiandrosterone 
DHEA-S 
Dehydroepiandrosterone-Sulfate 
DSMB 
Data and Safety Monitoring Board 
EC50 
Half maximal effective concentration 
ECG 
Electrocardiogram 
e-diary 
Electronic diary 
EMA 
European Medicines Agency 
FDA 
United States Food and Drug Administration 
FFP 
Fresh frozen plasma 
FLACC 
Faces, Legs, Activity, Cry, and Consolability (comportmental pain scale) 
FPS-R 
Faces Pain Scale-Revised 
FSH 
Follicle stimulating hormone 
GAM 
General additive model 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HAE 
Hereditary Angioedema 
hCG 
Human chorionic gonadotropin 
HGT 
Human Genetic Therapies 
hr 
Hour(s) 


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ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
kg 
Kilogram(s) 
L 
Liter(s) 
LBW 
Lean body weight 
LH 
Luteinizing hormone 
LOCF 
Last observation carried forward 
MCB 
Master Cell Bank 
MedDRA 
Medical Dictionary for Regulatory Activity  
mg 
Milligram 
min 
Minute(s) 
mL 
Milliliter(s) 
mm 
Millimeters 
MRT 
Mean residual time 
n 
Number 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ng 
Nanogram(s) 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic(s) 
SAE 
Serious adverse event 
SAS 
Statistical Analysis System® 
SC 
Subcutaneous 
SHBG 
Sex Hormone Binding Globulin 
SOC 
System organ class 
t1/2 
Terminal elimination half-life 
TBW 
Total body weight 
Tmax 
Time to maximum concentration 
US 
United States 
VAS 
Visual analog scale 
Vss 
Volume of distribution at steady state 
 


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1 
INTRODUCTION 
1.1 
Disease Background 
Bradykinin is responsible for the clinical symptoms of hereditary angioedema (HAE), causing 
increased vascular permeability, vasodilation, and contraction of visceral smooth muscle.  HAE 
is a rare autosomal dominant disorder characterized clinically by recurrent and self-limiting 
attacks of edema of the skin, gastrointestinal tract, and larynx.  Its prevalence is estimated at 
1:10,000 to 1:50,000.1   
The disease is generally caused by either a quantitative (Type I) or qualitative (Type II) 
deficiency of C1 inhibitor.  The functions of C1 inhibitor include the prevention of C1 
complement auto-activation, inactivation of coagulation factors XIIa, XIIf, XIa, and inhibition of 
activated kallikrein.  After a triggering event, the deficiency in C1 inhibitor results in accelerated 
release of bradykinin, the principal mediator of the increased vascular permeability characteristic 
of HAE, by its cleavage from high molecular weight kininogen by dysregulated, activated 
kallikrein.  There is a third, more rare type of HAE (Type III) which is of unknown etiology and 
pathophysiology and thus will not be considered further here. 
Icatibant is a synthetic decapeptide with a structure similar to bradykinin that acts as an 
antagonist of the bradykinin B2 receptor.2, 3  It is highly specific for the B2 receptor, and is 
characterized by high potency in vitro and in vivo, and sufficient biological half-life to allow 
systemic administration by subcutaneous (SC) injection.4, 5  Inhibition of bradykinin action 
through use of a B2 receptor antagonist is a therapeutic strategy for treatment of clinical 
symptoms of HAE, and represents the rationale for use of icatibant in treatment of acute attacks 
of angioedema in HAE patients.  In adults, SC icatibant 30 mg has been shown to produce a 
rapid and durable response in the treatment of cutaneous, abdominal, and laryngeal attacks of 
acute HAE.  A single SC injection is generally sufficient for accelerated relief of symptoms of 
acute HAE attacks irrespective of edema location.  Repeated use of icatibant over time for 
treatment of multiple acute HAE attacks in adults produces a consistent response at each attack, 
with no diminution of efficacy.  When self-administered by adult subjects experiencing an acute 
HAE attack, icatibant also produces a rapid and safe treatment response. 
The management of HAE in pediatric patients is complex.  The age at onset, the frequency and 
duration of symptoms, as well as the severity of attacks all exhibit substantial inter-individual 
variation.  Although acute episodes of HAE may occur at any age, the mean age at disease onset 
ranges from approximately 4 to 11 years.  Subcutaneous edema of the extremities, face, neck, 
torso and genitals is the most common, and usually the earliest, manifestation of HAE seen in 
children.  Analyses of the time of onset of disease symptoms have indicated an increase in the 
frequency and severity of manifestations between 3 and 6 years of age, as well as at around 
puberty, most likely related to the many physiological (endocrine, mental, and somatic) changes 
occurring during these periods of development.  In the gastrointestinal tract, submucosal edema 
may be associated with colicky abdominal pain, nausea, vomiting, and diarrhea.  Though 
infrequent compared to cutaneous and abdominal manifestations, attacks of acute HAE involving 
the larynx may result in submucosal edema of the upper airways and risk of death by 
asphyxiation if undiagnosed and/or untreated.  In comparison to adults asphyxia may ensue more 
rapidly in children because of smaller airway diameter.6  


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Prompt control of attacks, short-term prophylaxis, and intermittent therapy are recommended for 
the management of pediatric HAE.6  Treatment options for children with HAE according to 
current guidelines include antifibrinolytics, attenuated androgens, and C1 inhibitor (C1-INH) 
replacement therapy.  Antifibrinolytics are generally preferred (eg, tranexamic acid) for 
long-term prophylaxis because of their comparatively favorable safety profile relative to 
attenuated androgens; though their efficacy may be limited.  C1-INH replacement therapy has 
been used successfully for management of acute attacks of HAE in children; however, its use in 
children is associated with the same drawbacks (ie, requirement for intravenous [IV] 
administration, potential to elicit hypersensitivity reactions, possible transmission of blood-borne 
infectious agents) as in adults. 
1.2 
Previous Clinical Studies 
1.2.1 
Pharmacokinetics of Icatibant 
The pharmacokinetic (PK) properties of icatibant have been characterized extensively in studies 
using both IV and SC administration to healthy adult subjects and adult subjects with HAE.  The 
PK profile of icatibant in adults with HAE (JE049-2101 Clinical Study Report) is similar to that 
in healthy adults. 
After SC administration of a single 30 mg dose of icatibant to healthy adult subjects (N=96), a 
mean (± standard deviation) maximum plasma concentration (Cmax) of 974 ± 280 ng/mL was 
observed after approximately 0.75 hours.  The mean area under the concentration-time curve 
(AUC0-∞) after a single 30 mg dose was 2165 ± 568 ng•hr/mL, with no evidence of accumulation 
of icatibant after three 30 mg doses administered 6 hours apart.   
Plasma clearance after SC administration of icatibant was 245 ± 58 mL/min with a mean 
elimination half-life of 1.4 ± 0.4 hours and volume of distribution at steady state (Vss) of 
29.0 ± 8.7 L.  The information obtained from Phase III clinical studies clearly demonstrated that 
SC icatibant 30 mg is a clinically safe and effective treatment for attacks of acute angioedema 
across a wide range of subject demographics, including age, sex, and body weight.  
Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are 
primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug.  
Icatibant is not degraded by oxidative metabolic pathways, and is not an inhibitor of major 
cytochrome P450 (CYP) isoenzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 
3A4) and is not an inducer of CYP 1A2 and 3A4. 
Clinical PK studies demonstrate that for mild to moderate impairment of renal or hepatic 
function no dose adjustment is necessary.  In 10 subjects with hepatorenal syndrome (glomerular 
filtration rate (GFR) 30 to 60 mL/min), clearance of icatibant was not dependent on renal 
function.  Icatibant clearance in subjects with a wide range of hepatic impairment (Child-Pugh 
score ≥7 and ≤15) was similar to that in healthy subjects. 
1.2.2 
Phase III Investigation of SC Icatibant 
Despite the rarity of HAE, a comprehensive data set supports the efficacy and safety of SC 
icatibant.   


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In Phase I, II, and III clinical studies, SC icatibant 30 mg has been administered to 129 healthy 
adult subjects and to 236 adult subjects with HAE.  A total of 999 acute attacks of HAE have 
been treated with icatibant administered by a health care provider, and an additional 56 attacks 
have been treated with icatibant when self administered by patients (Integrated Summary of 
Safety 11 January 2011).  
In integrated analyses of pooled data from 3 controlled Phase III studies (HGT-FIR-054, 
JE049-2102, and JE049-2103), icatibant significantly decreased the time to onset of symptom 
relief for cutaneous and abdominal attacks relative to comparator agents (placebo, tranexamic 
acid) as demonstrated by the primary and key secondary endpoint analyses in subjects with 
non-laryngeal symptoms randomized to double-blind treatment.  Moreover, the median time to 
onset of symptom relief after icatibant treatment was consistent across all of the controlled 
Phase III studies and across the 2 endpoints, ranging from 1.5 to 2.3 hours.  Likewise, icatibant 
showed effectiveness in the treatment of laryngeal attacks.   
The recommended dose of icatibant in adults is 1 SC injection of 3 mL (30 mg) administered in 
the abdominal area for the treatment of acute attacks of HAE.  In case of insufficient relief or 
recurrence of symptoms, a second   injection of icatibant can be administered after 6 hours.  No 
more than 3 injections of icatibant should be administered in a 24 hour period.  In clinical trials, 
a single SC injection of icatibant was generally sufficient to treat an acute HAE attack.  No 
differences in the efficacy or safety of icatibant in clinical trials have been observed between 
sexes; therefore, dose adjustments for adult males or females are not considered necessary.  
Beyond exposure in clinical studies, it is estimated that over 8000 patient exposures to Firazyr® 
have occurred cumulatively in the postmarketing setting from the time of European Union 
regulatory approval in July 2008 through January 2011. 
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of icatibant. 
1.2.3 
Investigations of Potential Effects of Bradykinin Inhibition on Reproductive 
Function 
In nonclinical studies performed in rat and dog, high repeated doses of icatibant have been 
associated with effects on sexual organs and sexual maturation.  These findings are consistent 
with published data showing a role of bradykinin action through B2 receptors in the control of 
reproductive hormone release.  Potential effects of icatibant on sexual organs and sexual 
maturation are being investigated further in studies in juvenile rats.  These are a SC 
administration local tolerance study, and a 7-week toxicity study with assessment of fertility.  
The local tolerance study in juvenile rats established the doses for the 7-week toxicity study.  
Briefly, in the 7-week toxicity study juvenile males and females were dosed with icatibant at 3, 
9, 25 mg/kg/day during a 7-week maturation period.  In males, slightly but statistically 
significant delayed physical maturation and lowered prostate and testes weight were seen at the 
mid and high doses.  Small testes and epididymis were occasionally seen at the highest dose.  
Microscopically, tubular cell vacuolation and germ cell degeneration were seen in males in the 
testes at all doses.  Statistically significantly decreased sperm motility, velocity, and counts at 
recovery were observed at the highest dose.   


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Decreased fertility was observed in untreated females paired with treated males at the highest 
dose.  All microscopic and organ weight findings were either completely or partially reversible.  
The complete results will be reported in the final study reports.  
A retrospective analysis, prompted by nonclinical observations, of serum levels of gonadotrophic 
hormone levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) in male and 
female healthy volunteers in an Phase I study (JE049-1103) showed no clinically important 
changes from baseline in levels of FSH and LH after administration of 3 SC doses (30 mg each) 
of icatibant 6 hours apart on Day 1 followed by single SC doses (30 mg) on Day 8 and Day 15.  
Phase 1 study (HGT-FIR-062) was a double-blind, randomized, placebo-controlled, single center 
study to assess the effect of icatibant on serum reproductive hormone levels in male and 
premenopausal female healthy adult subjects and seminal fluid analysis in healthy male adult 
subjects.  This study was intended to definitively determine the effect of repeated administration 
of 3 SC doses of icatibant 30 mg on reproductive hormone levels in adults prior to any 
investigational use in pediatric subjects per the recommendation of the European Medicines 
Agency (EMA).  Subjects were randomized to receive icatibant or placebo as a single SC 
injection at 6 hour intervals 3 times daily on Days 1, 4, and 7 of the treatment week (total 
9 doses/week) with an approximately 8 week follow-up phase.   
Thirty-nine adult subjects (16 females and 23 males) were enrolled and treated in Study 
HGT-FIR-062; 32 subjects completed the study in its entirety (7 subjects did not return for 
follow-up visits).  No negative trends were seen with regard to the results of basal or 
gonadotrophin releasing hormone (GnRH)-stimulated reproductive hormone assessments in 
female and male subjects treated with icatibant or placebo.  Though the number of subjects 
participating was small, and the study was not powered for statistical significance, a suppressive 
effect of icatibant on GnRH-stimulated reproductive hormone concentrations was not generally 
observed in either sex.  Overall, there were no clinically significant changes from baseline in 
basal and GnRH-stimulated concentrations of reproductive hormones (estradiol, progesterone, 
prolactin, DHEA, DHEA-S, SHBG, FSH, and LH in females and testosterone, DHEA, DHEA-S, 
SHBG, FSH, LH, and Inhibin-B in males) in response to treatment with icatibant.  Additionally, 
there were no significant effects of icatibant on the concentration of luteal phase progesterone, an 
indicator of ovulation status and luteal function, or on menstrual cycle length in females, and 
there were no significant effects of icatibant on semen parameters in males.  Adrenal cortex 
function in male and female subjects, as assessed by serum cortisol concentrations, was 
unaffected by treatment with icatibant.  The complete results will be reported in the final clinical 
study report.   
1.3 
Rationale for Dose Selection 
Icatibant has not been evaluated in clinical trial subjects below the age of 18 years.  The 
proposed study will be the first in which icatibant is administered to pediatric subjects for 
treatment of acute HAE attacks.  All subjects in the proposed study will receive a single, 
weight-adjusted dose of 0.4 mg/kg per attack as a SC injection up to a maximum dose of 30 mg.   


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This dose regimen was selected to target an exposure (Cmax and area under the curve [AUC]) 
comparable to that observed in adults treated with icatibant.  Only 1 dose of icatibant will be 
permitted for treatment of a single attack.    
The 0.4 mg/kg dose was derived from pharmacokinetic/pharmacodynamic (PK/PD) modeling of 
data from a study (JE049-1001) which investigated the inhibitory potential of icatibant at various 
IV infusion doses and regimens after bradykinin challenge in healthy male subjects.  The PK and 
PD data sets were used to model the PK/PD relationship of icatibant using a sigmoidal Emax 
model.  A high degree of concordance of half maximal effective concentration (EC50) values was 
obtained for each of the PD parameters studied (heart rate, blood pressure, and cutaneous blood 
flow) with the majority of values being between 8.54 and 9.77 ng/mL.  Thus, a mean EC50 value 
of 9.5 ng/mL (7.3 nM) was used for subsequent PK/PD simulation.  Based on the PK/PD 
modeling, IV icatibant doses of 0.4 mg/kg and 0.8 mg/kg were predicted to provide duration of 
therapeutic effect of as much as 9 or 13 hours, respectively, when infused over 0.5 to 1 hour.  
These results supported a minimum effective dose of 0.4 mg/kg to treat acute attacks of HAE.  
This corresponds to a dose of 30 mg of icatibant in a 75 kg subject.   
A subsequent Phase II (JE049-2101) dose-ranging proof of concept efficacy study in HAE 
subjects was then conducted that examined the efficacy of doses ranging from 0.4 to 0.8 mg/kg 
IV (ie, 30 to 60 mg in a 75 kg person) and 30 to 45 mg SC.  The results of this study indicated 
that SC administration of icatibant 30 mg produced a rapid onset of symptom relief and that 
45 mg SC showed no improvement in efficacy over 30 mg SC.   
As a result of clinical exploration of the efficacy, safety and exposure-response relationship of 
icatibant, a single SC administration of 30 mg icatibant (10 mg/mL formulation) was selected 
and consistently employed in the Phase III studies in adult HAE subjects.  The totality of 
available efficacy information obtained from the Phase III clinical studies demonstrates that a 
single SC 30 mg dose of icatibant provides a sufficient magnitude and duration of effect to 
clinically manage the majority of acute attacks in adult HAE subjects across a wide range of 
demographics.  Therefore, 0.4 mg/kg SC is considered an appropriate dose to study the 
tolerability, safety and PK of icatibant in the pediatric population.  


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2 
STUDY OBJECTIVES 
2.1 
Objectives  
The objectives of this study are: 
• To investigate the PK, tolerability, and safety of a single SC dose of icatibant in children and 
adolescents with HAE during an acute HAE attack 
• To evaluate the efficacy of a single SC dose of icatibant in children and adolescents with 
HAE 
• To evaluate levels of reproductive hormones after a single SC dose of icatibant in children 
and adolescents with HAE  
 
2.2 
Other Objectives  
Other objectives of this study are: 
• To evaluate the continued safety of icatibant in pubertal/postpubertal children after repeat 
exposure  
• To evaluate reproductive hormone levels in pubertal/postpubertal children after repeat 
exposure  
• To evaluate the efficacy of icatibant in pubertal/postpubertal children after repeat exposure 
 


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3 
STUDY ENDPOINTS 
3.1 
Primary Endpoint(s)  
The primary endpoints of this study are: 
• The PK profile of icatibant after a single SC injection in pediatric subjects treated for acute 
attacks of HAE. 
• The tolerability and safety of SC icatibant as assessed by injection site reactions, AEs, vital 
signs, ECG recordings, physical examination, clinical laboratory parameters (serum 
chemistry [including liver function tests], hematology, urinalysis), reproductive hormone 
levels, and immunogenicity (presence of anti-icatibant antibodies).  
 
3.2 
Secondary Endpoint(s)  
The secondary endpoints of this study are: 
• For all subjects (2 to 17 years of age):  investigator assessment and scoring of cutaneous, 
abdominal, and laryngeal symptoms of acute HAE attacks by an investigator-rated symptom 
score.   
- 
The time to onset of relief of symptoms, defined as the earliest time at which a 20% 
improvement is seen in the average post-treatment score with no worsening of any single 
component score. 
- 
The time to minimal symptoms, defined as the earliest time post-treatment when all 
symptoms are either mild or absent based on the investigator-rated symptom score. 
• For subjects ≥4 years of age only:  subject self-assessment of HAE-related pain using the 
Faces Pain Scale-Revised (FPS-R).  The time to onset of relief of symptoms, defined as the 
earliest time at which a 20% improvement is seen in the post-treatment score. 
• For subjects <4 years of age only:  investigator assessment of HAE-related pain using the 
Faces, Legs, Activity, Cry, and Consolability (FLACC) scale.  The time to onset of relief of 
symptoms, defined as the earliest time at which a 20% improvement is seen in the total 
post-treatment score. 
• The incidence of rescue medication use. 
• The proportion of subjects with worsened intensity of clinical HAE symptoms between 2 and 
4 hours after treatment with SC icatibant using investigator-rated symptom scores. 
 


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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, and 
safety, including reproductive hormone assessments, of a single SC administration of icatibant in 
approximately 36 pediatric subjects with hereditary angioedema (HAE) during an initial acute 
attack.  The study is planned to enroll approximately 16 prepubertal and 20 pubertal/postpubertal 
subjects who are from 2 through 17 years of age and who present with a cutaneous, abdominal, 
or laryngeal attack of acute HAE.  
After treatment for an initial attack, further open-label treatment with icatibant will be offered to 
pubertal/postpubertal subjects contingent upon having been treated previously and presenting 
with a subsequent acute cutaneous, abdominal, or laryngeal attack of HAE at least 7 days 
after initial treatment.  Open-label treatment will continue until at least 15 pubertal/postpubertal 
subjects have been treated with icatibant for a total of 3 attacks each.  Tolerability and safety 
evaluations, including reproductive hormone assessments, will be performed at each subsequent 
icatibant-treated attack as for the initial treated attack. 
The study will consist of the following periods (Table 4-1). 
Table 4-1  Study Periods 
Study Periods  
Screening  
Day of informed consent through pretreatment on Day 1 of the initial 
attack 
Initial icatibant-treated attack (All subjects) 
    Treatment  
Day 1 
    Post-treatment 
Day 1 through Day 8 
    Follow-up 
Day 9 through Day 90 (±7 days) 
Two additional icatibant-treated attacks for a total of 3 icatibant-treated attacks 
(Pubertal/postpubertal subjects only) 
    Treatment  
Day 1 
    Post-treatment 
Day 1 through Day 8 
    Follow-up 
Day 9 through Day 90 (±7 days) 
 
The study will include a screening period to determine subject eligibility.  Eligibility will be 
evaluated after the subjects’ parent(s)/legal guardian(s) and the subject (if applicable) provide 
informed consent/assent.  Study activities at screening will include confirmation of diagnosis of 
HAE type I or II by review of the subject’s medical history and documentation of immunogenic 
and/or functional C1-INH deficiency (<50% of normal levels) indicative of HAE Type I or II.  


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


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Rescue medication use will be assessed through 48 hours after treatment, either in person or by 
telephone at the discretion of the investigator. 
Subjects will undergo safety assessments, including physical examination, vital signs, and 
clinical laboratory tests (serum chemistry [including liver function tests], hematology, and 
urinalysis), evaluation of injection site reactions, immunogenicity, and measurement of 
reproductive hormones on Day 8 after treatment. 
Subjects will be followed over a 90-day (±7 days) period after initial treatment.  All subjects will 
provide blood samples for immunogenicity testing and determination of reproductive hormone 
levels at the Day 90 visit and undergo safety assessments including physical examination, vital 
signs, and clinical laboratory tests (serum chemistry, hematology, and urinalysis).  Additionally, 
pubertal/postpubertal females will undergo urine pregnancy testing. 
Further open-label treatments with study drug will be offered to pubertal/postpubertal subjects 
who have been previously treated and who present with an eligible attack at least 7 days 
post-treatment.  Open-label treatment will continue until a total number of at least 15 adolescents 
have been treated with icatibant for a total of 3 eligible acute attacks (ie, after their first 
icatibant-treated attack, pubertal/postpubertal subjects only may receive further treatment with 
icatibant for up to 2 subsequent attacks of acute HAE).  All primary and secondary outcomes, 
including antibodies (except PK), are to be measured after each administration.  Safety, 
reproductive hormone, and other assessments in association with subsequent attacks of acute 
HAE will be performed 90 days (±7 days) after treatment (each treatment for a subsequent attack 
will require a Day 90 follow up visit).  If a subsequent attack occurs within 7 days of the 
Day 90 follow-up visit for the previous attack, the assessments on Day 8 and Day 90 will be 
combined.   
All assessments are outlined in full in the Schedule of Events in Appendix 1, Initial 
Icatibant-treated Attack and Appendix 2, Subsequent Icatibant-treated Attacks.     
4.2 
Rationale for Study Design 
This study has an open-label, single arm design.   
The study is intended to determine the PK profile of SC icatibant when administered to children 
and adolescents being treated for an acute attack of HAE and to identify an optimal pediatric 
dosing regimen.  In addition, the study is intended to establish the tolerability and safety of 
icatibant in children, particularly with respect to potential effects on reproductive development, 
and to demonstrate the effectiveness of icatibant in relieving the symptoms of acute HAE 
attacks.  Therefore, this study will help determine whether icatibant can address an unmet 
medical need for a safe and effective treatment for acute attacks of HAE in pediatric patients.   
4.3 
Study Duration 
The approximate overall duration of the study will be 36 months.   
 


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


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5 
STUDY POPULATION SELECTION 
5.1 
Study Population 
Pediatric subjects from 2 through 17 years of age who present with cutaneous, abdominal, or 
laryngeal attacks of acute HAE after a qualifying screening period will be eligible for enrollment 
in the study.  Subject enrollment will be stratified into 2 groups, based on Tanner staging,7, 8 to 
consist of a prepubertal group (defined as Tanner stage I) and a pubertal/postpubertal group 
(defined as Tanner stages II to V).   
A subject’s classification as prepubertal or pubertal/postpubertal will be determined at the time 
of the subject’s first attack. 
5.2 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study. 
1. Two through 17 years of age, inclusive (ie, from the second birthday until the day prior to the 
eighteenth birthday) at the time of the subject’s first attack. 
2. Documented diagnosis of HAE Type I or II.  Diagnosis must be confirmed by documented 
immunogenic (below the lower limit of normal) and/or functional (<50% of normal levels) 
C1-INH deficiency.  Diagnosis may be on the basis of historic data or by diagnostic testing 
conducted at the time of screening. 
3. Informed consent (and subject assent as appropriate) signed by the subject’s parent(s) or 
legal guardian(s). 
 
5.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Diagnosis of angioedema other than HAE. 
2. Participation in another clinical study during the 30 days prior to treatment.  
3. Any known factor/disease that might interfere with the treatment compliance, study conduct, 
or result interpretation. 
4. Congenital or acquired cardiac anomalies that interfere significantly with cardiac function.  
5. Treatment with ACE inhibitors within 7 days prior to treatment. 
6. Use of hormonal contraception within the 90 days prior to treatment. 
7. Androgen use (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) within 
the 90 days prior to treatment. 
8. The subject is pregnant or breastfeeding. 
 


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6 
STUDY TREATMENT(S) 
6.1 
Description of Treatment(s) 
6.1.1 
Investigational Product 
Icatibant is prepared as a sterile, isotonic, and acetate buffer solution containing sodium chloride, 
acetic acid, sodium hydroxide and water for SC injection, adjusted to pH 5.5 ± 0.3.  The solution 
does not contain any preservative.   
The product is supplied as a 10 mg/mL (free base) solution in 3-mL glass syringes, with 
elastomeric stoppers, tip cap, plunger rod, and backstop.  A fluid-dispensing connector will be 
used to secure a 1-mL or 3-mL syringe to the glass syringe.  A single dose (see Section 6.2) will 
be withdrawn and administered by SC injection. 
6.1.2 
Comparator 
Not applicable to this study. 
6.2 
Treatment(s) Administered 
All subjects will receive treatment with icatibant for an initial acute attack of HAE as a single, 
weight-adjusted dose of 0.4 mg/kg up to a maximum of 30 mg administered as a SC injection. 
Subsequent treatment with icatibant for up to 2 additional attacks of acute HAE will be offered to 
pubertal/postpubertal subjects who present with a new attack at least 7 days after prior treatment.  
The dosing regimen for treatment of subsequent attacks will be the same as that for treatment of 
the initial attack (ie, a single weight-adjusted dose of 0.4 mg/kg up to a maximum of 30 mg per 
attack administered as a SC injection).  Thus, no more than 3 doses of icatibant will be 
administered to any subject during the study. 
6.3 
Selection and Timing of Dose for Each Subject 
Each subject will be administered a single dose of icatibant as a SC injection within 12 hours 
after the onset of an acute HAE attack.  Subsequent treatment with icatibant for up to 
2 additional attacks of acute HAE for a total of 3 attacks will be offered to pubertal/postpubertal 
subjects who have been previously treated and who present with another attack at least 7 days 
post-treatment with study drug.   
6.4 
Method of Assigning Subjects to Treatment Groups 
Not applicable to this study.  All subjects will be administered study drug at a weight-adjusted 
dose of 0.4 mg/kg SC up to a maximum of 30 mg per treatment.   
6.5 
Blinding 
Not applicable to this open-label study. 


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6.6 
Concomitant Medication Usage 
All prescription and over-the-counter medications which are being taken by subjects during the 
study are regarded as concomitant medications and must be documented on the case report form 
(CRF) following informed consent. 
Use of the following concomitant medications is allowed during the study: 
• All chronically administered medications, except for treatments of HAE, are allowed, but the 
dose and regimen must have been stable for at least 1 month before the first dose of study 
drug. 
• Prophylactic therapies for HAE (eg, anti-fibrinolytics or C1-INH) other than attenuated 
androgens will be allowed, but therapies known to attenuate an acute HAE attack (eg, 
C1-INH concentrate, fresh-frozen plasma [FFP]) must not be used during the attack being 
treated with icatibant unless these are required as rescue medications (see Section 6.7).  An 
exception is that fibrinolysis inhibitors may be given in a subject’s usual, stable prophylactic 
regimen.  
 
Use of the following concomitant medications is forbidden during the study: 
• ACE inhibitors. 
• Androgens or attenuated androgens (eg, stanozolol, danazol, oxandrolone, 
methyltestosterone, testosterone). 
• Hormonal contraceptives (acceptable contraception during the study for sexually active 
females will consist of abstinence or a double barrier method such as condom plus 
diaphragm, condom or diaphragm plus spermicide, condom or diaphragm plus intrauterine 
device). 
 
6.7 
Rescue Therapy 
For the purposes of this protocol, rescue therapy is any medication used after the administration 
of icatibant which, in the opinion of the investigator, is immediately necessary to alleviate acute 
symptoms which are judged by the investigator as resultant from the current HAE attack.  Repeat 
administration of icatibant for a single attack is not allowed in this study.   
The determination of the necessity for pain medication or other rescue therapy will be at the 
discretion of the investigator.  If pain medication is required, the investigator may administer 
morphine sulfate at a dose of 0.05 mg/kg or an equivalent low dose narcotic.  Antiemetics may 
also be prescribed as necessary to treat nausea.  Other acceptable rescue therapies include FFP, 
epinephrine, C1-INH if available and intravenous or prescription-strength non-steroidal 
anti-inflammatory drugs (NSAIDs).  Medications provided for rescue therapy will be denoted as 
rescue medications on the appropriate CRF. 
Antihistamines (diphenhydramine, loratadine, cetirizine, etc) and glucocorticoids are considered 
ineffective for the alleviation of an acute HAE attack.  If administered during an acute attack that 
occurs during the study, they should be recorded as concomitant medications but will not be 
considered as rescue medications.   


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If rescue medication is provided, the investigator will document the drug name, amount, time, 
route of administration, frequency, and duration administered. 
6.8 
Restrictions 
Subjects are not to receive treatment with any investigational product(s) other than icatibant or 
any investigational device(s) at any point during this study.  
6.8.1 
Fluid and Food Intake  
No specific restrictions on fluid or food intake apply for this study. 
6.8.2 
Subject Activity Restrictions 
No specific restrictions on subject activity apply for this study. 
6.9 
Treatment Compliance 
During this study, the investigational product will be administered at the hospital/study 
center/site under controlled conditions; therefore, full subject compliance with treatment is 
anticipated. 
6.10 Packaging and Labeling 
The investigational product will be packaged as 3-mL solution in a pre-filled 3-mL syringe made 
of clear type I glass.  The back stopper consists of bromobutyl coated with fluorocarbon 
polymer.  Front closure is achieved by means of a luer-lock adaptor that allows secure 
attachment of the needle.  Secondary packaging consists of 1 icatibant syringe, labeled in a tray 
with a 25-guage needle placed inside a plain white carton, also labeled.  A fluid-dispensing 
adaptor will be used to secure a 1-mL or 3-mL syringe to the glass syringe for withdrawal of 
icatibant. 
See the Pharmacy Manual for additional details. 
6.11 Storage and Accountability 
The following information should be considered when storing and using the investigational 
product. 
The investigational product will be shipped at 2° to 8°C.  Icatibant 10 mg/mL formulated for SC 
administration should be stored at or below 25°C.  The syringes must not be frozen. 
The disposition of all investigational product delivered to a Principal Investigator must be 
recorded on a subject-by-subject basis by completing the Clinical Trial Material Accountability 
Log.  The date and time of administration of the investigational product must be documented on 
the appropriate CRF. 


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The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 
loss/damaged and return of used/unused product is complete, accurate, and ready for review at 
each monitoring visit and/or audit.   
The sites must ensure that the investigational product is available for the monitor to inventory 
and prepare for return shipment to the sponsor or designee, if required.  
6.12 Investigational Product Retention at Study Site 
The process for destruction of investigational product must be determined and documented 
during the study start-up phase.   
If the investigational product is to be destroyed by the study sites, sites must follow their own 
process/policy that describes such activities.  All drug destruction processes will be documented 
and the sites must retain copies of these documents within the Site Regulatory Binder.  The sites 
must ensure that the Clinical Trial Material Accountability and Destruction Log is complete, 
accurate, and ready for review and/or audit at each monitoring visit.   
All manifests documenting shipments of investigational product must be retained as well copies 
of any investigational product return forms.  See the Pharmacy Manual for additional details. 


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7 
STUDY PROCEDURES 
Detailed descriptions of subject evaluations required for this protocol are described in this 
section.  These evaluations will be performed during the indicated days and weeks of the study 
(see Schedule of Events Tables in Appendix 1, Initial Icatibant-treated Attack and Appendix 2, 
Subsequent Icatibant-treated Attacks).  
All data collected are to be recorded on the appropriate CRF or electronic diary (e-diary) page. 
Details for study procedures including sample collection are described in the Operations Manual 
for this study. 
7.1 
Informed Consent 
Prior to conducting any study-related procedures, written informed consent must be obtained 
from the subject’s parent(s) or legal guardian(s) and assent from the subject (if applicable). 
The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the subject, the subject’s parent(s), or the subject’s legal guardian by the 
investigator or designee in accordance with the guidelines described in Section 11.4. 
Documentation and filing of informed consent documents should be completed according to 
Section 11.4. 
7.2 
Study Entrance Criteria 
At screening, each subject will be reviewed for eligibility against the study entrance criteria.  
Subjects who do not meet the study entrance criteria will not be allowed to participate in the 
study.  The reason(s) for the subject’s ineligibility for the study will be documented. 
7.3 
Confirmation of Study Eligibility 
Subject eligibility according to the study inclusion and exclusion criteria will be confirmed at the 
screening and pretreatment (baseline) visits on the basis of review of the study entrance criteria. 
7.4 
Demographics 
Subject demographic information including gender, date of birth, and race will be collected prior 
to the subject receiving the first dose of investigational product.  
7.5 
Medical History 
Medical history will be recorded on the CRF.  Details of prior HAE attacks (eg, typical 
frequency, symptom duration, onset of relief, and type and frequency of medical interventions 
required) will be obtained at screening through pretreatment on Day 1.  Other important medical 
events, and concomitant medication and illnesses will be recorded at other visits on the 
appropriate CRF pages.  Any existing medical condition present prior to the time of of the first 
dose will be reported as medical history. 


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7.6 
Height and Weight 
Height and weight will be recorded for all subjects.   
7.7 
Tanner Staging 
The investigator will perform Tanner staging for all subjects to determine pubertal status.  A 
description of the Tanner stages of puberty is provided in Appendix 3. 
7.8 
Investigational Product Administration 
All subjects will receive treatment with icatibant for an initial acute attack of HAE as a single, 
weight-adjusted dose of 0.4 mg/kg administered as a SC injection up to a maximum dose of 
30 mg.  Treatment with icatibant will be administered within 12 hours of onset of an acute HAE 
attack.  Pubertal/postpubertal subjects who present with a subsequent attack at least 7 days 
post-treatment may receive further treatment with icatibant for a total of 3 attacks. 
7.9 
Pharmacokinetic Assessments  
7.9.1 
Pharmacokinetic Variables 
PK variables will be determined by full sampling and noncompartmental methods where 
possible, and elsewhere by sparse sampling (at least 4 to 7 time points) and a population PK 
approach using nonlinear mixed effects modeling software.  The methods to be used for 
estimation of PK parameter values are described in Section 10.5.1. 
PK parameter estimates will include, where appropriate:  actual icatibant and metabolite 
concentrations at each sampling time, time to peak concentration (Tmax), actual peak (Cmax) and 
minimum (Cmin) concentrations, clearance (CL/F), actual area under the plasma 
concentration-time curve (AUC0-last and AUC0-inf), mean residence time (MRT), volume of 
distribution at steady state (Vss/F) and elimination half-life (t1/2). 
7.9.2 
Pharmacokinetic Sampling 
Sampling for PK assessments will be collected according to the Schedule of Events Table in 
Appendix 1, Initial Icatibant-treated Attack.   
The time of study drug administration on Day 1 will be designated as Time 0.  All post-treatment 
assessments will be calculated from the time of study drug administration.  Detailed sample 
collection, processing, and shipping instructions will be provided in the study Operations 
Manual. 
Blood samples for determination of plasma concentrations of icatibant in pubertal/postpubertal 
subjects will be collected on Day 1 at pretreatment, 15 (±5) minutes, 30 (±5) minutes, 45 (±5) 
minutes, 1 (±0.17) hour, 2 (±0.17) hours, 4 (±0.5) hours, 6 (±0.5), and 8 (±0.5) hours after 
treatment with study drug.   


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Blood samples for determination of plasma concentrations of icatibant in prepubertal subjects 
will be collected on Day 1 at pretreatment, 15 (±5) minutes 30 (±5) minutes, 2 (±0.5) hours, 
4 (±0.5) hours and 8 (±0.5) hours.  
7.9.3 
Bioanalytical Method 
Plasma samples will be assayed for concentrations of icatibant and its metabolites (M1 and M2) 
using a validated method (see Section 7.19). 
7.10 Efficacy Assessments 
7.10.1 
Investigator Symptom Score  
The investigator will use a symptom score to assess the severities of symptoms of acute 
cutaneous, abdominal, and laryngeal attacks of HAE using the following 5-point scale.  
Symptom scores will be recorded on Day 1 at pretreatment and at predetermined time points 
after treatment.  Results will be recorded on the CRF. 
Investigator-rated Symptom Score 
0 = none; absence of symptoms 
1 = mild (no to mild interference with daily activities) 
2 = moderate (moderate interference with daily activities) 
3 = severe (severe interference with daily activities) 
4 = very severe (very severe interference with daily activities) 
 
For attacks classified as cutaneous and/or abdominal, investigator-rated symptom scores will be 
collected for 8 symptoms:  abdominal tenderness, nausea, vomiting, diarrhea, skin pain, 
erythema, skin irritation, and skin swelling.   
For attacks classified as laryngeal, investigator-assessed symptom scores will be collected for 
13 symptoms:  abdominal tenderness, nausea, vomiting, diarrhea, skin pain, erythema, skin 
irritation, skin swelling, dysphagia, voice change, breathing difficulties, stridor, and asphyxia.   
7.10.2 
Subject Self-assessment of Pain  
Subjects who are at least 4 years of age will self-assess HAE-related pain using the Faces Pain 
Scale-Revised (FPS-R).  A copy of the FPS-R is provided in Appendix 4. 
Self-assessment results will be recorded in the e-diary.  The self-assessment diaries will be 
provided to these subjects on Day 1 at pretreatment and at predetermined time points after 
treatment while at the hospital/study center and after their discharge.  Subjects will return the 
e-diary at the next scheduled visit on Day 8.  Subjects will receive detailed instructions on when 
and how to complete the diaries by the investigator and/or clinical site personnel. 


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7.10.3 
Investigator Assessment of Pain 
Subjects who are below 4 years of age will undergo investigator assessment of HAE-related 
symptoms using the Faces, Legs, Activity, Cry, and Consolability (FLACC) comportmental pain 
scale.  A copy of the FLACC scale is provided in Appendix 5. 
7.10.4 
Initial Symptom Relief 
The investigator will be asked to provide the following information on the CRF: 
• To record the date and time when overall subject improvement was first noted and mark the 
date and time accordingly. 
 
7.11 Reproductive Hormone Assessments 
Reproductive hormone levels will be measured in all subjects.  Blood samples will be collected 
to assess FSH, LH, estradiol, and progesterone in females, and FSH, LH, and testosterone in 
males. 
7.12 Safety Assessments 
7.12.1 
Physical Examination 
Physical examinations will include a review of the subject’s general appearance as well as 
evaluation of the body systems.  Any abnormal change in findings will be recorded as an adverse 
event (AE) on the appropriate CRF.  The physical examination will include the following: 
- 
General appearance 
- 
Eye, ears, nose, throat  
- 
Lymph nodes 
- 
Cardiovascular 
- 
Skin 
- 
Abdomen  
- 
Neurological  
- 
Spine and extremities 
- 
Lungs 
 
7.12.2 
Vital Signs 
Vital signs are to be recorded for all subjects and will include pulse, blood pressure, respiration 
rate, and temperature.   
7.12.3 
Electrocardiography 
A standard 12-lead ECG will be performed after 10 minutes at rest when the patient is seated or 
supine.  ECG results will be read locally at the clinical site.  Abnormalities will be recorded. 
7.12.4 
Clinical Laboratory Tests 
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing.  All blood samples will be collected via venipuncture.  Subjects will be in a seated or 
supine position during blood collection. 


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Clinical laboratory tests will include the following (See Table 7-1):  
Table 7-1  List of Laboratory Tests 
Hematology: 
- 
Hematocrit  
- 
Hemoglobin  
- 
Mean corpuscular hemoglobin  
- 
Mean corpuscular hemoglobin 
concentration  
- 
Mean corpuscular volume  
- 
Platelet count 
- 
Red blood cell count  
- 
White blood cell  count with 
differential  
 
Urinalysis:  
- 
Appearance 
- 
Bilirubin 
- 
Color 
- 
Glucose 
- 
Ketones 
- 
Nitrite  
- 
Occult blood 
- 
pH 
- 
Protein 
- 
Specific gravity 
Serum Chemistry: 
- 
Albumin  
- 
Alkaline phosphatase  
- 
Alanine aminotransferase 
- 
Aspartate aminotransferase  
- 
Calcium  
- 
Carbon dioxide  
- 
Chloride  
- 
Creatinine 
- 
Creatine kinase  
- 
Gamma-glutamyl transferase  
- 
Glucose 
- 
Lactate dehydrogenase  
- 
Phosphorus 
- 
Potassium  
- 
Sodium  
- 
Total bilirubin 
 
 
7.12.5 
Local Tolerability 
Injection site reactions (erythema, swelling, burning sensation, itching/pruritis, warm sensation, 
cutaneous pain, or other) will be evaluated by the investigator when the subject is at the 
hospital/study center, and the diameter of any erythema or swelling will be measured.   
After discharge, the subject (or the subject’s parent/legal guardian on behalf of the subject as 
appropriate) will be interviewed about injection site reactions, either in person or by telephone 
contact.   
7.12.6 
Immunogenicity 
The immunogenicity of icatibant will be assessed.  Serum samples for immunogenicity testing 
will be collected for determination of anti-icatibant antibodies.  Serum samples will be analyzed 
for anti-icatibant antibodies at Shire HGT or at a designated laboratory.  Details concerning 
sample collection and preparation will be provided in the study Operations Manual. 
Samples will be stored frozen at -65°C or below if not shipped on the day of collection.  Details 
for shipping will be provided in the study Operations Manual. 


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7.12.7 
Pregnancy Testing 
Pubertal and postpubertal female subjects will undergo pregnancy testing at time points specified 
in the Schedule of Events Tables in Appendix 1 and Appendix 2.  All pregnancy testing will be 
conducted using a urine human chorionic gonadotropin (hCG) test.  
7.13 Sample Collection, Storage, and Shipping 
Blood samples will be collected via venipuncture.  All samples will be stored and secured in a 
way that assures that unauthorized access is prohibited and the samples are not lost, allowed to 
deteriorate, or are accidentally or illegally destroyed.  Detailed sample collection, processing, 
and shipping instructions will be provided in the study Operations Manual. 
7.14 Recording of Concomitant Medications  
All medications administered to the study subjects from the time of informed consent through the 
Day 90 follow-up visit are regarded as concomitant and will be documented on the CRF.  
7.15 Adverse Events Assessments   
7.15.1 
Definitions of Adverse Events and Serious Adverse Events 
7.15.1.1 
Adverse Event 
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered investigational product-related.  This 
includes an exacerbation of a pre-existing condition.   
AEs include: 
• Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study. 
• Intercurrent illnesses. 
• Drug interactions. 
• Events related to or possibly related to concomitant medications. 
• Abnormal laboratory values (this includes significant shifts from baseline within the range of 
normal that the investigator considers to be clinically important). 
• Clinically significant abnormalities in physical examination, vital signs, and weight. 
 
The investigator must record all AEs on the AE CRF, regardless of the severity or relationship to 
investigational product.  The investigator should treat subjects with AEs appropriately and 
observe them at suitable intervals until the events stabilize or resolve.  Adverse events may be 
discovered through observation or examination of the subject, questioning of the subject, 
complaint by the subject, or by abnormal clinical laboratory values. 


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In addition, AEs may also include laboratory values that become significantly out of range.  In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the subject’s safety is not at risk. 
Additional illnesses present at the time when informed consent is given until the time of 
treatment are regarded as concomitant illnesses and will be documented on the medical history 
page of the CRF.  Illnesses first occurring or detected on or after study drug treatment, and 
worsening of a concomitant illness during the study, are to be regarded as AEs and must be 
documented as such in the CRF. 
The treated HAE attack is defined as any symptoms occurring in treated subjects within 48 hours 
of the onset of symptoms.  Any clinically relevant worsening of the signs and symptoms of a 
treated attack is considered to be related to the underlying disease of HAE and will be collected 
separately from general reports of AEs.  Symptoms reoccurring more than 48 hours after an 
initial attack will be considered a new attack, and will also not be reported as AEs.  Attacks not 
treated with icatibant will be documented in detail in the CRF.  They are considered to be 
pre-existing disease and will not be documented as AEs. 
Local tolerability will include symptoms at the site of study drug administration (injection site) 
and will be assessed separately from general reports of AEs.  Injection site reactions will be 
documented in the "local tolerability" page (or form) of the CRF.  Injection site reactions that 
have been reported previously with icatibant included erythema, swelling, burning sensation, 
itching, warmth and pain and were generally, mild to moderate, transient, and resolved without 
sequelae.  Injection site reactions that do not meet the criteria of a serious adverse event will not 
need to be additionally reported as AEs.   
7.15.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is any AE occurring at any dose that results in any of the 
following outcomes: 
• Death. 
• Is life-threatening. 
• Requires hospitalization. 
• Requires prolongation of existing hospitalization. 
• A persistent or significant disability or incapacity.  
• A congenital anomaly or birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  A life-threatening AE is defined as an AE that placed the 
subject, in the view of the initial reporter, at immediate risk of death from the AE as it occurred 
(ie, it does not include an AE that, had it occurred in a more severe form, might have caused 
death). 


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7.15.2 
Classification of Adverse Events and Serious Adverse Events 
The severity of AEs will be assessed by the investigator using the National Cancer Institute 
Common Terminology Criteria (NCI CTCAE) Version 4.0 grading scale.  If an AE is not 
described in the NCI CTCAE, the severity should be recorded based on the scale below (see 
Table 7-2).  The severity of all AEs/SAEs should be recorded on the appropriate CRF page as 
Grade 1, 2, 3, 4, or 5 corresponding, respectively, to a severity of mild, moderate, severe, 
life-threatening, or fatal.  
Table 7-2  Adverse Event Severity   
Severity 
Definition 
Grade 1 (Mild) 
No limitation of usual activities. 
Grade 2 (Moderate) 
Some limitation of usual activities. 
Grade 3 (Severe) 
Inability to carry out usual activities. 
Grade 4 (Life-threatening) 
Immediate risk of death. 
Grade 5 (Fatal) 
Death 
 
7.15.2.1 
Clarification between Serious and Severe 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (eg, severe headache).  This is not the same as “serious,” which is based on 
the outcome or action criteria usually associated with events that pose a threat to life or 
functioning.  Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations. 
7.15.3 
Relatedness of Adverse Events and Serious Adverse Events 
Relationship of an AE or SAE to investigational product is to be determined by the investigator 
based on the following definitions (See Table 7-3).   
Table 7-3  Adverse Event Relatedness 
Relationship to Product(s) 
Definition 
Not Related 
Unrelated to investigational product 
Possibly Related 
A clinical event or laboratory abnormality with a reasonable 
time sequence to administration of investigational product, but 
which could also be explained by concurrent disease or other 
drugs or chemicals. 
Probably Related 
A clinical event or laboratory abnormality with a reasonable 
time sequence to administration of investigational product, 
unlikely to be attributable to concurrent disease or other drugs 
and chemicals and which follows a clinically reasonable 
response on de-challenge.  The association of the clinical event 


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Table 7-3  Adverse Event Relatedness 
Relationship to Product(s) 
Definition 
or laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds. 
Definitely related 
The event follows a reasonable temporal sequence from 
administration of the investigational product, follows a known 
or suspected response pattern to the investigational product, is 
confirmed by improvement upon stopping the investigational 
product (de-challenge), and reappears upon repeated exposure 
(re-challenge).  Note that this is not to be construed as requiring 
re-exposure of the subject to investigational product; however, 
the determination of definitely related can only be used when 
recurrence of event is observed. 
 
7.15.4 
Procedures for Recording and Reporting Adverse Events 
7.15.4.1 
Adverse Event Monitoring and Period of Observation 
AEs will be monitored continuously.  For the purposes of this study, the period of observation 
will extend from the time of treatment until the subject’s final evaluation of the study.  For safety 
purposes, the final evaluation will be defined as the follow-up evaluation performed 
approximately 90 days after the last dose for subjects who complete the study. 
If the investigator considers it necessary to report an AE in a subject after the end of the safety 
observation period, he or she should contact the sponsor to determine how the AE should be 
documented and reported. 
7.15.4.2 
Reporting Serious Adverse Events 
Any SAE, regardless of relationship to investigational product, which occurs in a subject after 
informed consent, should be recorded by the clinical site on an SAE form.  The SAE must be 
completely described on the subject’s CRF, including the judgment of the investigator as to the 
relationship of the SAE to the investigational product.   
The investigator will promptly supply all information identified and requested by the sponsor (or 
contract research organization [CRO]) regarding the SAE.  The investigator must report the SAE 
to the Shire Pharmacovigilance and Risk Management Department AND to the Shire HGT 
Medical Monitor on an SAE form.  This form must be completed and faxed or emailed within 
24 hours of the investigator’s learning of the event to: 
Shire Pharmacovigilance and Risk Management Department: 
FAX: 
(Worldwide) OR 
(North America) 
Email: 
PPD
PPD
PPD


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


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7.17 Abuse, Overdose, and Medication Error 
• Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a 
dose higher than prescribed per protocol (but below the dose defined for overdose) or when 
used for non-medical purpose (eg, altering one’s state of consciousness). 
• Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note:  
this includes a situation where the test article is not used as directed at the dose prescribed by 
the protocol). 
• Overdose – No clinical information on overdose is available.  A dose of 3.2 mg/kg 
(approximately 8 times the therapeutic dose) caused transient erythema, itching or 
hypotension in healthy subjects.  No therapeutic intervention was necessary. 
• Medication Error – A mistake made in prescribing, dispensing, administration and/or use of 
the investigational medicinal product. 
 
All investigational medicinal product provided to pediatric subjects should be supervised by the 
parent(s)/legal guardian(s)/caregiver(s). 
7.18 Removal of Subjects from the Trial or Investigational Product 
A subject’s participation in the study may be discontinued at any time at the discretion of the 
investigator.  The following may be justifiable reasons for the investigator to remove a subject 
from the study: 
• Non-compliance, including failure to appear at one or more study visits. 
• The subject was erroneously included in the study. 
• The subject develops an exclusion criterion.  
• The subject suffers an intolerable adverse event. 
• The study is terminated by the sponsor. 
• The study is closed prior to the subject’s first eligible attack. 
 
The subject, the subject’s parent(s), or the subject’s legal guardian(s) acting on behalf of the 
subject is free to withdraw consent and discontinue participation in the study at any time without 
prejudice to further treatment. 
If a subject or the subject’s parent(s) or the subject’s legal guardian(s) acting on behalf of the 
subject, discontinues participation in the study, or the subject is discontinued by the investigator, 
the Subject Completion/Discontinuation Case Report Form (CRF) describing the reason for 
discontinuation must be completed.  Any AEs experienced up to the point of discontinuation 
must be documented on the AE CRF.  If AEs are present when the subject withdraws from the 
study, the subject will be re-evaluated within 30 days of withdrawal.  All ongoing SAEs at the 
time of withdrawal will be followed until resolution. 


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7.18.1 
Safety-Related Study Stopping Rules   
The Data and Safety Monitoring Board (see Section 11.8 for a description of the DSMB and its 
role) may elect to suspend the study until the DSMB can review any death that is drug or 
disease-related or unexplained, or if there is an unexpected drug-related severe AE. 
Following the review of safety data, the study will be either: 
• Resumed unchanged. 
• Resumed with modifications to the protocol.  
• Terminated. 
 
Subject safety will be monitored on a continuous basis during this study until the last subject 
completes his or her last scheduled study visit/assessment.   
Additional information on safety monitoring can be found in Section 11.8, Data and Safety 
Monitoring Board. 
7.19 Appropriateness of Measurements 
The safety assessments used in this study are standard and will provide a detailed measure of the 
safety of icatibant in the pediatric population.  
The measures of serum reproductive hormone concentration are accepted measures for assessing 
the function of reproductive organs.   
Plasma samples will be assayed for concentrations of icatibant and its 2 major metabolites 
(M1 and M2) using a validated high-performance liquid chromatography/tandem mass 
spectrometry (LC-MS/MS) method with a lower limit of quantification of 1 ng/mL and a range 
from 1 to 1000 ng/mL (Analytical Report SHR10-002).  PK variables will be determined by full 
sampling and noncompartmental methods where possible, and elsewhere by sparse sampling (at 
least 4 to 7 time points) and a population PK approach using non-linear mixed effects modeling 
software. 
The symptom score used in efficacy assessments in this study is an investigator-rated measure of 
symptom severity based on a standard 5-point scoring system (0-absence of symptoms, 1-mild, 
2-moderate, 3-severe, 4-very severe)  capturing symptoms of acute attacks of HAE that have 
been identified and validated to assess efficacy in adults.  For attacks classified as abdominal or 
cutaneous, investigator-rated symptom scores are collected for 8 symptoms:  abdominal 
tenderness, nausea, vomiting, diarrhea, skin pain, erythema, skin irritation, and skin swelling.   
For attacks classified as laryngeal, investigator-assessed symptom scores are collected for 
13 symptoms:  abdominal tenderness, nausea, vomiting, diarrhea, skin pain, erythema, skin 
irritation, skin swelling, dysphagia, voice change, breathing difficulties, stridor, and asphyxia.   
 


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In all pediatric subjects in the present study, irrespective of age, the investigator-rated symptom 
score will provide an appropriate means to measure the severity of primary symptoms (eg, 
cutaneous and/or abdominal pain, cutaneous swelling, or laryngeal symptoms) of acute attacks of 
HAE at pretreatment and the change in symptom severity, if any, after treatment with icatibant.  
Though subject-reported outcomes such as the symptom score and visual analog scale (VAS) 
have been employed successfully as efficacy measures in clinical studies of icatibant in adults, 
the use of these subject-reported outcomes in children poses special challenges.  The Faces Pain 
Scale is a validated, self-reported measure used to assess the intensity of children's pain in a wide 
variety of clinical contexts.9  The Faces Pain Scale-Revised (FPS-R) was adapted from the 
original FPS in order to make it possible to score pain on a widely accepted 0-to-10 metric.10  
The scales are suitable for use in assessment of the intensity of children's acute pain from age 
4 onward, are simple to administer, and require no specialized equipment other than the 
standardized images of faces.  Use of the FPS-R is planned for this study, and will provide an 
appropriate means to measure pain associated with acute attacks of HAE in pediatric subjects 
who are at least 4 years of age. 
Young children (ie, those below the age of 4 years) frequently lack the verbal and cognitive 
skills necessary to report physical discomfort and pain intensity.  Behavioral cues are the primary 
indicators of pain in children who are unable to report pain or follow instructions in the use of 
assessment tools.  The FLACC instrument comprises 5 categories of behavior (face, legs, 
activity, cry, consolability) to assess pain in young children.11  Each category is scored on a 
0-to-2 scale which results in a total score from 0 to 10. 
Collectively, the measures employed in this study are expected to allow for assessment of the 
PK, safety, and efficacy profiles of icatibant in the pediatric population. 


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8 
STUDY ACTIVITIES 
8.1 
Screening Period (Day of Informed Consent to Pretreatment on Day 1 of the 
Initial Attack)   
• Informed Consent/Assent 
• Inclusion/Exclusion Criteria 
• Medical History 
• Confirmation of documented HAE diagnosis 
• Measurement of C1-INH   
• Physical examination 
• Vital signs 
• ECG 
• Height and weight 
• Urine pregnancy test in pubertal/postpubertal females only 
• Recording of concomitant medications 
 
8.2 
Pretreatment (Baseline) Assessments (Day 1, Initial and Subsequent Attacks) 
The following assessments will be performed at both initial and subsequent icatibant-treated 
attacks unless otherwise indicated.  All evaluations and sample collections must be performed 
prior to treatment. 
• Medical history (at initial attack only) 
• Confirm inclusion/exclusion criteria (at initial attack only) 
• Physical examination 
• Tanner staging 
• Vital signs 
• ECG (at subsequent attacks only) 
• Height and weight 
• Subject self-assessment of HAE-related pain (in subjects ≥4 years of age only) using e-diary 
FPS-R 
• Investigator assessment of HAE symptoms 
• Investigator assessment of HAE-related pain (in subjects <4 years of age only) using FLACC 
• Clinical laboratory tests (serum chemistry, hematology and urinalysis) 
• Urine pregnancy test (in pubertal/postpubertal females only) 
• Assessment of reproductive hormones  
• Pharmacokinetic evaluation (prior to treatment at initial attack only) 
• Immunogenicity evaluation 
• Recording of concomitant medications 
• Assessment of AEs (at subsequent attacks only) 
 


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8.3 
Initial Attack  
8.3.1 
Treatment Period (Day 1 to Day 8) 
• Study drug administration (Day 1, Time 0) 
• Physical examination (Day 1, 8 hours post-dose and Day 8) 
• Vital signs (Day 1, 1 hour and 8 hours post-dose and Day 8) 
• ECG (Day 1, 8 hours post-dose) 
• Subject self-assessment of HAE-related pain (in subjects ≥4 years of age) using e-diary 
FPS-R (Day 1, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose, Day 2 [24 hours], 
Day 3 [48 hours]) 
• Investigator assessment of HAE symptoms (Day 1, 1 hour, 2 hours, 4 hours, 6 hours, and 
8 hours post-dose) 
• Investigator assessment of HAE-related pain (in subjects <4 years of age only) using FLACC 
(Day 1, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose) 
• Clinical laboratory tests (Day 1, 8 hours post-dose and Day 8) 
• Assessment of reproductive hormones (Day 1, 8 hours post-dose and Day 8) 
• Injection site reaction evaluation (Day 1, 1 hour, 6 hours, and 8 hours post-dose, 
Day 2 [24 hours], Day 3 [48 hours], and Day 8) 
• Sampling for PK evaluation in pubertal/post pubertal subjects (Day 1, 15 (±5) minutes, 
30 (±5) minutes, 45 (±5) minutes, 1 (±0.17) hour, 2 (±0.17) hours, 4 (±0.5) hours, 6 (±0.5) 
hours, and 8 (±0.5) hours post-dose at initial attack only) 
• Sampling for PK evaluations in prepubertal subjects (Day 1, 15 (±5) minutes, 30 (±5) 
minutes, 2 (±0.17) hours, 4 (±0.5) hours, and 8 (±0.5) hours post-dose at initial attack only) 
• Immunogenicity evaluation (Day 8) 
• Recording of concomitant medications   
• Assessment of AEs  
 
8.3.2 
Follow-up Visit (Day 90 ±7 days) 
In the event that a subject has a subsequent HAE attack within the 90 day follow-up period for 
the first treatment, the date of the Day 90 follow-up visit for the first treatment remains the same.  
Each subsequent treatment will have a corresponding Day 90 follow-up visit.   
• Physical examination 
• Tanner staging (for those subjects classified as Tanner stage IV or below at baseline) 
• Vital signs 
• Height and weight 
• Clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• Urine pregnancy test (in pubertal/postpubertal females only) 
• Assessment of reproductive hormones  
• Immunogenicity evaluation  
• Recording of concomitant medications 
• Assessment of AEs 


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


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


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10 PLANNED STATISTICAL METHODS 
10.1 General Considerations 
All statistical analyses will be performed using SAS® statistical software (SAS Institute, NC, 
USA).  Data will be summarized with respect to disposition, demographic, pretreatment 
characteristics, PK variables, safety variables, and efficacy variables.  Unless stated otherwise, 
tabular summaries will be presented by the subject’s stratification group at enrollment (ie, 
prepubertal group, pubertal/postpubertal group, and the overall subjects group).  
Summary statistics for continuous variables will include the number of subjects, the mean, 
median, standard deviation, and range.  For PK parameters, the coefficient of variation and 
geometric mean also will be provided.  For categorical data, summaries will include counts and 
percentages.  For time to event data, the median time to event and other summary statistics will 
be estimated using the method of Kaplan and Meier. 
10.2 Determination of Sample Size 
Enrollment of approximately 16 prepubertal and 20 pubertal/postpubertal subjects, who are from 
2 through 17 years of age and who present with a cutaneous, abdominal, or laryngeal attack of 
acute HAE, is planned.  This sample size is empirically derived and not based on a formal 
sample size calculation.  However, the inclusion of approximately 36 subjects will provide basic 
information for safety, tolerability, PK, and efficacy. 
10.3 Analysis Populations 
The following populations will be used in the analysis: 
• The Initial Non-laryngeal Treatment Population will consist of those subjects who were 
treated with icatibant for their initial attack and whose primary symptom was either 
cutaneous or abdominal.  
• The Second Non-laryngeal Treatment Population will consist of those subjects who had a 
second icatibant-treated attack for which the primary symptom was either cutaneous or 
abdominal, regardless of the primary symptom for the initial attack. 
• The Third Non-laryngeal Treatment Population will consist of those subjects who had a third 
icatibant-treated attack, for which the primary symptom was either cutaneous or abdominal, 
regardless of the primary symptom for the initial attack. 
• The Laryngeal Population will consist of those subjects who were treated with icatibant for 
any attack for which the primary symptom was laryngeal.  
• The PK Population will consist of those subjects who were treated with icatibant for their 
initial attack and who had at least 1 post-treatment icatibant concentration recorded.   
• The Initial Treatment Population will consist of those subjects who were treated with 
icatibant for the initial attack. 
• The Additional Treatment Population will consist of those pubertal/post-pubertal subjects 
who were treated with icatibant for more than 1 attack.   
 


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All efficacy analysis will be performed on the Initial Non-laryngeal Treatment Population, the 
Second Non-laryngeal Treatment Population, and the Third Non-laryngeal Treatment 
Population.  The PK analyses will be based on the PK population.  Safety and tolerability 
analyses will be based on the Initial Treatment Population and the Additional Treatment 
Population.  The Laryngeal Population will be used to explore the efficacy of icatibant for the 
treatment of laryngeal attacks.  All analyses conducted with this population will be limited to 
data corresponding to the subject’s first laryngeal attack. 
10.4 Demographics and Baseline Characteristics 
Demographic data and pretreatment characteristics will be summarized for each analysis 
population.  
10.5 Pharmacokinetic Analysis 
A primary objective of the study is to investigate the PK of a single SC injection of icatibant in 
pediatric subjects treated for acute attacks of HAE.  All PK analyses will use the PK population. 
Plasma concentrations of icatibant and metabolites (ie, M1 and M2) and actual blood sampling 
times will be listed by subject and sampling time.  Plasma concentrations will be summarized 
using descriptive statistics (number, mean and standard deviation).  PK parameters for icatibant 
and metabolites will be listed by subject and will be summarized using descriptive statistics 
(number, mean, standard deviation, coefficient of variation, geometric mean, minimum, median, 
maximum).  Individual and mean plasma concentrations of icatibant and metabolites versus time 
will be displayed on linear and semi-logarithmic axes. 
10.5.1 
Estimation of PK Parameters 
Noncompartmental modeling:  for subjects in whom the number of samples is sufficient to 
permit noncompartmental modeling, individual and mean PK parameters will be computed for 
icatibant and metabolites (M1 and M2) using standard noncompartmental methods, where 
possible, using the WinNonLin software package (Pharsight Corp., Mountain View, CA).  For 
descriptive statistical tabulation of mean plasma concentrations and graphical displays, nominal 
collection times will be used, while all PK analysis and parameter calculations will use actual 
collection times.  Plasma concentrations <LOQ will be treated as 0 for the calculation of the 
descriptive statistics for plasma concentrations at each sampling time.  For the pharmacokinetic 
analysis, plasma concentrations <LOQ that occurred from pre-dose to the first concentration 
≥LOQ will be treated as 0 and those that occur thereafter will be treated as missing. 
PK parameter estimates will include, where appropriate:  icatibant and metabolite concentrations 
at each sampling time, time to peak concentration (Tmax), actual peak (Cmax) and minimum (Cmin) 
concentrations, clearance (CL/F), area under the plasma concentration-time curve (AUC0-last and 
AUC0-inf), mean residence time (MRT), volume of distribution at steady state (Vss/F) and 
elimination half-life (t1/2). 
 


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The distribution of continuous data will be evaluated using parametric tests.  A transformation, 
such as logs, will be used where appropriate.  Multiple regression analysis, with an appropriate 
transformation on the dependent variable, will be used to assess the contribution of potential PK 
covariates while controlling for demographic covariates (eg, subject’s age and gender) to the 
inter-subject variability of icatibant PK parameters.  The multivariable analysis will be 
considered the primary statistical analysis.  A p-value of 0.05 will be considered statistically 
significant for all analyses. 
Compartmental modeling using population methods:  nonlinear mixed effects modeling will be 
used to define individual subject profiles and if possible, parameter estimates.  The structural PK 
model will be developed and validated using PK information obtained from adult subjects and 
will enable delineation of the impact of age-dependent changes on icatibant disposition.  
Development of this model will allow for characterization and better prediction of the 
dose-concentration-exposure relationship for icatibant in pediatric subjects.  Population PK 
modeling will be performed with nonlinear mixed effect modeling software (eg, NONMEM, 
Globomax LLC or WinNonMix, Pharsight Corp.).  The program will estimate the inter- and 
intra-individual variability of PK parameter estimates.  Both weight-normalization and allometric 
scaling principles will be evaluated.  For selecting preliminary meaningful covariates the general 
additive model (GAM) analysis will be used.  Variables to be considered will include (but are 
not limited to):  age, sex, ethnicity, total and lean bodyweight (TBW, LBW), body mass index 
(BMI), and body surface area (BSA). 
Monte Carlo simulation experiments based on the model(s) developed above may be performed 
by a validated simulation software program (eg, Trial Simulator, Pharsight Corp.) to assess the 
response patterns for various dosage regimens of icatibant treatments in the pediatric population. 
10.6 Safety and Tolerability Analysis 
Another primary objective of the study is to investigate the safety and tolerability of a single SC 
dose of icatibant in pediatric subjects with HAE during an acute HAE attack.  The corresponding 
analyses will be based on the Initial Treatment Population. 
The safety and tolerability parameters include AEs, vital signs, ECG, local tolerability at the 
injection site, reproductive hormone levels, immunogenicity, and standard hematology, serum 
chemistry, and urinalysis. 
AEs will be categorized using MedDRA Version 8.1 or higher.  The assessment of safety will be 
based mainly on the frequency of treatment emergent AEs.  AEs will be summarized by system 
organ class (SOC) and preferred term.  The number and proportion of subjects experiencing an 
AE will be tabulated by the subject stratification group and for the overall subject group.  AEs by 
SOC and preferred term also will be tabulated by severity and by relationship to treatment.  In 
the case of multiple occurrences of the same AEs (at the preferred term level) in an individual 
subject, the AE that is classified as the most severe (ie, maximum severity) will be identified for 
the analysis by severity and the AE that has the highest relationship to study drug will be 
identified for the analysis by relationship.  SAEs will be provided in a data listing. 


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Laboratory data will be listed by subject and stratification group.  Subjects with newly occurring 
abnormalities outside the normal range will be flagged and listed separately.  Actual values and 
mean change from pretreatment values will be summarized by the stratification group.  Shift 
tables will also be tabulated by stratification group and time point. 
Vital signs data will be listed by subject and stratification group.  Furthermore, actual values and 
mean changes from baseline will be summarized for each stratification group as well as the 
overall subject group.  Shift tables may be presented, utilizing reference ranges.  Subjects with 
notably abnormal values will be identified and listed separately along with their values. 
Local tolerability will be tabulated and summarized according to the type and severity of attack. 
The impact of icatibant on the reproductive hormone levels will be assessed by presenting 
tabular summaries for FSH, LH, estradiol, and progesterone for females, and FSH, LH, and 
testosterone for males.  The change from baseline values will also be summarized.  Subjects with 
newly occurring abnormalities outside the normal range will be flagged and listed separately. 
Data from other tests (eg, immunogenicity, ECG) will be listed and summarized as appropriate. 
The assessment of safety and tolerability after repeated treatment with icatibant is also of 
interest.  The analyses described above will be repeated using the Additional Treatment 
Population.  The summary tables and listings will be presented by attack number (ie, Attack 1, 
Attack 2, and Attack 3). 
10.7 Efficacy Analysis 
The primary efficacy endpoint is the time to onset of symptom relief measured using the 
investigator-reported symptom score.  The investigator will report symptom scores at 
pretreatment and 1, 2, 4, 6, and 8 hours post-treatment.  Eight symptoms will be assessed for 
abdominal and cutaneous attacks, and 13 symptoms will be assessed for laryngeal attacks.  Time 
of symptom relief is defined as the earliest time post-treatment at which there is a 20% 
improvement in the average post-treatment symptom score with no worsening of any single 
component score.  The median time and the 95% confidence interval will be calculated using the 
Kaplan-Meier methodology. 
A tabular summary of the average investigator-reported symptom score and the change from 
baseline in the average investigator-reported symptom score will be presented by the 
stratification group and the overall subjects group.  An alternative analysis of time to onset of 
symptom relief will focus on the time to minimal symptoms.  In this case, symptom relief is 
defined as the earliest time post-treatment when all symptoms are either absent or mild.  
For individual investigator-reported symptom scores, a shift table from baseline will be 
presented for each post-treatment time point.  The analysis will be repeated to assess shift in the 
individual symptom scores from the 2 hour time-point.  Also, for individual symptoms that are 
moderate or worse at pretreatment, the median and 95% confidence interval will be presented for 
the time to the symptom being mild or absent.  


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Two subsets of subjects, those 4 years of age or older and those below 4 years of age, will assess 
pain using the FPS-R and FLACC instruments, respectively.  Time to onset of symptom relief 
will be computed in a manner similar to that for the average investigator-reported symptom 
scores.  
All efficacy analysis will be performed on the initial treatment population, the second treatment 
population, and the third treatment population.  The efficacy data for subjects with laryngeal 
attacks will be listed.  If there are at least 5 subjects with laryngeal attacks, then the average 
investigator-reported symptom scores and the change from baseline in the average 
investigator-reported symptom score will be summarized.  Additionally, time to symptom relief 
analysis will be performed on the investigator-reported symptom scores. 
10.8 Other Analyses 
The number and percentage of subjects who received rescue medications before the onset of 
symptom relief will be summarized by the stratification group.  Time to first use of rescue 
medication prior to symptom relief will be calculated from the time of study drug administration 
to the first use of rescue medication prior to symptom relief.  The median time and the 
95% confidence interval will be calculated using Kaplan-Meier methodology if there are at least 
5 subjects who used rescue medication prior to attaining symptom relief. 
10.9 Data Monitoring and Interim Analysis 
A Data and Safety Monitoring Board (DSMB) will be set up to review the safety, tolerability, 
PK, and efficacy data on an ongoing basis.  The goal of the DSMB will be to assess the 
risk/benefit of icatibant treatment in this pediatric population.  An analysis of the data for DSMB 
review is planned after the first 4 subjects in the pubertal/postpubertal group have been treated.  
Because no formal hypothesis testing is planned, multiplicity concerns regarding repeated 
analyses are not an issue.  
10.10 Handling of Missing Data 
Individual pretreatment symptom scores, FPS-R scores, and FLACC scores will be assigned a 
value of zero.  For missing post-treatment scores, imputation will be employed using the Last 
Observation Carried Forward (LOCF) approach.  The pretreatment values may also be used in 
the imputation.  For missing or partial rescue medication dates, the imputation will be performed 
such that the earliest possible time post-treatment will be assigned to the rescue medication use.  
Similar approach will be followed in case of missing or partial AE dates.  


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


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


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


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Regulatory approval and notification as required must also be available; these are the 
responsibility of the sponsor. 
11.8 Data and Safety Monitoring Board 
In view of the role of bradykinin and B2 receptors in reproductive development, the study will 
use an external Data and Safety Monitoring Board (DSMB).  The DSMB will provide an 
ongoing, independent review and assessment of the safety data to protect the interests and safety 
of subjects participating in the study.  The DSMB will adhere to a prospectively determined 
charter which will be proposed by sponsor and approved by the DSMB.  The charter will define 
the membership of the DSMB, the responsibilities of the DSMB and the sponsor, describe the 
conduct of meetings, and define the data to be reviewed.   
Enrollment of pediatric subjects in the proposed study will be stratified into 2 groups (2 years of 
age to the older prepubertal children, and pubertal/postpubertal children to those 17 years of 
age).  It is planned that subjects in both groups will receive an icatibant dose (0.4 mg/kg to a 
maximum dose of 30 mg) selected to target an exposure comparable to that observed in adults 
treated with icatibant.  Initially, enrollment and dosing of pubertal/postpubertal subjects will 
precede that of prepubertal subjects.  After the first 4 subjects in the pubertal/postpubertal group 
have been treated, icatibant concentration measurements and PK analysis, safety, and tolerability 
data will be reviewed and assessed by the DSMB.  This review must be completed prior to 
initiating enrollment of subjects in the prepubertal group.  As the outcome of its review, the 
DSMB may make a recommendation to continue enrolling subjects in the pubertal/postpubertal 
group, to initiate dosing of subjects in the prepubertal group, or to administer a different dose, or 
to terminate the study.  
11.9 Protocol Violations/Deviations 
The investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to subjects.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations. 
A record of subjects screened, but not entered into the study, is also to be maintained.  For any 
subject who does not meet the inclusion or exclusion criteria a protocol exemption may be 
requested by the investigator.  This exemption may be approved by the Shire HGT Medical 
Monitor prior to enrollment and the protocol exception must be fully documented in the source 
documents and on the appropriate page of the CRF. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the investigator will contact the sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.   


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


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


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12 LIST OF REFERENCES 
1. Bowen T, Cicardi M, Bork K, et al. Hereditary angioedema: a current state-of-the-art review, 
VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, 
Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol 
2008;100:S30-40. 
2. Davis AE, 3rd. New treatments addressing the pathophysiology of hereditary angioedema. 
Clin Mol Allergy 2008;6:2. 
3. Knolle J, Breipohl G, Henke S, Wirth K, Scholkens B. New and highly potent bradykinin 
antagonists. Agents Actions Suppl 1992;38 ( Pt 1):559-64. 
4. Hock FJ, Wirth K, Albus U, et al. Hoe 140 a new potent and long acting 
bradykinin-antagonist: in vitro studies. B J Pharmacol 1991;102:769-73. 
5. Wirth K, Hock FJ, Albus U, et al. Hoe 140 a new potent and long acting 
bradykinin-antagonist: in vivo studies. B J Pharmacol 1991;102:774-7. 
6. Farkas H. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma 
Clin Immunol 2010;6:18. 
7. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Disease 
Childhood 1969;44:291-303. 
8. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch 
Disease Childhood 1970;45:13-23. 
9. Bieri D RRACGDALZJB. The Faces Pain Scale for the self-assessment of the severity of 
pain experienced by children: development, initial validation, and preliminary investigation 
for ratio scale properties. Pain 1990;41:139-50. 
10. Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain 
Scale-Revised: toward a common metric in pediatric pain measurement. Pain 
2001;93:173-83. 
11. The FLACC: A Behavioral Scale for Scoring Postoperative Pain in Young Children. Pediatr 
Nurs 1997;23:293-97. 
 
 














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


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


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Appendix 6 
Protocol Signature Page 
Study Title: 
A Multicenter, Open-Label, Non-Randomized Study to Assess 
the Pharmacokinetics, Tolerability, and Safety of a Single 
Subcutaneous Administration of Icatibant in Children and 
Adolescents with Hereditary Angioedema 
Study Number: 
HGT-FIR-086 
Original Protocol 
Date: 
14 June 2011 
Amendment 1 Date: 
05 August 2011 
I have read the protocol described above.  I agree to comply with all applicable regulations and 
to conduct the study as described in the protocol.   
Signatory: 
 
 
 
 
 
 
 
 
 
 
 
Investigator 
 
 
 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
Printed Name 
 
 
I have read and approve the protocol described above. 
Signatory: 
 
 
 
 
 
 
 
 
 
 
 
Shire HGT 
Medical 
Monitor 
 
 
 
Signature 
Date 
 
 
 
 
 
 
 
 MD 
 
 
Printed Name 
 
 
 
PPD


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


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


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


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Open-label treatment will continue until a total number of at least 15 adolescents have been treated 
with icatibant for a total of 3 eligible acute attacks (ie, after their first icatibant-treated attack, 
pubertal/postpubertal subjects only may receive further treatment with icatibant for up to 2 subsequent 
attacks of acute HAE).  All primary and secondary outcomes, including antibodies (except PK), are to 
be measured after each administration.  Safety, reproductive hormone, and other assessments in 
association with subsequent attacks of acute HAE will be performed 90 days (±7 days) after treatment (each 
treatment for a subsequent attack will require a Day 90 follow up visit).  If a subsequent attack occurs within 
7 days of the Day 90 follow-up visit for the previous attack, the assessments on Day 8 and Day 90 will be 
combined.   
Other sections impacted by this change:  None 
 
Change:  Clarification to inclusion criterion 
Section impacted by this change:  5.2 Inclusion Criteria 
Revised Text:  
2.  Documented diagnosis of HAE Type I or II.  Diagnosis must be confirmed by documented immunogenic 
(below the lower limit of normal) and/or functional (<50% of normal levels) C1-INH deficiency and/or 
functional C1 INH deficiency results (<50% of normal levels). Diagnosis may be on the basis of historic 
data or by diagnostic testing conducted at the time of screening. 
Other sections impacted by this change:  Synopsis 
 
Change:  Clarification to concomitant medication usage 
Section impacted by this change:  6.6 Concomitant Medication Usage 
New Text:  
All prescription and over-the-counter medications which are being taken by subjects during the study 
are regarded as concomitant medications and must be documented on the case report form (CRF) 
following informed consent. 
Other sections impacted by this change:  None 
 
Change:  Clarification to medical history 
Section impacted by this change: 7.5 Medical History 
Revised Text:  
Medical history will be recorded on the CRF.  Details of prior HAE attacks (eg, typical frequency, symptom 
duration, onset of relief, and type and frequency of medical interventions required) will be obtained at 
screening through pretreatment on Day 1.  Other important medical events, and concomitant medication 
and illnesses will be recorded at other visits on the appropriate CRF pages.   
Other sections impacted by this change:  None 
 
Change:  Addition of Tanner Staging information 
Section impacted by this change: 7.7 Tanner Staging 
Revised Text:  
The investigator will perform Tanner staging for all subjects to determine pubertal status.  A description of 
the Tanner stages of puberty is provided in Appendix 3. 
Other sections impacted by this change:  Appendix 3 Tanner Stages of Puberty, Appendix 1 Study Schedule 
of Events (Initial Icatibant-Treated Attack), Appendix 2 Study Schedule of Events (Subsequent Icatibant-
Treated Attacks) 
 
Change:  Addition of investigator assessment of pain 
Section impacted by this change:  7.10.3 Investigator Assessment of Pain 


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New Text:  
Subjects who are below 4 years of age will undergo investigator assessment of HAE-related symptoms 
using the Faces, Legs, Activity, Cry, and Consolability (FLACC) comportmental pain scale.  A copy of 
the FLACC scale is provided in Appendix 5. 
Other sections impacted by this change:  Appendix 5  Faces, Legs, Activity, Cry, and Consolability Scale 
(FLACC), Appendix 1 Study Schedule of Events (Initial Icatibant-Treated Attack), Appendix 2 Study 
Schedule of Events (Subsequent Icatibant-Treated Attacks) 
 
Change:  Addition of ECGs 
Section impacted by this change:  7.12.3 Electrocardiography 
New Text:  
A standard 12-lead ECG will be performed after 10 minutes at rest when the patient is seated or 
supine.  ECG results will be read locally at the clinical site.  Abnormalities will be recorded. 
Other sections impacted by this change:  Appendix 1 Study Schedule of Events (Initial Icatibant-Treated 
Attack), Appendix 2 Study Schedule of Events (Subsequent Icatibant-Treated Attacks) 
 
Change:  Deleted instruction for focusing on AEs with a temporal association with study treatment 
Section impacted by this change: Section 7.15.1, Adverse Events 
Revised Text:  
Though AEs will be collected throughout the study, due to the acute nature of HAE attacks and the half life 
of icatibant, it is particularly important to focus on AEs which have a temporal association with treatment.  
Treatment emergent AEs will be collected over a 48 hour window after the time of study drug 
administration. 
Other sections impacted by this change: None 
 
Change:  Clarification to concomitant illnesses 
Section impacted by this change:  7.15.1.1 Adverse Event 
Revised Text:  
Additional illnesses present at the time when informed consent is given are regarded as concomitant 
illnesses and will be documented on the appropriate pages of the CRF.  Illnesses first occurring or detected 
during the study, and worsening of a concomitant illness during the study, are to be regarded as AEs and 
must be documented as such in the CRF. Additional illnesses present at the time when informed consent 
is given until the time of treatment are regarded as concomitant illnesses and will be documented on 
the medical history page of the CRF.  Illnesses first occurring or detected on or after study drug 
treatment, and worsening of a concomitant illness during the study, are to be regarded as AEs and 
must be documented as such in the CRF. 
Other sections impacted by this change:  None 
 
Change:  Clarification to adverse event monitoring 
Section impacted by this change:  7.15.4.1 Adverse Event Monitoring and Period of Observation 
Revised Text:  
AEs will be monitored continuously throughout the study.  For the purposes of this study, the period of 
observation will extend from the time of informed consent treatment until the subject’s final evaluation of 
the study.  For safety purposes, the final evaluation will be defined as the follow-up evaluation performed 
approximately 90 days after the last dose for subjects who complete the study. 
Other sections impacted by this change:  None 
 
Change:  Clarification to SAE reporting 
Section impacted by this change:  7.15.4.2 Reporting Serious Adverse Events 


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Revised Text:  
This form must be completed and faxed or emailed within 24 hours of the investigator’s learning of the 
event to: 
Shire Pharmacovigilance and Risk Management Department: 
FAX:  
(UK Worldwide) OR
(United States North America) 
Email:  
Any follow-up information must also be completed on an SAE form and faxed or emailed to the same 
numbers listed above. 
Other sections impacted by this change:  None 
 
Change:  Alignment of study stopping rules with DSMB charter language 
Section impacted by this change:  7.18.1 Study Stopping Rules 
Revised Text:  
The Data and Safety Monitoring Board (see Section 11.8 for a description of the DSMB and its role) 
may elect to suspend the study until the DSMB can review any death that is drug or disease-related or 
unexplained, or if there is an unexpected drug-related severe AE. 
This study will be stopped and safety data reviewed if any subject experiences a life threatening (Grade 4) 
AE or a death occurs, if either is considered possibly, probably or definitely related to the investigational 
product.  
Other sections impacted by this change:  None 
 
Change:  Description of FLACC Scale  
Section impacted by this change:  7.19 Appropriateness of  Measures 
New Text:  
Young children (ie, those below the age of 4 years) frequently lack the verbal and cognitive skills 
necessary to report physical discomfort and pain intensity. Behavioral cues are the primary indicators 
of pain in children who are unable to report pain or follow instructions in the use of assessment tools.  
The FLACC instrument comprises 5 categories of behavior (face, legs, activity, cry, consolability) to 
assess pain in young children. 11 Each category is scored on a 0-to-2 scale which results in a total score 
from 0 to 10. 
Collectively, the measures employed in this study are expected to allow for assessment of the PK, 
safety, and efficacy profiles of icatibant in the pediatric population. 
Other sections impacted by this change:  None 
 
Change:  Clarification to statistical analysis 
Section impacted by this change:  10.8 Other Analyses 
Revised Text:  
The median time and the 95% confidence interval will be calculated using Kaplan-Meier methodology 
methodology if there are at least 5 subjects who used rescue medication prior to attaining symptom 
relief. 
Other sections impacted by this change:  None 
 
Change:  Clarification to Tanner Staging 
Section impacted by this change:  8.3.2 Follow-up Visit (Day 90 ±7 days) 
New Text:  
• 
Tanner staging (for those subjects classified as Tanner stage IV or below at baseline) 
Other sections impacted by this change:  8.4.2 Follow-up Visit (Day 90 ±7 days)Appendix 1 Study Schedule 
of Events (Initial Icatibant-Treated Attack), Appendix 2 Study Schedule of Events (Subsequent Icatibant-
Treated Attacks) 
 
PPD
PPD
PPD


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

Prot_000.pdf: 
Cli nic al Tri al Pr ot oc ol:  H G T- FI R- 0 8 6 
St u d y Title: 
A M ultice nter, O pe n- La bel, N o n- Ra n d o mize d St u d y t o Assess t he 
P har mac o ki netics, T olera bilit y, a n d Safet y of a Si n gle S u bc uta ne o us 
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St u d y N u m ber: 
H G T- FI R- 0 8 6 
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Icati ba nt ( Firaz yr® ) 
I n dic ati o n: 
Here ditar y a n gi oe de ma 
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M ultice nter 
S p o ns or: 
S hire H u ma n Ge netic T hera pies, I nc. 
S p o ns or C o nt act: 
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Ca m bri d ge, M A  0 2 1 3 9 U S A 
Me dic al M o nit or: 
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 S hire H u man Ge netic T hera pies ( H G T) 
 
 
Date 
Ori gi n al Pr ot oc ol: 
1 4 J u ne 2 0 1 1 
 
C o nfi de nti alit y St ate me nt 
T his d oc u me nt is t he pr o prie tar y a n d c o nfi de ntial pr o pert y of S hire H u ma n Ge netic 
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P P D
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SYNOPSIS 
Sponsor: 
Shire Human Genetic 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 
Primary Objective:  
The primary 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.  
Secondary Objectives: 
The secondary objectives of this study are: 
• To evaluate the efficacy of a single SC dose of icatibant in children and 
adolescents with HAE. 
• To evaluate levels of reproductive hormones after a single SC dose of icatibant in 
children and adolescents with HAE.  
Other Objectives:  
Other objectives of this study are: 
• To evaluate the continued safety of icatibant in pubertal/postpubertal children after 
repeat exposure.  
• To evaluate reproductive hormone levels in pubertal/postpubertal children after 
repeat exposure.  
• To evaluate the efficacy of icatibant in pubertal/postpubertal children after repeat 
exposure. 
Study Endpoints:  
The primary endpoints of this study are: 
• The PK profile of icatibant after a single SC injection in pediatric subjects treated 
for acute attacks of HAE. 


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• The tolerability and safety of SC icatibant as assessed by injection site reactions, 
adverse events (AEs), vital signs, physical examination, clinical laboratory 
parameters (serum chemistry [including liver function tests], hematology, 
urinalysis), and immunogenicity (anti-icatibant antibodies). 
The secondary endpoints of this study are: 
• The time to onset of relief of symptoms, measured using investigator-reported and 
subject-reported outcomes, defined as the earliest time at which a 20% 
improvement is seen in the average post-treatment score with no worsening of any 
single component score). 
o 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. 
o For subjects ≥4 years of age only:  subject self-assessment of HAE-related 
pain using the Faces Pain Scale-Revised (FPS-R). 
• The time to minimal symptoms, defined as all symptoms mild or absent based on 
the investigator-rated symptom score. 
• The incidence of rescue medication use. 
• The proportion of subjects with worsened intensity of clinical HAE 
symptoms between 2 and 4 hours after treatment with SC icatibant using 
investigator-rated symptom scores. 
• The levels of reproductive hormones (follicle stimulating hormone [FSH], 
luteinizing hormone [LH], estradiol, progesterone in females and FSH, LH, and 
testosterone in males). 
Study Population:  
The study will enroll approximately 36 pediatric subjects from 2 through 17 years of age 
who present with cutaneous, abdominal, or laryngeal attacks of acute HAE after a 
qualifying screening period.   
Subject enrollment will be stratified into 2 groups based on Tanner Staging:  a prepubertal 
group (defined as Tanner stage I) and a pubertal/postpubertal group (defined as Tanner 
stages II to V).  A subject’s classification as prepubertal or pubertal/postpubertal will be 
determined at the time of the subject’s first attack. 
Study Design: 
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, 
and safety, including reproductive hormone assessments, of a single SC administration of 
icatibant in up to approximately 36 pediatric subjects with HAE during an initial acute 
attack.  The study is planned to enroll up to approximately 16 prepubertal and 
20 pubertal/postpubertal subjects who are from 2 through 17 years of age and who present 
with an acute cutaneous, abdominal, or laryngeal HAE attack.  
After treatment for an initial attack, further open-label treatment with icatibant will be 
offered to pubertal/postpubertal subjects contingent upon having been treated previously 
and presenting with a subsequent acute cutaneous, abdominal, or laryngeal attack of HAE 


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at least 7 days after initial treatment.  Open-label treatment will continue until at least 
15 pubertal/postpubertal subjects have been treated with icatibant for a total of 3 attacks 
each.  Tolerability and safety evaluations, including reproductive hormone assessments, 
will be performed at each subsequent icatibant-treated attack in a manner similar to that 
performed for the initial treated attack. 
Study Duration: 
Once subject eligibility is established at screening, the minimal planned duration of 
participation for subjects who present with an initial attack of acute HAE will be 
approximately 90 days and will consist of treatment with a single SC administration of 
icatibant on Day 1 and a 90-day follow-up period after treatment.  
Subjects will be closely monitored in the hospital/study center for at least 6-8 hours after 
administration.  Follow-up to assess the subject’s condition at 24 hours and 48 hours after 
discharge will be conducted in person or via a telephone call by study personnel. 
After receiving treatment for an initial attack, at least 15 pubertal/postpubertal subjects 
who present with subsequent attacks of acute HAE may continue to receive treatment with 
icatibant for a total of 3 attacks each.   
Once the sixteenth prepubertal subject and the twentieth pubertal/postpubertal subject 
have completed the Day 90 follow-up after treatment for an initial attack, and the fifteenth 
pubertal/postpubertal subject has completed the Day 90 follow-up after the third and final 
treatment, the study will be closed.   
Study Inclusion and Exclusion Criteria: 
Subjects must meet all of the following criteria to be considered eligible for enrollment: 
1. Two through 17 years of age, inclusive (ie, from the second birthday through the day 
prior to the eighteenth birthday) at the time of the subject’s first attack. 
2. Documented diagnosis of HAE type I or II.  Diagnosis must be confirmed by 
documented immunogenic and/or functional C1 inhibitor (C1-INH) deficiency results 
(<50% of normal levels).  Diagnosis may be on the basis of historic data or by 
diagnostic testing conducted at the time of screening. 
3. Informed consent (and subject assent as appropriate) signed by the subject’s parent or 
legal guardian. 
 
Subjects will be excluded from the study if there is evidence of any of the following 
criteria at screening or at any time prior to the time of the first attack: 
1. Diagnosis of angioedema other than HAE. 
2. Participation in another clinical study during the 30 days prior to treatment.  
3. Any known factor/disease that might interfere with the treatment compliance, study 
conduct, or result interpretation. 
4. Congenital or acquired cardiac anomalies that interfere significantly with cardiac 
function. 
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. The subject is pregnant or breastfeeding.   
 
Pharmacokinetic Variables: 
PK variables will be determined by full sampling and noncompartmental methods where 
possible, and elsewhere by sparse sampling (at least 4 to 7 time points) and a population 
PK approach using non-linear mixed effects modeling software.   
PK parameter estimates will include, where appropriate:  actual icatibant and metabolite 
concentrations at each sampling time, time to peak concentration (Tmax), actual peak 
(Cmax) and minimum (Cmin) concentrations, clearance (CL/F), actual area under the plasma 
concentration-time curve (AUC0-last and AUC0-inf), mean residence time (MRT), volume of 
distribution at steady state (Vss/F) and elimination half-life (t1/2). 
Safety Assessments: 
Safety will be assessed by standard criteria including physical examination, vital signs, 
clinical laboratory evaluations (clinical chemistry [including liver function tests], 
hematology, urinalysis), and immunogenicity (presence of anti-icatibant antibodies), 
recording of concomitant medications, and monitoring of AEs.  Local tolerability will be 
assessed by evaluation of reactions at the site of study drug administration (injection site).  
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 Faces Pain Scale-Revised (FPS-R).  
Subjects who are below 4 years of age will have symptoms assessed by the investigator 
only.  The time of initial symptom relief as assessed by the investigator will be recorded 
for all subjects. 
Reproductive Hormone Assessments: 
Levels of reproductive hormones will be assessed in female (FSH, LH, estradiol, 
progesterone) and male (FSH, LH, and testosterone) subjects. 
Statistical Methods:  
Summary statistics for continuous variables will include the number of subjects, the mean, 
median, standard deviation, and range.  For PK parameters, the coefficient of variation 
and geometric mean also will be provided.  For categorical data, summaries will include 
counts and percentages.  For time-to-event data, the median time to event and other 
summary statistics will be estimated using Kaplan-Meier methodology. 
The following populations will be used in the analysis: 
• The Initial Non-laryngeal Treatment Population will consist of those subjects who 
were treated with icatibant for their initial attack and whose primary symptom was 
either cutaneous or abdominal.  
• 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. 


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• The Third Non-laryngeal Treatment Population will consist of those subjects who 
had a third icatibant-treated attack, for which the primary symptom was either 
cutaneous or abdominal, regardless of the primary symptom for the initial attack. 
• The Laryngeal Population will consist of those subjects who were treated with 
icatibant for any attack for which the primary symptom was laryngeal.  
• The PK Population will consist of those subjects who were treated with icatibant 
for their initial attack and who had at least 1 post-treatment icatibant concentration 
recorded.   
• The Initial Treatment Population will consist of those subjects who were treated 
with icatibant for the initial attack.  Safety and tolerability analyses will use this 
population. 
• The Additional Treatment Population will consist of those pubertal/post-pubertal 
subjects who were treated with icatibant for more than 1 attack.  Safety and 
tolerability analyses will use this population.  
Subject disposition, demographic and baseline characteristics, medical history, and use of 
concomitant medications will be summarized for each analysis population.   
Efficacy endpoints, including change from baseline when appropriate, will be summarized 
descriptively for the Initial, Second, and Third Non-laryngeal Treatment Populations.  The 
primary efficacy endpoint is the time to onset of symptom relief measured using the 
investigator-rated symptom score.  Time of symptom relief is defined as the earliest time 
post-treatment at which there is a 20% improvement in the average post-treatment 
symptom score with no worsening of any single component score.  The efficacy data 
associated with the laryngeal attacks will be provided in data listings for the Laryngeal 
Population. 
Plasma concentrations of icatibant by time point and the PK parameters will be 
summarized descriptively. 
The assessment of safety will be based mainly on the frequency of AEs.  AEs will be 
summarized by presenting the number and percentage of subjects having any adverse 
event (AE), having an AE in each body system, and having each individual AE using the 
Medical Dictionary for Regulatory Activity (MedDRA).  The total number of AEs within 
each of these categories will be reported.  AEs also will be tabulated by severity and 
relationship to treatment. 
Local tolerability will include symptoms at the injection site and will be assessed 
separately from general reports of AEs.  Local tolerability will be tabulated and 
summarized according to the type and severity of attack. 
The change from baseline in the secretion of reproductive hormones and the change from 
baseline in HAE symptoms (as reported by the investigator or subject) will be summarized 
descriptively. 
Date of Original Protocol:  14 June 2011 


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TABLE OF CONTENTS 
SYNOPSIS.................................................................................................................................2 
TABLE OF CONTENTS...........................................................................................................7 
LIST OF IN-TEXT TABLES..................................................................................................10 
LIST OF APPENDICES..........................................................................................................10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................11 
1 
INTRODUCTION ...........................................................................................................13 
1.1 
Disease Background...............................................................................................13 
1.2 
Previous Clinical Studies.......................................................................................14 
1.2.1 
Pharmacokinetics of Icatibant......................................................................14 
1.2.2 
Phase III Investigation of SC Icatibant........................................................14 
1.2.3 
Investigations of Potential Effects of Bradykinin Inhibition on Reproductive 
Function .......................................................................................................15 
1.3 
Rationale for Dose Selection .................................................................................16 
2 
STUDY OBJECTIVES....................................................................................................18 
2.1 
Primary Objective..................................................................................................18 
2.2 
Secondary Objectives.............................................................................................18 
2.3 
Other Objectives ....................................................................................................18 
3 
STUDY ENDPOINTS.....................................................................................................19 
3.1 
Primary Endpoint(s)...............................................................................................19 
3.2 
Secondary Endpoint(s)...........................................................................................19 
4 
INVESTIGATIONAL PLAN..........................................................................................20 
4.1 
Overall Study Design and Plan..............................................................................20 
4.2 
Rationale for Study Design....................................................................................22 
4.3 
Study Duration.......................................................................................................22 
5 
STUDY POPULATION SELECTION ...........................................................................24 
5.1 
Study Population....................................................................................................24 
5.2 
Inclusion Criteria ...................................................................................................24 
5.3 
Exclusion Criteria ..................................................................................................24 
6 
STUDY TREATMENT(S)..............................................................................................25 
6.1 
Description of Treatment(s)...................................................................................25 
6.1.1 
Investigational Product ................................................................................25 
6.1.2 
Comparator ..................................................................................................25 
6.2 
Treatment(s) Administered....................................................................................25 
6.3 
Selection and Timing of Dose for Each Subject....................................................25 
6.4 
Method of Assigning Subjects to Treatment Groups.............................................25 
6.5 
Blinding..................................................................................................................25 
6.6 
Concomitant Medications......................................................................................26 


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6.7 
Rescue Therapy......................................................................................................26 
6.8 
Restrictions ............................................................................................................27 
6.8.1 
Fluid and Food Intake..................................................................................27 
6.8.2 
Subject Activity Restrictions .......................................................................27 
6.9 
Treatment Compliance...........................................................................................27 
6.10 
Packaging and Labeling.........................................................................................27 
6.11 
Storage and Accountability....................................................................................27 
6.12 
Investigational Product Retention at Study Site ....................................................28 
7 
STUDY PROCEDURES .................................................................................................29 
7.1 
Informed Consent...................................................................................................29 
7.2 
Study Entrance Criteria..........................................................................................29 
7.3 
Confirmation of Study Eligibility..........................................................................29 
7.4 
Demographics ........................................................................................................29 
7.5 
Medical History .....................................................................................................29 
7.6 
Height and Weight.................................................................................................30 
7.7 
Tanner Staging.......................................................................................................30 
7.8 
Investigational Product Administration.................................................................30 
7.9 
Pharmacokinetic Assessments ...............................................................................30 
7.9.1 
Pharmacokinetic Variables ..........................................................................30 
7.9.2 
Pharmacokinetic Sampling ..........................................................................30 
7.9.3 
Bioanalytical Method...................................................................................31 
7.10 
Efficacy Assessments.............................................................................................31 
7.10.1 
Investigator Symptom Score........................................................................31 
7.10.2 
Subject Self Assessment of Pain..................................................................31 
7.10.3 
Initial Symptom Relief.................................................................................31 
7.11 
Reproductive Hormone Assessments ....................................................................32 
7.12 
Safety Assessments................................................................................................32 
7.12.1 
Physical Examination...................................................................................32 
7.12.2 
Vital Signs....................................................................................................32 
7.12.3 
Clinical Laboratory Tests.............................................................................32 
7.12.4 
Local Tolerability.........................................................................................33 
7.12.5 
Immunogenicity...........................................................................................33 
7.12.6 
Pregnancy Testing........................................................................................34 
7.13 
Sample Collection, Storage, and Shipping ............................................................34 
7.14 
Concomitant Medications......................................................................................34 
7.15 
Adverse Events Assessments.................................................................................34 
7.15.1 
Definitions of Adverse Events and Serious Adverse Events.......................34 
7.15.2 
Classification of Adverse Events and Serious Adverse Events...................36 


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7.15.3 
Relatedness of Adverse Events and Serious Adverse Events......................36 
7.15.4 
Procedures for Recording and Reporting Adverse Events ..........................37 
7.16 
Pregnancy...............................................................................................................39 
7.17 
Abuse, Overdose, and Medication Error................................................................39 
7.18 
Removal of Subjects from the Trial or Investigational Product ............................39 
7.18.1 
Safety-Related Study Stopping Rules..........................................................40 
7.19 
Appropriateness of Measurements.........................................................................40 
8 
STUDY ACTIVITIES .....................................................................................................42 
8.1 
Screening Period (Day of Informed Consent through Pretreatment on Day 1 of the 
Initial Attack).........................................................................................................42 
8.2 
Pretreatment (Baseline) Assessments (Day 1, Initial and Subsequent Attacks)....42 
8.3 
Initial Attack ..........................................................................................................42 
8.3.1 
Treatment Period (Day 1 to Day 8)..............................................................42 
8.3.2 
Follow-up Visit (Day 90 ±7 days) ...............................................................43 
8.4 
Subsequent Attacks (Pubertal/postpubertal Subjects Only) ..................................43 
8.4.1 
Treatment Period (Day 1 to Day 8)..............................................................43 
8.4.2 
Follow-up Visit (Day 90 ±7 days) ...............................................................44 
9 
QUALITY CONTROL AND ASSURANCE .................................................................45 
10 PLANNED STATISTICAL METHODS ........................................................................46 
10.1 
General Considerations..........................................................................................46 
10.2 
Determination of Sample Size ...............................................................................46 
10.3 
Analysis Populations..............................................................................................46 
10.4 
Demographics and Baseline Characteristics..........................................................47 
10.5 
Pharmacokinetic Analysis......................................................................................47 
10.5.1 
Estimation of PK Parameters.......................................................................47 
10.6 
Safety and Tolerability Analysis............................................................................48 
10.7 
Efficacy Analysis...................................................................................................49 
10.8 
Analysis of Reproductive Hormone Levels...........................................................50 
10.9 
Other Analyses.......................................................................................................50 
10.10 Data Monitoring and Interim Analysis ..................................................................50 
10.11 Handling of Missing Data......................................................................................50 
11 ADMINISTRATIVE CONSIDERATIONS....................................................................51 
11.1 
Investigators and Study Administrative Structure.................................................51 
11.2 
Institutional Review Board or Independent Ethics Committee Approval .............51 
11.3 
Ethical Conduct of the Study.................................................................................51 
11.4 
Subject Information and Consent/Assent...............................................................51 
11.5 
Subject Confidentiality ..........................................................................................52 
11.6 
Study Monitoring...................................................................................................53 


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11.7 
Case Report Forms and Study Records .................................................................53 
11.7.1 
Critical Documents ......................................................................................53 
11.8 
Data and Safety Monitoring Board........................................................................54 
11.9 
Protocol Violations/Deviations..............................................................................54 
11.10 Premature Closure of the Study.............................................................................55 
11.11 Access to Source Documentation ..........................................................................55 
11.12 Data Generation and Analysis ...............................................................................55 
11.13 Retention of Data...................................................................................................56 
11.14 Financial Disclosure...............................................................................................56 
11.15 Publication and Disclosure Policy .........................................................................56 
12 LIST OF REFERENCES.................................................................................................57 
 
LIST OF IN-TEXT TABLES 
Table 4-1  
Study Periods ...............................................................................................20 
Table 7-1  
List of Laboratory Tests...............................................................................33 
Table 7-2  
Adverse Event Severity................................................................................36 
Table 7-3  
Adverse Event Relatedness..........................................................................36 
 
LIST OF APPENDICES 
Appendix 1 
Study Schedule of Events (Initial Icatibant-Treated Attack).............58 
Appendix 2 
Study Schedule of Events (Subsequent Icatibant-Treated Attacks) ..60 
Appendix 3 
Faces Pain Scale-Revised (FPS-R)....................................................61 
Appendix 4 
Protocol Signature Page.....................................................................62 
 
 


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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 
DSMB 
Data and Safety Monitoring Board 
EC50 
Half maximal effective concentration 
EMA 
European Medicines Agency 
FDA 
United States Food and Drug Administration 
FFP 
Fresh frozen plasma 
FPS 
Faces Pain Scale 
FSH 
Follicle stimulating hormone 
GAM 
General additive model 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HAE 
Hereditary Angioedema 
hCG 
Human chorionic gonadotropin 
HGT 
Human Genetic Therapies 
hr 
Hour(s) 
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) 


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LBW 
Lean body weight 
LH 
Luteinizing hormone 
LOCF 
Last observation carried forward 
MCB 
Master Cell Bank 
MedDRA 
Medical Dictionary for Regulatory Activity  
mg 
Milligram 
min 
Minute(s) 
mL 
Milliliter(s) 
mm 
Millimeters 
MRT 
Mean residual time 
n 
Number 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ng 
Nanogram(s) 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic(s) 
SAE 
Serious adverse event 
SAS 
Statistical Analysis System® 
SC 
Subcutaneous 
SOC 
System organ class 
T1/2 
Terminal elimination half-life 
TBW 
Total body weight 
Tmax 
Time to maximum concentration 
US 
United States 
VAS 
Visual analog scale 
Vss 
Volume of distribution at steady state 
 


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1 
INTRODUCTION 
1.1 
Disease Background 
Bradykinin is responsible for the clinical symptoms of hereditary angioedema (HAE), causing 
increased vascular permeability, vasodilation, and contraction of visceral smooth muscle.  HAE 
is a rare autosomal dominant disorder characterized clinically by recurrent and self-limiting 
attacks of edema of the skin, gastrointestinal tract, and larynx.  Its prevalence is estimated at 
1:10,000 to 1:50,000.1   
The disease is generally caused by either a quantitative (Type I) or qualitative (Type II) 
deficiency of C1 inhibitor.  The functions of C1 inhibitor include the prevention of C1 
complement auto-activation, inactivation of coagulation factors XIIa, XIIf, XIa, and inhibition of 
activated kallikrein.  After a triggering event, the deficiency in C1 inhibitor results in accelerated 
release of bradykinin, the principal mediator of the increased vascular permeability characteristic 
of HAE, by its cleavage from high molecular weight kininogen by dysregulated, activated 
kallikrein.  There is a third, more rare type of HAE (Type III) which is of unknown etiology and 
pathophysiology and thus will not be considered further here. 
Icatibant is a synthetic decapeptide with a structure similar to bradykinin that acts as an 
antagonist of the bradykinin B2 receptor.2, 3  It is highly specific for the B2 receptor, and is 
characterized by high potency in vitro and in vivo, and sufficient biological half-life to allow 
systemic administration by subcutaneous (SC) injection.4, 5  Inhibition of bradykinin action 
through use of a B2 receptor antagonist is a therapeutic strategy for treatment of clinical 
symptoms of HAE, and represents the rationale for use of icatibant in treatment of acute attacks 
of angioedema in HAE patients.  In adults, SC icatibant 30 mg has been shown to produce a 
rapid and durable response in the treatment of cutaneous, abdominal, and laryngeal attacks of 
acute HAE.  A single SC injection is generally sufficient for accelerated relief of symptoms of 
acute HAE attacks irrespective of edema location.  Repeated use of icatibant over time for 
treatment of multiple acute HAE attacks in adults produces a consistent response at each attack, 
with no diminution of efficacy.  When self-administered by adult subjects experiencing an acute 
HAE attack, icatibant also produces a rapid and safe treatment response. 
The management of HAE in pediatric patients is complex.  The age at onset, the frequency and 
duration of symptoms, as well as the severity of attacks all exhibit substantial inter-individual 
variation.  Although acute episodes of HAE may occur at any age, the mean age at disease onset 
ranges from approximately 4 to 11 years.  Subcutaneous edema of the extremities, face, neck, 
torso and genitals is the most common, and usually the earliest, manifestation of HAE seen in 
children.  Analyses of the time of onset of disease symptoms have indicated an increase in the 
frequency and severity of manifestations between 3 and 6 years of age, as well as at around 
puberty, most likely related to the many physiological (endocrine, mental, and somatic) changes 
occurring during these periods of development.  In the gastrointestinal tract, submucosal edema 
may be associated with colicky abdominal pain, nausea, vomiting, and diarrhea.  Though 
infrequent compared to cutaneous and abdominal manifestations, attacks of acute HAE involving 
the larynx may result in submucosal edema of the upper airways and risk of death by 
asphyxiation if undiagnosed and/or untreated.  In comparison to adults asphyxia may ensue more 
rapidly in children because of smaller airway diameter.6  


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Prompt control of attacks, short-term prophylaxis, and intermittent therapy are recommended for 
the management of pediatric HAE.6  Treatment options for children with HAE according to 
current guidelines include antifibrinolytics, attenuated androgens, and C1 inhibitor (C1-INH) 
replacement therapy.  Antifibrinolytics are generally preferred (eg, tranexamic acid) for 
long-term prophylaxis because of their comparatively favorable safety profile relative to 
attenuated androgens; though their efficacy may be limited.  C1-INH replacement therapy has 
been used successfully for management of acute attacks of HAE in children; however, its use in 
children is associated with the same drawbacks (ie, requirement for intravenous [IV] 
administration, potential to elicit hypersensitivity reactions, possible transmission of blood-borne 
infectious agents) as in adults. 
1.2 
Previous Clinical Studies 
1.2.1 
Pharmacokinetics of Icatibant 
The pharmacokinetic (PK) properties of icatibant have been characterized extensively in studies 
using both IV and SC administration to healthy adult subjects and adult subjects with HAE.  The 
PK profile of icatibant in adults with HAE (JE049-2101 Clinical Study Report) is similar to that 
in healthy adults. 
After SC administration of a single 30 mg dose of icatibant to healthy adult subjects (N=96), a 
mean (± standard deviation) maximum plasma concentration (Cmax) of 974 ± 280 ng/mL was 
observed after approximately 0.75 hours.  The mean area under the concentration-time curve 
(AUC0-∞) after a single 30 mg dose was 2165 ± 568 ng•hr/mL, with no evidence of accumulation 
of icatibant after three 30 mg doses administered 6 hours apart.   
Plasma clearance after SC administration of icatibant was 245 ± 58 mL/min with a mean 
elimination half-life of 1.4 ± 0.4 hours and volume of distribution at steady state (Vss) of 
29.0 ± 8.7 L.  The information obtained from Phase III clinical studies clearly demonstrated that 
SC icatibant 30 mg is a clinically safe and effective treatment for attacks of acute angioedema 
across a wide range of subject demographics, including age, sex, and body weight.  
Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are 
primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug.  
Icatibant is not degraded by oxidative metabolic pathways, and is not an inhibitor of major 
cytochrome P450 (CYP) isoenzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 
3A4) and is not an inducer of CYP 1A2 and 3A4. 
Clinical PK studies demonstrate that for mild to moderate impairment of renal or hepatic 
function no dose adjustment is necessary.  In 10 subjects with hepatorenal syndrome (glomerular 
filtration rate (GFR) 30 to 60 mL/min), clearance of icatibant was not dependent on renal 
function.  Icatibant clearance in subjects with a wide range of hepatic impairment (Child-Pugh 
score ≥7 and ≤15) was similar to that in healthy subjects. 
1.2.2 
Phase III Investigation of SC Icatibant 
Despite the rarity of HAE, a comprehensive data set supports the efficacy and safety of SC 
icatibant.   


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In Phase I, II, and III clinical studies, SC icatibant 30 mg has been administered to 129 healthy 
adult subjects and to 236 adult subjects with HAE.  A total of 999 acute attacks of HAE have 
been treated with icatibant administered by a health care provider, and an additional 56 attacks 
have been treated with icatibant when self administered by patients (Integrated Summary of 
Safety 11 January 2011).  
In integrated analyses of pooled data from 3 controlled Phase III studies (HGT-FIR-054, 
JE049-2102, and JE049-2103), icatibant significantly decreased the time to onset of symptom 
relief for cutaneous and abdominal attacks relative to comparator agents (placebo, tranexamic 
acid) as demonstrated by the primary and key secondary endpoint analyses in subjects with 
non-laryngeal symptoms randomized to double-blind treatment.  Moreover, the median time to 
onset of symptom relief after icatibant treatment was consistent across all of the controlled 
Phase III studies and across the 2 endpoints, ranging from 1.5 to 2.3 hours.  Likewise, icatibant 
showed effectiveness in the treatment of laryngeal attacks.   
The recommended dose of icatibant in adults is 1 SC injection of 3 mL (30 mg) administered in 
the abdominal area for the treatment of acute attacks of HAE.  In case of insufficient relief or 
recurrence of symptoms, a second   injection of icatibant can be administered after 6 hours.  No 
more than 3 injections of icatibant should be administered in a 24 hour period.  In clinical trials, 
a single SC injection of icatibant was generally sufficient to treat an acute HAE attack.  No 
differences in the efficacy or safety of icatibant in clinical trials have been observed between 
sexes; therefore, dose adjustments for adult males or females are not considered necessary.  
Beyond exposure in clinical studies, it is estimated that over 8000 patient exposures to Firazyr® 
have occurred cumulatively in the postmarketing setting from the time of European Union 
regulatory approval in July 2008 through January 2011. 
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of icatibant. 
1.2.3 
Investigations of Potential Effects of Bradykinin Inhibition on Reproductive 
Function 
In nonclinical studies performed in rat and dog, high repeated doses of icatibant have been 
associated with effects on sexual organs and sexual maturation.  These findings are consistent 
with published data showing a role of bradykinin action through B2 receptors in the control of 
reproductive hormone release.  Potential effects of icatibant on sexual organs and sexual 
maturation are being investigated further in studies in juvenile rats.  These are a SC 
administration local tolerance study, and a 7-week toxicity study with assessment of fertility 
before and after recovery.  The local tolerance study in juvenile rats established the doses for the 
7-week toxicity study.  The results will be reported in the final study reports.  
 
 
 


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A retrospective analysis, prompted by nonclinical observations, of serum levels of gonadotrophic 
hormone levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) in male and 
female healthy volunteers in an Phase I study (JE049-1103) showed no clinically important 
changes from baseline in levels of follicle-stimulating hormone [FSH] and luteinizing hormone 
[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) is 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 is 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 are 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 subjects have been enrolled and 
treated; 38 subjects have completed the study (1 subject did not return for follow-up).  The 
results will be reported in the final clinical study report.   
1.3 
Rationale for Dose Selection 
Icatibant has not been evaluated in clinical trial subjects below the age of 18 years.  The 
proposed study will be the first in which icatibant is administered to pediatric subjects for 
treatment of acute HAE attacks.  All subjects in the proposed study will receive a single, 
weight-adjusted dose of 0.4 mg/kg per attack as a SC injection up to a maximum dose of 30 mg.  
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.   


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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 
Primary Objective  
The primary objective of this study is: 
• 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. 
 
2.2 
Secondary Objectives  
The secondary objectives of this study are: 
• To evaluate the efficacy of a single SC dose of icatibant in children and adolescents with 
HAE. 
• To evaluate levels of reproductive hormones after a single SC dose of icatibant in children 
and adolescents with HAE.  
 
2.3 
Other Objectives  
Other objectives of this study are: 
• To evaluate the continued safety of icatibant in pubertal/postpubertal children after repeat 
exposure.  
• To evaluate reproductive hormone levels in pubertal/postpubertal children after repeat 
exposure.  
• To evaluate the efficacy of icatibant in pubertal/postpubertal children after repeat exposure. 
 


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3 
STUDY ENDPOINTS 
3.1 
Primary Endpoint(s)  
The primary endpoints of this study are: 
• The PK profile of icatibant after a single SC injection in pediatric subjects treated for acute 
attacks of HAE. 
• The tolerability and safety of SC icatibant as assessed by injection site reactions, adverse 
events, vital signs, physical examination, clinical laboratory parameters (serum chemistry 
[including liver function tests], hematology, urinalysis), and immunogenicity (presence of 
anti-icatibant antibodies).  
 
3.2 
Secondary Endpoint(s)  
The secondary endpoints of this study are: 
• The time to onset of relief of symptoms, measured using investigator-reported and 
subject-reported outcomes, defined as the earliest time at which a 20% improvement is seen 
in the average post-treatment score with no worsening of any single component score. 
o 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. 
o For subjects ≥4 years of age only:  subject self-assessment of HAE-related pain using the 
Faces Pain Scale-Revised (FPS-R). 
• The time to minimal symptoms, defined as all symptoms mild or absent based on the 
investigator-rated symptom score. 
• The incidence of rescue medication use. 
• The proportion of subjects with worsened intensity of clinical HAE symptoms between 2 and 
4 hours after treatment with SC icatibant using investigator-rated symptom scores. 
• The levels of reproductive hormones (FSH, LH, estradiol, progesterone in females and FSH, 
LH, and testosterone in males). 
 


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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, and 
safety, including reproductive hormone assessments, of a single SC administration of icatibant in 
approximately 36 pediatric subjects with hereditary angioedema (HAE) during an initial acute 
attack.  The study is planned to enroll approximately 16 prepubertal and 20 pubertal/postpubertal 
subjects who are from 2 through 17 years of age and who present with a cutaneous, abdominal, 
or laryngeal attack of acute HAE.  
After treatment for an initial attack, further open-label treatment with icatibant will be offered to 
pubertal/postpubertal subjects contingent upon having been treated previously and presenting 
with a subsequent acute cutaneous, abdominal, or laryngeal attack of HAE at least 7 days 
after initial treatment.  Open-label treatment will continue until at least 15 pubertal/postpubertal 
subjects have been treated with icatibant for a total of 3 attacks each.  Tolerability and safety 
evaluations, including reproductive hormone assessments, will be performed at each subsequent 
icatibant-treated attack in a manner similar to that performed for the initial treated attack. 
The study will consist of the following periods (Table 4-1). 
Table 4-1  Study Periods 
Study Periods  
Screening  
Day of informed consent through pretreatment on Day 1 of the initial 
attack 
Initial icatibant-treated attack (All subjects) 
    Treatment  
Day 1 
    Post-Treatment 
Day 1 though Day 8 
    Follow-up 
Day 9 through Day 90 (±7 days) 
Two additional icatibant-treated attacks for a total of 3 icatibant-treated attacks 
(Pubertal/postpubertal subjects only) 
    Treatment  
Day 1 
    Post-Treatment 
Day 1 though Day 8 
    Follow-up 
Day 9 through Day 90 (±7 days) 
 
The study will include a screening period to determine subject eligibility.  Eligibility will be 
evaluated after the subjects’ parent(s)/legal guardian(s) and the subject (if applicable) provide 
informed consent/assent.  Study activities at screening will include confirmation of diagnosis of 
HAE type I or II by review of the subject’s medical history and documentation of immunogenic 
and/or functional C1-INH deficiency (<50% of normal levels) indicative of HAE Type I or II.  


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


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Rescue medication use will be assessed through 48 hours after treatment, either in person or by 
telephone at the discretion of the investigator. 
Subjects will undergo safety assessments, including physical examination, vital signs, and 
clinical laboratory tests (serum chemistry, hematology, and urinalysis), evaluation of injection 
site reactions, immunogenicity, and measurement of reproductive hormones, as well as 
investigator assessments and subject self assessments (subjects ≥4 years of age only) of HAE 
symptoms on Day 8 after treatment. 
Subjects will be followed over a 90-day (±7 days) period after initial treatment.  All subjects will 
provide blood samples for immunogenicity testing and determination of reproductive hormone 
levels at the Day 90 visit and undergo safety assessments including physical examination, vital 
signs, and clinical laboratory tests (serum chemistry, hematology, and urinalysis).  Additionally, 
pubertal/postpubertal females will undergo urine pregnancy testing. 
Pubertal/postpubertal subjects may receive further treatment with icatibant for up to 2 additional 
attacks of acute HAE.  Safety, reproductive hormone, and other assessments in association with 
subsequent attacks of acute HAE will be performed 90 days (±7 days) after treatment.  Each 
treatment for a subsequent attack will require a Day 90 follow up visit.  If a subsequent attack 
occurs within 7 days of the Day 90 follow-up visit for the previous attack, the assessments on 
Day 8 and Day 90 will be combined.   
Adverse events (AEs) and concomitant medication will be collected throughout the study.   
All assessments are outlined in full in the Schedule of Events in Appendix 1, Initial 
Icatibant-treated Attack and Appendix 2, Subsequent Icatibant-treated Attacks.     
4.2 
Rationale for Study Design 
This study has an open-label, single arm design.   
The study is intended to determine the PK profile of SC icatibant when administered to children 
and adolescents being treated for an acute attack of HAE and to identify an optimal pediatric 
dosing regimen.  In addition, the study is intended to establish the tolerability and safety of 
icatibant in children, particularly with respect to potential effects on reproductive development, 
and to demonstrate the effectiveness of icatibant in relieving the symptoms of acute HAE 
attacks.  Therefore, this study will help determine whether icatibant can address an unmet 
medical need for a safe and effective treatment for acute attacks of HAE in pediatric patients.   
Furthermore, this study is designed to fulfill a regulatory commitment to the European Medicines 
Agency according to the approved pediatric investigational plan (EMEA-000408-PIP01-08-
M02) for icatibant of 05 May 2010. 
4.3 
Study Duration 
The approximate overall duration of the study will be 36 months.   


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


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5 
STUDY POPULATION SELECTION 
5.1 
Study Population 
Pediatric subjects from 2 through 17 years of age who present with cutaneous, abdominal, or 
laryngeal attacks of acute HAE after a qualifying screening period will be eligible for enrollment 
in the study.  Subject enrollment will be stratified into 2 groups, based on Tanner Staging,7, 8 to 
consist of a prepubertal group (defined as Tanner stage I) and a pubertal/postpubertal group 
(defined as Tanner stages II to V).   
A subject’s classification as prepubertal or pubertal/postpubertal will be determined at the time 
of the subject’s first attack. 
5.2 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study. 
1. Two through 17 years of age, inclusive (ie, from the second birthday until the day prior to the 
eighteenth birthday) at the time of the subject’s first attack. 
2. Documented diagnosis of HAE Type I or II.  Diagnosis must be confirmed by documented 
immunogenic and/or functional C1-INH deficiency results (<50% of normal levels).  
Diagnosis may be on the basis of historic data or by diagnostic testing conducted at the time 
of screening. 
3. Informed consent (and subject assent as appropriate) signed by the subject’s parent(s) or 
legal guardian(s). 
 
5.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Diagnosis of angioedema other than HAE. 
2. Participation in another clinical study during the 30 days prior to treatment.  
3. Any known factor/disease that might interfere with the treatment compliance, study conduct, 
or result interpretation. 
4. Congenital or acquired cardiac anomalies that interfere significantly with cardiac function.  
5. Treatment with ACE inhibitors within 7 days prior to treatment. 
6. Use of hormonal contraception within the 90 days prior to treatment. 
7. Androgen use (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) within 
the 90 days prior to treatment. 
8. The subject is pregnant or breastfeeding. 
 


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6 
STUDY TREATMENT(S) 
6.1 
Description of Treatment(s) 
6.1.1 
Investigational Product 
Icatibant is prepared as a sterile, isotonic, and acetate buffer solution containing sodium chloride, 
acetic acid, sodium hydroxide and water for SC injection, adjusted to pH 5.5 ± 0.3.  The solution 
does not contain any preservative.   
The product is supplied as a 10 mg/mL (free base) solution in 3-mL glass syringes, with 
elastomeric stoppers, tip cap, plunger rod, and backstop.  A fluid-dispensing connector will be 
used to secure a 1-mL or 3-mL syringe to the glass syringe.  A single dose (see Section 6.2) will 
be withdrawn and administered by SC injection. 
6.1.2 
Comparator 
Not applicable to this study. 
6.2 
Treatment(s) Administered 
All subjects will receive treatment with icatibant for an initial acute attack of HAE as a single, 
weight-adjusted dose of 0.4 mg/kg up to a maximum of 30 mg administered as a SC injection. 
Subsequent treatment with icatibant for up to 2 additional attacks of acute HAE will be offered to 
pubertal/postpubertal subjects who present with a new attack at least 7 days after prior treatment.  
The dosing regimen for treatment of subsequent attacks will be the same as that for treatment of 
the initial attack (ie, a single weight-adjusted dose of 0.4 mg/kg up to a maximum of 30 mg per 
attack administered as a SC injection).  Thus, no more than 3 doses of icatibant will be 
administered to any subject during the study. 
6.3 
Selection and Timing of Dose for Each Subject 
Each subject will be administered a single dose of icatibant as a SC injection within 12 hours 
after the onset of an acute HAE attack.  Subsequent treatment with icatibant for up to 
2 additional attacks of acute HAE for a total of 3 attacks will be offered to pubertal/postpubertal 
subjects who have been previously treated and who present with another attack at least 7 days 
post-treatment with study drug.   
6.4 
Method of Assigning Subjects to Treatment Groups 
Not applicable to this study.  All subjects will be administered study drug at a weight-adjusted 
dose of 0.4 mg/kg SC up to a maximum of 30 mg per treatment.   
6.5 
Blinding 
Not applicable to this open-label study. 


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6.6 
Concomitant Medications 
Use of the following concomitant medications is allowed during the study: 
• All chronically administered medications, except for treatments of HAE, are allowed, but the 
dose and regimen must have been stable for at least 1 month before the first dose of study 
drug. 
• Prophylactic therapies for HAE (eg, anti-fibrinolytics or C1-INH) other than attenuated 
androgens will be allowed, but therapies known to attenuate an acute HAE attack (eg, 
C1-INH concentrate, fresh-frozen plasma [FFP]) must not be used during the attack being 
treated with icatibant unless these are required as rescue medications (see Section 6.7).  An 
exception is that fibrinolysis inhibitors may be given in a subject’s usual, stable prophylactic 
regimen.  
 
Use of the following concomitant medications is forbidden during the study: 
• ACE inhibitors. 
• Androgens or attenuated androgens (eg, stanozolol, danazol, oxandrolone, 
methyltestosterone, testosterone). 
• Hormonal contraceptives (acceptable contraception during the study for sexually active 
females will consist of abstinence or a double barrier method such as condom plus 
diaphragm, condom or diaphragm plus spermicide, condom or diaphragm plus intrauterine 
device). 
 
6.7 
Rescue Therapy 
For the purposes of this protocol, rescue therapy is any medication used after the administration 
of icatibant which, in the opinion of the investigator, is immediately necessary to alleviate acute 
symptoms which are judged by the investigator as resultant from the current HAE attack.  Repeat 
administration of icatibant for a single attack is not allowed in this study.   
The determination of the necessity for pain medication or other rescue therapy will be at the 
discretion of the investigator.  If pain medication is required, the investigator may administer 
morphine sulfate at a dose of 0.05 mg/kg or an equivalent low dose narcotic.  Antiemetics may 
also be prescribed as necessary to treat nausea.  Other acceptable rescue therapies include FFP, 
epinephrine, C1-INH if available and intravenous or prescription-strength non-steroidal 
anti-inflammatory drugs (NSAIDs).  Medications provided for rescue therapy will be denoted as 
rescue medications on the appropriate case report form (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. 


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6.8 
Restrictions 
Subjects are not to receive treatment with any investigational product(s) other than icatibant or 
any investigational device(s) at any point during this study.  
6.8.1 
Fluid and Food Intake  
No specific restrictions on fluid or food intake apply for this study. 
6.8.2 
Subject Activity Restrictions 
No specific restrictions on subject activity apply for this study. 
6.9 
Treatment Compliance 
During this study, the investigational product will be administered at the hospital/study 
center/site under controlled conditions; therefore, full subject compliance with treatment is 
anticipated. 
6.10 Packaging and Labeling 
The investigational product will be packaged as 3-mL solution in a pre-filled 3-mL syringe made 
of clear type I glass.  The back stopper consists of bromobutyl coated with fluorocarbon 
polymer.  Front closure is achieved by means of a luer-lock adaptor that allows secure 
attachment of the needle.  Secondary packaging consists of 1 icatibant syringe, labeled in a tray 
with a 25-guage needle placed inside a plain white carton, also labeled.  A fluid-dispensing 
adaptor will be used to secure a 1-mL or 3-mL syringe to the glass syringe for withdrawal of 
icatibant. 
See the Pharmacy Manual for additional details. 
6.11 Storage and Accountability 
The following information should be considered when storing and using the investigational 
product. 
The investigational product will be shipped at 2° to 8°C.  Icatibant 10 mg/mL formulated for SC 
administration should be stored at or below 25°C.  The syringes must not be frozen. 
The disposition of all investigational product delivered to a Principal Investigator must be 
recorded on a subject-by-subject basis by completing the Clinical Trial Material Accountability 
Log.  The date and time of administration of the investigational product must be documented on 
the appropriate CRF. 
The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 
loss/damaged and return of used/unused product is complete, accurate, and ready for review at 
each monitoring visit and/or audit.   


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The sites must ensure that the investigational product is available for the monitor to inventory 
and prepare for return shipment to the sponsor or designee, if required.  
6.12 Investigational Product Retention at Study Site 
The process for destruction of investigational product must be determined and documented 
during the study start-up phase.   
If the investigational product is to be destroyed by the study sites, sites must follow their own 
process/policy that describes such activities.  All drug destruction processes will be documented 
and the sites must retain copies of these documents within the Site Regulatory Binder.  The sites 
must ensure that the Clinical Trial Material Accountability and Destruction Log is complete, 
accurate, and ready for review and/or audit at each monitoring visit.   
All manifests documenting shipments of investigational product must be retained as well copies 
of any investigational product return forms.  See the Pharmacy Manual for additional details. 


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7 
STUDY PROCEDURES 
Detailed descriptions of subject evaluations required for this protocol are described in this 
section.  These evaluations will be performed during the indicated days and weeks of the study 
(see Schedule of Events Tables in Appendix 1, Initial Icatibant-treated Attack and Appendix 2, 
Subsequent Icatibant-treated Attacks).  
All data collected are to be recorded on the appropriate case report form (CRF) or 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 Screening and Pretreatment visits on the basis of review of the study entrance criteria. 
7.4 
Demographics 
Subject demographic information including gender, date of birth, and race will be collected prior 
to the subject receiving the first dose of investigational product.  
7.5 
Medical History 
Medical history will be recorded on the CRF.  Details of prior HAE attacks (eg, typical 
frequency, symptom duration, onset of relief, and type and frequency of medical interventions 
required) will be obtained at Screening.  Other important medical events, and concomitant 
medication and illnesses will be recorded at other visits.  Any existing medical condition present 
prior to the time of of the first dose will be reported as medical history. 


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7.6 
Height and Weight 
Height and weight will be recorded for all subjects.   
7.7 
Tanner Staging 
The investigator will perform Tanner staging for all subjects to determine pubertal status. 
7.8 
Investigational Product Administration 
All subjects will receive treatment with icatibant for an initial acute attack of HAE as a single, 
weight-adjusted dose of 0.4 mg/kg administered as a SC injection up to a maximum dose of 
30 mg.  Treatment with icatibant will be administered within 12 hours of onset of an acute HAE 
attack.  Pubertal/postpubertal subjects who present with a subsequent attack at least 7 days 
post-treatment may receive further treatment with icatibant for a total of 3 attacks. 
7.9 
Pharmacokinetic Assessments  
7.9.1 
Pharmacokinetic Variables 
PK variables will be determined by full sampling and noncompartmental methods where 
possible, and elsewhere by sparse sampling (at least 4 to 7 time points) and a population PK 
approach using nonlinear mixed effects modeling software.  The methods to be used for 
estimation of PK parameter values are described in Section 10.5.1. 
PK parameter estimates will include, where appropriate:  actual icatibant and metabolite 
concentrations at each sampling time, time to peak concentration (Tmax), actual peak (Cmax) and 
minimum (Cmin) concentrations, clearance (CL/F), actual area under the plasma 
concentration-time curve (AUC0-last and AUC0-inf), mean residence time (MRT), volume of 
distribution at steady state (Vss/F) and elimination half-life (t1/2). 
7.9.2 
Pharmacokinetic Sampling 
Sampling for PK assessments will be collected according to the Schedule of Events Table in 
Appendix 1, Initial Icatibant-treated Attack.   
The time of study drug administration on Day 1 will be designated as Time 0.  All post-treatment 
assessments will be calculated from the time of study drug administration.  Detailed sample 
collection, processing, and shipping instructions will be provided in the study Operations 
Manual. 
Blood samples for determination of plasma concentrations of icatibant in pubertal/postpubertal 
subjects will be collected on Day 1 at pretreatment, 15 (±5) minutes, 30 (±5) minutes, 45 (±5) 
minutes, 1 (±0.17) hour, 2 (±0.17) hours, 4 (±0.5) hours, 6 (±0.5), and 8 (±0.5) hours after 
treatment with study drug.   


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Blood samples for determination of plasma concentrations of icatibant in prepubertal subjects 
will be collected on Day 1 at pretreatment, 15 (±5) minutes 30 (±5) minutes, 2 (±0.5) hours, 4 
(±0.5) hours and 6 (±0.5) hours.  
7.9.3 
Bioanalytical Method 
Plasma samples will be assayed for concentrations of icatibant and its metabolites (M1 and M2) 
using a validated method (see Section 7.19). 
7.10 Efficacy Assessments 
7.10.1 
Investigator Symptom Score  
The investigator will use a symptom score to assess the severities of symptoms of acute 
cutaneous, abdominal, and laryngeal attacks of HAE using the following 5-point scale.  
Symptom scores will be recorded on Day 1 at pretreatment and at predetermined time points 
after treatment.  Results will be recorded on the CRF. 
Investigator-rated Symptom Score 
0 = none; absence of symptoms 
1 = mild (no to mild interference with daily activities) 
2 = moderate (moderate interference with daily activities) 
3 = severe (severe interference with daily activities) 
4 = very severe (very severe interference with daily activities) 
 
For attacks classified as cutaneous and/or abdominal, investigator-rated symptom scores will be 
collected for 8 symptoms:  abdominal tenderness, nausea, vomiting, diarrhea, skin pain, 
erythema, skin irritation, and skin swelling.   
For attacks classified as laryngeal, investigator-assessed symptom scores will be collected for 
13 symptoms:  abdominal tenderness, nausea, vomiting, diarrhea, skin pain, erythema, skin 
irritation, skin swelling, dysphagia, voice change, breathing difficulties, stridor, and asphyxia.   
7.10.2 
Subject Self Assessment of Pain  
Subjects who are at least 4 years of age will self assess HAE-related pain using the Faces Pain 
Scale-Revised (FPS-R).  A copy of the FPS-R is provided in Appendix 3. 
Self-assessment results will be recorded in the diary.  The self-assessment diaries will be 
provided to these subjects on Day 1 at pretreatment and at predetermined time points after 
treatment while at the hospital/study center and after their discharge.  Subjects will return the 
diary at the next scheduled visit on Day 8.  Subjects will receive detailed instructions on when 
and how to complete the diaries by the investigator and/or clinical site personnel. 
7.10.3 
Initial Symptom Relief 
The investigator will be asked to provide the following information on the CRF: 


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• To record the date and time when overall subject improvement was first noted and mark the 
date and time accordingly. 
 
7.11 Reproductive Hormone Assessments 
Reproductive hormone levels will be measured in all subjects.  Blood samples will be collected 
to assess FSH, LH, estradiol, and progesterone in females, and FSH, LH, and testosterone in 
males. 
7.12 Safety Assessments 
7.12.1 
Physical Examination 
Physical examinations will include a review of the subject’s general appearance, Tanner stage, 
neurological examination, as well as evaluation of the following body systems.  Any abnormal 
change in findings will be recorded as an adverse event (AE) on the appropriate CRF.  The 
physical examination will include: 
- 
General appearance 
- 
Eye, ears, nose, throat  
- 
Lymph nodes 
- 
Cardiovascular 
- 
Skin 
- 
Abdomen  
- 
Neurological  
- 
Spine and extremities 
- 
Lungs 
 
7.12.2 
Vital Signs 
Vital signs are to be recorded for all subjects and will include pulse, blood pressure, respiration 
rate, and temperature.   
7.12.3 
Clinical Laboratory Tests 
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing.  All blood samples will be collected via venipuncture.  Subjects will be in a seated or 
supine position during blood collection. 
Clinical laboratory tests will include the following (See Table 7-1):  


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Table 7-1  List of Laboratory Tests 
Hematology: 
- 
Hematocrit  
- 
Hemoglobin  
- 
Mean corpuscular hemoglobin  
- 
Mean corpuscular hemoglobin 
concentration  
- 
Mean corpuscular volume  
- 
Platelet count 
- 
Red blood cell count  
- 
White blood cell  count with 
differential  
 
Urinalysis:  
- 
Appearance 
- 
Bilirubin 
- 
Color 
- 
Glucose 
- 
Ketones 
- 
Nitrite  
- 
Occult blood 
- 
pH 
- 
Protein 
- 
Specific gravity 
Serum Chemistry: 
- 
Albumin  
- 
Alkaline phosphatase  
- 
Alanine aminotransferase) 
- 
Aspartate aminotransferase  
- 
Calcium  
- 
Carbon dioxide  
- 
Chloride  
- 
Creatinine 
- 
Creatine kinase  
- 
Gamma-glutamyl transferase  
- 
Glucose 
- 
Lactate dehydrogenase  
- 
Phosphorus 
- 
Potassium  
- 
Sodium  
- 
Total bilirubin 
 
 
7.12.4 
Local Tolerability 
Injection site reactions (erythema, swelling, burning sensation, itching/pruritis, warm sensation, 
cutaneous pain, or other) will be evaluated by the investigator when the subject is at the 
hospital/study center, and the diameter of any erythema or swelling will be measured.   
After discharge, the subject (or the subject’s parent/legal guardian on behalf of the subject as 
appropriate) will be interviewed about injection site reactions, either in person or by telephone 
contact.   
7.12.5 
Immunogenicity 
The immunogenicity of icatibant will be assessed.  Serum samples for immunogenicity testing 
will be collected for determination of anti-icatibant antibodies.  Serum samples will be analyzed 
for anti-icatibant antibodies at Shire HGT or at a designated laboratory.  Details concerning 
sample collection and preparation will be provided in the study Operations Manual. 
Samples will be stored frozen at -65°C or below if not shipped on the day of collection.  Details 
for shipping will be provided in the study Operations Manual. 


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7.12.6 
Pregnancy Testing 
Pubertal and postpubertal female subjects will undergo pregnancy testing at time points specified 
in the Schedule of Events Tables in Appendix 1 and Appendix 2.  All pregnancy testing will be 
conducted using a urine human chorionic gonadotropin (hCG) test.  
7.13 Sample Collection, Storage, and Shipping 
Blood samples will be collected via venipuncture.  All samples will be stored and secured in a 
way that assures that unauthorized access is prohibited and the samples are not lost, allowed to 
deteriorate, or are accidentally or illegally destroyed.  Detailed sample collection, processing, 
and shipping instructions will be provided in the study Operations Manual. 
7.14 Concomitant Medications  
All medications administered to the study subjects from the time of informed consent through the 
Day 90 follow-up contact are regarded as concomitant and will be documented on the CRF.  
7.15 Adverse Events Assessments   
7.15.1 
Definitions of Adverse Events and Serious Adverse Events 
7.15.1.1 
Adverse Event 
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered investigational product-related.  This 
includes an exacerbation of a pre-existing condition.   
AEs include: 
• Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study. 
• Intercurrent illnesses. 
• Drug interactions. 
• Events related to or possibly related to concomitant medications. 
• Abnormal laboratory values (this includes significant shifts from baseline within the range of 
normal that the investigator considers to be clinically important). 
• Clinically significant abnormalities in physical examination, vital signs, and weight. 
 
Throughout the study, the investigator must record all AEs on the AE CRF, regardless of the 
severity or relationship to investigational product.  The investigator should treat subjects with 
AEs appropriately and observe them at suitable intervals until the events stabilize or resolve.  
Adverse events may be discovered through observation or examination of the subject, 
questioning of the subject, complaint by the subject, or by abnormal clinical laboratory values. 


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In addition, AEs may also include laboratory values that become significantly out of range.  In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the subject’s safety is not at risk. 
Additional illnesses present at the time when informed consent is given are regarded as 
concomitant illnesses and will be documented on the appropriate pages of the CRF.  Illnesses 
first occurring or detected during the study, and worsening of a concomitant illness during the 
study, are to be regarded as AEs and must be documented as such in the CRF. 
The treated HAE attack is defined as any symptoms occurring in treated subjects within 48 hours 
of the onset of symptoms.  Any clinically relevant worsening of the signs and symptoms of a 
treated attack is considered to be related to the underlying disease of HAE and will be collected 
separately from general reports of AEs.  Symptoms reoccurring more than 48 hours after an 
initial attack will be considered a new attack, and will also not be reported as AEs.  Attacks not 
treated with icatibant will be documented in detail in the CRF.  They are considered to be 
pre-existing disease and will not be documented as AEs. 
Local tolerability will include symptoms at the site of study drug administration (injection site) 
and will be assessed separately from general reports of AEs.  Local tolerability will include 
symptoms at the site of study drug administration (injection site) and will be assessed separately 
from general reports of AEs.  Injection site reactions will be documented in the "local 
tolerability" page (or form) of the CRF.  Injection site reactions that have been reported 
previously with icatibant included erythema, swelling, burning sensation, itching, warmth and 
pain and were generally, mild to moderate, transient, and resolved without sequelae.  Injection 
site reactions that do not meet the criteria of a serious adverse event will not need to be 
additionally reported as AEs. 
Though AEs will be collected throughout the study, due to the acute nature of HAE attacks and 
the half-life of icatibant, it is particularly important to focus on AEs which have a temporal 
association with treatment.  Treatment-emergent AEs will be collected over a 48-hour window 
after the time of study drug administration.   
7.15.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is any AE occurring at any dose that results in any of the 
following outcomes: 
• Death. 
• Is life-threatening. 
• Requires hospitalization. 
• Requires prolongation of existing hospitalization. 
• A persistent or significant disability or incapacity.  
• A congenital anomaly or birth defect. 
 
 


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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  A life-threatening AE is defined as an AE that placed the 
subject, in the view of the initial reporter, at immediate risk of death from the AE as it occurred 
(ie, it does not include an AE that, had it occurred in a more severe form, might have caused 
death). 
7.15.2 
Classification of Adverse Events and Serious Adverse Events 
The severity of AEs will be assessed by the investigator using the National Cancer Institute 
Common Terminology Criteria (NCI CTCAE) Version 4.0 grading scale.  If an AE is not 
described in the NCI CTCAE, the severity should be recorded based on the scale below (see 
Table 7-2).  The severity of all AEs/SAEs should be recorded on the appropriate CRF page as 
Grade 1, 2, 3, 4, or 5 corresponding, respectively, to a severity of mild, moderate, severe, 
life-threatening, or fatal.  
Table 7-2  Adverse Event Severity   
Severity 
Definition 
Grade 1 (Mild) 
No limitation of usual activities. 
Grade 2 (Moderate) 
Some limitation of usual activities. 
Grade 3 (Severe) 
Inability to carry out usual activities. 
Grade 4 (Life-threatening) 
Immediate risk of death. 
Grade 5 (Fatal) 
Death 
 
7.15.2.1 
Clarification between Serious and Severe 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (eg, severe headache).  This is not the same as “serious,” which is based on 
the outcome or action criteria usually associated with events that pose a threat to life or 
functioning.  Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations. 
7.15.3 
Relatedness of Adverse Events and Serious Adverse Events 
Relationship of an AE or SAE to investigational product is to be determined by the investigator 
based on the following definitions (See Table 7-3). 
Table 7-3  Adverse Event Relatedness 
Relationship to Product(s) 
Definition 
Not Related 
Unrelated to investigational product 
Possibly Related 
A clinical event or laboratory abnormality with a reasonable 


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Table 7-3  Adverse Event Relatedness 
Relationship to Product(s) 
Definition 
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. 
 
7.15.4 
Procedures for Recording and Reporting Adverse Events 
7.15.4.1 
Adverse Event Monitoring and Period of Observation 
AEs will be monitored continuously throughout the study.  For the purposes of this study, the 
period of observation extends from the time of informed consent until the subject’s final 
evaluation of the study.  For safety purposes, the final evaluation will be defined as the follow-up 
evaluation performed approximately 90 days after the last dose for subjects who complete the 
study. 
If the investigator considers it necessary to report an AE in a subject after the end of the safety 
observation period, he or she should contact the sponsor to determine how the AE should be 
documented and reported. 
7.15.4.2 
Reporting Serious Adverse Events 
Any SAE, regardless of relationship to investigational product, which occurs in a subject after 
informed consent, should be recorded by the clinical site on an SAE form.  The SAE must be 
completely described on the subject’s CRF, including the judgment of the investigator as to the 
relationship of the SAE to the investigational product.   
 


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Cli nic al Tri al Pr ot oc ol: H G T- FI R- 0 8 6 
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c o ntract researc h or ga nizati o n [ C R O]) re gar di n g t he S A E.  T he i n vesti gat or m ust re p ort t he S A E 
t o t he S hire P har mac o vi gila nce a n d Ris k Mana ge me nt De part me nt A N D t o t he S hire H G T 
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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: 
I nter n ati o n al F A X:  
( U K) O R U nite d St ates F A X: 
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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 S A E f or m as state d a b o ve.  T he f oll o wi n g pr o vi des c o ntact i nf or mati o n f or t he 
S hire H G T Me dical M o nit or.  
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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 R B)/I n de pe n de nt Et hics C o m mittee (I EC).  It is t he res p o nsi bilit y of t he s p o ns or t o e ns ure t hat 
eac h i n vesti gat or recei ves a c o p y of a n y C o u nc il f or I nter nati o nal Or ganizati o ns of Me dical 
Scie nces ( CI O M S I)/ Me d Watc h re p ort t hat ha s bee n s u b mitte d t o t he a p pr o priate re g ulat or y 
a ge ncies n otif yi n g t he m of a n  u ne x pecte d relate d S A E.   
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
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P P D


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The investigator or sponsor must ensure that the IRB/IEC receives a copy of the report and that a 
copy is also filed within their study files. 
7.16 Pregnancy 
Pregnancy and lactation are exclusion criteria for this study.  The sponsor must be notified in the 
event of a pregnancy occurring during the course of the study and through 90 days after the 
subject’s last dose of investigational product.  Pregnancy is not to be reported as an AE; the 
pregnancy reporting form should be used to report the pregnancy.  The pregnancy will be 
followed up through delivery or final outcome. 
7.17 Abuse, Overdose, and Medication Error 
• Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a 
dose higher than prescribed per protocol (but below the dose defined for overdose) or when 
used for non-medical purpose (eg, altering one’s state of consciousness). 
• Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note:  
this includes a situation where the test article is not used as directed at the dose prescribed by 
the protocol). 
• Overdose – No clinical information on overdose is available.  A dose of 3.2 mg/kg 
(approximately 8 times the therapeutic dose) caused transient erythema, itching or 
hypotension in healthy subjects.  No therapeutic intervention was necessary. 
• Medication Error – A mistake made in prescribing, dispensing, administration and/or use of 
the investigational medicinal product. 
 
All investigational medicinal product provided to pediatric subjects should be supervised by the 
parent(s)/legal guardian(s)/caregiver(s). 
7.18 Removal of Subjects from the Trial or Investigational Product 
A subject’s participation in the study may be discontinued at any time at the discretion of the 
investigator.  The following may be justifiable reasons for the investigator to remove a subject 
from the study: 
• Non-compliance, including failure to appear at one or more study visits. 
• The subject was erroneously included in the study. 
• The subject develops an exclusion criterion.  
• The subject suffers an intolerable adverse event. 
• The study is terminated by the sponsor. 
• The study is closed prior to the subject’s first eligible attack. 
 
The subject, the subject’s parent(s), or the subject’s legal guardian(s) acting on behalf of the 
subject is free to withdraw consent and discontinue participation in the study at any time without 
prejudice to further treatment. 


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If a subject or the subject’s parent(s) or the subject’s legal guardian(s) acting on behalf of the 
subject, discontinues participation in the study, or the subject is discontinued by the investigator, 
the Subject Completion/Discontinuation Case Report Form (CRF) describing the reason for 
discontinuation must be completed.  Any AEs experienced up to the point of discontinuation 
must be documented on the AE CRF.  If AEs are present when the subject withdraws from the 
study, the subject will be re-evaluated within 30 days of withdrawal.  All ongoing SAEs at the 
time of withdrawal will be followed until resolution. 
7.18.1 
Safety-Related Study Stopping Rules   
This study will be stopped and safety data reviewed if any subject experiences a life-threatening 
(Grade 4) AE or a death occurs, if either is considered possibly, probably or definitely related to 
the investigational product.  
Following the review of safety data, the study will be either: 
• Resumed unchanged. 
• Resumed with modifications to the protocol.  
• Terminated. 
 
Subject safety will be monitored on a continuous basis during this study until the last subject 
completes his or her last scheduled study visit/assessment.   
Additional information on safety monitoring can be found in Section 11.8, Data and Safety 
Monitoring Board. 
7.19 Appropriateness of Measurements 
The safety assessments used here are standard and will provide a detailed measure of the safety 
of icatibant in the pediatric population.  
The measures of serum reproductive hormone concentration used in this study are standard 
validated 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). 
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.   


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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.9  The Faces Pain Scale-Revised (FPS-R) was adapted from the 
original FPS in order to make it possible to score pain on a widely accepted 0-to-10 metric.10  
The scales are suitable for use in assessment of the intensity of children's acute pain from age 
4 onward, are simple to administer, and require no specialized equipment other than the 
standardized images of faces.  Use of the FPS-R is planned for this study, and will provide an 
appropriate means to measure pain associated with acute attacks of HAE in pediatric subjects 
who are at least 4 years of age. 


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8 
STUDY ACTIVITIES 
8.1 
Screening Period (Day of Informed Consent through Pretreatment on Day 1 
of the Initial Attack)   
• Inclusion/Exclusion Criteria 
• Informed Consent/Assent 
• Medical History 
• Confirmation of documented HAE diagnosis 
• Physical examination, including Tanner staging 
• Vital signs 
• Height and weight 
• Recording of concomitant medications 
• Measurement of C1-INH   
• Urine pregnancy test in pubertal/postpubertal females only 
 
8.2 
Pretreatment (Baseline) Assessments (Day 1, Initial and Subsequent Attacks) 
The following assessments will be performed at both initial and subsequent icatibant-treated 
attacks unless otherwise indicated.  All evaluations and sample collections must be performed 
prior to treatment. 
• Medical history (at initial attack only) 
• Confirm inclusion/exclusion criteria (at initial attack only) 
• Physical examination, including Tanner staging 
• Vital signs 
• Height and weight 
• Recording of concomitant medications 
• Subject self-assessment of HAE-related pain (in subjects ≥4 years of age only) 
• Investigator assessment of HAE symptoms 
• Clinical laboratory evaluation (serum chemistry, hematology and urinalysis) 
• Urine pregnancy test (in pubertal/postpubertal females only) 
• Assessment of reproductive hormones  
• Pharmacokinetic evaluations (prior to treatment at initial attack only) 
• Immunogenicity evaluations 
• AE assessment 
 
8.3 
Initial Attack 
8.3.1 
Treatment Period (Day 1 to Day 8) 
• Study drug administration (Day 1, Time 0) 
• Physical examination (Day 1, 6 hours post-dose and Day 8) 


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• Vital signs (Day 1, 1 hour and 6 hours post-dose and Day 8) 
• Subject self-assessment of HAE-related pain in subjects ≥4 years of age (Day 1, 1 hour, 
2 hours, 4 hours, and 6 hours post-dose, Day 2 [24 hours], Day 3 [48 hours], and Day 8) 
• Investigator assessment of HAE symptoms (Day 1, 1 hour, 2 hours, 4 hours, and 6 hours 
post-dose, Day 2 [24 hours], Day 3 [48 hours], and Day 8) 
• Clinical laboratory evaluation (Day 1, 6 hours post-dose and Day 8) 
• Assessment of reproductive hormones (Day 1, 6 hours post-dose and Day 8) 
• Injection site reaction evaluation (Day 1, 1 hour and 6 hours post-dose, Day 2 [24 hours], 
Day 3 [48 hours], and Day 8) 
• Sampling for PK evaluations in pubertal/post pubertal subjects (Day 1, 15 (±5) minutes, 
30 (±5) minutes, 45 (±5) minutes, 1 (±0.17) hour, 2 (±0.17) hours, 4 (±0.5) hours, 6 (±0.5) 
hours, and 8 (±0.5) hours post-dose at initial attack only) 
• Sampling for PK evaluations in prepubertal subjects (Day 1, 15 (±5) minutes, 30 (±5) 
minutes, 2 (±0.17) hours, 4 (±0.5) hours, and 6 (±0.5) hours post-dose at initial attack only) 
• Immunogenicity evaluation (Day 8) 
• Recording of concomitant medications   
• Monitoring of AEs  
 
8.3.2 
Follow-up Visit (Day 90 ±7 days) 
In the event that a subject has a subsequent HAE attack within the 90 day follow-up period for 
the first treatment, the date of the Day 90 follow-up visit for the first treatment remains the same.  
Each subsequent treatment will have a corresponding Day 90 follow-up visit.   
• Physical examination, including Tanner staging 
• Vital signs 
• Height and weight 
• Recording of concomitant medications 
• Clinical laboratory evaluation (serum chemistry, hematology, and urinalysis) 
• Urine pregnancy test in pubertal/postpubertal females only 
• Assessment of reproductive hormones  
• Immunogenicity evaluation  
• Monitoring of AEs 
 
8.4 
Subsequent Attacks (Pubertal/postpubertal Subjects Only) 
Pubertal/postpupertal subjects may receive treatment for up to 2 subsequent HAE attacks.  Each 
treatment for a subsequent attack will require a Day 90 follow up visit.  If a subsequent attack 
occurs within 7 days of the Day 90 follow-up visit for the previous attack, the assessments on 
Day 8 and Day 90 will be combined.    
8.4.1 
Treatment Period (Day 1 to Day 8) 
• Study drug administration (Day 1, Time 0) 


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• Physical examination (Day 1, 6 hours post-dose and Day 8)  
• Vital signs (Day 1, 1 hour and 6 hours post-dose and Day 8) 
• Subject assessment of HAE symptoms in subjects ≥4 years of age (Day 1, 1 hour, 2 hours, 
4 hours, and 6 hours post-dose, Day 2 [24 hours], Day 3 [48 hours], and Day 8) 
• Investigator assessment of HAE symptoms (Day 1, 1 hour, 2 hours, 4 hours, and 6 hours 
post-dose, Day 2 [24 hours], Day 3 [48 hours], and Day 8) 
• Clinical laboratory evaluation (Day 1, 6 hours post-dose and Day 8) 
• Assessment of reproductive hormones (Day 1, 6 hours post-dose and Day 8) 
• Injection site reaction evaluation (Day 1, 1 hour and 6 hours post-dose, Day 2 [24 hours], 
Day 3 [48 hours], and Day 8) 
• Immunogenicity evaluation (Day 8) 
• Recording of concomitant medications 
• Monitoring of AEs  
 
8.4.2 
Follow-up Visit (Day 90 ±7 days) 
• Physical examination, including Tanner staging 
• Vital signs 
• Height and weight 
• Recording of concomitant medications 
• Clinical laboratory evaluation (serum chemistry, hematology, and urinalysis) 
• Urine pregnancy test in pubertal/postpubertal females only 
• Assessment of reproductive hormones  
• Immunogenicity evaluation  
• Monitoring of AEs 
 


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


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10 PLANNED STATISTICAL METHODS 
10.1 General Considerations 
All statistical analyses will be performed using SAS® statistical software (SAS Institute, NC, 
USA).  Data will be summarized with respect to disposition, demographic, pretreatment 
characteristics, PK variables, safety variables, and efficacy variables.  Unless stated otherwise, 
tabular summaries will be presented by the subject’s stratification group at enrollment (ie, 
prepubertal group, pubertal/postpubertal group, and the overall subjects group.  
Summary statistics for continuous variables will include the number of subjects, the mean, 
median, standard deviation, and range.  For PK parameters, the coefficient of variation and 
geometric mean also will be provided.  For categorical data, summaries will include counts and 
percentages.  For time to event data, the median time to event and other summary statistics will 
be estimated using the method of Kaplan and Meier. 
10.2 Determination of Sample Size 
Enrollment of approximately 16 prepubertal and 20 pubertal/postpubertal subjects, who are from 
2 through 17 years of age and who present with a cutaneous, abdominal, or laryngeal attack of 
acute HAE, is planned.  This sample size is empirically derived and not based on a formal 
sample size calculation.  However, the inclusion of approximately 36 subjects will provide basic 
information for safety, tolerability, PK, and efficacy. 
10.3 Analysis Populations 
The following populations will be used in the analysis: 
• The Initial Non-laryngeal Treatment Population will consist of those subjects who were 
treated with icatibant for their initial attack and whose primary symptom was either 
cutaneous or abdominal.  
• The Second Non-laryngeal Treatment Population will consist of those subjects who had a 
second icatibant-treated attack for which the primary symptom was either cutaneous or 
abdominal, regardless of the primary symptom for the initial attack. 
• The Third Non-laryngeal Treatment Population will consist of those subjects who had a third 
icatibant-treated attack, for which the primary symptom was either cutaneous or abdominal, 
regardless of the primary symptom for the initial attack. 
• The Laryngeal Population will consist of those subjects who were treated with icatibant for 
any attack for which the primary symptom was laryngeal.  
• The PK Population will consist of those subjects who were treated with icatibant for their 
initial attack and who had at least 1 post-treatment icatibant concentration recorded.   
• The Initial Treatment Population will consist of those subjects who were treated with 
icatibant for the initial attack. 
• The Additional Treatment Population will consist of those pubertal/post-pubertal subjects 
who were treated with icatibant for more than 1 attack.   
 


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All efficacy analysis will be performed on the Initial Non-laryngeal Treatment Population, the 
Second Non-laryngeal Treatment Population, and the Third Non-laryngeal Treatment 
Population.  The PK analyses will be based on the PK population.  Safety and tolerability 
analyses will be based on the Initial Treatment Population and the Additional Treatment 
Population.  The Laryngeal Population will be used to explore the efficacy of icatibant for the 
treatment of laryngeal attacks.  All analyses conducted with this population will be limited to 
data corresponding to the subject’s first laryngeal attack. 
10.4 Demographics and Baseline Characteristics 
Demographic data and pretreatment characteristics will be summarized for each analysis 
population.  
10.5 Pharmacokinetic Analysis 
A primary objective of the study is to investigate the PK of a single SC injection of icatibant in 
pediatric subjects treated for acute attacks of HAE.  All PK analyses will use the PK population. 
Plasma concentrations of icatibant and metabolites (ie, M1 and M2) and actual blood sampling 
times will be listed by subject and sampling time.  Plasma concentrations will be summarized 
using descriptive statistics (number, mean and standard deviation).  PK parameters for icatibant 
and metabolites will be listed by subject and will be summarized using descriptive statistics 
(number, mean, standard deviation, coefficient of variation, geometric mean, minimum, median, 
maximum).  Individual and mean plasma concentrations of icatibant and metabolites versus time 
will be displayed on linear and semi-logarithmic axes. 
10.5.1 
Estimation of PK Parameters 
Noncompartmental modeling:  for subjects in whom the number of samples is sufficient to 
permit noncompartmental modeling, individual and mean PK parameters will be computed for 
icatibant and metabolites (M1 and M2) using standard noncompartmental methods, where 
possible, using the WinNonLin software package (Pharsight Corp., Mountain View, CA).  For 
descriptive statistical tabulation of mean plasma concentrations and graphical displays, nominal 
collection times will be used, while all PK analysis and parameter calculations will use actual 
collection times.  Plasma concentrations <LOQ will be treated as 0 for the calculation of the 
descriptive statistics for plasma concentrations at each sampling time.  For the pharmacokinetic 
analysis, plasma concentrations <LOQ that occurred from pre-dose to the first concentration 
≥LOQ will be treated as 0 and those that occur thereafter will be treated as missing. 
PK parameter estimates will include, where appropriate:  icatibant and metabolite concentrations 
at each sampling time, time to peak concentration (Tmax), actual peak (Cmax) and minimum (Cmin) 
concentrations, clearance (CL/F), area under the plasma concentration-time curve (AUC0-last and 
AUC0-inf), mean residence time (MRT), volume of distribution at steady state (Vss/F) and 
elimination half-life (t1/2). 
 


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The distribution of continuous data will be evaluated using parametric tests.  A transformation, 
such as logs, will be used where appropriate.  Multiple regression analysis, with an appropriate 
transformation on the dependent variable, will be used to assess the contribution of potential PK 
covariates while controlling for demographic covariates (eg, subject’s age and gender) to the 
inter-subject variability of icatibant PK parameters.  The multivariable analysis will be 
considered the primary statistical analysis.  A p-value of 0.05 will be considered statistically 
significant for all analyses. 
Compartmental modeling using population methods:  nonlinear mixed effects modeling will be 
used to define individual subject profiles and if possible, parameter estimates.  The structural PK 
model will be developed and validated using PK information obtained from adult subjects and 
will enable delineation of the impact of age-dependent changes on icatibant disposition.  
Development of this model will allow for characterization and better prediction of the 
dose-concentration-exposure relationship for icatibant in pediatric subjects.  Population PK 
modeling will be performed with nonlinear mixed effect modeling software (eg, NONMEM, 
Globomax LLC or WinNonMix, Pharsight Corp.).  The program will estimate the inter- and 
intra-individual variability of PK parameter estimates.  Both weight-normalization and allometric 
scaling principles will be evaluated.  For selecting preliminary meaningful covariates the general 
additive model (GAM) analysis will be used.  Variables to be considered will include (but are 
not limited to):  age, sex, ethnicity, total and lean bodyweight (TBW, LBW), body mass index 
(BMI), and body surface area (BSA). 
Monte Carlo simulation experiments based on the model(s) developed above may be performed 
by a validated simulation software program (eg, Trial Simulator, Pharsight Corp.) to assess the 
response patterns for various dosage regimens of icatibant treatments in the pediatric population. 
10.6 Safety and Tolerability Analysis 
Another primary objective of the study is to investigate the safety and tolerability of a single SC 
dose of icatibant in pediatric subjects with HAE during an acute HAE attack.  The corresponding 
analyses will be based on the Initial Treatment Population. 
The safety and tolerability parameters include AEs, vital signs, local tolerability at the injection 
site, immunogenicity, standard hematology, serum chemistry, and urinalysis. 
AEs will be categorized using MedDRA Version 8.1 or higher.  The assessment of safety will be 
based mainly on the frequency of treatment emergent AEs.  AEs will be summarized by system 
organ class (SOC) and preferred term.  The number and proportion of subjects experiencing an 
AE will be tabulated by the subject stratification group and for the overall subject group.  AEs by 
SOC and preferred term also will be tabulated by severity and by relationship to treatment.  In 
the case of multiple occurrences of the same AEs (at the preferred term level) in an individual 
subject, the AE that is classified as the most severe (ie, maximum severity) will be identified for 
the analysis by severity and the AE that has the highest relationship to study drug will be 
identified for the analysis by relationship.  SAEs will be provided in a data listing. 
 


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Laboratory data will be listed by subject and stratification group.  Subjects with newly occurring 
abnormalities outside the normal range will be flagged and listed separately.  Actual values and 
mean change from pretreatment values will be summarized by the stratification group.  Shift 
tables will also be tabulated by stratification group and time point. 
Vital signs data will be listed by subject and stratification group.  Furthermore, actual values and 
mean changes from baseline will be summarized for each stratification group as well as the 
overall subject group.  Shift tables may be presented, utilizing reference ranges.  Subjects with 
notably abnormal values will be identified and listed separately along with their values. 
Local tolerability will be tabulated and summarized according to the type and severity of attack 
Data from other tests (eg, immunogenicity) will be listed and summarized as appropriate. 
The assessment of safety and tolerability after repeated treatment with icatibant is also of 
interest.  The analyses described above will be repeated using the Additional Treatment 
Population.  The summary tables and listings will be presented by attack number (ie, Attack 1, 
Attack 2, and Attack 3). 
10.7 Efficacy Analysis 
The primary efficacy endpoint is the time to onset of symptom relief measured using the 
investigator-reported symptom score.  The investigator will report symptom scores at 
pretreatment and 1, 2, 4, 6, 24, and 48 hours post-treatment.  Eight symptoms will be assessed 
for abdominal and cutaneous attacks, and 13 symptoms will be assessed for laryngeal attacks.  
Time of symptom relief is defined as the earliest time post-treatment at which there is a 20% 
improvement in the average post-treatment symptom score with no worsening of any single 
component score.  The median time and the 95% confidence interval will be calculated using the 
Kaplan-Meier methodology. 
A tabular summary of the average investigator-reported symptom score and the change from 
baseline in the average investigator-reported symptom score will be presented by the 
stratification group and the overall subjects group.  An alternative analysis of time to onset of 
symptom relief will focus on the time to minimal symptoms.  In this case, symptom relief is 
defined as the earliest time post-treatment when all symptoms are either absent or mild.  
For individual investigator-reported symptom scores, a shift table from baseline will be 
presented for each post-treatment time point.  The analysis will be repeated to assess shift in the 
individual symptom scores from the 2 hour time-point.  Also, for individual symptoms that are 
moderate or worse at pretreatment, the median and 95% confidence interval will be presented for 
the time to the symptom being mild or absent.  
A subset of subjects, 4 years of age or older, will assess pain using the Faces Pain Scale-Revised 
(FPS-R).  Time to onset of symptom relief will be computed in a manner similar to that for the 
average investigator-reported symptom scores.  
 


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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 Analysis of Reproductive Hormone Levels 
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. 
10.9 Other Analyses 
The number and percentage of subjects who received rescue medications before the onset of 
symptom relief will be summarized by the stratification group.  Time to first use of rescue 
medication prior to symptom relief will be calculated from the time of study drug administration 
to the first use of rescue medication prior to symptom relief.  The median time and the 
95% confidence interval will be calculated using Kaplan-Meier methodology. 
10.10 Data Monitoring and Interim Analysis 
A Data and Safety Monitoring Board (DSMB) will be set up to review the safety, tolerability, PK 
and efficacy data on an ongoing basis.  The goal of the DSMB will be to assess the risk/benefit 
of icatibant treatment in this pediatric population.  An analysis of the data for DSMB review is 
planned after the first 4 subjects in the pubertal/ postpubertal group have been treated.  Because 
no formal hypothesis testing is planned, multiplicity concerns regarding repeated analyses are 
not an issue.  
10.11 Handling of Missing Data 
Individual pretreatment symptom scores and FPS-R scores will be assigned a value of zero.  For 
missing post-treatment scores, imputation will be employed using the Last Observation Carried 
Forward (LOCF) approach.  The pretreatment values may also be used in the imputation.  For 
missing or partial rescue medication dates, the imputation will be performed such that the earliest 
possible time post-treatment will be assigned to the rescue medication use.  Similar approach 
will be followed in case of missing or partial AE dates.  


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


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


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11.6 Study Monitoring 
Monitoring procedures that comply with current Good Clinical Practice (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 Shire HGT 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 Shire 
HGT or their designee: 
• Completed FDA Form 1572 (Statement of Investigator), signed, dated, and accurate. 
• Curricula vitae of investigator and sub-investigator(s) (current, dated and signed within 
12 months of study initiation). 
• Copy of investigator(s) and sub-investigator(s) current medical license (indicating license 
number and expiration date). 
• Signed and dated agreement of the final protocol. 
• Signed and dated agreement of any amendment(s), if applicable. 
• Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed by 
name, number and date of approval or re approval:  protocol, any amendments, Subject 
Information/Informed Consent Form, and any other written information to be provided 
regarding subjects recruitment procedures. 
• Copy of IRB/IEC approved Subject Information/Informed Consent Form/any other written 
information/advertisement (with IRB approval stamp and date of approval). 
• Current list of IRB/IEC Committee members/constitution (dated within 12 months prior to 
study initiation). 
• Financial Disclosure Form signed by investigator(s) and sub-investigator(s). 
• Current laboratory reference ranges (if applicable). 
• Certification/QA scheme/other documentation (if applicable). 
 


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Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire HGT. 
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 Shire HGT and approved by the DSMB.  The charter will 
define the membership of the DSMB, the responsibilities of the DSMB and Shire HGT, describe 
the conduct of meetings, and define the data to be reviewed.   
Enrollment of pediatric subjects in the proposed study will be stratified into 2 groups (2 years of 
age to the older prepubertal children, and pubertal/postpubertal children to those 17 years of 
age).  It is planned that subjects in both groups will receive an icatibant dose (0.4 mg/kg to a 
maximum dose of 30 mg) selected to target an exposure comparable to that observed in adults 
treated with icatibant.  Initially, enrollment and dosing of pubertal/postpubertal subjects will 
precede that of prepubertal subjects.  After the first 4 subjects in the pubertal/postpubertal group 
have been treated, icatibant concentration measurements and PK analysis, safety, and tolerability 
data will be reviewed and assessed by the DSMB.  This review must be completed prior to 
initiating enrollment of subjects in the prepubertal group.  As the outcome of its review, the 
DSMB may make a recommendation to continue enrolling subjects in the pubertal/postpubertal 
group, to initiate dosing of subjects in the prepubertal group, or to administer a different dose, or 
to terminate the study.  
11.9 Protocol Violations/Deviations 
The investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to subjects.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations. 
A record of subjects screened, but not entered into the study, is also to be maintained.  For any 
subject who does not meet the inclusion or exclusion criteria a protocol exemption may be 
requested by the investigator.  This exemption may be approved by the Shire Medical Monitor 
prior to enrollment and the protocol exception must be fully documented in the source 
documents and on the appropriate page of the CRF. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the investigator will contact the sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.   


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


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11.13 Retention of Data 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  The sponsor will notify the investigator if these documents must be 
retained for a longer period of time.  It is the responsibility of the sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained. 
11.14 Financial Disclosure 
The investigator should disclose any financial interests in the sponsor as described in 21 CFR 
Part 54 prior to beginning this study.  The appropriate form will be provided to the investigator 
by the sponsor, which will be signed and dated by the investigator, prior to the start of the study, 
at the end of the study, and one year post-study (or site) closure.  
11.15 Publication and Disclosure Policy 
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the sponsor and not 
previously published are considered confidential and will remain the sole property of the 
sponsor.  The investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes. 
It is understood by the investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies.  In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the sponsor with complete test results and all data developed 
in the study in a timely manner. 
The investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire HGT, 
provided Shire HGT a copy of the draft document intended for publication, and obtained Shire 
HGT’s written consent 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. Ann Allergy Asthma Immunol 
2008;100:S30-40. 
2. Davis AE, 3rd. New treatments addressing the pathophysiology of hereditary angioedema. 
Clin Mol Allergy 2008;6:2. 
3. Knolle J, Breipohl G, Henke S, Wirth K, Scholkens B. New and highly potent bradykinin 
antagonists. Agents Actions Suppl 1992;38 ( Pt 1):559-64. 
4. Hock FJ, Wirth K, Albus U, et al. Hoe 140 a new potent and long acting 
bradykinin-antagonist: in vitro studies. 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 
Clin Immunol 2010;6:18. 
7. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of 
disease in childhood 1969;44:291-303. 
8. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of 
disease in childhood 1970;45:13-23. 
9. Bieri D RRACGDALZJB. The Faces Pain Scale for the self-assessment of the severity of 
pain experienced by children: development, initial validation, and preliminary investigation 
for ratio scale properties. Pain 1990;41:139-50. 
10. Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain 
Scale-Revised: toward a common metric in pediatric pain measurement. Pain 
2001;93:173-83. 
 
 
 








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Appendix 3 
Faces Pain Scale-Revised (FPS-R) 


Pediatric Pain Sourcebook 
 
 
 
 
Document information 
Title: The Faces Pain Scale - Revised (English & French) 
a scale for measurement of pain intensity
Purpose: in children by self-report, in both English & French 
Approval/ revision May 5, 2001
date: 
Keywords 
document type:
 
Intended audience:
 
Institution type:
 
Drug type:
 
Pain type: 
Delivery technique:
 
Nonpharmacological 
treatments: 
Age:
 
Disease type:
 
protocol, guidelines, scale 
healthcare professionals 
children’s hospital, general hospital 
N/A 
disease, procedural, surgical/trauma, 
treatment related 
N/A 
N/A 
child, adolescent 
N/A 
Submitter and institution information
Name: 
Title: 
Institution:
 
Location:
 
Type of institution: 
Number of beds: 
Supervising 
specialist availability: 
Carl L. von Baeyer, PhD 
Professor of Psychology & Associate 
Member in Pediatrics 
University of Saskatchewan 
Saskatoon, Saskatchewan, Canada 
N/A 
N/A 
N/A 
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Submitter's commentary: 
The Faces Pain Scale - Revised (FPS-R) was adapted from the 
Faces Pain Scale (Bieri et al, 1990) in order to make it possible 
to score on the widely accepted 0-to-10 metric. It shows a close 
linear relationship with visual analog pain scales across the age 
range 4 through 16 years. It is easy to administer and requires 
no equipment except for the photocopied faces. The absence of 
smiles and tears in this faces scale may be advantageous. The 
FPS-R is recommended for use with younger children in parallel 
with numerical self-rating scales (0-to-10) for older children and 
behavioural observation scales for those unable to provide self-
report.
References: 
Hicks CL, von Baeyer CL, Spafford P, van Korlaar I, & 
Goodenough, B. The Faces Pain Scale - Revised: Toward a 
common metric in pediatric pain measurement. Pain 2001;93:
173-183.
von Baeyer CL, Spafford P, van Korlaar I, Hicks CL, 
Goodenough B. Validation of the Faces Pain Scale - Revised 
(FPS-R): Pain intensity in clinical and non-clinical samples. 
Poster presented to Canadian Pain Society, Montreal, May 
2001.
Bieri D, Reeve R, Champion GD, Addicoat L and Ziegler J. 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;41:139-150.
von Baeyer CL, Hicks CL. Support for a common metric for 
pediatric pain intensity scales. Pain Research and Management 
2000;5:157-160.
Reviewer’s commentary: 
published in peer-reviewed journal (see first reference above) 
Reviewer: N/A 
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Faces Pain Scale – Revised  (FPS-R)  
From Pediatric Pain Sourcebook, www.painsourcebook.ca 
Version: 7 Aug 2007  CL von Baeyer 
In the following instructions, say "hurt" or "pain," whichever seems right for a particular child.  
"These faces show how much something can hurt. This face [point to left-most face] shows no pain. The faces show 
more and more pain [point to each from left to right] up to this one [point to right-most face] – it shows very much pain. 
Point to the face that shows how much you hurt [right now]." 
Score the chosen face 0, 2, 4, 6, 8, or 10, counting left to right, so '0' = 'no pain' and '10' = 'very much pain.'  Do not use words 
like 'happy' and 'sad'. This scale is intended to measure how children feel inside, not how their face looks. 
Permission for use.   Copyright in the FPS-R is held by the International Association for the Study of Pain (IASP) © 2001.  This material may be photocopied for non-
commercial clinical and research use.  To request permission from IASP to reproduce the FPS-R in a publication, or for any commercial use, please e-mail 
iaspdesk@iasp-pain.org  For all other information regarding the FPS-R contact Tiina.Jaaniste@sesiahs.health.nsw.gov.au (Pain Medicine Unit, Sydney Children’s 
Hospital, Randwick NSW 2031, Australia). 
Sources. Hicks CL, von Baeyer CL, Spafford P, van Korlaar I, Goodenough B. The Faces Pain Scale – Revised: Toward a common metric in pediatric pain measurement. 
Pain 2001;93:173-183.  Bieri D, Reeve R, Champion GD, Addicoat L, Ziegler J. 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;41:139-150.   
 
0 
 
 
 
 
2
4 
Fold here
6
8
10
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Pediatric Pain Sourcebook, www.painsourcebook.ca 
Version: 7 Aug 2007  CL von Baeyer 
Faces Pain Scale – Revised (FPS-R)  
 
"Ces visages montrent combien on peut avoir mal. Ce visage (montrer celui de gauche) montre quelqu’un qui n’a pas 
mal du tout. Ces visages (les montrer un à un de gauche à droite) montrent quelqu’un qui a de plus en plus mal, jusqu’à 
celui-ci (montrer celui de droite), qui montre quelqu’un qui a très très mal. Montre-moi le visage qui montre combien tu 
as mal en ce moment."  
Les scores sont de gauche à droite : 0, 2, 4, 6, 8, 10. 0 correspond donc à “pas mal du tout” et 10 correspond à “très très mal”.  
Exprimez clairement les limites extrêmes : “pas mal du tout” et “très très mal”. N’utilisez pas les mots “triste” ou “heureux”. 
Précisez bien qu’il s’agit de la sensation intérieure, pas de l’aspect affiché de leur visage.  
 
Permission pour l’usage. Copyright International Association for the Study of Pain (IASP) © 2001. Ce matériel peut être photocopié pour une utilisation clinique ou en 
recherches. Pour demander la permission de l'IASP de reproduire le FPS-R dans une publication, ou pour tout usage commercial, s’adresser à  iaspdesk@iasp-pain.org 
Pour toute autre information concernant le FPS-R, s’adresser à Tiina.Jaaniste@sesiahs.health.nsw.gov.au (Pain Medicine Unit, Sydney Children’s Hospital, Randwick 
NSW 2031, Australia). 
Sources. Hicks CL, von Baeyer CL, Spafford P, van Korlaar I, Goodenough B. The Faces Pain Scale – Revised: Toward a common metric in pediatric pain measurement. 
Pain 2001;93:173-183.  Bieri D, Reeve R, Champion GD, Addicoat L, Ziegler J. 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;41:139-150.   
 
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Icatibant (Firazyr®) 
 
 
Clinical Trial Protocol: HGT-FIR-086                                                                                                                                                                           14 June 2011 
65


Ic ati b a nt ( Fir az yr ® ) 
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SAP_005.pdf: 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol 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 
Protocol Number: 
HGT-FIR-086 
Protocol Version/Date 
Amendment 4.0 
18 March 2016 
Indication: 
Hereditary angioedema 
Study Phase 
III 
SAP Author 
, Ph.D. 
SAP Analysis Type 
Final Analysis 
SAP Version/Date 
Final 
24 April 2018 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is the proprietary and confidential property of Shire  
 
PPD


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS ..................................................... 5 
 
Abbreviations ................................................................................................................. 5 
1.1
2. 
INTRODUCTION .......................................................................................................... 6 
 
Purpose of the Statistical Analysis Plan ......................................................................... 6 
2.1
 
Background .................................................................................................................... 6 
2.2
 
Study Rationale .............................................................................................................. 6 
2.3
3. 
STUDY OBJECTIVES .................................................................................................. 7 
 
Objectives ....................................................................................................................... 7 
3.1
 
Other Objectives ............................................................................................................. 7 
3.2
4. 
STUDY DESIGN ........................................................................................................... 8 
 
General Description ........................................................................................................ 8 
4.1
 
Discussion of Study Design ........................................................................................... 8 
4.2
 
Method of Assigning Subjects to Treatment Group ....................................................... 9 
4.3
 
Blinding .......................................................................................................................... 9 
4.4
 
Determination of Sample Size ........................................................................................ 9 
4.5
5. 
STUDY ENDPOINTS ................................................................................................. 10 
6. 
EFFICACY AND SAFETY VARIABLES ................................................................. 12 
 
Schedule of Evaluations ............................................................................................... 12 
6.1
 
Safety Assessments ...................................................................................................... 12 
6.2
 
Efficacy Assessments ................................................................................................... 12 
6.3
 
Investigator Symptom Score .................................................................................. 12 
6.3.1
 
FPS-R ..................................................................................................................... 12 
6.3.2
 
FLACC................................................................................................................... 12 
6.3.3
7. 
STATISTICAL ANALYSES ....................................................................................... 14 
 
General Considerations ................................................................................................ 14 
7.1
 
Analysis Populations .................................................................................................... 14 
7.2
 
Subject Disposition ....................................................................................................... 15 
7.3
 
Demographics and Pre-treatment Characteristics ........................................................ 15 
7.4
 
Medical and HAE History ............................................................................................ 15 
7.5
 
On-Study HAE Attacks and Drug Exposure ................................................................ 16 
7.6


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Protocol Deviations ...................................................................................................... 16 
7.7
 
Efficacy Analysis ......................................................................................................... 16 
7.8
 
Investigator Symptom Score .................................................................................. 16 
7.8.1
 
FPS-R ..................................................................................................................... 17 
7.8.2
 
FLACC................................................................................................................... 18 
7.8.3
 
Other Efficacy Analyses ........................................................................................ 18 
7.8.4
 
Safety Analyses ............................................................................................................ 19 
7.9
 
Adverse Events ...................................................................................................... 19 
7.9.1
 
Symptoms at Injection Site .................................................................................... 20 
7.9.2
 
Immunogenicity ..................................................................................................... 20 
7.9.3
 
Laboratory Results ................................................................................................. 21 
7.9.4
 
Electrocardiogram (ECG) ...................................................................................... 21 
7.9.5
 
Vital Signs.............................................................................................................. 22 
7.9.6
 
Reproductive Hormone Assessments .................................................................... 22 
7.9.7
 
Pregnancy Test Results .......................................................................................... 22 
7.9.8
 
Concomitant Medication........................................................................................ 22 
7.9.9
 Rescue Medication ................................................................................................. 22 
7.9.10
8. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANED ANALYSES ...... 24 
 
Changes in the Conduct of the Study ........................................................................... 24 
8.1
 
Changes from the Analyses Planned in the Protocol ................................................... 24 
8.2
9. 
STATISTICAL/ANALYTIC ISSUES ......................................................................... 25 
 
Adjustment for Covariates ............................................................................................ 25 
9.1
 
Handling of Dropouts or Missing Data ........................................................................ 25 
9.2
 
Handling of Missing Data in Efficacy Assessments .............................................. 25 
9.2.1
 
Handling of Missing Start Dates for Adverse Event Reporting ............................ 25 
9.2.2
 
Interim Analyses and Data Monitoring ........................................................................ 25 
9.3
 
Multicenter Studies ....................................................................................................... 26 
9.4
 
Multiple Comparisons/Multiplicity .............................................................................. 26 
9.5
 
Examination of Subgroups and Interactions ................................................................ 26 
9.6
 
Sensitivity Analyses ..................................................................................................... 26 
9.7
10. 
APPENDICES .............................................................................................................. 27 
 
APPENDIX I: List of Statistical Outputs ..................................................................... 27 
10.1
 List of Statistical Tables ........................................................................................ 27 
10.1.1
 List of Statistical Figures ....................................................................................... 32 
10.1.2
 List of Data Listings .............................................................................................. 33 
10.1.3


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APPENDIX II:  Definitions and Programming Conventions ...................................... 34 
10.2
 Age Calculation ..................................................................................................... 34 
10.2.1
 BMI Calculation .................................................................................................... 34 
10.2.2
 Weight and Height Percentile Calculation............................................................. 34 
10.2.3
 Time-to-Event Endpoints ....................................................................................... 34 
10.2.4
 Study Day of an Event ........................................................................................... 34 
10.2.5
 Duration of an Event .............................................................................................. 34 
10.2.6
 Attribution of Concomitant Medications ............................................................... 34 
10.2.7
 Calculating Years since Diagnosis and Months since Last Attack with 
10.2.8
Partial Dates ........................................................................................................... 35 
 Handling of Missing Individual Symptom Assessment at Baseline ...................... 35 
10.2.9
 Deriving Time to First Use of Rescue Medication for Subjects with Missing 
10.2.10
Time to Onset of Symptom Relief ......................................................................... 35 
 Attribution of AEs ................................................................................................. 35 
10.2.11
 Handling of Missing Data for Adverse Events ...................................................... 35 
10.2.12
 Handling of Immunogenicity Data for the Second and Third Study Drug 
10.2.13
Exposure ................................................................................................................ 36 
 Defining Rescue Medications ................................................................................ 36 
10.2.14
 
Appendix III: Schedule of Events ................................................................................ 37 
10.3
 Study Schedule of Events (No Attack) .................................................................. 37 
10.3.1
 Study Schedule of Events (Initial Icatibant-treated Attack) .................................. 41 
10.3.2
 Study Schedule of Events (Subsequent Icatibant-treated Attacks) ........................ 46 
10.3.3


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1. 
LIST OF ABBREVIATIONS AND DEFINITIONS 
 
Abbreviations 
1.1
AE 
Adverse Event   
BMI 
Body Mass Index  
C1-INH 
C1 inhibitor  
CRF 
Case Report Form 
ECG 
Electrocardiogram  
FLACC 
Faces, Legs, Activity, Cry, and Consolability 
FPS-R 
Faces Pain Scale – Revised  
HAE 
Hereditary Angioedema 
ITT 
Intent To Treat 
IV 
Intravenous 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
Protocol Deviation   
PK 
Pharmacokinetic 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SOC 
System Organ Class  
SOP 
Standard Operating Procedure 
WHO 
World Health Organization  
WHO-DD 
World Health Organization-Drug Dictionary 


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2. 
INTRODUCTION 
 
Purpose of the Statistical Analysis Plan 
2.1
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
planned statistical analyses on safety and efficacy endpoints for protocol HGT-FIR-086, a 
multicenter, open-label, non-randomized study to assess the pharmacokinetics (PK), 
tolerability, and safety of a single subcutaneous (SC) administration of icatibant in children 
and adolescents with hereditary angioedema. SAP for PK endpoints will be provided in a 
separate document.  
This study evaluated the effect of a single administration of icatibant in children and 
adolescents with hereditary angioedema (HAE). It also examined the effect of repeated 
exposures of icatibant in adolescents. This SAP presents the statistical analysis methods on 
complete safety and efficacy results for single administration of icatibant in at least 10 
prepubertal children and at least 20 adolescents with HAE treated once with icatibant and 
repeated exposure of icatibant during subsequent HAE attacks in adolescents. 
 
Background 
2.2
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, 
safety including reproductive hormone assessments, and efficacy of a single SC 
administration of icatibant in approximately 30 pediatric subjects with HAE during an initial 
acute attack. Details of the study design, rationale, and procedures are documented in Protocol 
HGT-FIR-086. 
 
Study Rationale 
2.3
Three controlled Phase III studies established the safety and efficacy of icatibant as a 
treatment for acute attacks of HAE. Icatibant has not been evaluated in clinical trial subjects 
below the age of 18 years. This study was designed to evaluate the PK, tolerability, safety 
including reproductive hormone assessments, and efficacy of a single SC administration of 
icatibant in subjects from 2 to less than 18 years of age. 


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3. 
STUDY OBJECTIVES 
The study objectives are listed below.  
 
Objectives  
3.1
The objectives of this study are: 
• To investigate the PK, tolerability, and safety of a single SC dose of icatibant in children 
and adolescents with HAE. 
• To evaluate the efficacy of a single SC dose of icatibant in children and adolescents with 
HAE. 
• To evaluate the effect on reproductive hormone levels after a single SC dose of icatibant 
in children and adolescents with HAE.  
 
 
Other Objectives  
3.2
Other objectives of this study are: 
• To evaluate the continued safety of icatibant in pubertal/postpubertal children after 
repeated exposures.  
• To evaluate the efficacy of icatibant in the treatment of acute HAE attacks in 
pubertal/postpubertal children after repeated exposures. 
• To evaluate the effect on reproductive hormone levels in pubertal/postpubertal children 
after repeated exposures.  


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4. 
STUDY DESIGN 
 
General Description 
4.1
This is an open-label, non-randomized, single-arm study to evaluate the PK, tolerability, and 
safety, including effects on reproductive hormones, of a single SC administration of icatibant 
in pediatric subjects with HAE. 
The study enrolled children and adolescents from 2 to less than 18 years of age, divided into 2 
groups: prepubertal (Tanner stage I) and pubertal/postpubertal (Tanner stages II to V).   
After a qualifying screening period, the PK, safety/tolerability, and efficacy of treatment with 
SC icatibant was evaluated in at least 20 subjects (10 prepubertal and 10 pubertal/postpubertal 
subjects) who presented with cutaneous, abdominal, or laryngeal symptoms of an acute attack 
of HAE.  
The PK and safety/tolerability of SC icatibant was evaluated in at least 10 additional 
pubertal/postpubertal subjects who met screening criteria, but received treatment with SC 
icatibant in the absence of a current acute HAE attack. 
Subjects will receive treatment with a single SC administration of icatibant on Day 1 and will 
be monitored closely in the hospital/study center for at least 6 to 8 hours after treatment. 
Subjects will undergo PK and safety assessments; efficacy assessments will be performed if 
treatment occurs during an acute HAE attack. All subjects will have serum reproductive 
hormone measurements. 
A subject may be discharged after completion of assessments at 6 hours post treatment, if 
deemed medically stable in the investigator’s clinical judgment and, if applicable, the 
subject’s HAE symptoms have resolved (the subject’s investigator-rated symptom score must 
be zero, denoting the absence of symptoms). If HAE symptoms have not completely resolved 
at 6 hours (ie, the investigator-rated symptom score is >0), the subject shall remain in the 
hospital/study center for at least 8 hours after icatibant administration for further evaluation. 
Telephone follow-up will occur at both 24 and 48 hours after treatment. Subjects will return 
to the hospital/study center for scheduled assessments on Day 8 and for a follow-up visit on 
Day 90. 
A table showing the Schedule of Events for the study is provided in Appendix III: Schedule of 
Events. 
 
Discussion of Study Design  
4.2
This study has an open-label, single arm design.   
The study is intended to determine the PK profile of SC icatibant when administered to 
children and adolescents with HAE and to identify an optimal pediatric dosing regimen.  


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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. 
 
Method of Assigning Subjects to Treatment Group  
4.3
Not applicable to this single arm study. 
 
Blinding  
4.4
Not applicable to this open-label study.   
 
Determination of Sample Size  
4.5
The study will enroll a sufficient number of children and adolescents to ensure study 
completion of 30 evaluable subjects.  The study population is planned to consist of at least 10 
prepubertal and 20 pubertal/postpubertal subjects from 2 to less than 18 years of age.  Though 
empirically derived and not based on a formal sample size calculation, this sample size will 
provide basic information concerning the PK, tolerability and safety, and efficacy of icatibant 
in children and adolescents with HAE. 


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5. 
STUDY ENDPOINTS 
The primary endpoints of this study are: 
 
 The PK profile of icatibant after a single SC injection in pediatric subjects (in prepubertal 
children with an acute attack of HAE and pubertal/postpubertal children with or without 
an acute attack of HAE). 
 The tolerability and safety of SC icatibant as assessed by injection site reactions, adverse 
events, vital signs, ECG recordings, physical examination, clinical laboratory parameters 
(serum chemistry [including liver function tests], hematology, urinalysis), reproductive 
hormone levels, and immunogenicity (presence of anti-icatibant antibodies).  
 
The secondary endpoints (only for subjects treated with icatibant during a HAE attack) of this 
study are: 
 
Time to onset of relief of symptoms and time to minimal symptoms, as measured by 
investigator- and subject-reported outcomes 
 For all subjects (2 to <18 years of age): investigator assessment and scoring of 
cutaneous, abdominal, and laryngeal symptoms of acute HAE attacks by an 
investigator-rated symptom score. 
o 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. 
o 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).  
o The time to onset of relief of symptoms, defined as the earliest time at which 
the post-treatment score improves by at least one level. 
o The time to minimal symptoms, defined as the earliest time at which the post-
treatment score improves to zero (or no pain).  
 
 For subjects <4 years of age only: investigator assessment of HAE-related pain 
(cutaneous, abdominal, and laryngeal) using a validated pain scale (Faces, Legs, 
Activity, Cry, and Consolability [FLACC] ).  
o 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.  
o The time to minimal symptoms, defined as the earliest time at which the total 
post-treatment score improves to zero.  
 
 Incidence of rescue medication use. 


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 Proportion of subjects with worsened intensity of clinical HAE symptoms between 2 
and 4 hours after treatment with icatibant. 
 


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6. 
EFFICACY AND SAFETY VARIABLES 
 
Schedule of Evaluations 
6.1
Please refer to Appendix III: Schedule of Events for details of assessments performed at each 
visit. 
 
Safety Assessments 
6.2
The safety and tolerability parameters include AEs, vital signs, ECG, local tolerability at the 
injection site, reproductive hormone levels, immunogenicity, and standard hematology, serum 
chemistry, and urinalysis. 
 
Efficacy Assessments 
6.3
 
Investigator Symptom Score 
6.3.1
The investigator will use a symptom score to assess the severity of symptoms of acute 
cutaneous, abdominal, and laryngeal attacks of HAE using the following 5-point scale.  
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. 
 
FPS-R 
6.3.2
The Faces Pain Scale – Revised (FPS-R) is a self-reported measure used to assess the 
intensity of children's pain and  it is scored using a 0 to 10 scale (‘0’=’no pain’ and ‘10’=’very 
much pain’). Subjects who are at least 4 years of age will self-assess HAE-related pain using 
the FPS-R.  
 
FLACC 
6.3.3
Subjects who are below 4 years of age will undergo investigator assessment of HAE-related 
symptoms using the Faces, Legs, Activity, Cry, and Consolability (FLACC) comportmental 


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pain scale. The FLACC is a behavior pain assessment scale for use in preverbal children or 
children with limited verbal capability who are unable to provide reports of pain. Each of the 
five categories (F) Face; (L) Legs; (A) Activity; (C) Cry; (C) Consolability is scored from 0-
2, which results in a total score between zero and ten. 
 


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7. 
STATISTICAL ANALYSES 
 
General Considerations 
7.1
All statistical analyses will be performed using SAS® statistical software (SAS Institute, 
North Carolina, USA) except for the population PK modeling which will be performed with 
nonlinear mixed effect modeling software (eg, Phoenix NLME module, Pharsight Corp.). A 
separate analytic plan will be developed to support the analysis of PK data. The analysis 
methods for all other study data (demographic and pretreatment characteristics, efficacy 
variables, and safety variables) will be detailed in the SAP. 
Data will be summarized with respect to disposition, demographic, pre-treatment 
characteristics, safety variables, and efficacy variables. Summary statistics for continuous 
variables will include the number of subjects, the mean, median, standard deviation, and 
range. For categorical data, summaries will include counts and percentages. Time-to-event 
data will be summarized using Kaplan-Meier estimates of the 25th, 50th (median), and 75th 
percentiles with associated 2-sided 95% confidence intervals, as well as percentage of 
censored observations. Plots of the Kaplan-Meier curves and supporting data listings detailing 
each subject’s contribution to the analysis will be provided. 
 
 
Analysis Populations 
7.2
The following populations will be used in the analysis: 
 The Efficacy Population will consist of those subjects who were treated with icatibant for 
their first and any additional attacks during the study. 
 The Safety Population will consist of those subjects who were treated with icatibant at 
least once during the study (irrespective of the presence of an HAE attack). 
All efficacy analyses will be performed on the Efficacy Population. The corresponding tabular 
summaries will be presented by the icatibant exposure number. For the initial icatibant 
exposure, the analyses will be presented by the pubertal status (Pre-pubertal vs. Pubertal/Post-
pubertal) and overall; for the subsequent icatibant exposures, the analyses will be presented 
by the administration type (Study Site Personnel (HCP Administration) vs. Home Healthcare 
Providers/Patient/Parent/Legal Guardian/Caregiver (Caregiver Administration)) and overall. 
Safety and tolerability analyses will be based on the Safety Population. All tabular summaries 
within this population will be presented by the icatibant exposure number. For the initial 
icatibant exposure, the analyses will be presented by the pubertal status (Pre-pubertal vs. 
Pubertal/Post-pubertal) and overall; for the subsequent icatibant exposures, the analyses will 
be presented by the administration type (HCP Administration vs. Caregiver Administration) 
and overall. 


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Subject Disposition 
7.3
The number and percentage of subjects who completed assessments (complete assessments up 
to Day 8 and complete assessment up to Day 90) and discontinued prematurely by reason will 
be summarized separately for the Efficacy Population and the Safety Population, by the 
icatibant exposure number. For the initial icatibant exposure, the analyses will be presented by 
the pubertal status and overall; for the subsequent icatibant exposures, the analyses will be 
presented by the administration type (HCP Administration vs. Caregiver Administration) and 
overall.  
The number and percentage of subjects who completed assessments and discontinued 
prematurely by reason will be summarized separately for the Efficacy Population and the 
Safety Population by pubertal status stratification level. 
 
Demographics and Pre-treatment Characteristics 
7.4
Demographic and pre-treatment characteristics (age at screening [years], age at exposure 
[years], age group at exposure [<6 years, 6-11 years, >11 years], sex [male, female], race 
[American Indian or Alaskan Native, Asian, Black or African American, Native Hawaiian or 
other Pacific Islander, White, Other], ethnicity [Hispanic or Latino, Not Hispanic or Latino], 
weight at exposure [kg], weight group at exposure [<75 kg, ≥75 kg], weight percentile at 
exposure, height at exposure [cm], height percentile at exposure [cm], BMI [kg/m2] at 
exposure, BMI percentile at exposure, and country) will be summarized separately for the 
Efficacy Population and the Safety Population, and by icatibant exposure number. For the 
initial icatibant exposure, the analyses will be presented by the pubertal status and overall; for 
the subsequent icatibant exposures, the analyses will be presented by the administration type 
(HCP Administration vs. Caregiver Administration) and overall. 
 
Medical and HAE History 
7.5
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 16.0 and summarized by system organ class (SOC) and preferred term 
(PT) for the Efficacy Population and the Safety Population, and by icatibant exposure number. 
For the initial icatibant exposure, the analyses will be presented by the pubertal status and 
overall; for the subsequent icatibant exposures, the analyses will be presented by the 
administration type (HCP Administration vs. Caregiver Administration) and overall. 
History of HAE (family history [yes, no], time since diagnosis at first treatment [years], type of last 
attack[cutaneous, abdominal, cutaneous and abdominal, or laryngeal], and time since last attack at first 
treatment [months]) and details on previous HAE attacks (number of attacks in last 12 months, 
average duration of attacks [days], average time between onset of symptoms and relief [days], and 
most frequent  severity of attacks [mild, moderate, or severe]) for each attack type (cutaneous, 
abdominal, cutaneous and abdominal, and laryngeal) will be summarized separately for the Efficacy 
Population and the Safety Population, and by icatibant exposure number. For the initial icatibant 
exposure, the analyses will be presented by the pubertal status and overall; for the subsequent 
icatibant exposures, the analyses will be presented by the administration type (HCP 
Administration vs. Caregiver Administration) and overall. 


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Medical history and HAE history will also be provided in listings. 
 
On-Study HAE Attacks and Drug Exposure  
7.6
Type of attack (cutaneous, abdominal, laryngeal) and time from attack onset to study drug 
administration (hours) will be summarized for the Efficacy Population, by icatibant exposure 
number. For the initial icatibant exposure, the analyses will be presented by the pubertal status 
and overall; for the subsequent icatibant exposures, the analyses will be presented by the 
administration type (HCP Administration vs. Caregiver Administration) and overall. 
Number of injections will be summarized for the Efficacy Population and Safety Population, 
by icatibant exposure number. For the initial icatibant exposure, the analyses will be presented 
by the pubertal status and overall; for the subsequent icatibant exposures, the analyses will be 
presented by the administration type (HCP Administration vs. Caregiver Administration) and 
overall. 
The exposure information for all icatibant administrations given as part of the study will also 
be presented in a listing.   
 
Protocol Deviations 
7.7
Prior to the interim data cut, protocol deviations will be reviewed by the study team and the 
subset of protocol deviations that may have significantly impacted the completeness, 
accuracy, and/or reliability of the study data or that may significantly affected a subject’s 
rights, safety, or well-being will be identified as significant protocol deviations. 
A listing of the protocol deviations will be provided for each subject. 
 
Efficacy Analysis 
7.8
Efficacy will be assessed using data from the investigator symptom score, FPS-R and 
FLACC. The corresponding analyses will be based on the Efficacy Population. All efficacy 
summaries will be presented by icatibant exposure number. For the initial icatibant exposure, 
the analyses will be presented by the pubertal status and overall; for the subsequent icatibant 
exposures, the analyses will be presented by the administration type (HCP Administration vs. 
Caregiver Administration) and overall. 
All efficacy results will be listed by subject. 
 
Investigator Symptom Score 
7.8.1
The primary efficacy endpoint is the time to onset of symptom relief measured using the 
investigator-reported symptom score. Eight symptoms will be assessed for abdominal and 
cutaneous attacks, and 13 symptoms will be assessed for laryngeal attacks. Time to onset of 
symptom relief is defined as the duration of time in hours from study drug administration to 
the earliest time post-treatment at which there is at least a 20% improvement in the composite 
(or average) post-treatment symptom score with no worsening of any single component score. 


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Subjects not achieving the onset of symptom relief will be censored at the time of their last 
symptom assessment. Time to onset of symptom relief will be summarized using the Kaplan-
Meier method.  
An alternative efficacy endpoint is the time to minimum symptoms measured using the 
investigator-reported symptom score. It is defined as the earliest time post-treatment when all 
symptoms are either mild or absent. Subjects not achieving the minimum symptom criteria 
will be censored at the time of their last symptom assessment. Time to minimum symptoms 
will be summarized using the Kaplan-Meier method.  Subjects with all symptoms as mild or 
absent at pretreatment will be excluded from this analysis. 
The composite investigator-reported symptom score and the change from pre-treatment in the 
composite investigator-reported symptom score will be summarized by study time-point. 
Furthermore, the symptom scores associated with individual symptoms will be summarized 
by study time-point. The mean composite investigator-assessed symptom score will be plotted 
by study time-point by pubertal status stratification group. 
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.  
Time to onset of symptom relief for individual symptom is defined as duration of time in 
hours from study drug administration to the earliest time post-treatment when the specific 
symptom is either mild or absent. Subjects not achieving the relief for individual symptom 
criteria will be censored at the time of their last symptom assessment. Time to onset of 
symptom relief for individual symptoms will be summarized using the Kaplan-Meier method. 
Subjects with the individual symptom as mild or absent at pretreatment will be excluded from 
the analysis on that symptom.  
Analyses on investigator symptom score will be performed for the initial icatibant exposure 
and both subsequent exposures. 
 
FPS-R 
7.8.2
Pain will be assessed in subjects 4 years of age or older using the FPS-R. Time to onset of 
symptom relief in this case will be defined as the duration of time in hours from the time of 
study drug administration to the earliest time at which the post-treatment score improves by at 
least one level. Subjects not achieving the onset of symptom relief for FPS-R will be censored 
at the time of their last FPS-R assessment. Time to onset of symptom relief will be 
summarized using the Kaplan-Meier method.  Subjects with pretreatment value of zero will 
be excluded from this analysis.  
Time to minimum symptom for FPS-R is defined as the duration of time in hours from the 
time of study drug administration to the earliest time at which the post-treatment score 
improves to zero (or no pain). Subjects not achieving minimum symptom for FPS-R will be 
censored at the time of their last FPS-R assessment. Time to minimum symptom for FPS-R 


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will be summarized using the Kaplan-Meier method.  Subjects with pretreatment value of 
zero will be excluded from this analysis.  
The observed values and change from pre-treatment in the FPS-R score will be summarized 
by study time-point.  
Analyses on the FPS-R will be performed for the initial icatibant exposure and both 
subsequent icatibant exposures. 
 
FLACC 
7.8.3
For subjects less than 4 years of age, the investigator will assess HAE-related pain (cutaneous, 
abdominal, and laryngeal) using FLACC. Time to onset of symptom relief will be calculated 
from the time of study drug administration to the earliest time at least a 20% improvement is 
seen in the total post-treatment pain score. Subjects not achieving the onset of symptom relief 
for FLACC will be censored at the time of their last FLACC assessment.  Time to onset of 
symptom relief will be summarized using the Kaplan-Meier method. Subjects with 
pretreatment value of zero will be excluded from this analysis.  
Time to minimum symptom for FLACC is defined as the duration of time in hours from the 
time of study drug administration to the earliest time at which the post-treatment total score 
improves to zero (or no pain). Subjects not achieving minimum symptom for FLACC will be 
censored at the time of their last FLACC assessment. Time to minimum symptom for FLACC 
will be summarized using the Kaplan-Meier method.  Subjects with pretreatment value of 
zero will be excluded from this analysis.  
The observed values and changes from pre-treatment in the total pain score will be 
summarized by study time-point. Similarly, the scores in each of the five domains will be 
summarized by the study time-point. 
Analyses on FLACC will be performed for the initial icatibant exposure only. 
 
Other Efficacy Analyses 
7.8.4
Time to First Use of Rescue Medication 
The number and percentage of subjects who received rescue medications before the onset of 
symptom relief will be summarized. Time to first use of rescue medication prior to onset of 
symptom relief will be calculated from the time of study drug administration to the first use of 
rescue medication prior to the onset of symptom relief. Subjects not using rescue medication 
prior to the onset of symptom relief will be censored at the time of their onset of symptom 
relief. Time to first use of rescue medication will be summarized using the Kaplan-Meier 
method. This analysis will only be performed if there are at least 5 subjects for a given attack 
who used rescue medication prior to attaining symptom relief.  


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Subjects who received rescue medication before the onset of symptom relief will be denoted 
in the listing on rescue medication for the efficacy population.  
Analyses on time to first use of rescue medication will be performed for the initial icatibant 
exposure and both subsequent icatibant exposures. 
Time to 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. The time to initial 
symptom relief will be defined as the duration of time in hours from study drug 
administration until the time when overall subject improvement was first noted. Subjects not 
achieving the initial symptom relief will be censored at the time of their last assessment. Time 
to initial symptom relief will be summarized using the Kaplan-Meier method.  
Analyses on time to initial symptom relief will be performed for the initial icatibant exposure 
and both subsequent icatibant exposures. 
 
Safety Analyses 
7.9
All safety summaries will be presented by icatibant exposure number, if not otherwise 
specified. For the initial icatibant exposure, the analyses will be presented by the pubertal 
status and overall; for the subsequent icatibant exposures, the analyses will be presented by 
the administration type (HCP Administration vs. Caregiver Administration) and overall.  
All safety summaries will be presented for the initial icatibant exposure and both subsequent 
icatibant exposures.  
All safety outcomes will be listed by subject.  
 
Adverse Events 
7.9.1
Adverse events (AE) 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). Any serious 
adverse events (SAE), regardless of relationship to investigational product, which occurs in a 
subject after informed consent, should be recorded by the clinical site on a serious adverse 
event form. 
AEs will be coded using MedDRA Version 16.0. A summary of subjects with treatment-
emergent adverse events defined as AEs which occurred or worsened on or after the time of 
the first study drug administration will be presented. The summary will include the number 
and percentage of subjects who experience any AEs, any related AE, any severe AE, any 
related severe AE, any SAE, any related SAE, and any injection site reaction which was 
deemed an SAE; as well as the number of events in each category.  Additionally, the 
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Related AEs are AEs assessed as possibly, probably, or definitely related to the study 
treatment. 
Treatment emergent AEs will be summarized by system organ class (SOC) and preferred term 
by pubertal status stratification level and icatibant exposure number. Tabulations will be 
presented sorted by SOC in alphabetical order and by PT within each SOC by descending 
frequency. The number and percentage of subjects experiencing an AE, as well as total 
number of AEs, will be tabulated. Treatment emergent AEs by SOC and preferred term also 
will be tabulated by severity and by relationship to treatment. In the case of multiple 
occurrences of the same AEs (at the preferred term level) in an individual subject, the AE that 
is classified as the most severe (i.e., maximum severity) will be identified for the analysis by 
severity and the AE that has the closest relationship to study drug will be identified for the 
analysis by relationship. Treatment emergent SAEs will be tabulated according to SOC and 
preferred term and provided in a data listing.  
For analyses on treatment emergent AEs, in addition to summaries by icatibant exposure 
number, the analyses on all treatment emergent AEs by pubertal status stratification level and 
overall will be performed as well.  
Pre-treatment AEs will be presented in a listing. 
 
Symptoms at Injection Site 
7.9.2
Injection site reactions (erythema, swelling, burning sensation, itching/pruritus, warm 
sensation, cutaneous pain) will be evaluated by the investigator or home healthcare 
provider/parent/legal guardian/caregiver when the subject is at the hospital/study center.  
The number and percentage of subjects with any injection site reactions, and any severe 
reactions, will be summarized by type of reaction. 
The number and percentage of subjects with injection site reactions will be summarized by 
maximum severity at any time point and for each study time point. 
 
Immunogenicity 
7.9.3
Serum samples for immunogenicity testing for determination of anti-icatibant antibodies will 
be collected pre-treatment and 8 and 90 days post-treatment. A subject will be considered as 
anti-icatibant antibody positive if he/she has at least 1 positive antibody result after the pre-
treatment visit.  
The number and percentage of subjects with a positive post-treatment antibody test result will 
be summarized.  
For analyses on immunogenicity, in addition to summaries by icatibant exposure number, the 
analyses on all immunogenicity measurements by pubertal status stratification level and 
overall will be performed as well. 


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Laboratory Results 
7.9.4
Laboratory test results will be presented in conventional units. Serum chemistry, hematology, 
and urinalysis parameters will be collected at pre-treatment, 6 hours post-treatment and at 8 
and 90 days post-treatment for the initial icatibant treatment.  
Observed values and changes from pre-treatment will be summarized by study time-point. 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the investigator. The number of subjects with a non-missing 
result, and the number and percentage of subjects with a clinically significant result less than 
the lower limit of normal, non-clinically significant result less than the lower limit of normal, 
within the normal range, non-clinically significant result more than the upper limit of normal, 
and clinically significant result more than the upper limit of normal will be summarized by 
study time point. If more than one laboratory result is reported per study time point per 
parameter, the result yielding the most severe classification will be selected for analysis.  
Listings of abnormal results and records with missing reference ranges (eliminated from the 
summary analysis), as well as results of the same laboratory parameter for the subject across 
all study time points, will be presented. 
Laboratory parameters collected are listed below. 
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. 
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. 
 
Electrocardiogram (ECG) 
7.9.5
ECGs will be performed at screening and at 6 hours (or 8 hours for subjects who did not have 
complete resolution of HAE symptoms at 6 hours) post-treatment for the initial icatibant 
treatment. ECG results (abnormal or normal) will be summarized by study time point. 
Listings of treatment-emergent abnormalities, as well as results for the subject across all study 
time points, will be presented. 


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Vital Signs 
7.9.6
Vital signs (temperature [°C], pulse [bpm], blood pressure [systolic and diastolic, mmHg], 
and respiration [per min]) will be collected at screening, pre-treatment, and 1 hour, 6 hours (or 
8 hours for subjects who did not have complete resolution of HAE symptoms at 6 hours), 8 
days and 90 days post-treatment for the initial icatibant treatment; and at pretreatment, 8 days 
and 90 days post-treatment for subsequent icatibant-treated attacks. Observed values and 
changes from pre-treatment will be summarized by study time-point. 
 
Reproductive Hormone Assessments 
7.9.7
Reproductive hormone levels will be measured in all subjects at pre-treatment, and 6 hours, 8 
days and 90 days post-treatment for the initial icatibant treatment, and pretreatment, 8 days 
and 90 days post-treatment for subsequent icatibant-treated attacks.  FSH, LH, estradiol, and 
progesterone will be summarized for females, and FSH, LH, and testosterone will be 
summarized for males. Observed values and changes from pre-treatment will be summarized 
by study time-point. The number and percentage of subjects with levels outside the normal 
range defined for their sex and pubertal status will be summarized by study time-point. 
Observations below the limit of detection will be considered abnormal if the lower limit of 
normal is not zero. 
 
Pregnancy Test Results 
7.9.8
Female subjects of childbearing potential will undergo pregnancy testing at screening, pre-
treatment and 90 days post-treatment.  A listing of pregnancy test results will be presented by 
site number, subject number, icatibant exposure number, and study time point. 
 
Concomitant Medication  
7.9.9
Concomitant medications will be coded using the WHO Drug Dictionary (Version 2011, Q4). 
Concomitant medications administered after the treatment start and within 5 days from the 
treatment start will be summarized by icatibant exposure number, therapeutic class, and 
preferred term for the Efficacy Population and the Safety Population. For medications with 
partial onset times, non-missing date parts will be used to determine if the medication 
qualifies as concomitant. If it cannot be definitively determined that a concomitant medication 
was used within 5 days from treatment start then it will be included in the summary. 
 
Rescue Medication 
7.9.10
Rescue medications will be coded using the WHO Drug Dictionary (Version 2011, Q4).  
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.  


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Repeat administration of icatibant for the treatment of a single attack is not allowed in this 
study.   
Antihistamines and corticosteroids 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 rescue medications.  
Rescue medications administered after the treatment start and within 48+4 hours after the 
treatment start will be summarized by icatibant exposure number, therapeutic class, and 
preferred term for the Efficacy Population and the Safety Population.  For medications with 
partial onset times, non-missing date parts will be used to determine if the rescue medication 
was used within 3 days of treatment.  If it cannot be definitely determined that the rescue 
medication was used within 3 days of treatment, the rescue medication will be excluded from 
the summary. See Section 10.2.14 for the detailed definition of rescue medication.  


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8. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANED 
ANALYSES 
 
Changes in the Conduct of the Study 
8.1
There was no change in the conduct of the study. 
 
Changes from the Analyses Planned in the Protocol 
8.2
There was no change from the analyses planned in the protocol. 
 


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9. 
STATISTICAL/ANALYTIC ISSUES 
 
Adjustment for Covariates 
9.1
Given the small number of subjects treated in the study, no modelling approach will be 
performed to analyze the study data. Therefore, adjustment for covariates is not necessary. 
 
Handling of Dropouts or Missing Data 
9.2
 
Handling of Missing Data in Efficacy Assessments 
9.2.1
In general, a conservative approach that is unlikely to bias the results will be used to deal with 
missing data.  Individual missing pretreatment scores, when the assessment was performed 
(i.e., other instrument-specific pretreatment scores are non-missing), will be assigned a value 
of mean value from the other available symptom scores when calculating the composite 
symptom scores at baseline. 
Individual missing post-treatment scores, when the assessment was performed (i.e., other 
instrument-specific scores are non-missing), will be assigned the last non-missing value using 
last observation carried forward (LOCF).  If the baseline observation is the last non-missing 
value it will be carried forward as well.  This imputation method assumes that if an 
investigator did not rate a symptom at a particular assessment, then there was no change from 
the previous assessment. 
 
Handling of Missing Start Dates for Adverse Event Reporting 
9.2.2
For AEs with partial onset times, non-missing date parts will be used to determine if the AE is 
treatment-emergent or not. If a determination cannot be made using the non-missing date 
parts as to when the AE occurred relative to study drug administration then the AE will be 
classified as treatment-emergent. 
 
Interim Analyses and Data Monitoring 
9.3
An interim analysis was performed when at least 10 prepubertal children and at least 20 
adolescents have been enrolled in the study to support a regulatory filing fulfilling Shire’s 
commitment in the Paediatric Investigation Plan (PIP) for Firazyr (EMEA-000408-PIP01-08-
M05). Also, an independent DSMB was established to provide ongoing, independent review 
and assessment of the safety data, and to safeguard the interests and safety of the participating 
subjects in the study.  Analysis of the data for DSMB review was conducted according to the 
DSMB Charter and DSMB SAP. Because no formal hypothesis testing was planned, 
multiplicity concerns regarding repeated analyses were not an issue. 


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Multicenter Studies 
9.4
Data from all centers that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analysis. Given the small number of subjects treated 
at each study site, no analysis on study center effects is planned. 
 
Multiple Comparisons/Multiplicity 
9.5
Given the small number of subjects treated in the study, no modelling approach will be 
performed to analyze the study data. Therefore, adjustment for multiple testing is not 
necessary. 
 
Examination of Subgroups and Interactions 
9.6
Given the small sample size of this study, no analysis is planned to examine subgroups. 
 
Sensitivity Analyses 
9.7
No sensitivity analysis is planned for this study. 








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Table  
Table Title  
 14.3.2.2 
Treatment-Emergent Adverse Events forIcatibant Exposure Number 1, System Organ 
Class and Preferred Term (Safety Population)  
 14.3.2.3 
Treatment-Emergent Adverse Events by Icatibant Exposure Number, System Organ 
Class and Preferred Term for Icatibant Exposure Number 2 and 3 (Safety Population)  
 14.3.3.1 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, Maximum 
Severity, and Pubertal Status Stratification Group (Safety Population) 
 14.3.3.2 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Maximum Severity for Icatibant Exposure Number 1 (Safety Population)  
 14.3.3.3 
Treatment-Emergent Adverse Events by Icatibant Exposure Number, System Organ 
Class, Preferred Term, and Maximum Severity for Icatibant Exposure Number 2 and 3 
(Safety Population)  
 14.3.4.1 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, 
Relationship to Study Drug, and Pubertal Status Stratification Group (Safety Population) 
 14.3.4.2 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Relationship to Study Drug for Icatibant Exposure Number 1 (Safety Population)  
 14.3.4.3 
Treatment-Emergent Adverse Events by Icatibant Exposure Number, System Organ 
Class, Preferred Term, and Relationship to Study Drug for Icatiant Exposure Number 2 
and 3 (Safety Population)  
 14.3.5.1 
Treatment-Emergent SAE by System Organ Class, Preferred Term, and Pubertal Status 
Stratification Group (Safety Population) 
 14.3.5.2 
Treatment-Emergent SAE by System Organ Class and Preferred Term for Icatibant 
Exposure Number 1 - Safety Population (Safety Population)  
 14.3.5.3 
Treatment-Emergent SAE by Icatibant Exposure Number, System Organ Class, and 
Preferred Term for Icatibant Exposure Number 2 and 3 - Safety Population (Safety 
Population)  
 14.3.6.1 
Injection Site Reactions (ISR) for Icatibant Exposure Number 1 (Safety Population)  
 14.3.6.2 
Injection Site Reactions (ISR) by Icatibant Exposure Number for Icatibant Exposure 
Number 2 and 3 (Safety Population)  
 14.3.6.3 
Injection Site Reactions by Severity and Study Time Point for Icatibant Exposure 
Number 1 (Safety Population)  
 14.3.6.4 
Injection Site Reactions by Icatibant Exposure Number, Severity, and Study Time Point 
for Icatibant Exposure 2 and 3 (Safety Population)  
 14.3.7.1 
Anti-Icatibant Antibodies for Icatibant Exposure Number (Safety Population)  
 14.3.7.2 
Anti-Icatibant Antibodies by Icatibant Exposure Number for Icatibant Exposure Number 
2 and 3 (Safety Population)  
 14.3.8.1 
Serum Chemistry Laboratory Values: Actual Value and Change from Pre-treatment by 
Study Time Point for Icatibant Exposure Number 1 (Safety Population)  
 14.3.8.2 
Serum Chemistry Laboratory Values: Actual Value and Change from Pre-treatment by 
Icatibant Exposure Number and Study Time Point for Icatibant Exposure Number 2 and 
3 (Safety Population)  
 14.3.8.3 
Serum Chemistry Laboratory Values: Categorical Clinical Laboratory Results for 
Icatibant Exposure Number 1 (Safety Population)  
 14.3.8.4 
Serum Chemistry Laboratory Values: Categorical Clinical Laboratory Results by 
Icatibant Exposure Number for Icatibant Exposure Number 2 and 3 (Safety Population)  
 14.3.9.1 
Hematology Laboratory Values: Actual Value and Change from Pre-treatment by Study 
Time Point for Icatibant Exposure Number 1 (Safety Population)  
 14.3.9.2 
Hematology Laboratory Values: Actual Value and Change from Pre-treatment by 


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Table  
Table Title  
Icatibant Exposure Number and Study Time Point for Icatibant Exposure Number 2 and 
3 (Safety Population)  
 14.3.9.3 
Hematology Laboratory Values: Categorical Clinical Laboratory Results for Icatibant 
Exposure Number 1 (Safety Population)  
 14.3.9.4 
Hematology Laboratory Values: Categorical Clinical Laboratory Results by Icatibant 
Exposure Number for Icatibant Exposure Number 2 and 3 (Safety Population)  
 14.3.10.1 
Urinalysis Values: Actual Value and Change from Pre-treatment by Study Time Point for 
Icatibant Exposure Number 1 (Safety Population)  
 14.3.10.2 
Urinalysis Values: Actual Value and Change from Pre-treatment by Icatibant Exposure 
Number and Study Time Point for Icatibant Exposure Number 2 and 3 (Safety 
Population)  
 14.3.10.3 
Urinalysis Values: Categorical Clinical Laboratory Results for Icatibant Exposure 
Number 1 (Safety Population)  
 14.3.10.4 
Urinalysis Values: Categorical Clinical Laboratory Results by Icatibant Exposure 
Number for Icatibant Exposure Number 2 and 3 (Safety Population)  
 14.3.11.1 
ECG Results by Study Time point for Icatibant Exposure Number 1 (Safety Population)  
 14.3.11.2 
ECG Results by Study Time point by Icatibant Exposure Number for Icatibant Exposure 
Number 2 and 3 (Safety Population)  
 14.3.12.1 
Vital Signs: Actual Value and Change from Pre-treatment by Study Time point for 
Icatibant Exposure Number 1 (Safety Population)  
 14.3.12.2 
Vital Signs: Actual Value and Change from Pre-treatment by Icatibant Exposurue 
Number and Study Time point for Icatibant Exposure Number 2 and 3 (Safety 
Population)  
 14.3.13.1 
Reproductive Hormone Assessments (Males): Actual Value and Change from Pre-
treatment by Study Time point for Icatibant Exposure Number 1 (Safety Population)  
 14.3.13.2 
Reproductive Hormone Assessments (Males): Actual Value and Change from Pre-
treatment by Icatibant Exposure Number and Study Time point for Icatibant Exposure 
Number 2 and 3 (Safety Population)  
 14.3.13.3 
Reproductive Hormone Assessments (Males): Categorized According to Reference 
Ranges by Study Time point for Icatibant Exposure Number 1 (Safety Population)  
 14.3.13.4 
Reproductive Hormone Assessments (Males): Categorized According to Reference 
Ranges by Icatibant Exposure Number and Study Time point for Icatibant Exposure 
Number 2 and 3 (Safety Population)  
 14.3.13.5 
Reproductive Hormone Assessments (Females): Actual Value and Change from Pre-
treatment by Study Time point for Icatibant Exposure Number 1 (Safety Population)  
 14.3.13.6 
Reproductive Hormone Assessments (Females): Actual Value and Change from Pre-
treatment by Icatibant Exposure Number and Study Time point for Icatibant Exposure 
Number 2 and 3 (Safety Population)  
 14.3.13.7 
Reproductive Hormone Assessments (Females): Categorized According to Reference 
Ranges by Study Time point for Icatibant Exposure Number 1 (Safety Population)  
 14.3.13.8 
Reproductive Hormone Assessments (Females): Categorized According to Reference 
Ranges by Icatibant Exposure Number and Study Time point for Icatibant Exposure 
Number 2 and 3 (Safety Population)  
 
 
 




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 List of Data Listings 
10.1.3
Listings 
Data Listing Heading 
16.2.1.1 
Subject Disposition – Safety Population 
16.2.1.2 
Inclusion/Exclusion Criteria - All Population 
16.2.2 
Protocol Deviations – All Subjects 
16.2.4.1 
Demographic and Pre-treatment Characteristics - Safety Population 
16.2.4.2.1 
Medical History – Safety Population 
16.2.4.2.2 
HAE History – Safety Population 
16.2.4.3.1 
Concomitant Medications Other than Rescue Medication – Efficacy 
Population 
16.2.4.3.2 
Concomitant Medications Other than Rescue Medication - Safety Population 
16.2.4.4.1 
Rescue Medication - Efficacy Population 
16.2.4.4.2 
Rescue Medication - Safety Population 
16.2.4.5 
Details of Attack – Efficacy Population 
16.2.5  
Study Drug Administration – Safety Population 
16.2.6.1 
Symptom Score Assessed by Investigator – Efficacy Population 
16.2.6.2 
FLACC – Efficacy Population 
16.2.6.3 
FPS-R – Efficacy Population 
16.2.6.4 
Initial Symptom Relief Assessed by Investigator - Efficacy Population 
16.2.7.1 
Pre-Treatment Adverse Events - Safety Population 
16.2.7.2 
Treatment-Emergent Adverse Events - Safety Population 
16.2.7.3 
Treatment-Emergent Serious Adverse Events - Safety Population 
16.2.7.4 
Treatment-emergent Adverse Events Resulted in Study Discontinuation – 
Safety Population 
16.2.7.5 
Serious Adverse Events – All Subjects 
16.2.7.6 
Local Tolerability Assessed by Investigator – Safety Population 
16.2.8.2.1 
Clinical Laboratory Evaluations – Hematology - Safety Population 
16.2.8.2.2 
Abnormal Laboratory Values – Hematology - Safety Population 
16.2.8.3.1 
Clinical Laboratory Evaluations – Chemistry - Safety Population 
16.2.8.3.2 
Abnormal Laboratory Values – Chemistry - Safety Population 
16.2.8.4.1 
Clinical Laboratory Evaluations – Urinalysis - Safety Population 
16.2.8.4.2 
Abnormal Laboratory Values – Urinalysis - Safety Population 
16.2.8.5.1 
Reproductive Hormone Assessments - Safety Population 
16.2.8.5.2 
Reproductive Hormone Assessments deemed Abnormal - Safety Population 
16.2.8.6 
Urine Pregnancy Test (Females Only) - Safety Population 
16.2.8.7 
Immunogenicity - Safety Population 
16.2.8.8.1 
Electrocardiogram Data- Safety Population 
16.2.8.8.2 
Abnormal Electrocardiogram Data - Safety Population 
16.2.8.9 
Vital Signs - Safety Population 
16.2.8.10 
Menstrual Cycle History (Pubertal/Post-pubertal Females Only) - Safety 
Population 


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APPENDIX II:  Definitions and Programming Conventions 
10.2
 
Age Calculation       
 
10.2.1
Age will be calculated as the date of study drug administration minus the date of birth and 
displayed rounded to one decimal place.   
If the date of birth is not complete (i.e., contains only partial information such as month and 
year or only year), then the non-missing date parts will be used to calculate the subject’s age. 
If the date of birth is completely missing, then the age reported in the clinical database will be 
used as the subject’s age. 
 
BMI Calculation         
10.2.2
BMI will be calculated using the standard formula (below) and displayed rounded to one 
decimal place. 
BMI (kg/m2) = (body weight in kilograms) / (height in meters)2 
 
Weight and Height Percentile Calculation 
10.2.3
Weight and height will be converted to percentiles using CDC growth charts based on the 
subject’s sex and age. 
 
Time-to-Event Endpoints 
10.2.4
Time-to-event endpoints will be calculated from the time of study drug administration to the 
earliest time point at which endpoint is achieved. The actual study drug administration date 
and time, and the first assessment date and time at which at the endpoint criteria is satisfied 
will be used for this calculation.  
 
Study Day of an Event 
10.2.5
Study day is calculated as the date of event of interest – date of treatment + 1 for dates on or 
after treatment, and date of event of interest – date of treatment for dates prior to treatment.   
 
Duration of an Event 
10.2.6
The duration of an event is calculated as the event stop date/time – event start date/time if 
time is not missing, and event stop date – event start date + 1 if either the start or stop time is 
missing. 
 Attribution of Concomitant Medications  
10.2.7
For subjects treated with study drug for more than once during the study, concomitant 
medications will be programmatically assigned to the appropriate attack(s) by comparing the 
reported dates and times of study drug administration for all exposures with that of start and 


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end dates and times of concomitant medication.  Medications will be assigned to the study 
drug administration(s) for which the concomitant medication was administered during the 5-
day interval after the study drug administration.  
If the concomitant medication start time is missing, but the concomitant medication start date 
is the same as a dosing date, then the concomitant medication will be attributed to the attack 
that was dosed on that day. 
 Calculating Years since Diagnosis and Months since Last Attack with Partial Dates 
10.2.8
For the calculation of durations using dates with a missing day component, but non-missing month and 
year components, the date will be assumed to occur at the first of the month.   For the calculation of 
durations using dates with missing day and month components, but a non-missing year component, the 
date will be assumed to occur at the first of the year.  If the year component is missing the duration 
will be missing. 
 Handling of Missing Individual Symptom Assessment at Baseline 
10.2.9
If an individual symptom assessment was missing at baseline before an on-study icatibant 
exposure, then the missing symptom assessment will be considered as the mean of other 
individual symptom severity in the calculation of the composite symptom severity at baseline. 
 Deriving Time to First Use of Rescue Medication for Subjects with Missing Time to 
10.2.10
Onset of Symptom Relief 
Subjects with missing pretreatment symptom assessments would be excluded from the time to 
onset of symptom relief analysis. If a subject was excluded from the time to onset of symptom 
relief analysis, but received a rescue medication within 48+4 hours after an on-study icatibant 
exposure, then the time between the icatibant treatment and the first rescue treatment use 
would be considered as time to first use of rescue medication. 
 
Attribution of AEs  
10.2.11
For subjects treated with study drug for more than one attack during the study, adverse events 
will be programmatically assigned to the appropriate attack by comparing the reported dates 
and times of first study drug administration for all attacks with that of AE onset.  Events will 
be assigned to the latest attack for which the study drug administration preceded the AE onset.  
If the adverse event start time is missing, but the adverse event start date is the same as a 
dosing date, then the adverse event will be attributed to the attack that was dosed on that day. 
 Handling of Missing Data for Adverse Events 
10.2.12
For the analysis of AEs, the following assumptions will be applied. 
 If the AE severity is missing, it will be assumed that the AE was severe. 
 If the AE relationship is missing, it will be assumed that the AE was definitely related 
to study drug. 
 


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 Handling of Immunogenicity Data for the Second and Third Study Drug Exposure 
10.2.13
Combined Visits 
In case of combined study visits according to scheduled visit dataset, immunogenicity data 
supporting two combined visits will be programmatically copied to both visits.  
Baseline 
The baseline measurements for immunogenicity data for the subsequent exposures were 
collected every six months, regardless of the dates of icatibant exposures. Therefore, the last 
non-missing baseline immunogenicity measurement that was prior to a post-baseline 
measurement will be considered as the baseline measurement for that post-baseline 
measurement. 
 Defining Rescue Medications 
10.2.14
Rescue medications are the medications that were 
1. Recorded as rescue medication in the CRF form, started within 48+4 hours (or 3 days 
where the time is missing) of a study drug exposure for an HAE attack, 
or, 
2. Recorded as concomitant medication in the CRF form, started within 48+4 hours (or 3 
days where the time is missing) after a study drug exposure, is not ongoing, and had 
an indication that include ‘HAE’ or ‘Swelling’. 




















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Study Schedule of Events (Subsequent Icatibant-treated Attacks)   
10.3.3
Subsequent 
Icatibant-
Treated 
Attack 
Baseline a 
(Site) 
Every 
Month  
after 
Baseline 
(Home)b 
Treatment 
Post Treatment 
Day 1 
(Site or Home) 
Day 2 
(Home) 
Day 8 
(±1)c 
(Site) 
Day 90 
(±7)c 
(Site) 
Time Post Treatment (hours) 
 
 
Prior to 
Dosing 
0 
1  
2  
6-8 
24  
 
 
Window (hours or minutes) 
 
 
 
 
(±10) min (±10) min (±4) hr (±4) hr 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Assessment 
X 
X 
 
 
 
 
 
 
 
 
Menstrual Cycle History 
X 
 
 
 
 
 
 
 
 
X 
Documentation of HAE Attack(s) Not Treated with 
icatibant 
X 
X 
 
 
 
 
 
 
 
X 
Physical Examination  
X 
 
 
 
 
 
 
 
 
X  
Vital Signs 
X 
 
 
 
 
 
 
 
X 
X 
Height and Weight 
X 
 
 
 
 
 
 
 
 
X 
Clinical Laboratory Tests (serum chemistry/hematology) 
X 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy Test (in females of childbearing 
potential) 
X 
 
X 
 
 
 
 
 
 
X 
Reproductive Hormone Assessments (FSH, LH, 
estradiol, progesterone in females; FSH, LH, testosterone 
in males) 
X 
 
 
 
 
 
 
 
X 
X 
Immunogenicity Evaluation 
X 
 
 
 
 
 
 
 
X 
X 
Training on icatibant administration d 
X 
 
 
 
 
 
 
 
 
 
Training on how to assess HAE symptoms, time to initial 
symptom relief, and injection site reactions d 
X 
 
 
 
 
 
 
 
 
 
Dispense 1 syringe of icatibant d 
X 
 
 
 
 
 
 
 
 
 
Contact investigator with weight to confirm dose d 
 
X 
 
 
 
 
 
 
 
 
Contact investigator in the event of an HAE attack 
 
 
Xb 
 
 
 
 
 
 
 
Investigational Product Administration (single SC dose) 
 
 
 
Xe 
 
 
 
 
 
 
Subject Self-assessment of HAE-related Pain Using FPS-
R 
 
 
X 
 
X 
Xf 
Xf 
X 
 
 
Investigator Assessment of HAE Symptoms 
 
 
Xg 
 
Xg,h 
Xg,h 
Xg,h 
 
 
 


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Subsequent 
Icatibant-
Treated 
Attack 
Baseline a 
(Site) 
Every 
Month  
after 
Baseline 
(Home)b 
Treatment 
Post Treatment 
Day 1 
(Site or Home) 
Day 2 
(Home) 
Day 8 
(±1)c 
(Site) 
Day 90 
(±7)c 
(Site) 
Time Post Treatment (hours) 
 
 
Prior to 
Dosing 
0 
1  
2  
6-8 
24  
 
 
Window (hours or minutes) 
 
 
 
 
(±10) min (±10) min (±4) hr (±4) hr 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
Home Healthcare Provider or Parent/Legal 
Guardian/Caregiver Assessment of HAE Symptoms 
 
 
X 
 
Xh 
Xh 
Xh 
 
 
 
Record Injection Site Reactions  
 
 
 
 
Xb, i 
Xb, i 
Xb, i 
Xe 
X 
 
Safety Follow-up Contact 
 
 
 
 
 
 
Xb 
 
 
 
Concomitant Medications 
X 
X 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
X 
X 
Adverse Events  
X 
X 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
X 
X 
Return study drugd 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: FPS-R=Faces Pain Scale-Revised; FSH=follicle stimulating hormone; HAE=hereditary angioedema; LH=luteinizing hormone; SC = 
subcutaneous 
a 
All evaluations and sample collections must be performed at the hospital/study center within 6 months prior to treatment if a repeat attack does not 
occur within 6 months.  If a second “baseline” visit is conducted due to lack of repeat attacks, one of the monthly phone calls may overlap with the 
onsite visit.  In this case, a monthly call would not be necessary.   
b 
These assessments may be conducted by telephone contact. 
c 
If a subsequent attack occurs within 3 days of the Day 8 follow-up visit for the previous attack, the visits for Day 1 (of the subsequent icatibant-treated 
attack) and Day 8 (of the prior icatibant-treated attack) will be combined.  If a subsequent attack occurs within 7 days of the Day 90 follow-up visit for 
the previous attack, the visits for Day 8 (of the subsequent icatibant-treated attack) and Day 90 (of the prior icatibant-treated attack) will be combined. 
d 
For subjects who have expressed an interest in self-administering or having a parent/legal guardian/caregiver administer icatibant in the home. 
e 
For subsequent attacks, study drug may be administered by study site personnel at the hospital/study center or by qualified home healthcare personnel 
at the subject’s home.  Alternatively, a parent/legal guardian/caregiver will be allowed to administer or the subject (under the supervision of a 
parent/legal guardian/caregiver) will be allowed to self-administer the investigational product after having received appropriate training.  For all 
subsequent laryngeal attacks, subjects should be advised to seek medical attention in an appropriate healthcare facility immediately following treatment 
with icatibant. 
f 
If after the completion of the assessments scheduled for 2 hours post-treatment, the subject’s pain is absent, no further Day 1 assessments are required.  
If the subject’s pain at 2 hours post-treatment is NOT absent, the subject will be assessed every 2 hours until pain is absent. 
g 
For subjects treated at the hospital/study center only. 


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h 
The subject will be observed for a minimum of 2 hours after icatibant administration.  If after the completion of the assessments scheduled for 2 hours 
post-treatment, the subject’s symptoms are absent or mild, no further Day 1 assessments are required.  If the subject’s symptoms at 2 hours post-
treatment are moderate, severe, or very severe, the subject will be assessed every 2 hours until the subject’s symptoms are absent or mild. 
i 
Injection site reaction will be recorded (1 hour [±10 minutes] post dose and 2 [±0.5] hours post dose, and every 2 [±0.5] hours until injection site 
reaction is mild or absent (if the subject’s injection site reaction is not mild or absent at 2 hours post dose)