Conditions: Hereditary Angioedema
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
The main aim of the study is to check for side effects from icatibant in children and teenagers with hereditary angioedema (HAE). Other aims are to check how well icatibant controls HAE symptoms in these children and teenagers, and how much icatibant stays in their blood.

At the first visit, the study doctor will check if each child or teenager can take part. For those who can take part, participants and their parents or caregivers will visit the clinic or hospital when they have their next HAE attack. Participants will receive 1 injection (shot) of icatibant in a vein and will stay at the clinic or hospital until their HAE symptoms are under control. Participants can receive up to 2 more injections of icatibant over time if their HAE symptoms don't improve or get worse.

After the participants go home, the study staff will follow up with them by a telephone call 1 to 2 days later. Then, the participants will visit the clinic or hospital 1 week after they received the icatabant injection.

The participant can visit the clinic or hospital and be treated with icatibant in the same way for up to 3 HAE attacks in total.

Detailed description:
The drug being tested in this study is called TAK-667. TAK-667 is being tested to treat Japanese Children and Adolescents who experience acute attack of HAE. This study will look at safety, efficacy and pharmacokinetics (PK) of people who take TAK-667.

The study will enroll at least up to 3 participants. Participants will take TAK-667 with SC administration on the abdomen. The dose of TAK-667 will be dependent on the participant's body weight (Up to 30 mg; 10 mg for 12 kg to 25 kg, 15 mg for 26 kg to 40 kg, 20 mg for 41 kg to 50kg, 25 mg for 51 kg to 65 kg, 30 mg for \>65 kg).

This multi-center trial will be conducted in Japan. The overall time to participate in this study is 25 days as a maximum (screening day for initial attack plus 8 days post dose for each 3 attacks as a maximum). Participants will make multiple visits to the clinic and will be closely monitored in the hospital/study center for at least 8 hours after administration and receive physical examination and assessment to evaluate safety, efficacy and PK. Hospitalization may be prolonged until, in the opinion of the investigator, the participant is clinically stable and onset of HAE attack is completely resolved.

Arms:
arm 1: TAK-667, single SC administration on the abdomen on Day 1. The dose of TAK-667 will be dependent on the participant's body weight (Up to 30 mg; 10 mg for 12 kg to 25 kg, 15 mg for 26 kg to 40 kg, 20 mg for 41 kg to 50kg, 25 mg for 51 kg to 65 kg, 30 mg for \>65 kg).

Interventions: intervention 1: TAK-667
Intervention descriptions: intervention 1: TAK-667 single SC administration

Protocol document:
Prot_000.pdf: 
Title: A Multicenter, Open-Label, Non-randomized Phase 3 Study to Assess the Safety, 
Efficacy and Pharmacokinetics of Subcutaneous Administration of Icatibant (TAK-667) 
in Japanese Children and Adolescents with Acute Attacks of Hereditary Angioedema 
NCT Number: NCT04654351 
Protocol Approve Date: 21-DEC-2020 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered
confidential information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners,
personal information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


 
 
 
TAKEDA PHARMACEUTICALS 
PROTOCOL 
 
A Multicenter, Open-Label, Non-randomized Phase 3 Study to Assess the Safety, Efficacy 
and Pharmacokinetics of Subcutaneous Administration of Icatibant (TAK-667) in Japanese 
Children and Adolescents with Acute Attacks of Hereditary Angioedema 
 
An Open-Label, Phase 3 Study of Icatibant (TAK-667) in Japanese Children and 
Adolescents with Acute Attacks of Hereditary Angioedema 
 
 
 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka, Japan 
Study Number: 
TAK-667-3001 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
TAK-667 
Date: 
21 December 2020 
Amendment Number: 1 
 
Amendment History:  
Date 
Amendment 
Number 
Region 
19 October 2020 
Initial version 
All sites 
21 December 2020 
Amendment No.1 
All sites 
 
 
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1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
See the annexes. 
1.2 
Principles of Clinical Studies 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this study protocol and also in accordance with the following: 
x The ethical principles that have their origin in the Declaration of Helsinki. 
x International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline. 
x All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 
 
SIGNATURES 
The signature of the responsible Takeda medical officer can be found on the signature page. 
Electronic Signatures are provided on the last page of this document. 
 
 
 
 
Date 
 
 
Date 
Date 
PPD
PPD
PPD
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol. 
• Terms outlined in the study site agreement. 
• Responsibilities of the Investigator. (Appendix B) 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Provence) 
Location of Facility (Country) 
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1.3 
Protocol Amendment 1 Summary of Changes 
This document describes the changes in reference to the Protocol Amendment No.1. 
The primary purpose of this amendment is to provide an additional example for the basis of 
medical judgement on the diagnosis of hereditary angioedema (HAE), and also to add description 
so that the information planned to be obtained will be clear. Minor grammatical and editorial 
changes are included for clarification purposes only. Full details on changes of text are given in 
Appendix G, including detailed rationale. The following is a summary of the changes made in the 
amendment: 
● “Information of genetic mutation” is added as an additional example for the basis of 
medical judgement on the diagnosis of HAE. 
● “Presence of previous icatibant administration” and “any clinically significant conditions 
or diseases relevant to treatment" are added so that the information planned to be obtained 
will be clear. 
● Clarification of representation in the original protocol. 
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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES ........................................................................................................................ 2 
1.1 
Contacts and Responsibilities of Study-Related Activities .......................................... 2 
1.2 
Principles of Clinical Studies ..................................................................................... 2 
1.3 
Protocol Amendment 1 Summary of Changes ............................................................ 4 
2.0 
STUDY SUMMARY .................................................................................................... 10 
3.0 
LIST OF ABBREVIATIONS ........................................................................................ 16 
4.0 
INTRODUCTION ......................................................................................................... 18 
4.1 
Background ............................................................................................................. 18 
4.2 
Rationale for the Proposed Study ............................................................................. 19 
4.3 
Benefit/Risk Profile ................................................................................................. 20 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 22 
5.1 
Objective ................................................................................................................. 22 
5.2 
Endpoints................................................................................................................. 22 
5.2.1 
Primary Endpoint ............................................................................................. 22 
5.2.2 
Secondary Endpoints ....................................................................................... 22 
6.0 
STUDY DESIGN AND DESCRIPTION ....................................................................... 24 
6.1 
Study Design ........................................................................................................... 24 
6.2 
Justification for Study Design, Dose, and Endpoints ................................................ 27 
6.3 
Premature Termination or Suspension of Study or Study Site ................................... 29 
6.3.1 
Criteria for Premature Termination or Suspension of the Study ........................ 29 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites ..................... 29 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites .............................................................................. 29 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS .............. 30 
7.1 
Inclusion Criteria ..................................................................................................... 30 
7.1.1 
Justification of Inclusion Criteria ..................................................................... 31 
7.2 
Exclusion Criteria .................................................................................................... 31 
7.2.1 
Justification of Exclusion Criteria .................................................................... 32 
7.3 
Excluded Medications, Procedures, and Treatments ................................................. 32 
7.3.1 
Justification of Excluded Medications .............................................................. 33 
7.4 
Activity Control and Treatment Facilities................................................................. 33 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject ........................................... 34 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject...................................... 35 
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8.0 
CLINICAL STUDY MATERIAL MANAGEMENT ..................................................... 36 
8.1 
Study Drug and Materials ........................................................................................ 36 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling .................................. 36 
8.1.1.1 
Study Drug .............................................................................................. 36 
8.1.2 
Storage ............................................................................................................ 36 
8.1.3 
Dose and Regimen ........................................................................................... 37 
8.1.3.1 
Self-Injection Training (Optional; for Subjects Who Will 
Self-Administer Icatibant Only) ............................................................... 38 
8.1.4 
Overdose ......................................................................................................... 38 
8.2 
Study Drug Assignment and Dispensing Procedures ................................................ 38 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs ..................................... 38 
9.0 
STUDY PLAN .............................................................................................................. 39 
9.1 
Study Procedures ..................................................................................................... 39 
9.1.1 
Informed Consent and Assent Procedure .......................................................... 39 
9.1.2 
Demographics, Medical History, and Medication History Procedure ................ 39 
9.1.3 
Physical Examination Procedure ...................................................................... 39 
9.1.4 
Weight, Height ................................................................................................ 39 
9.1.5 
Vital Sign Procedure ........................................................................................ 40 
9.1.6 
Medical History of HAE / Current HAE Attack ............................................... 40 
9.1.7 
Menstrual Cycle History .................................................................................. 40 
9.1.8 
Pubertal Status Determination .......................................................................... 41 
9.1.9 
Primary Efficacy Measurement ........................................................................ 41 
9.1.9.1 
Investigator or Subinvestigator Symptom Score ....................................... 41 
9.1.9.2 
Subject Self-assessment of Pain ............................................................... 42 
9.1.9.3 
Investigator or Subinvestigator Assessment of Pain ................................. 42 
9.1.9.4 
Initial Symptom Improvement Reported by Investigator and Subject ....... 42 
9.1.10 
Self-Administration Assessment (Optional; for Subjects or Caregiver Who 
Will Self-Administer Icatibant Only) ............................................................... 42 
9.1.11 
Reproductive Hormone Assessments ............................................................... 42 
9.1.12 
Documentation of Concomitant Medications ................................................... 42 
9.1.13 
Documentation of Concurrent Medical Conditions........................................... 43 
9.1.14 
Procedures for Clinical Laboratory Samples .................................................... 43 
9.1.15 
Injection Site Reactions ................................................................................... 45 
9.1.16 
Immunogenicity Evaluation ............................................................................. 45 
9.1.17 
Contraception and Pregnancy Avoidance Procedure ........................................ 46 
9.1.18 
Pregnancy ........................................................................................................ 46 
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9.1.19 
ECG Procedure ................................................................................................ 47 
9.1.20 
Pharmacokinetic Sample Collection and Analysis ............................................ 47 
9.1.20.1 Collection of Plasma for Pharmacokinetic Sampling ................................ 47 
9.1.20.2 Bioanalytical Methods ............................................................................. 47 
9.1.21 
Documentation of Screen Failure ..................................................................... 48 
9.1.22 
Documentation of Study Entrance .................................................................... 48 
9.2 
Monitoring Subject Treatment Compliance .............................................................. 48 
9.3 
Schedule of Observations and Procedures ................................................................ 49 
9.3.1 
Screening ......................................................................................................... 49 
9.3.2 
Initial Icatibant-Treated Attack ........................................................................ 49 
9.3.2.1 
Study Entrance/Baseline (Day 1:Up to 3 hours before the start of study 
drug administration) ................................................................................ 49 
9.3.2.2 
After Treatment (Day 1) .......................................................................... 49 
9.3.2.3 
After Treatment (Day 2) .......................................................................... 50 
9.3.2.4 
Follow-up (Day 8) ................................................................................... 50 
9.3.3 
Subsequent Icatibant-Treated Attack ................................................................ 50 
9.3.3.1 
Study Entrance/Baseline (Day 1:Up to 3 hours before the start of study 
drug administration) ................................................................................ 50 
9.3.3.2 
After Treatment (Day 1 and Day 2) and Follow-up (Day 8) ..................... 50 
9.3.4 
Final Visit or Early Termination ...................................................................... 50 
9.3.5 
Post Study Care ............................................................................................... 51 
10.0 
ADVERSE EVENTS .................................................................................................... 52 
10.1 
Definitions ............................................................................................................... 52 
10.1.1 
AEs ................................................................................................................. 52 
10.1.2 
Additional Points to Consider for AEs ............................................................. 52 
10.1.3 
SAEs ............................................................................................................... 54 
10.1.4 
AEs of Special Interest..................................................................................... 55 
10.1.4.1 Injection Site Reaction ............................................................................. 55 
10.1.4.2 Immunogenicity (Hypersensitivity) .......................................................... 56 
10.1.4.3 Reproductive Hormone Level in Pubertal/ Post-Pubertal Children ........... 56 
10.1.4.4 Hypotension and Cardiac Dysfunction ..................................................... 56 
10.1.5 
Intensity of AEs ............................................................................................... 56 
10.1.6 
Causality of AEs .............................................................................................. 57 
10.1.7 
Relationship to Study Procedures ..................................................................... 57 
10.1.8 
Start Date and Time ......................................................................................... 57 
10.1.9 
Stop Date and Time ......................................................................................... 58 
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10.1.10 Frequency ........................................................................................................ 58 
10.1.11 Action Concerning Study Drug ........................................................................ 58 
10.1.12 Outcome .......................................................................................................... 58 
10.1.13 Product Complaints ......................................................................................... 59 
10.2 
Procedures ............................................................................................................... 59 
10.2.1 
Collection and Reporting of AEs ..................................................................... 59 
10.2.1.1 AE Collection Period ............................................................................... 59 
10.2.1.2 AE Reporting........................................................................................... 59 
10.2.1.3 AEs of Special Interest ............................................................................ 60 
10.2.2 
Collection and Reporting of SAEs ................................................................... 60 
10.2.3 
Reporting of Abnormal Liver Function Tests ................................................... 61 
10.3 
Follow-up of SAEs .................................................................................................. 61 
10.3.1 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities................ 61 
11.0 
STUDY-SPECIFIC COMMITTEES ............................................................................. 62 
12.0 
DATA HANDLING AND RECORDKEEPING ............................................................ 63 
12.1 
CRFs (Electronic) .................................................................................................... 63 
12.2 
Record Retention ..................................................................................................... 63 
13.0 
STATISTICAL METHODS .......................................................................................... 65 
13.1 
Statistical and Analytical Plans ................................................................................ 65 
13.1.1 
Analysis Sets ................................................................................................... 65 
13.1.1.1 Safty Analysis Sets .................................................................................. 65 
13.1.1.2 Full Analysis Set...................................................................................... 65 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ......................... 65 
13.1.3 
Efficacy Analysis ............................................................................................. 65 
13.1.4 
Pharmacokinetic Analysis ................................................................................ 66 
13.1.5 
Safety Analysis ................................................................................................ 67 
13.2 
Interim Analysis and Criteria for Early Termination ................................................ 68 
13.3 
Determination of Sample Size .................................................................................. 68 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE............................................... 69 
14.1 
Study-Site Monitoring Visits ................................................................................... 69 
14.2 
Protocol Deviations.................................................................................................. 69 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................ 69 
15.0 
ETHICAL ASPECTS OF THE STUDY ........................................................................ 71 
15.1 
IRB Approval .......................................................................................................... 71 
15.2 
Subject Information, Informed Consent/Assent, and Subject Authorization .............. 71 
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15.3
Subject Confidentiality ............................................................................................ 73
15.4
Publication, Disclosure, and Clinical Trial Registration Policy ................................. 73
15.4.1
Publication and Disclosure ............................................................................... 73
15.4.2
Clinical Trial Registration ................................................................................ 74
15.4.3
Clinical Trial Results Disclosure ...................................................................... 74
15.5
Insurance and Compensation for Injury .................................................................... 74
16.0
REFERENCES .............................................................................................................. 75
 
LIST OF IN-TEXT TABLES 
Table 8.a
Dosage ............................................................................................................... 37
Table 9.a
Clinical Laboratory Tests ................................................................................... 44
Table 9.b
Severity Scoring for Injection Site Reactions...................................................... 45
Table 10.a
Takeda Medically Significant AE List ................................................................ 55
 
LIST OF IN-TEXT FIGURES 
Figure 6.a
Schematic of Study Design ................................................................................ 26
 
LIST OF APPENDICES 
Appendix A
 76
Appendix B
 89
Appendix C
 90
Appendix D
 91
Appendix E
 93
Appendix F
 94
Appendix G
 95
 
CCI
CCI
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CCI
CCI
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2.0 
STUDY SUMMARY 
Name of Sponsoren: 
Takeda Pharmaceutical Company Limited 
Compound: 
TAK-667 
Title of Protocol:  
A Multicenter, Open-Label, Non-randomized, Phase 3 
Study to Assess the Safety, Efficacy and Pharmacokinetics 
of Subcutaneous Administration of Icatibant (TAK-667) in 
Japanese Children and Adolescents with Acute Attacks of 
Hereditary Angioedema 
IND No.:  
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Number: TAK-667-3001 
Phase: 3 
Study Design: 
This is a multicenter, open-label, phase 3 study to evaluate the safety, efficacy and pharmacokinetics (PK) of 
subcutaneous (SC) administration of icatibant in Japanese children and adolescents from 2 to less than 18 years of age 
with acute attacks of hereditary angioedema (HAE). 
Once informed consent is obtained and subject eligibility is established at screening, subjects will begin to receive 
treatment with icatibant after they present with an acute attack of cutaneous, abdominal, or laryngeal edema. The 
region and severity of the attack is assessed by investigators. 
Subjects eligible at pre-treatment physical examination and assessment will receive treatment with single-dose SC 
administration of icatibant per attack according to the subject’s body weight within 12 hours after the onset of 
symptom. Up to 2 additional injections are permitted per attack with a time interval of at least 6 hours within 48 hours 
of the initial injection if there is insufficient relief or worsening of symptoms. If symptoms get worse or recur after 
more than 48 hours of the initial administration, it will be considered as a new attack. Icatibant will be administered by 
a healthcare professional, or be self-administered by the subject or the subject’s caregiver, e.g. the subject’s family, at 
the study site under the supervision of a healthcare professional. In the case that icatibant is administered by whom 
other than healthcare professionals, if the subject and his/her legal guardian agree and the investigator considers it 
appropriate after the subject receives education and training, the patient or his/her caregiver, e.g. the subject’s family, 
will be allowed to self-administer icatibant under the supervision of a healthcare professional. 
Subjects will be closely monitored in the hospital/study center for at least 8 hours after administration and receive 
physical examination and assessment to evaluate safety, efficacy and PK. Hospitalization may be prolonged until, in 
the opinion of the investigator, the subject is clinically stable and onset of HAE attack is completely resolved. 
After discharge, follow-up to assess the subject’s condition at >24-48 hours after the final administration (Day 2) will 
be conducted via a telephone call by investigators and follow-up of safety assessment will be conducted 7 days after 
initial administration of icatibant (Day 8) at the study site. 
After having received initial treatment with icatibant, subjects who subsequently experience acute attacks may 
continue to receive treatment with icatibant for a total of 3 eligible icatibant-treated attacks if the subject and the 
subject’s parent or the subject’s legal guardian consent to further treatment. Further treatment with icatibant is 
contingent upon presentation of an acute cutaneous, abdominal, or laryngeal edema attack of HAE at least 7 days after 
first treatment for a prior attack. The new attack of within less than 7 days after first treatment for a prior attack should 
be treated in accordance with standard of care for HAE without being administrated icatibant. Except for PK 
assessment, all outcomes are to be measured after each attack as with the initial attack.  
The period of active participation in the study may depend on the number of subsequent treatment and thus could be a 
maximum of approximately 25 days. 
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Objective: 
To evaluate the safety, efficacy and PK of icatibant for the treatment of acute attacks in Japanese children and 
adolescents with type I or type II HAE. 
Subject Population:  
Japanese children and adolescents from 2 through <18 years of age who present with cutaneous, abdominal, or 
laryngeal attacks of acute HAE 
Number of Subjects: 
At least 3 subjects* 
* The enrollment will be continued until the end of the 
enrollment period and the sample size may exceed 3 
subjects. 
Number of Sites:  
4 sites 
Dose Levels: 
Regimen; A single, SC administration on the abdomen. If 
there is insufficient relief or worsening of symptoms, up to 
2 additional injections are permitted per attack with a time 
interval of at least 6 hours within 48 hours of the initial 
injection. 
Dosage; According to the table below, subjects will receive 
icatibant based on the subject’s body weight. (Up to 30 mg) 
 
Subsequent treatment with icatibant for up to 2 additional 
acute attacks of HAE, for a total of 3 acute attacks, will be 
offered to subjects who present with a new attack at least 7 
days after first treatment for a prior attack if the subject and 
the subject’s parent or the subject’s legal guardian consent 
to further treatment. The dose selection and interval for 
treatment of subsequent attacks will be the same as that for 
treatment of the initial attack. 
Weight Group 
Dose (Injection Volume) 
12 kg to 25 kg 
10 mg (1.0 mL) 
26 kg to 40 kg 
15 mg (1.5 mL) 
41 kg to 50kg 
20 mg (2.0 mL) 
51 kg to 65 kg 
25 mg (2.5 mL) 
>65 kg 
30 mg (3.0 mL) 
   
Route of Administration: 
SC injection 
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Duration of Treatment: 
Single administration 
Per attack, if necessary, up to 2 additional injections are 
permitted. 
 
Subjects may receive treatment with icatibant for a total of 3 
attacks.  
Period of Evaluation: 
• 
For the initial attack 
9 days: screening period (1 day), pre-treatment, 
treatment, and post-treatment (2 days), follow-up (7 
days after first treatment) 
• 
For the subsequent attacks (second attack and third 
attack) 
8 days: pre-treatment, treatment, and post-treatment (2 
days), follow-up (7 days after first treatment) 
 
The period of evaluation in the study may vary 
depending on the number of subsequent treatment and 
could be a maximum of approximately 25 days.  
Main Criteria for Inclusion: 
1. In the opinion of the investigator or subinvestigator, the subject’s parent or legal guardian is capable of 
understanding and complying with protocol requirements. 
2. The subject’s parent or the subject’s legal guardian is capable of signing and dating a written informed consent 
form on behalf of the subject prior to the initiation of any study procedures. Written informed assent is also 
obtained from the subject as much as possible. 
3. The subject is in Japan and is Japanese; defined as born in Japan and having Japanese parents and Japanese 
maternal and paternal grandparents. 
4. The subject is male or female and 2 to <18years of age (ie, from the second birthday through the day prior to the 
eighteenth birthday) at the time of informed consent. 
5. The subject weighs ≥12 kg at the time of the current HAE attack. 
6. The subject who has a documented and confirmed diagnosis of HAE type I or II. Diagnosis may be based on 
historical data using the following criteria: 
a. Family history of angioedema 
b. Characteristic attack manifestations, recurrent attacks 
c. Functional Complement 1 esterase inhibitor (C1-INH) deficiency 
d. In the absence of a family history of angioedema, exclusion of other forms of angioedema (eg. angiotensin 
converting enzyme (ACE)-induced angioedema, allergic angioedema) based on medical judgement (eg, 
concomitant medication, response to antihistamines or glucocorticoids, information of genetic mutation). 
7. If the subject does not have a documented and confirmed diagnosis of HAE type I or II based on historical data, 
including C1-INH deficiency, the subject’s diagnosis must be determined prior to treatment by C1-INH test 
results which demonstrate a functional C1-INH deficiency. 
a. HAE type I: Low amount of C1-INH protein and low level of C1-INH activity; HAE type II: Normal or 
increased amount of C1-INH protein and low level of C1-INH activity 
b. In the absence of a family history of angioedema, exclusion of other forms of angioedema (eg. ACE-induced 
angioedema, allergic angioedema ) based on medical judgement (eg, concomitant medication, response to 
antihistamines or glucocorticoids, information of genetic mutation). 
8. The current HAE attack must be in the cutaneous, abdominal, and/or laryngeal (inclusive of laryngeal and 
pharyngeal) areas, but no prespecified attack severity criteria are required for treatment. 
9. The subject commences treatment within 12 hours after the onset of current HAE attack. 
10. A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to use 
routinely adequate contraception from signing of informed consent throughout the duration of the study, and 
proves negative in the pregnancy test at screening. 
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Criteria for Exclusion: 
1. The subject will require an intervention to support the airway (eg, intubation, tracheotomy, cricothyrotomy) due 
to the current HAE attack. 
2. The subject presents with an HAE attack with laryngeal/upper respiratory tract symptoms which are considered 
severe in the investigator’s clinical judgment and which may necessitate urgent care and/or impede the conduct of 
study efficacy assessments. 
3. The subject has a diagnosis of angioedema other than HAE 
4. The subject has evidence of stroke or coronary artery disease based on medical history at the screening 
examination or at pretreatment; eg, acute ischemic heart disease, unstable angina pectoris, severe coronary heart 
disease or congestive heart failure, that in the investigator’s judgment would be a contraindication for 
participation in the trial (New York Heart Association [NYHA] class 3 and 4) 
5. The subject has received treatment with any pain medication since the onset of the current HAE attack. 
6. The subject has received replacement therapy (C1-INH products, fresh frozen plasma [FFP]) within 5 days (120 
hours) from the onset of the current HAE attack. 
7. The subject has received treatment with ACE inhibitors within 7 days prior to treatment. 
8. The subject has used hormonal contraceptive within 90 days prior to treatment. 
9. The subject has received androgen or attenuated androgens (eg, danazol, testosterone) within 90 days prior to 
treatment. 
10. The subject has participated in another clinical study within the past 30 days before screening. 
11. The subject, the subject’s parent, or legal guardian is unable to understand the nature, scope, and possible 
consequences of the protocol, or is unlikely to comply with the protocol assessments, unable to return for follow 
up visits, or unlikely to complete the study for any reason. 
12. If female, the subject is pregnant or lactating or intending to become pregnant before participating in this study, 
during the study, and within 30 days after last dose of icatibant. 
13. The subject has a history of hypersensitivity or allergies to icatibant. 
14. The subject is judged by the investigator as being ineligible for any other reason; eg. a serious concomitant illness 
or condition. 
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Criteria for Evaluation and Analyses: 
(1)Primary Endpoint 
<Safety> 
• 
Frequency and severity of treatment emergent adverse events (TEAEs), including injection site reactions 
(2)Secondary Endpoints 
<Safety> 
• 
Resting 12-lead electrocardiogram parameters in comparison to baseline 
• 
Vital sign measurements in comparison to baseline 
• 
Clinical laboratory parameters (serum chemistry, hematology and urinalysis) in comparison to baseline 
• 
Reproductive hormone levels in comparison to baseline 
• 
Immunogenicity (presence of anti-icatibant antibodies) in comparison to baseline 
<Efficacy> 
• 
Time to onset of symptom relief and time to minimal symptom, 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. 
 For subjects ≥4 to <18 years of age only: subject self-assessment of HAE-related pain using the Faces Pain 
Scale-Revised (FPS-R). 
 For subjects 2 to <4 years of age only: investigator assessment of HAE-related pain using the Faces, Legs, 
Activity, Cry, and Consolability (FLACC) scale. 
• 
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. 
• 
Time to initial symptom improvement reported by investigator or subject. 
<Pharmacokinetics> 
Plasma concentrations of icatibant and its major metabolites (M-I and M-II) at 0.5, 1.0, 2.0, and 4.0 hours after the first 
SC injection for an initial attack. 
Statistical Considerations: 
(1)Safety 
TEAE is defined as an AE that occurs on or after administration of icatibant for each attack and until the end of 
follow-up period (Day 8). TEAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology and tabulated by the system organ class (SOC) and the Preferred Term (PT), and by icatibant-treated 
attacks and the total. Injection site reactions will be summarized by severity, and by icatibant-treated attacks and the 
total, and by severity. 
For continuous values of laboratory parameters, vital signs and other safety parameters, summary statistics will be 
provided for observed values and change from baseline at each evaluation time point and icatibant-treated attack. Pre- 
and post-dose shift tables will be provided for categorical variables. 
(2)Efficacy 
All efficacy endpoints will be summarized by icatibant-treated attacks and listed. For the time-to-event endpoints, the 
survival function (e.g. proportion of subjects not achieving symptom relief) for each assessment time will be 
calculated by Kaplan-Meier method using the first icatibant-treated attacks within each subject. The second and third 
icatibant-treated attacks will be listed. Assuming independency in recurrent events within a subject, the survival 
function for each assessment time will be also calculated by Kaplan-Meier method. Due to the small sample size, no 
statistical inferences (statistical test nor confidence interval) will be performed. 
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(3)Pharmacokinetics 
Plasma concentrations of icatibant and its metabolites (M-I and M-II) will be summarized at each time point.  
Data collected in this study will be combined with those from global studies, and the population PK modeling and 
simulations will be performed. 
Individual pharmacokinetic parameters (e.g. Cmax and AUC) will be estimated by population PK analysis, if possible. 
Analysis plan and report of population pharmacokinetic analysis will be provided separately from the clinical study 
report. 
Sample Size Justification:  
The planned sample size chosen of 3 subjects administered icatibant in this study is based on the feasibility and is not 
statistically determined. 
 
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3.0 
LIST OF ABBREVIATIONS 
ACE 
angiotensin converting enzyme 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
aPTT 
activated partial thromboplastin time 
AUC 
area under the concentration-time curve 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
C1-INH 
complement 1 esterase inhibitor 
ECG 
12-Lead Electrocardiogram 
eCRF 
electronic case report form 
FPS-R 
Faces Pain Scale-Revised 
FLACC 
Faces, Legs, Activity, Cry, and Consolability 
FFP 
fresh frozen plasma 
FSH 
follicle stimulating hormone 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HAE 
hereditary angioedema 
hCG 
human chorionic gonadotropin 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
IRB 
institutional review board 
IgG 
immunoglobulin G 
LDH 
lactate dehydrogenase 
LH 
luteinizing hormone 
M&S 
Modeling & Simulation 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NYHA 
New York Heart Association 
PMDA 
Pharmaceuticals and Medical Devices Agency of Japan 
PT 
prothrombin time 
PT 
preferred Term 
QOL 
quality of life 
RMP 
risk management plan 
SAE 
serious adverse event 
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SC 
subcutaneous 
SUSARs 
suspected unexpected serious adverse reactions 
SOC 
system organ class 
TEAE 
treatment emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
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4.0 
INTRODUCTION 
4.1 
Background 
Hereditary angioedema (HAE) is an autosomal dominant, rare, inherited disorder characterized by 
repeated episodes of edema in various parts of the body, including the skin, gastrointestinal tract, 
and larynx, resulting from a quantitative deficiency/dysfunction of complement 1 (C1) esterase 
inhibitor (C1-INH) caused by mutations of the C1 INH gene and thereby-induced increase of the 
bradykinin concentration. Skin edema is characterized primarily by disfiguring swelling, and 
gastrointestinal edema is characterized by acute colicky abdominal pain with vomiting and 
diarrhea. Laryngeal edema is particularly severe and can result in asphyxiation due to upper airway 
obstruction. Attacks of HAE usually begin in childhood, increase in frequency and severity around 
puberty, and recur throughout the patient's life. The attack is induced by various factors, and in 
many cases, it suddenly appears without recognizing the clear inducers. Therefore, the patients are 
always forced to live with anxiety and fear of the attack, and the quality of life (QOL) remarkably 
lowers, and the social participation may become difficult. This is also true for children, especially 
those who experience attacks, who are prone to anxiety, have difficulty in daily life and schooling, 
and may experience further attacks. Children also have a smaller airway diameter, which increases 
more risks of asphyxiation due to a laryngeal attack. Thus, HAE is a serious and life-threatening 
disease that begins in childhood. 
The prevalence of HAE is estimated to be about 1 in 50,000, regardless of race [1]. Based on the 
estimated prevalence and the national population, the number of HAE patients in Japan is 
estimated to be about 2,500. However, the number of HAE patients actually reported is even 
smaller [2][3], and the number of patients diagnosed or treated is estimated to be around 400. The 
reason may be misdiagnosis due to the similar symptoms of HAE to other common angioedema, 
and the possibility that some patients may not be diagnosed due to insufficient recognition of the 
characteristics of the disease. 
As for the number of pediatric HAE patients in Japan, there have been no accurate reports to date. 
The number is estimated to be approximately 30 to 50 patients based on the population estimate in 
2020 (percentage of patients aged <15 years: 12.0%) and the percentage of children (aged 0 to 19 
years) among 171 Japanese HAE patients confirmed in the latest Japanese HAE survey (8.2%, 14 
patients) [3] and is extremely small compared to adults. 
As for the treatment for pediatric patients, multiple therapies for acute attack have been developed 
to date. On the other hand, there is no therapeutic drug for children in Japan, and the development 
of a drug for pediatric use is an urgent issue. 
Icatibant (Generic name: Icatibant Acetate), which is a synthetic decapeptide alleviates symptoms 
of acute attacks of HAE through a potent and specific competitive antagonism against bradykinin 
B2 receptor. In Japan, icatibant was approved in September 2018 as “Firazyr® Subcutaneous 
Injection 30 mg Syringe” for the indication of “acute attacks of hereditary angioedema” in adults. 
Overseas, it has been approved in approximately 40 countries as of July 2020, including the EU 
(approved in July 2008) and the US (approved in August 2011). In addition, development of 
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icatibant for pediatric use was initiated overseas and in October 2017, the indication related to 
“acute attacks of HAE in children aged 2 years and older” was approved in the EU, and icatibant 
has been approved in approximately 30 countries as of July 2020. 
Global phase 3 study in 98 adult patients with HAE (HGT-FIR-054), Japanese phase 3 study in 8 
adult patients with HAE (SHP-FIR-301), and global phase 3 study in 32 pediatric patients with 
HAE (HGT-FIR-086) were conducted as major clinical studies of icatibant in HAE patients. 
In the placebo-controlled, double-blind study in adult patients with HAE (HGT-FIR-054), in the 
subjects with cutaneous and/or abdominal edema, subjects treated with icatibant consistently had 
an earlier onset of symptom relief than those who received placebo. The median time to symptom 
relief was 2.0 hours in the icatibant group and 19.8 hours in the placebo group, showing that 
icatibant is superior to placebo (p <0.001). In the subjects with laryngeal edema, early symptom 
relief as seen in the non-laryngeal edema population was indicated. In Japanese open-label, 
uncontrolled study in 8 adult patients with HAE (SHP-FIR-301), the median time to symptom 
relief in all subjects was 1.75 hours, showing that the similar efficacy results as seen in the global 
study were obtained. In terms of safety, SC administration of icatibant was well tolerated in both 
studies. Although injection site reaction was observed as a common AE, it was mild or moderate in 
severity and generally transient.  
In the open-label, non-randomized study in pediatric patients aged 2 to <18 years with HAE 
(HGT-FIR-086), the median time to symptom relief in the efficacy analysis set was 1.0 hours, with 
approximately 60% and 95% of patients showing symptom relief at 1 and 2 hours post-dose, 
respectively. Icatibant was generally well tolerated, the safety profile was similar to that of adult 
patients and no new safety concern was observed.  
In the juvenile toxicity studies, the effects on hormone levels, reproductive organs, and sexual 
maturation in juvenile/immature rats and dogs repeatedly administered high doses of icatibant was 
observed. However, these findings were reversible and were less marked when icatibant was 
administered on an intermittent, clinically relevant dosing regimen. Furthermore, examination of 
effects on reproductive parameters in clinical studies demonstrated no effects of repeatedly 
administered icatibant on reproductive hormones, semen parameters, or menstrual cycle length. 
As described above, HAE is a serious and life-threatening disease that begins in childhood, but 
there is still no medication for children in Japan. Therefore, in order to meet the unmet needs for 
pediatric HAE medication in Japan,  pediatric development has been started with the aim of 
obtaining the pediatric dosage and administration of icatibant. 
4.2 
Rationale for the Proposed Study 
As of now, there are no clinical study data of the safety, efficacy and PK of icatibant in pediatric 
patients in Japan. Therefore, this study was designed to assess the safety, efficacy and PK of 
icatibant in the planned dosage and administration in pediatric patients in Japan. 
This protocol has been prepared in accordance with Good Clinical Practice (GCP). 
For conducting this study, the sponsor had the end of phase 2 meeting with the Pharmaceuticals 
and Medical Devices Agency of Japan (PMDA) on 
 
CCI
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4.3 
Benefit/Risk Profile 
The efficacy and safety of icatibant have been confirmed to be consistent in the global phase 3 
study in adult patients with HAE (HGT-FIR-054), global phase 3 study in pediatric patients with 
HAE (HGT-FIR-086) and Japanese phase 3 study in adult patients with HAE (SHP-FIR-301). 
The differences between the reference population, e.g. non-Japanese adult and pediatric patients 
and Japanese adult patients, and the target Japanese pediatric population are the ethnic factors and 
age (adults and children). Based on multiple researches, relevant guidelines in and outside of Japan 
and other pathological data, the disease pathophysiology, natural course, and disease course of 
HAE are considered to be similar between these ethnic groups and ages. An examination of the 
exposure-response relationships among the reference populations showed that ethnic and age 
differences had no substantial impact on the treatment response to icatibant, with similar treatment 
responses observed between non-Japanese and Japanese adult patients and between non-Japanese 
adult and pediatric patients. Therefore, favorable efficacy similar to that in non-Japanese adult and 
pediatric patients and Japanese adult patients is expected in Japanese pediatric patients. In addition, 
no specific safety risks to Japanese children are expected. 
The risks of icatibant identified in Japanese and EU risk management plan (RMP) are as follows. 
This study defines these as adverse events of special interest and is carefully monitored. 
• Injection site reaction – listed as important identified risk in Japan/EU RMP; Local injection 
site reactions were observed in almost all icatibant-treated subjects. Most injection site 
reactions were transient, mild to moderate in severity, and completely resolved within 4-8 
hours of treatment. Injection site reactions 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. 
• Immunogenicity (Hypersensitivity) – listed as important potential risk in Japan RMP; In 
clinical studies, icatibant was generally nonimmunogenic. In over repeated treatment, transient 
positivity in test results for the presence of anti-icatibant immunoglobulin G (IgG) antibodies 
was observed in rare cases. The immunogenicity of icatibant will be assessed. Serum samples 
for immunogenicity testing will be collected for determination of anti-icatibant antibodies. 
• Reproductive hormone level in pubertal/ post-pubertal children – listed as important potential 
risk in EU RMP; Although in the juvenile toxicity studies, the effects on hormone levels, 
reproductive organs, and sexual maturation in juvenile/immature rats and dogs was observed, 
no clinically significant changes in reproductive hormones were observed during global 
clinical studies in pediatric HAE patients. Blood samples will be collected to assess follicle 
stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone in females, 
and FSH, LH, and testosterone in males. 
• Hypotension and cardiac dysfunction – listed as important potential risk in Japan RMP; In 
vitro studies have shown that icatibant activates human mast cells and decrease of blood 
pressure was observed in a high-volume bolus intravenous injection study of icatibant. In 
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addition, the bradykinin antagonism of icatibant may pose a potential risk to patients with 
cardiovascular disease. Although no clinically significant hypotensive action and safety 
concerns for cardiovascular system was observed in clinical studies, hypotension and cardiac 
dysfunction will be assessed by standard safety testing including vital signs and ECG. 
The Investigator's Brochure should be referred for more detailed safety of icatibant. 
Based on the benefits that can be conferred to pediatric HAE subjects, as well as the risks and the 
appropriate measures to mitigate them, a favorable benefit-risk profile is expected for this 
population. 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objective 
To evaluate the safety, efficacy and PK of icatibant for the treatment of acute attacks in Japanese 
children and adolescents with type I or type II HAE. 
5.2 
Endpoints 
5.2.1 
Primary Endpoint 
Safety: 
• Frequency and severity of treatment-emergent adverse events (TEAEs), including injection 
site reactions 
5.2.2 
Secondary Endpoints 
Safety: 
• Resting 12-lead electrocardiogram parameters in comparison to baseline 
• Vital sign measurements in comparison to baseline 
• Clinical laboratory parameters (serum chemistry, hematology and urinalysis) in comparison to 
baseline 
• Reproductive hormone levels in comparison to baseline 
• Immunogenicity (presence of anti-icatibant antibodies) in comparison to baseline 
Efficacy: 
• Time to onset of symptom relief and time to minimal symptom, 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 symptom relief, defined as the duration of time in hours from the 
time of icatibant administration to the earliest time at which at least a 20% 
improvement is observed in the average post-treatment score with no worsening of any 
single component score. 
 The time to minimal symptoms, defined as the duration of time in hours from the time 
of icatibant administration to the earliest time post-treatment when all symptoms are 
either mild or absent based on the investigator-rated symptom score. 
 For subjects ≥4 to <18 years of age only: subject self-assessment of HAE-related pain 
using the Faces Pain Scale-Revised (FPS-R). 
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 The time to onset of symptom relief, defined as the duration of time in hours from the 
time of icatibant administration to the earliest time at which the post-treatment score 
improved by at least 1 level. 
 The time to minimal symptoms, defined as the duration of time in hours from the time 
of icatibant administration to the earliest time at which the post-treatment score 
improved to 0. 
 For subjects 2 to <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 symptom relief, defined as the earliest time at which a 20% 
improvement is observed in the total post-treatment score. 
 The time to minimal symptoms, defined as the duration of time in hours from the time 
of icatibant administration to the earliest time at which the total post-treatment score 
improved to 0. 
• 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. 
• Time to initial symptom improvement reported by investigator or subject 
 Time to initial symptom improvement reported by investigator, defined as the duration 
of time in hours from icatibant administration until the time when overall subject 
improvement was first noted by investigator.  
 Time to initial symptom improvement reported by subject, defined as the duration of 
time in hours from icatibant administration until the time when overall subject 
improvement was first noted by subject, subject’s parent or subject’s legal guardian. 
Pharmacokinetics: 
Plasma concentrations of icatibant and its major metabolites (M-I and M-II) at 0.5, 1.0, 2.0, and 4.0 
hours after the first SC injection for an initial attack. 
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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a multicenter, open-label, phase 3 study to evaluate the safety, efficacy and PK of SC 
administration of icatibant in Japanese children and adolescents from 2 to less than 18 years of age 
with acute attacks of HAE. 
Once informed consent is obtained and subject eligibility is established at screening, subjects will 
begin to receive treatment with icatibant after they present with an acute attack of cutaneous, 
abdominal, or laryngeal edema. The region and severity of the attack is assessed by investigators. 
Subjects eligible at pre-treatment physical examination and assessment will receive treatment with 
single-dose SC administration of icatibant per attack according to the subject’s body weight within 
12 hours after the onset of symptom. Up to 2 additional injections are permitted per attack with a 
time interval of at least 6 hours within 48 hours of the initial injection if there is insufficient relief 
or worsening of symptoms. If symptoms get worse or recur after more than 48 hours of the initial 
administration, it will be considered as a new attack. Icatibant will be administered by a healthcare 
professional, or be self-administered by the subject or the subject’s caregiver, e.g. the subject’s 
family, at the study site under the supervision of a healthcare professional. In the case that icatibant 
is administered by whom other than healthcare professionals, if the subject and his/her legal 
guardian agree and the investigator considers it appropriate after the subject receives education 
and training, the subject or his/her caregiver, e.g. the subject’s family, will be allowed to 
self-administer icatibant under the supervision of a healthcare professional. 
Subjects will be closely monitored in the hospital/study center for at least 8 hours after 
administration and receive physical examination and assessment to evaluate safety, efficacy and 
PK. Hospitalization may be prolonged until, in the opinion of the investigator, the subject is 
clinically stable and onset of HAE attack is completely resolved. 
After discharge, follow-up to assess the subject’s condition at >24-48 hours after the final 
administration (Day 2) will be conducted via a telephone call by investigators and follow-up of 
safety assessment will be conducted 7 days after initial administration of icatibant (Day 8) at the 
study site. 
After having received initial treatment with icatibant, subjects who subsequently experience acute 
attacks may continue to receive treatment with icatibant for a total of 3 eligible icatibant-treated 
attacks if the subject and the subject’s parent or the subject’s legal guardian consent to further 
treatment. Further treatment with icatibant is contingent upon presentation of an acute cutaneous, 
abdominal, or laryngeal edema attack of HAE at least 7 days after first treatment for a prior attack. 
The new attack of within less than 7 days after first treatment for a prior attack should be treated in 
accordance with standard of care for HAE without being administrated icatibant. Except for PK 
assessment, all outcomes are to be measured after each attack as with the initial attack. 
The period of active participation in the study may depend on the number of subsequent treatment 
and thus could be a maximum of approximately 25 days. 
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Sites will employ all efforts to see subjects in the hospital/study center for assessments. In 
unavoidable circumstances (eg, a widespread disease outbreak such as the coronavirus disease 
2019 (COVID-19) pandemic or natural disaster), exceptions may be consulted for alternative visits 
or assessments for conducting subject visits with approval by the Medical Monitor and/or sponsor. 
Such instances will be documented in the study records as related to unavoidable circumstances 
(eg, COVID-19). 
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A. 
 
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Figure 6.a 
Schematic of Study Design 
 
a) Hospitalization may be prolonged until the investigator determines that the clinical condition is stable and the subject’s HAE symptoms are resolved. 
In this case, as a general rule, the efficacy evaluation (investigator-rated symptom score, FPS-R, FLACC scale) and injection site reaction evaluation 
are performed every 2 hours including 8 hours after administration, until discharge. Initial symptom improvement (investigator and subject), adverse 
events, and concomitant medications will be continuously evaluated until discharge. Physical examination, vital signs, ECG, clinical laboratory tests 
and reproductive hormone assessments are performed only at discharge.  
b) A contact via telephone is scheduled at >24-48 hours after the final administration. If hospitalization continues 48 hours after the last dose, 
assessments are performed at the hospital. 
c) Investigator-rated symptom score, FPS-R, FLACC scale will be performed within 1 hour prior to treatment. Other assessments are performed within 
the acceptable range up to 3 hours before administration. 
d) Administration of icatibant will consist of 1 SC injection of icatibant. However, a maximum of 3 SC injections of icatibant with at least 6 hours 
intervals can be given for treatment of an attack if, within 48 hours of the initial injection, there is insufficient relief or worsening of symptoms. 
e) The vomiting and diarrhea assessments will be performed every 2 hours and, therefore, are excluded from the investigator-rated symptom score at the 
time points indicated. 
f) 
In the event that a subsequent attack occurs at least 7 days after first treatment for a prior attack, but within the window (+1 day) allowed for 
performance of follow-up (Day 8) assessments associated with a prior attack, the follow-up (Day 8) assessments may also serve as the pretreatment 
(baseline) assessments for the subsequent attack. 
 
 
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6.2 
Justification for Study Design, Dose, and Endpoints 
<Justification for Study Design> 
The purpose of this study is to evaluate the safety, efficacy and PK of icatibant in the treatment of 
acute attacks in Japanese pediatric patients with HAE Type I or II. Considering the ethical point of 
view that this is a pediatric study and from feasibility point of view, it was determined to conduct 
the study as an open-label, single-arm study. 
Studies HGT-FIR-086 and SHP-FIR-301, which were also conducted as open-label studies from 
the viewpoint of feasibility, confirmed that the efficacy and safety were consistent with those in 
the placebo-controlled comparative study in non-Japanese adult patients (HGT-FIR-054) and 
verified the effectiveness of icatibant in non-Japanese pediatric patients and Japanese adult 
patients. Therefore, it is considered possible to evaluate the safety, efficacy and PK of icatibant in 
Japanese children in the same way by conducting this study. 
<Justification for Dose> 
The dose was set to be the same as the dosage and administration planned for pediatric application 
in Japan. This dose is the same as the approved dosage and administration in the EU. 
In Study HGT-FIR-086, a single dose of icatibant 0.4 mg/kg (up to 30 mg) was administered 
subcutaneously to pediatric patients who presented with an acute attack, and the symptoms of the 
attack were relieved within 2 hours after administration. Based on this result, in the application for 
pediatric indication in the EU, etc., a Modeling & Simulation (M&S) approach was used to set the 
recommended dose for each body weight category and it was approved. 
Ethnic differences and age in light of the treatment response to icatibant were examined, and the 
results showed similar efficacy and safety between Japanese adults and non-Japanese adults as 
well as between adults and children. In the preliminary M&S conducted in Japanese pediatric 
patients, the exposure to icatibant after subcutaneous icatibant administration at body weight 
category-based doses in Japanese pediatric patients was predicted as lower than the exposure in 
non-Japanese pediatric patients after administration of icatibant at 0.4 mg/kg (up to 30 mg), but 
was similar to that in Japanese adult patients and within the range of the exposure, at which effects 
of symptom relief was observed. This was considered to indicate that the efficacy in Japanese 
pediatric patients is expected to be similar to that in Japanese adult patients and non-Japanese 
pediatric patient. On the other hand, the exposure estimated in Japanese pediatric patients is not 
expected to exceed the exposure for which safety has been confirmed in Japanese adults and 
non-Japanese children, and therefore, we consider that there is no particular safety concern in 
Japanese pediatric patients. 
Based on the above, the doses for children in this study was set to be the same as the doses for each 
body weight category already approved in Europe. 
The dosage and administration approved for adults in Japan is as follows: “In adults, icatibant 
30 mg per dose is usually injected subcutaneously. If response is inadequate or symptoms recur, an 
additional injection of 30 mg may be administered at an interval of at least 6 hours. Do not 
administer more than 3 injections in 24 hours.” If symptoms are inadequately relieved or worsen 
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within 48 hours after the first dose, it will also be allowed for an attack in this study to administer 
up to 3 doses, including the first dose, at intervals of at least 6 hours. In the global studies in adults, 
icatibant was administered for up to 3 times at maximum in patients whose symptoms were not 
adequately relieved by single-dose administration. As a result, symptom relief was observed in all 
patients with no safety concerns.  
Since attack symptoms generally peak by approximately 24 hours after onset [4, 5], worsening of 
symptoms not less than 48 hours after the first dose will be considered as a new attack episode, and 
a maximum of 3 doses per attack should be administered within 48 hours of the first dose. 
<Justification for Methods of administration> 
Icatibant is an injection solution that is administered urgently for symptom relief at the time of 
attacks. Therefore, the method of administration in children is intended to be self-administration 
outside the medical institution, such as home, as well as administration by a healthcare 
professional as is the case with adults. For this reason, icatibant will be administered by a 
healthcare professional, or the patient or his/her caregiver, e.g. the subject’s family under the 
supervision of a healthcare professional, within 12 hours after the onset of an attack if the subject 
and his/her legal guardian agree and the investigator considers it appropriate after the subject 
receives education and training. For subsequent treatment, the subject and the subject’s caregiver 
will be encouraged to self-administer icatibant under the supervision of a healthcare professional. 
Since dose adjustment is required in pediatric patients weighing ≤65 kg, the same graduated 
syringe and connecter for children as that used overseas will be used. 
<Justification for Endpoints> 
For safety evaluation, general safety endpoints and injection site reaction, which is an important 
identified risk of icatibant, were selected as endpoints because no new safety risk in Japanese 
children is expected based on the results of Studies HGT-FIR-086 and SHP-FIR-301, etc. 
Immunogenicity (hypersensitivity), hypotension and cardiac dysfunction, which are potential risks 
of icatibant, were selected as adverse event of special interest, and presence of anti-icatibant 
antibodies is to be assessed for immunogenicity. Taking into consideration the fact that the 
subjects of this study are children, it was also determined to evaluate the effects on reproductive 
hormones. 
For the efficacy evaluation, it was determined to evaluate the time to symptom relief using the 
symptom score for acute attack symptoms of HAE (severity scale of 8 symptoms related to skin 
and abdominal attacks or 13 symptoms including these 8 symptoms and laryngeal edema-related 
symptoms) by investigators, because it is expected that preschoolers will also be enrolled in this 
study, similarly to Study HGT-FIR-086. This endpoint has also been evaluated in the global phase 
3 studies in adults and children as well as the Japanese phase 3 study in adults (HGT-FIR-054, 
HGT-FIR-086, and SHP-FIR-301), and the results can be compared among studies. In addition, 
FPS-R that enables children to visually assess pain and FLACC that enables the investigator to 
objectively assess pain in children with immature language ability will be used together for 
subjects aged 4 years and older and subjects aged less than 4 years, respectively. For these 
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endpoints, time to symptom relief and time to symptom minimization were defined in the same 
manner, taking into consideration the comparability of the results with Study HGT-FIR-086. 
For PK, since the subjects of the study are children, blood sampling will be performed at 5 time 
points, which is considered to be the minimum to allow investigation of the PK characteristics of 
icatibant in Japanese pediatric patients, to reduce the burden on the subjects. 
6.3 
Premature Termination or Suspension of Study or Study Site 
6.3.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 or more of the following criteria are satisfied that 
require temporary suspension or early termination of the study. 
• New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the compound, such that the risk 
/benefit is no longer acceptable for subjects participating in the study. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety. 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement. 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
early termination or suspension will be provided by the sponsor; the procedure will be followed by 
applicable study sites during the course of termination or study suspension. 
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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed before icatibant is administered for 
initial attack and subsequent attacks. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study:  
1. In the opinion of the investigator or subinvestigator, the subject’s parent or legal guardian is 
capable of understanding and complying with protocol requirements. 
2. The subject’s parent or the subject’s legal guardian is capable of signing and dating a written 
informed consent form on behalf of the subject prior to the initiation of any study procedures. 
Written informed assent is also obtained from the subject as much as possible. 
3. The subject is in Japan and is Japanese; defined as born in Japan and having Japanese parents 
and Japanese maternal and paternal grandparents. 
4. The subject is male or female and 2 to <18 years of age (ie, from the second birthday through 
the day prior to the eighteenth birthday) at the time of informed consent. 
5. The subject weighs ≥12 kg at the time of the current HAE attack. 
6. The subject who has a documented and confirmed diagnosis of HAE type I or II. Diagnosis 
may be based on historical data using the following criteria: 
a. Family history of angioedema 
b. Characteristic attack manifestations, recurrent attacks 
c. Functional C1-INH deficiency 
d. In the absence of a family history of angioedema, exclusion of other forms of angioedema (eg. 
ACE-induced angioedema, allergic angioedema) based on medical judgement (eg, 
concomitant medication, response to antihistamines or glucocorticoids, information of 
genetic mutation). 
7. If the subject does not have a documented and confirmed diagnosis of HAE type I or II based 
on historical data, including C1-INH deficiency, the subject’s diagnosis must be determined 
prior to treatment by C1-INH test results which demonstrate a functional C1-INH deficiency. 
a. HAE type I: Low amount of C1-INH protein and low level of C1-INH activity; HAE type II: 
Normal or increased amount of C1-INH protein and low level of C1-INH activity 
b. In the absence of a family history of angioedema, exclusion of other forms of angioedema (eg. 
ACE-induced angioedema, allergic angioedema) based on medical judgement (eg, 
concomitant medication, response to antihistamines or glucocorticoids, information of 
genetic mutation). 
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8. The current HAE attack must be in the cutaneous, abdominal, and/or laryngeal (inclusive of 
laryngeal and pharyngeal) areas, but no prespecified attack severity criteria are required for 
treatment. 
9. The subject commences treatment within 12 hours after the onset of current HAE attack. 
10. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception from signing of informed consent 
throughout the duration of the study, and proves negative in the pregnancy test at screening. 
*Definitions and highly effective methods of contraception are defined in Section 9.1.17 and 
reporting responsibilities are defined in Section 9.1.18. 
7.1.1 
Justification of Inclusion Criteria 
Criteria 1 and 2 were set as basic matters to conduct clinical studies in pediatric subjects 
Criteria 3 to 5 and 8 were set because of the specific requirements of the study population. 
Criteria 6 and 7 were set for subjects with a diagnosis of hereditary angioedema, and therefore 
"Hereditary angioedema (HAE) guidelines (2019 revision)" [4] and " The international 
WAO/EAACI guideline for the management of hereditary angioedema – the 2017 revision and 
update” [6] diagnostic criteria. 
Criteria 9 was set to suppress the variation in administration timing among subjects. 
Criteria 10 was set as basic matters to conduct clinical studies. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject will require an intervention to support the airway (eg, intubation, tracheotomy, 
cricothyrotomy) due to the current HAE attack. 
2. The subject presents with an HAE attack with laryngeal/upper respiratory tract symptoms 
which are considered severe in the investigator’s clinical judgment and which may necessitate 
urgent care and/or impede the conduct of study efficacy assessments. 
3. The subject has a diagnosis of angioedema other than HAE 
4. The subject has evidence of stroke or coronary artery disease based on medical history at the 
screening examination or at pretreatment; eg, acute ischemic heart disease, unstable angina 
pectoris, severe coronary heart disease or congestive heart failure, that in the investigator’s 
judgment would be a contraindication for participation in the trial (New York Heart 
Association [NYHA] class 3 and 4). 
5. The subject has received treatment with any pain medication since the onset of the current 
HAE attack. 
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6. The subject has received replacement therapy (C1-INH products, fresh frozen plasma [FFP]) 
within 5 days (120 hours) from the onset of the current HAE attack. 
7. The subject has received treatment with ACE inhibitors within 7 days prior to treatment. 
8. The subject has used hormonal contraceptive within 90 days prior to treatment.  
9. The subject has received androgen or attenuated androgens (eg, danazol, testosterone) within 
90 days prior to treatment.  
10. The subject has participated in another clinical study within the past 30 days before screening. 
11. The subject, the subject’s parent, or legal guardian is unable to understand the nature, scope, 
and possible consequences of the protocol, or is unlikely to comply with the protocol 
assessments, unable to return for follow up visits, or unlikely to complete the study for any 
reason.  
12. If female, the subject is pregnant or lactating or intending to become pregnant before 
participating in this study, during the study, and within 30 days after last dose of the icatibant. 
13. The subject has a history of hypersensitivity or allergies to icatibant. 
14. The subject is judged by the investigator as being ineligible for any other reason; eg. a serious 
concomitant illness or condition. 
7.2.1 
Justification of Exclusion Criteria 
Criteria 1, 2 and 4 were set to ensure overall safety of the study participants and because of the 
potential for bias in evaluation of the safety and the efficacy. 
Criteria 3, 9 and 10 were set because of the potential for bias in evaluation of the safety and the 
efficacy. 
Criteria 5 to 7 were set because of the potential for bias in evaluation of the efficacy. 
Criteria 8 and 12 were set because of the potential for bias in evaluation of the safety. 
Criteria 11 was set as basic matters to conduct clinical studies. 
Criteria13 and 14 were set to ensure overall safety of the study participants. 
7.3 
Excluded Medications, Procedures, and Treatments 
• Other investigational product (drug or device): within 30 days prior to screening and during the 
study 
• Pain medication: after onset of the current HAE attack and during the hospitalization 
• ACE inhibitors: within 7 days prior to treatment and during the study 
• Androgens or attenuated androgens (eg, danazol, testosterone): within 90 days prior to 
treatment and during the study 
• Hormonal contraceptives: within 90 days prior to treatment and during the study 
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• Replacement therapy (C1-INH products, FFP): within 5 days (120 hours) from the onset of the 
current HAE attack and during the hospitalization 
Prophylactic therapies for HAE (eg, anti-fibrinolytics or C1-INH products) other than attenuated 
androgens (eg, danazol) will be allowed when it is used in a stable regimen, but therapies known to 
attenuate an acute HAE attack (eg, C1-INH products, FFP) must not be used during the attack 
being treated with icatibant unless these are required as rescue medications. 
Any medicinal product may be used as rescue medication at the discretion of the investigator or 
subinvestigator. 
For the purposes of this protocol, rescue medication is defined as 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 to be resultant from the current 
HAE attack. Rescue medication includes therapies for HAE (eg, C1-INH products, FFP) used for 
HAE attack and symptomatic treatment used in order to improve symptoms of angioedema (eg, 
pain and nausea). The determination of the necessity for rescue medication will be at the discretion 
of the investigator.  
7.3.1 
Justification of Excluded Medications 
“Other investigational product (drug or device)”, and “Androgens or attenuated androgens” were 
selected for its potential to interfere with the evaluation of safety/efficacy endpoints. 
“Hormonal contraceptives” was selected for its potential to interfere with the reproductive 
hormones assessment. 
“Pain medication”, “ACE inhibitors” and “Replacement therapy” was selected for its potential to 
interfere with the evaluation of efficacy endpoints 
7.4 
Activity Control and Treatment Facilities 
The investigator, the subinvestigator, and the study collaborator should instruct the subject, the 
subject’s parent or the subject’s legal guardian to adhere the following study requirements.  
1. Subjects will be instructed to inform the investigator or subinvestigator before receiving 
treatment from another doctor, or to provide details of treatment the subject received in case of 
reporting afterwards. Subjects receiving treatment by another doctor will be instructed to 
inform another doctor of their participation in this study before the participation, as far as 
possible. 
2. Subjects will be instructed to consult the investigator or subinvestigator before using or 
changing the dosage of any drug not prescribed by the investigator or subinvestigator 
(including vitamins supplements, over-the-counter medications, and herbal preparations). 
Subjects will be instructed to promptly provide the details when they use any such drug. 
3. Subjects will be instructed to visit the study site at the scheduled times to undergo 
examinations and tests by the investigator or subinvestigator. Subjects will be instructed to 
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promptly inform the investigator or subinvestigator when they are unable to visit the study site 
as scheduled. 
4. Female subjects of childbearing potential (eg, a female subject of childbearing potential is 
defined by the investigator’s or subinvestigator’s positive opinion about the subject’s 
reproductive potential) will be instructed to use appropriate contraception from signing of 
informed consent to 30 days after completing the study (Section 9.1.17). 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the case report form ([e]CRF) using the following categories. For screen 
failure subjects, refer to Section 9.1.21. 
1. Death. The subject died on study. 
Note: If the subject dies on study, the event will be considered as serious adverse event (SAE). 
See Section 10.2.2 for the reporting procedures. 
2. Adverse event (AE). The subject has experienced an AE that requires early termination 
because continued participation imposes an unacceptable risk to the subject’s health or the 
subject is unwilling to continue because of the AE. 
● Liver Function Test (LFT) Abnormalities 
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 10.2.3), if the following circumstances occur at any 
time during study drug treatment: 
– Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit 
of normal (ULN), or 
– ALT or AST >5 × ULN and persists for more than 2 weeks, or 
– ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5, or 
– ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
3. Significant protocol deviation. The discovery after the first dose of study drug that the subject 
failed to meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health. 
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documents. 
5. Voluntary withdrawal by the subject. The subject wishes to withdraw from the study. The 
reason for withdrawal, if provided, should be recorded in the eCRF. 
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Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category. Similarly, lack of efficacy 
should not be recorded in the “voluntary withdrawal” category.). If a subject chooses to 
withdraw from study participation due to personal concerns related to the COVID-19 
pandemic (other than a COVID-19-related adverse event), this should be specified as the 
reason for “voluntary withdrawal” in the eCRF. 
6. Voluntary withdrawal by subject’s parent/subject’s legal guardian. The subject’s 
parent/subject’s legal guardian wishes to withdraw from the study. The reason for withdrawal, 
if provided, should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an 
AE should not be recorded in the “voluntary withdrawal” category. Similarly, lack of efficacy 
should not be recorded in the “voluntary withdrawal” category.). If a subject chooses to 
withdraw from study participation due to personal concerns related to the COVID-19 
pandemic (other than a COVID-19-related adverse event), this should be specified as the 
reason for “voluntary withdrawal” in the eCRF. 
7. Study termination. The sponsor, IRB, or regulatory agency terminates the study. 
8. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.18. 
9. Lack of efficacy. The investigator has determined that the subject is not benefiting from study 
treatment; and, continued participation would pose an unacceptable risk to the subject. 
10. Other. 
Note: The specific reasons including unavoidable circumstances such as the COVID-19 
pandemic should be recorded in the “specify” field of the eCRF. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit. 
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8.0 
CLINICAL STUDY MATERIAL MANAGEMENT 
This section contains information regarding all medications and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material. 
8.1 
Study Drug and Materials 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
In this protocol, the term study drug refers to all or any of the drugs defined below. 
8.1.1.1 
Study Drug 
(1) Dosage form and manufacturing  
Code name: TAK-667 
Generic name: Icatibant Acetate (JAN) 
Chemical name: 
D-Arginyl-L-arginyl-L-prolyl-(R)-4-hydroxy-L-prolylglycyl-3-(thiophen-2-yl)-
L-alanyl-L-seryl-(R)-[(1,2,3,4-tetrahydroisoquinolin-3-yl)carbonyl]-(2S,3aS,7a
S)-[(hexahydroindolin-2-yl)carbonyl]-L-arginine triacetate 
Dosage form: Injection 
Formulation: Colorless to pale yellow clear liquid 
Strength: Contains 34.14 mg of Icatibant Acetate (30.00 mg as Icatibant) in a syringe (3.0 mL) 
Manufacturing: Takeda Pharmaceutical Company Limited 
(2) Package and labeling 
1) Package 
Firazyr® 30 mg subcutaneous injection Syringe: 3.0 mL×1 Syringe 
2) Labeling 
Each outer box indicates the following information: the drug is for the study use only, study drug 
name, protocol number, the sponsor’s name and address, batch number, storage condition and 
expiry date. 
8.1.2 
Storage 
The study drugs are to be stored from 2 to 25°C. 
Study drug must be kept in an appropriate, limited-access, secure place until it is used or returned 
to the sponsor or designee for destruction. Study drug must be stored under the conditions 
specified on the label, and remain in the original container until dispensed. A daily temperature log 
of the drug storage area must be maintained every working day. 
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8.1.3 
Dose and Regimen 
A single, five-weight-band dosing up to a maximum of 30 mg SC administration. Injection site is 
abdomen in principle. If there is insufficient relief or worsening of symptoms, up to 2 additional 
injections are permitted per attack with a time interval of at least 6 hours within 48 hours of the 
initial injection. Dosage is shown in Table 8.a. Weight group will be selected based on body 
weight measured at baseline visit. 
Subsequent treatment with icatibant for up to 2 additional acute attacks of HAE, for a total of 3 
acute attacks, will be offered to subjects who present with a new attack at least 7 days after first 
treatment for a prior attack if the subject and the subject’s parent or the subject’s legal guardian 
consent to further treatment. The dose selection and interval for treatment of subsequent attacks 
will be the same as that for treatment of the initial attack (Table 8.a).  
Dose is to be adjusted using a graduated syringe (sales name; BD Disposable Syringe capacity; 
3 mL, sales company; Nippon Becton Dickinson) and a connecter (sales name; Dispensing 
Connector, sales company; Braun Aesculap Japan). The prefilled syringe is connected to a 
graduated syringe. Required dosage is transferred from prefilled syringe to empty graduated 
syringe and administrated. 
Doses for an initial attack are to be administered by a healthcare professional as per instructions of 
investigators, or be self-administered by the subject or the subject’s caregiver, e.g. the subject’s 
family, at the study site under the supervision of a healthcare professional. In the case that icatibant 
is administered by whom other than healthcare professionals, if the subject and his/her legal 
guardian agree and the investigator considers it appropriate after the subject receives education 
and training, the patient or his/her caregiver, e.g. the subject’s family, will be allowed to 
administer incatibant under the supervision of a healthcare professional. Especially for subsequent 
treatment, the subject and the subject’s caregiver will be encouraged to self-administer icatibant 
under the supervision of a healthcare professional (refer to Section 8.1.3.1). 
Icatibant dose and methods of administration should be recorded in eCRF (refer to Section 9.2). 
Table 8.a 
Dosage 
Weight Group* 
Dose (Injection volume) of Icatibant (TAK-667) 
12 to 25 kg 
10 mg (1.0 mL) 
26 to 40 kg 
15 mg (1.5 mL) 
41 to 50 kg 
20 mg (2.0 mL) 
51 to 65 kg 
25 mg (2.5 mL) 
>65 kg 
30 mg (3.0 mL) 
*Body weight of 12 kg or more is the subject of this study. For each weight, round to the nearest whole number for 
calculation. 
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8.1.3.1 
Self-Injection Training (Optional; for Subjects Who Will Self-Administer Icatibant 
Only) 
Subjects or the subject’s caregiver, e.g. the subject’s family, will be encouraged to self-administer 
icatibant under supervision and will receive training on the appropriate self-injection technique 
from a healthcare professional as per instructions of investigators prior to treatment. 
The implementation status of self-administration training should be recorded in eCRF (refer to 
Section 9.2) 
8.1.4 
Overdose 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol. 
All cases of overdose (with or without associated AEs) will be recorded in eCRF, in order to 
capture this important safety information consistently in the database. Cases of overdose without 
manifested signs or symptoms are not considered AEs. AEs associated with an overdose will be 
documented on AE eCRF(s) according to Section 10.0. 
SAEs associated with overdose should be reported according to the procedure outlined in Section 
10.2.2. 
In the event of drug overdose, the subject should be treated symptomatically.  
8.2 
Study Drug Assignment and Dispensing Procedures 
The investigator or subinvestigator will dispense the study drug to subjects according to the study 
procedure (refer to Appendix A). 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs 
The on-site pharmacist (site designee) will receive the pharmacy manual created by the sponsor, 
according to which the site designee will appropriately manage the sponsor-supplied drug. The 
investigator will also receive those procedures from the sponsor. The procedures include those for 
ensuring appropriate receipt, handling, storage, management, dispensation of the sponsor-supplied 
drug, and collection of unused medications as well as return of them to the sponsor or destruction 
of them.  
The on-site pharmacist (site designee) will immediately return unused study drugs to the sponsor 
after the study is closed at the study site. 
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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A. 
9.1.1 
Informed Consent and Assent Procedure 
The requirements of the informed consent and assent are described in Section 15.2. 
Informed consent of the subject’s parent or the subject’s legal guardian, and assent of the subject if 
deemed possible by the investigator or subinvestigator, must be obtained prior to the subject 
entering into the study, and before any protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study. 
9.1.2 
Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained at screening will include date of birth, sex, race. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease being studied and eligibility criteria that resolved 
within 1 year prior to signing of informed consent. Ongoing conditions are considered concurrent 
medical conditions (see Section 9.1.13). Any clinically significant conditions or diseases relevant 
to treatment on prior HAE attacks to be obtained as described in Section 9.1.6. 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria, except for treatments of HAE, stopped at or within 90 days prior to signing of informed 
consent. Medication history on prior HAE attacks to be obtained as described in Section 9.1.6. 
9.1.3 
Physical Examination Procedure 
A baseline physical examination (defined as the assessment prior to first dose of study drug) will 
consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; 
(4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; 
(8) musculoskeletal system; (9) nervous system; (10) lymph nodes; (11) other. All subsequent 
physical examinations should assess clinically significant changes from the assessment prior to 
first dose examination. Clinically significant findings will be recorded as an AE if it starts after the 
first dose of study drug on this study. 
9.1.4 
Weight, Height 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. Height is recorded in centimeters without decimal places. Weight is collected in kilograms 
(kg) with 1 decimal place. 
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9.1.5 
Vital Sign Procedure 
Vital signs will include body temperature, respiratory rate, sitting blood pressure (systolic and 
diastolic, resting more than 5 minutes), and pulse (bpm). 
When vital signs are scheduled at the same time as blood draws, vital signs will be obtained before 
the scheduled blood draw. 
9.1.6 
Medical History of HAE / Current HAE Attack  
(1) HAE attacks occurring before the screening 
Details of HAE diagnosis (eg. time of first onset of symptom, time of diagnosis, HAE type [I or II], 
C1-INH activity functional/protein level, genetic mutation, family history), presence of previous 
icatibant administration and detail of prior HAE attacks during the 12 months prior to the 
screening visit (eg. frequency of attack, frequency of attack required medical interventions and 
detail of symptoms for each attack [time of onset, location, trigger, prodromal symptoms, severity, 
time of onset of relief and complete relief, and medical interventions required, start time of 
treatment, any clinically significant conditions or diseases relevant to treatment]) will be obtained 
at screening in principle and recorded in the eCRF. 
(2) HAE attacks occurring after the screening 
• HAE attack not treated with study drug 
The subject, the subject’s parent or the subject’s legal guardian will note down detail of symptoms 
for each HAE attack not treated with study drug (time of onset, location, trigger, prodromal 
symptoms, severity, time of onset of relief and complete relief, and medical interventions required, 
start time of treatment). The investigator or subinvestigator will basically obtain this information 
at baseline visit prior to study drug administration for initial or subsequent attack and recorded in 
the eCRF. 
• Current HAE attack treated with study drug 
The subject, the subject’s parent or the subject’s legal guardian will note down detail of current 
HAE attack to be treated with study drug (time of onset, location, trigger, prodromal symptoms). 
The investigator or subinvestigator will obtain this information to establish subject eligibility at 
baseline visit prior to study drug administration for initial or subsequent attack and will be 
recorded in the eCRF. 
9.1.7 
Menstrual Cycle History 
A menstrual cycle history will be determined historically for female subjects and will be recorded 
in the eCRF. 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.  
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To assist in this determination, investigator or subinvestigator  should obtain the following 
information and document in the eCRF.  
• Age of menarche. 
• Normal duration of menstrual flow. 
• Normal interval in between menstrual periods. 
• Date of last menstrual bleeding. 
• Prospectively ask female subjects to write down subsequent dates of onset and cessation of 
menstrual bleeding between Day 1 and Day 8. 
• Date of ovulation may be documented if subjects can identify ovulation from feeling (eg. 
ovulation pain, mid-cycle pain or mittelschmerz) or basal body temperature, etc. 
9.1.8 
Pubertal Status Determination 
The investigator or subinvestigator will perform an examination for all subjects to determine 
whether they are prepubertal or pubertal/postpubertal. A description of the sexual maturation scale 
originally described by Marshall and Tanner (1969 and 1970) (Appendix C) should be referred for 
the determination. 
9.1.9 
Primary Efficacy Measurement 
9.1.9.1 
Investigator or Subinvestigator Symptom Score 
For subjects treated at the hospital/study center, the investigator or subinvestigator 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 
eCRF. 
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 (over 2 hours), diarrhea (over 2 
hours), 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 (over 2 hours), diarrhea (over 2 hours), skin 
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pain, erythema, skin irritation, skin swelling, dysphagia, voice change, breathing difficulties, 
stridor, and asphyxia. 
9.1.9.2 
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 D. 
FPS-R self-assessment data will be recorded in a FPS-R self-assessment sheet. Subjects will 
record self-assessments on Day 1 at pretreatment and at predetermined time points after treatment. 
Subjects or subject’s parent/legal guardian will receive detailed instruction on when and how to 
use the FPS-R self-assessment sheet from the investigator or subinvestigator and/or clinical site 
personnel. 
9.1.9.3 
Investigator or Subinvestigator 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 compartmental pain scale. A copy of the 
FLACC scale is provided in Appendix E. 
9.1.9.4 
Initial Symptom Improvement Reported by Investigator and Subject 
The investigator or subinvestigator will record the time when overall subject improvement of HAE 
symptoms is first noted. And subjects (or the subject’s parent/legal guardian on behalf of the 
subject as appropriate) will be asked to report the time when subject feel that his/her HAE 
symptoms start to improve, and the investigator or subinvestigator will record in eCRF. 
9.1.10 
Self-Administration Assessment (Optional; for Subjects or Caregiver Who Will 
Self-Administer Icatibant Only) 
Subjects or caregiver, e.g. the subject’s family who self-administer icatibant will be asked to 
provide information on convenience and satisfaction with the self-administration of the study drug 
to treat each HAE attacks. Results will be recorded in the eCRF. The Self-Administration 
Assessment is located in Appendix F. 
9.1.11 
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. 
9.1.12 
Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug. These may be prescribed 
by a physician or obtained by the subject over the counter. Concomitant medication does not 
include the drug provided by the sponsor. At each study visit, subjects will be asked whether they 
have taken any medication other than the study drug (including vitamin supplements, 
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over-the-counter medications, and herbal preparations) that is used from signing of informed 
consent through the end of the study, and it will be recorded in the eCRF. 
During the period from the end of the follow-up (Day 8) to the baseline (Day 1) for the subsequent 
icatibant-treated attacks, concomitant medication need not be recorded, except that information on 
excluded medications, medications used for SAEs, medications used for AEs leading to study 
discontinuation, and medications used for HAE attacks not treated with study drug will be 
collected at the baseline visit for the subsequent icatibant-treated attacks, and recorded in the eCRF. 
All medications being used at the baseline visit for subsequent icatibant-treated attacks will be 
collected as concomitant medications. 
Rescue medication (Section 7.3) for icatibant-treated HAE attack must be recorded in the 
applicable page of the eCRF separately from concomitant medications. 
9.1.13 
Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are clinically significant ongoing conditions or diseases that are 
present at signing of informed consent. Those include abnormalities in laboratory test, ECG, or 
physical examination observed at first examination, observation and assessment after obtaining 
informed consent, those are judged to be clinically significant by the investigator or 
subinvestigator. Concurrent conditions (ie, diagnosis) should be recorded. 
9.1.14 
Procedures for Clinical Laboratory Samples 
All samples will be collected via venipuncture and in accordance with acceptable laboratory 
procedures. The volume of blood will be determined at each site. 
Table 9.a lists the items those will be tested for each laboratory specimen. 
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Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Red blood cells (RBC) 
White blood cells (WBC) count with 
differential (%) (neutrophil, basophil, 
eosinophil, lymphocyte, monocyte) 
Hemoglobin 
Hematocrit 
Platelets 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Mean corpuscular volume (MCV) 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Total bilirubin 
Creatinine 
Creatine kinase 
Gamma-Glutamyl transferase (GGT) 
Chloride 
Potassium 
Sodium 
Calcium 
Glucose 
Lactate dehydrogenase (LDH) 
Carbon dioxide (CO2) 
Phosphorus 
Blood urea nitrogen (BUN) 
Magnesium 
Total protein 
Uric acid 
Glucose 
Specific gravity 
pH 
Protein 
Occult blood 
Ketones 
Clarity 
Bilirubin 
Color 
Nitrites 
Other: 
Urine qualitative human chorionic gonadotropin (hCG) pregnancy test (only female subjects of childbearing potential) 
Coagulation: 
Prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
 
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis (not necessary with fasting). The results of laboratory tests will be returned to the 
investigator or subinvestigator, who is responsible for reviewing and filing these results. Results 
will be recorded in the eCRF. 
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase (ALP), ALT, AST, total bilirubin, GGT, and INR) should be performed 
within a maximum of 7 days and preferably within 48-72 hours after the abnormality was noted. 
(Refer to Section 7.5 and Section 10.2.3 for the appropriate guidance on reporting abnormal liver 
function tests.) 
If ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions, the investigator or 
subinvestigator must contact the monitor to discuss additional testing, close monitoring, possible 
discontinuation of study drug, relevant subject details and possible alternative etiologies. The 
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abnormality should be recorded as an AE (for reporting abnormal liver function tests, please refer 
to Section 10.2.3). 
Only female subjects of childbearing potential, defined by the investigator’s or subinvestigator’s 
positive opinion about the subject’s reproductive potential, will undergo a qualitative human 
chorionic gonadotropin (hCG) pregnancy test. The local laboratory will perform the test. 
The investigator or subinvestigator reviews and files the laboratory test results. The investigator or 
subinvestigator will also maintain a copy of the normal reference ranges including the archival 
records for the laboratory used. 
9.1.15 
Injection Site Reactions 
Injection site reactions will be assessed by the investigator or subinvestigator at specified time 
points after study drug administration (1.0, 4.0, 8.0 hours after the administration, Day 2 and 
Day 8). Injection sites will be examined for erythema, swelling, cutaneous pain, burning sensation, 
itching/pruritus, and warm sensation. The injection site reaction data will be recorded on the eCRF. 
The diameter of any erythema or swelling should be measured to obtain the severity grading. The 
severity of injection site reactions will be graded as absent, mild, moderate, or severe using the 
scoring criteria shown in Table 9.b. 
After discharge, 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. 
Table 9.b 
Severity Scoring for Injection Site Reactions 
Injection Site Reactions 
Severity 
Mild 
Moderate 
Severe 
Erythema 
>0 to 5 cm 
>5 to 10 cm 
>10 cm 
Swelling 
>0 to 5 cm 
>5 to 10 cm 
>10 cm 
Cutaneous Pain 
Mild discomfort to touch 
Discomfort with movement Significant discomfort at 
rest 
Burning Sensation 
Mild burning sensation, 
which is easily tolerated 
Moderate burning 
sensation, causing some 
discomfort 
Severe burning sensation, 
causing significant 
discomfort 
Itching/pruritus 
Mild itching/pruritus, which 
is easily tolerated 
Moderate itching/pruritus, 
causing some discomfort 
Severe itching/pruritus, 
causing significant 
discomfort 
Warm Sensation 
Mild warmth to touch 
Moderate warmth to touch 
Significant warmth to touch 
 
Data for injection site reactions will be collected separately from general reports of AEs. An 
injection site reaction not meeting SAE criteria does not need to be reported additionally as an AE. 
9.1.16 
Immunogenicity Evaluation 
The immunogenicity of icatibant will be assessed. Serum samples for immunogenicity testing will 
be collected according to the study schedule (Appendix A) for determination of anti-icatibant 
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antibodies. Serum samples will be analyzed for anti-icatibant antibodies at a Takeda 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. 
9.1.17 
Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent, throughout the duration of the study, and for 30 days after the 
last dose of study drug, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception (listed below). In addition they must 
be advised not to preserve or donate ova during this period. 
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation), who are postmenopausal (defined as at 
least 2 years since last regular menses, confirmed before any study drug is administered), or who 
have no possibility of childbearing in the opinion of investigator or subinvestigator. 
**Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy. 
 
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, female subjects of childbearing potential must use copper intrauterine devices 
(IUDs) combined with male condom or female condom. Medications and devices containing 
hormones are excluded in this study. 
The subject and the subject’s parent, or the subject’s legal guardian will be provided with 
information on acceptable methods of contraception as part of the subject informed consent/assent 
process and will be asked to sign a consent/assent form stating that they understand the 
requirements for avoidance of pregnancy, preservation or donation of ova from providing the 
consent/assent until 1 month has passed from the end of the study. 
During the course of the study, regular urine hCG pregnancy tests will be performed only for 
female subjects of childbearing potential according to the study schedule (Appendix A) and 
subjects will receive continued guidance with respect to the avoidance of pregnancy. 
This protocol does not condone or endorse under-age sexual activity.  
9.1.18 
Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. 
If the pregnancy occurs during administration of active study drug, eg, after or within 30 days of 
the last dose of active study drug, the pregnancy should be reported immediately, using a 
pregnancy notification form, to the contact listed in Annex. 
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If the female subject and her parent, or the subject’s legal guardian agrees to the primary care 
physician being informed, the investigator should notify the primary care physician that the female 
subject was participating in a clinical study at the time she became pregnant and provide details of 
the study drug the subject received. 
All pregnancies in subjects on active study drug will be followed up to final outcome, using the 
pregnancy form. The outcome, including any premature termination, must be reported to the 
sponsor. An evaluation after the birth of the child will also be conducted. 
9.1.19 
ECG Procedure 
A resting 12-lead ECG will be recorded. The investigator (or a qualified observer at the study site) 
will interpret the ECG using the following categories: within normal limits, abnormal but not 
clinically significant, or abnormal and clinically significant. 
The following parameters will be recorded on the eCRF from the subject’s ECG trace: heart rate, 
RR interval (msec), PR interval (msec), QT interval (msec), and QRS interval (msec).  QTc (msec) 
will be calculated by the sponsor using the Fredericia’s formula (QT/RR0.33). 
9.1.20 
Pharmacokinetic Sample Collection and Analysis 
Collect blood samples for pharmacokinetic evaluation according to the study schedule (Appendix 
A). 
9.1.20.1 
Collection of Plasma for Pharmacokinetic Sampling 
Blood samples (one 1 mL sample per scheduled time) for pharmacokinetic analysis of icatibant 
and its metabolites (M-I and M-II) will be collected via venipuncture into vacutainers containing 
ethylenediaminetetraacetic acid dipotassium salt dihydrate (EDTA-K2). Use of an indwelling 
catheter is encouraged for collection of serial blood samples for PK assessments when feasible. 
After mixing the vacutainers by inversion immediately, vacutainers will be centrifuged at 4°C. The 
plasma will be dispensed from the vacutainers to two polypropylene tubes with roughly equal 
volume and be stored frozen at or below -20°C in a freezer until being shipped to the analytical 
institute.  
Details on the collection and processing of specimens are described in the Study Laboratory 
Manual. 
For each sample, the date and time of the latest study drug administration and the actual time of 
blood sample collection will be recorded in the eCRF. 
9.1.20.2 
Bioanalytical Methods 
Plasma samples will be assayed for concentrations of icatibant and its 2 major metabolites (M-I 
and M-II) using a validated high-performance liquid chromatography/tandem mass spectrometry 
(LC-MS/MS) method. 
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9.1.21 
Documentation of Screen Failure 
If the subject who signed informed consent is withdrawn at the screening visit, the investigator 
should complete the eCRF. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
• Death. 
• AE. 
• Did not meet inclusion criteria or did meet exclusion criteria. <specify reason> 
• Significant protocol deviation. 
• Lost to follow-up. 
• Withdrawal by subject <specify reason>. 
• Withdrawal by parent or legal guardian <specify reason>. 
• Study termination by sponsor. 
• Pregnancy 
• The study is closed prior to the subject’s eligible attack. 
• Other <specify reason>. 
Subject identification numbers assigned to subjects who fail screening should not be reused. 
9.1.22 
Documentation of Study Entrance 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the treatment phase. 
If the subject is found to be not eligible for treatment phase, the investigator should record the 
primary reason for failure on the applicable eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
During this study, the study drug will be administered by study site personnel, the subject, or 
caregiver, therefore, full subject compliance with treatment is anticipated. 
The investigator will record all study drug administered to the subject in the eCRF. 
The investigator or subinvestigator will record the implementation status of self-administration 
training, the administration method of this drug (administration by medical personnel, subjects, or 
caregivers), the usage status of the graduated syringe and connecter for pediatric administration, 
and the dose of study drug in the eCRF. 
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9.3 
Schedule of Observations and Procedures 
The schedule for study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time points. 
In unavoidable circumstances (eg, a widespread disease outbreak such as COVID-19 pandemic or 
natural disaster), exceptions may be consulted for alternative visits or assessments for conducting 
subject visits with approval by the Medical Monitor and/or sponsor. 
9.3.1 
Screening 
Subjects will be screened within 180 days prior to Baseline (Day1). Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.21 for procedures for documenting screening failures. 
9.3.2 
Initial Icatibant-Treated Attack 
9.3.2.1 
Study Entrance/Baseline (Day 1:Up to 3 hours before the start of study drug 
administration) 
The subject will visit the hospital after the onset of HAE attack. 
Prescribed tests, observations, and evaluations will be performed as baseline assessment in the 
period from 3 hours before icatibant administration to icatibant administration and subject 
eligibility is confirmed based on inclusion/exclusion criteria. Efficacy assessment must be 
performed within 1 hour prior to treatment. 
If the screening test and the pre-dose (baseline) test are performed at the same time, duplicate tests 
should be performed only once. 
9.3.2.2 
After Treatment (Day 1) 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be started 
administrating icatibant within 12 hours of the onset of HAE attack. Up to 2 additional injections 
are permitted per attack with a time interval of at least 6 hours within 48 hours of the initial 
injection if there is insufficient relief or worsening of symptoms. 
Subjects will be hospitalized for at least 8 hours after administration and prescribed tests, 
observations, and evaluations will be performed. Subject can be discharged from the hospital after 
finishing the evaluation of 8 hours after administration. Hospitalization may be prolonged until the 
investigator determines that the clinical condition is stable and the subject’s HAE symptoms is 
resolved. 
When the hospitalization period extended, as a general rule, the efficacy evaluation 
(investigator-rated symptom score, FPS-R, FLACC scale) and injection site reaction evaluation 
are performed every 2 hours, including 8 hours after administration, until discharge. Initial 
symptom improvement (investigator and subject), adverse events, and concomitant medications 
will be continuously evaluated until discharge. Physical examination, vital signs, ECG, clinical 
laboratory tests and reproductive hormone assessments are performed only at discharge. 
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9.3.2.3 
After Treatment (Day 2) 
At 24 to 48 hours after final administration of the study drug, all subjects who received the study 
drug will be subjected to prescribed examinations, observations, and evaluations by telephone, and 
recorded in the eCRF. If hospitalization continues 48 hours after the last dose, it is not necessary to 
perform an evaluation that overlaps with the evaluation items of 8 hours after administration or at 
discharge. 
9.3.2.4 
Follow-up (Day 8) 
On the 7th day after the first administration of the study drug, the subject comes to the hospital for 
follow-up. Perform prescribed examinations, observations and evaluations, and record them in the 
eCRF. 
9.3.3 
Subsequent Icatibant-Treated Attack 
9.3.3.1 
Study Entrance/Baseline (Day 1:Up to 3 hours before the start of study drug 
administration) 
Further treatments with study drug for up to 2 additional acute attacks of HAE, for a total of 3 acute 
attacks, will be offered to subjects who present with cutaneous, abdominal or laryngeal edema 
attack at least 7 days after first treatment for a prior attack if the subject and the subject’s parent or 
the subject’s legal guardian consent to further treatment. 
In the event that a subsequent attack occurs within the window (+1 day) allowed for performance 
of follow-up (Day 8) assessments associated with a prior attack, the follow-up (Day 8) assessments 
may also serve as the pretreatment (baseline) assessments for the subsequent attack. 
The subject will visit the hospital after the onset of a HAE attack. 
Prescribed tests, observations, and evaluations will be performed as baseline assessment in the 
period from 3 hours before icatibant administration to icatibant administration and subject 
eligibility is confirmed based on inclusion/exclusion criteria. Efficacy assessment must be 
performed within 1 hour prior to treatment. 
9.3.3.2 
After Treatment (Day 1 and Day 2) and Follow-up (Day 8) 
Assessments listed in Appendix A will be performed in the same manner as that for the initial 
attack (Section 9.3.2.2 to 9.3.2.4). 
9.3.4 
Final Visit or Early Termination 
The last visit is follow-up (Day 8) of final attack treated with study drug. 
For subjects who early terminate the study during hospitalization after the start of the study drug 
administration, the same tests, observations and evaluations as those scheduled at 8 hours should 
be performed. For subjects who early terminate the study after discharge, the same tests, 
observations and evaluations as those scheduled at follow-up (Day 8) should be performed. In 
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addition, assessment of adverse events and injection site reactions, and collection of concomitant 
medications should be performed 7 days after initial administration of icatibant by telephone. 
For all subjects receiving icatibant, the investigator must complete the end of study eCRF page. 
If the subject’s parent or the subject’s legal guardian consent and subject assent to participation for 
only initial icatibant-treated attack, final visit is follow-up (Day 8) of initial icatibant-treated 
attack. 
If the subject’s parent or the subject’s legal guardian consent and subject assent to participation for 
subsequent icatibant-treated attacks, final visit is follow-up (Day 8) for third attack treated with 
study drug. In case subject does not experience third attack treated with study drug, study 
participation will be continued until early termination or completion of the study, and final visit 
will be follow-up (Day 8) of final attack treated with study drug within this period. 
9.3.5 
Post Study Care 
Study drug will not be available upon completion of the subject’s participation in the study. The 
subject should be returned to the care of a physician and standard therapies as required. 
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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with this treatment or study participation. An AE can therefore be any unfavorable and 
unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease 
temporally associated with the study participation whether or not it is considered related to the 
drug or study procedures. 
In addition, drug-device AEs related to quality or malfunction will be collected. 
10.1.2 
Additional Points to Consider for AEs 
An untoward finding generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.) (Acute 
HAE attacks are not considered AEs unless meeting the criteria for an SAE. If the criteria for 
SAEs are met, follow the procedure for reporting SAEs.) 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require discontinuation or a change in dose of study drug or a concomitant medication. 
• Be considered unfavorable by the investigator for any reason. 
• AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as an AE. 
Diagnoses vs signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s). 
Laboratory values and ECG findings: 
• Changes in laboratory values or ECG findings are only considered to be AEs if they are judged 
to be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory or 
ECG re-test and/or continued monitoring of an abnormal value or finding are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention. 
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• If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE. 
Pre-existing conditions: 
• Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as AEs. Baseline evaluations (eg, 
laboratory tests, ECG, X-rays etc.) should NOT be recorded as AEs unless related to study 
procedures. However, if the subject experiences a worsening or complication of such a 
concurrent medical condition, after informed consent is signed,the worsening or complication 
should be recorded appropriately as an AE (worsening or complication occurs after informed 
consent is signed). Investigators should ensure that the event term recorded captures the 
change in the condition (eg, “worsening of…”). 
• If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) any 
occurrence of an episode should only be captured as an AE if the condition becomes more 
frequent, serious or severe in nature. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg “worsening of…”). 
• If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as an AE if occurring to a greater 
extent to that which would be expected. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”). 
Worsening of AEs: 
• If the subject experiences a worsening or complication of an AE after starting administration of 
the study drug, or if a sign or a symptom appears secondarily due to an AE, the worsening or 
complication should be recorded appropriately as a new AE. The investigator or 
subinvestigator should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”). 
• If the subject experiences a worsening or complication of an AE after any change in study drug, 
the worsening or complication should be recorded as a new AE. Investigators should ensure 
that the AE term recorded captures the change in the condition (eg, “worsening of…”). 
Changes in intensity of AEs: 
• If the subject experiences changes in intensity of an AE, the event should be captured once 
with the maximum intensity recorded. 
Preplanned procedures (surgeries or interventions): 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be recorded as an AE. Complications resulting from any planned surgery 
should be reported as AEs. 
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Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy. 
Overdose: 
• Cases of overdose with any medication without manifested side effects are NOT considered 
AEs, but instead will be documented on an Overdose page of the eCRF. Any manifested side 
effects will be considered AEs and will be recorded on the AE page of the eCRF. 
10.1.3 
SAEs 
An SAE is defined as any untoward medical occurrence in a subject who has signed informed 
consent to participate in a study: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
● The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
● May require intervention to prevent items 1 through 5 above. 
● May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
● Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a). 
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Table 10.a 
Takeda Medically Significant AE List 
Term 
Acute respiratory failure / acute respiratory distress 
syndrome 
Hepatic necrosis 
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
Acute liver failure 
Anaphylactic shock 
Malignant hypertension 
Acute renal failure 
Convulsive seizure (including seizure and epilepsy) 
Pulmonary hypertension 
Agranulocytosis 
Pulmonary fibrosis (including interstitial lung disease) 
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by a 
medicinal product 
 
Neuroleptic malignant syndrome / malignant hyperthermia 
 
Spontaneous abortion / stillbirth and fetal death 
 
COVID-19 related disease 
 
COVID-19 pneumonia 
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements.  
10.1.4 
AEs of Special Interest 
An AE of special interest (only AEs that occurred after the start of study drug administration, 
serious or non-serious) is one of scientific and medical concern specific to the compound or 
program, for which ongoing monitoring and rapid communication by the investigator to Takeda 
may be appropriate. Such events may require further investigation in order to characterize and 
understand them and would be described in protocols and instructions provided for investigators as 
to how and when they should be reported to Takeda. 
10.1.4.1 
Injection Site Reaction 
• Injection site reaction – listed as important identified risk in Japan/EU RMP; Local injection 
site reactions were observed  in almost all icatibant -treated subjects. Most injection site 
reactions were transient, mild to moderate in severity, and completely resolved within 4-8 
hours of treatment. Injection site reactions 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. Injection site reaction data will be collected separately from the general AE 
report. Injection site reactions that do not meet the criteria for SAE need not be reported as 
additional AE. 
• The evaluation of Injection site reaction is shown in 9.1.15. 
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10.1.4.2 
Immunogenicity (Hypersensitivity) 
• Immunogenicity (Hypersensitivity) – listed as important potential risk in Japan RMP; In 
clinical studies, icatibant was generally nonimmunogenic. In over repeated treatment, transient 
positivity in test results for the presence of anti icatibant IgG antibodies was observed in rare 
cases. The immunogenicity of icatibant will be assessed. Serum samples for immunogenicity 
testing will be collected for determination of anti-icatibant antibodies. If hypersensitivity is 
observed, it should be reported as an AEs of special interest. 
10.1.4.3 
Reproductive Hormone Level in Pubertal/ Post-Pubertal Children 
• Reproductive hormone level in pubertal/ post-pubertal children – listed as important potential 
risk in EU RMP; Although in the juvenile toxicity studies, the effects on hormone levels, 
reproductive organs, and sexual maturation in juvenile/immature rats and dogs was observed, 
no clinically significant changes in reproductive hormones were observed during global 
clinical studies in pediatric HAE patients. Blood samples will be collected to assess FSH, LH, 
estradiol, and progesterone in females, and FSH, LH, and testosterone in males. If a clinically 
significant change in reproductive hormone concentration is observed, it is reported as an AEs 
of special interest with clinical symptoms. 
10.1.4.4 
Hypotension and Cardiac Dysfunction 
• Hypotension and cardiac dysfunction – listed as important potential risk in Japan RMP; In 
vitro studies have shown that icatibant activates human mast cells and decrease of blood 
pressure was observed in a high-volume bolus intravenous injection study of icatibant. In 
addition, the bradykinin antagonism of icatibant may pose a potential risk to patients with 
cardiovascular disease. Although no clinically significant hypotensive action and safety 
concerns for cardiovascular system was observed in clinical studies, hypotension and cardiac 
dysfunction will be assessed by standard safety testing including vital signs and 12-lead ECG. 
If clinically significant hypotension and cardiac dysfunction are observed, it is reported as an 
AEs of special interest. 
10.1.5 
Intensity of AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
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10.1.6 
Causality of AEs 
The relationship of each AE to study drug(s) will be assessed using the following categories: 
Related: An AE that follows a reasonable temporal sequence from administration of a drug (including the course 
after withdrawal of the drug), or for which possible involvement of the drug cannot be ruled out, although 
factors other than the drug, such as underlying diseases, complications, concomitant medications and 
concurrent treatments, may also be responsible. 
Not 
Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or that can 
reasonably be explained by other factors, such as underlying diseases, complications, concomitant 
medications and concurrent treatments. 
10.1.7 
Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all AEs. 
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related.  
10.1.8 
Start Date and Time 
The start date and time of the AE is the date and time that the first signs/symptoms were noted by 
the subject and/or investigator. 
The start date and time of AEs will be determined using the following criteria; 
AEs 
Start Date and Time 
Any signs/symptoms/diseases 
(diagnosis) 
The date and time that the first signs/symptoms/diseases were noted by the 
subject and/or the investigator should be recorded. 
Asymptomatic diseases 
The date and time when examination was performed for diagnosis and 
diagnosis was confirmed should be recorded. 
The date and time when diagnosis was confirmed should also be recorded 
even when values or findings showed previous values or findings or the onset 
time can be estimated. 
Worsening or complication of 
concurrent medical conditions or any 
signs/symptoms/diseases before 
treatment 
The date and time that a worsening or complication of the condition was 
noted first by the subject and/or the investigator should be recorded. 
The examination after start of the 
study drug showed abnormal 
values/findings. 
The date and time of examination when an abnormal value or findings that 
was judged to be clinically significant was noted should be recorded. 
The examination at the start of the 
study drug showed abnormal 
values/findings and the subsequent 
examinations showed worsening of 
the symptoms. 
The date and time of examination when apparent elevation, reduction, 
increase or decrease was confirmed in judgment according to the trends in 
those values or findings should be recorded. 
 
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10.1.9 
Stop Date and Time 
The stop date and time of the AE is the date and time at which the subject recovered, the event 
resolved but with sequelae or the subject died. 
10.1.10 Frequency  
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous. 
10.1.11 Action Concerning Study Drug  
• Drug withdrawn – a study drug is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study drug. 
• Unknown – only to be used if it has not been possible to determine what action has been taken. 
• Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE, or the AE occurred before the study drug administration. 
• Dose Reduced – the dose was reduced due to the particular AE. 
• Dose Increased – the dose was increased due to the particular AE. 
• Dose Interrupted – the dose was interrupted due to the particular AE. 
10.1.12 Outcome 
• Recovered/Resolved – Subject returned to first assessment status with respect to the AE. 
• Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE with the condition remaining “recovering/resolving”. 
• Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved”. 
• Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis). 
• Fatal – the AEs which are considered as the cause of death.  
• Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study. 
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10.1.13 Product Complaints 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product and/or device. 
An investigator who is made aware of or identifies a potential product complaints should 
immediately report the event to Takeda in accordance with the contact list provided to the site. 
Whenever possible, the associated product should be maintained in accordance with pharmacy 
manual pending further guidance from a Takeda representative. 
10.2 
Procedures 
10.2.1 
Collection and Reporting of AEs 
10.2.1.1 
AE Collection Period 
Collection of AEs will commence from the time the subject signs the informed consent to 
participate in the study. Routine collection of AEs will continue until the end of the study (Day 8). 
During the period from the end of the follow-up (Day 8) to the onset of icatibant-treated 
subsequent HAE attacks, as a general rule, this period is excluded from the collection period of 
AEs, only SAEs and AEs leading to study discontinuation are detailed in eCRF. All AEs ongoing 
at the time of the onset of icatibant-treated subsequent HAE attacks will be collected and recorded 
in the eCRF. 
Collection of device defects will commence from the time that the subject is first administered 
study drug. Routine collection of device defects will continue until the end of the study. 
10.2.1.2 
AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
SAE that occurs prior to the first exposure to study drug must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to baseline or there 
is a satisfactory explanation for the change. Non-SAEs, related or unrelated to the study procedure, 
need not to be followed-up for the purposes of the protocol. 
All subjects experiencing AEs after the first exposure to study drug, whether considered associated 
with the use of the study drug or not, must be monitored until the symptoms subside and any 
clinically relevant changes in laboratory values have returned to baseline or until there is a 
satisfactory explanation for the changes observed. All AEs will be documented in the AE page of 
the eCRF, whether or not the investigator concludes that the event is related to the drug treatment. 
The following information will be documented for each event: 
1. Event term. 
2. Start and stop date and time. 
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3. Frequency. 
4. Intensity. 
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related). 
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure. 
7. Action concerning study drug. 
8. Outcome of event. 
9. Seriousness. 
A clinically relevant worsening of the signs and symptoms of an attack treated with icatibant is 
considered to be related to the underlying disease of HAE, and is collected in the eCRF separately 
from general reports of AEs unless meeting the criteria of an SAE. 
10.2.1.3 
AEs of Special Interest 
If the subject experiences immunogenicity (hypersensitivity), a clinically significant change in 
reproductive hormone concentration in pubertal/ post-pubertal children, or hypotension and 
cardiac dysfunction, during the treatment period or the safety follow-up period as described in 
Section 10.1.4, the investigator or the subinvestigator will record it in the eCRF and report it to the 
sponsor within 1 working day after the occurrence of the event. If necessary, prepare the AEs 
report as a backup, and submit it to the sponsor/designated person (see attached annex for contact 
information). 
If an injection site reaction occurs during the study, the investigators should document it following 
9.1.15. 
10.2.2 
Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
The investigator or the subinvestigator will report the SAE to the sponsor within 24 hours after the 
occurrence of the SAE, using the eCRF. If necessary, prepare the SAE report as a backup, and 
submit it to the sponsor/designated person (see attached annex for contact information). The 
information should be completed as fully as possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s name. 
• Name of the study drug(s) 
• Causality assessment. 
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The investigator should submit the original copy of the SAE form to the sponsor. 
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation. 
10.2.3 
Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the monitor or the sponsor’s designee for 
discussion of the relevant subject details and possible alternative etiologies, such as acute viral 
hepatitis A or B or other acute liver disease or medical history/concurrent medical conditions. 
Follow-up laboratory tests as described in Section 9.1.14 must also be performed. 
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form (copy) or provide other written 
documentation and fax it immediately. Copies of any relevant data from the hospital notes (eg, 
ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the addressee, if 
requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs /the 
head of the study site . Relative to the first awareness of the event by/or further provision to the 
sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory authorities as 
expedited report within 7 days for fatal and life-threatening events and 15 days for other serious 
events, unless otherwise required by national regulations. The sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current benefit-risk 
assessment of a study drug/sponsor supplied drug or that would be sufficient to consider changes 
in the study drug/sponsor supplied drug administration or in the overall conduct of the trial. The 
study site also will forward a copy of all expedited reports to his or her IRB. 
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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 
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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary. 
12.1 
CRFs (Electronic) 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply study sites with access to eCRFs.The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor and regulatory authorities. 
eCRFs must be completed in English. Data are transcribed directly onto eCRFs. 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change.  
The principal investigator must review the eCRFs for completeness and accuracy and must e-sign 
the appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs. 
The following data will not be recorded into the eCRFs. 
• Results of pharmacokinetics conducted at the analytical institute 
• Results of immunogenicity (anti-icatibant antibodies) 
After the lock of the study database, any change of, modification of or addition to the data on the 
eCRFs should be made by the investigator with use of change and modification records of the 
eCRFs (Data Clarification Form) provided by the sponsor. The principal investigator must review 
the data change for completeness and accuracy, and must sign, or sign and seal, and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor. 
12.2 
Record Retention 
The investigator and the head of the study site agree to keep the records stipulated in Section 12.1 
and those documents that include (but are not limited to) the study-specific documents, the 
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identification log of all participating subjects, medical records, temporary media such as thermal 
sensitive paper, source worksheets, all original signed and dated informed consent forms, 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. 
The investigator and the head of the study site are required to retain essential relevant documents 
until the day specified as 1) or 2) below, whichever comes later. However, if the sponsor requests 
a longer time period for retention, the head of the study site should discuss how long and how to 
retain those documents with the sponsor. 
1. The day on which marketing approval of the study drug is obtained (or the day 3 years after the 
date of notification in the case that the investigation is discontinued.) 
2. The day 3 years after the date of early termination or completion of the study. 
In addition, the investigator and the head of the study site should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required. 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be finalized the first versoin prior to the first subject enrolled 
and finalized amendments prior to database lock. This document will provide further details 
regarding the definition of analysis variables and analysis methodology to address all study 
objectives. 
A data review will be conducted prior to database lock. This review will assess the accuracy and 
completeness of the study database, subject evaluability, and appropriateness of the planned 
statistical methods. 
13.1.1 
Analysis Sets 
13.1.1.1 
Safty Analysis Sets 
The safety analysis set will be defined as all subjects who received at least 1 dose of study drug. 
13.1.1.2 
Full Analysis Set 
The full analysis set will be defined as all subjects who received at least 1 dose of study drug. The 
definition of full analysis set is the same as the safety analysis set in this study. 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized using the safety analysis set. 
13.1.3 
Efficacy Analysis 
Secondary endpoints and analytical methods 
[Secondary Endpoints] 
• Time to onset of symptom relief and time to minimal symptom, 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 symptom relief, defined as the duration of time in hours from the 
time of icatibant administration to the earliest time at which at least a 20% 
improvement is observed in the average post-treatment score with no worsening of any 
single component score. 
 The time to minimal symptoms, defined as the duration of time in hours from the time 
of icatibant administration to the earliest time post-treatment when all symptoms are 
either mild or absent based on the investigator-rated symptom score. 
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 For subjects ≥4 to <18 years of age only: subject self-assessment of HAE-related pain 
using the FPS-R. 
 The time to onset of symptom relief, defined as the duration of time in hours from the 
time of icatibant administration to the earliest time at which the post-treatment score 
improved by at least 1 level. 
 The time to minimal symptoms, defined as the duration of time in hours from the time 
of icatibant administration to the earliest time at which the post-treatment score 
improved to 0. 
 For subjects 2 to <4 years of age only: investigator assessment of HAE-related pain using 
the FLACC scale. 
 The time to onset of symptom relief, defined as the earliest time at which a 20% 
improvement is observed in the total post-treatment score. 
 The time to minimal symptoms, defined as the duration of time in hours from the time 
of icatibant administration to the earliest time at which the total post-treatment score 
improved to 0. 
• 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. 
• Time to initial symptom improvement reported by investigator or subject 
 Time to initial symptom improvement reported by investigator, defined as the duration 
of time in hours from icatibant administration until the time when overall subject 
improvement was first noted by investigator.  
 Time to initial symptom improvement reported by subject, defined as the duration of 
time in hours from icatibant administration until the time when overall subject 
improvement was first noted by subject, subject’s parent or subject’s legal guardian. 
[Analytical methods] 
All efficacy endpoints will be summarized by icatibant-treated attacks using the full analysis set 
and listed. For the time-to-event endpoints, the survival function (e.g. proportion of subjects not 
achieving symptom relief) for each assessment time will be calculated by Kaplan-Meier method 
using the first icatibant-treated attacks within each subject. The second and third icatibant-treated 
attacks will be listed. Assuming independency in recurrent events within a subject, the survival 
function for each assessment time will be also calculated by Kaplan-Meier method using all 
icatibant-treated attacks. Due to the small sample size, no statistical inferences (statistical test nor 
confidence interval) will be performed. 
13.1.4 
Pharmacokinetic Analysis 
Secondary endpoints and analytical methods 
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[Secondary Endpoints] 
Plasma concentrations of icatibant and its major metabolites (M-I and M-II) at 0.5, 1.0, 2.0, and 
4.0 hours after the first SC injection for an initial attack. 
[Analytical methods] 
Plasma concentrations of icatibant and its metabolites (M-I and M-II) will be summarized at each 
time point.  
Data collected in this study will be combined with those from global studies, and the population 
PK modeling and simulations will be performed. Individual pharmacokinetic parameters (e.g. Cmax 
and AUC) will be estimated by population PK analysis, if possible. Analysis plan and report of 
population pharmacokinetic analysis will be provided separately from the clinical study report. 
13.1.5 
Safety Analysis 
Primary endpoints and analytical methods 
[Primary Endpoints] 
• Frequency and severity of TEAEs , including injection site reactions 
[Analytical methods] 
The following analysis will be performed using the safety analysis set. TEAE is defined as an AE 
that occurs on or after administration of icatibant for each attack and until the end of follow-up 
period (Day 8). TEAEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology and tabulated by the system organ class (SOC) and the Preferred Term 
(PT), and by icatibant-treated attacks and the total. 
Injection site reactions will be summarized by icatibant-treated attacks and the total, and by 
severity. 
Secondary endpoints and analytical methods 
[Secondary Endpoints] 
• Resting 12-lead electrocardiogram parameters in comparison to baseline 
• Vital sign measurements in comparison to baseline 
• Clinical laboratory parameters (serum chemistry, hematology and urinalysis) in comparison to 
baseline 
• Reproductive hormone levels in comparison to baseline 
• Immunogenicity (presence of anti-icatibant antibodies) in comparison to baseline 
[Analytical methods] 
For continuous values of laboratory parameters, vital signs and other safety parameters, summary 
statistics will be provided for observed values and change from baseline at each evaluation time 
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point and icatibant-treated attack. Pre- and post-dose shift tables will be provided for categorical 
variables. 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size 
Total of at least 3 subjects*  
* The enrollment will be continued until the end of the enrollment period and the sample size may 
exceed 3 subjects. 
[Justification for Determination of Sample Size] 
The planned sample size chosen of 3 subjects administered icatibant in this study is based on the 
feasibility and is not statistically determined. 
Although there have been no accurate reports regarding the number of pediatric HAE patients in 
Japan, it is estimated approximately 30 to 50 patients based on the population estimate and the 
percentage of children among Japanese HAE patients confirmed in the latest Japanese HAE survey. 
However, comprehensive feasibility assessment for medical institutions across Japan found much 
less candidate subjects and only few clinical sites possible to conduct the study due to some 
hurdles in implementation. In addition, considering a difficulty to obtain informed consent in a 
pediatric study, the number of patients to be enrolled was assumed to be 3. 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and head of the study site guarantee access to source documents by the sponsor or 
its designee (contract research organization: CRO) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or sponsor’s 
designee , including but not limited to the Investigator’s Binder, study drug, subject medical 
records, informed consent documentation, and review of eCRFs and associated source documents. 
It is important that the investigator and other study personnel are available during the monitoring 
visits and that sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise (eg, a 
widespread disease outbreak such as the COVID-19 pandemic or natural disaster) that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB, as required) to determine the appropriate course of action. Deviations from the 
protocol-specified procedures will be recorded as related to unexpected circumstances (eg, 
COVID-19). There will be no exemptions (a prospectively approved deviation) from the inclusion 
or exclusion criteria. 
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from IRB. In the event of a deviation or change, the principal 
investigator should notify the sponsor and the head of the study site of the deviation or change as 
well as its reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the study site as soon as possible and an approval from IRB should be obtained. 
The investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, (eg, the 
PMDA). If the study site is contacted for an inspection by a regulatory body, the sponsor should be 
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notified immediately. The investigator and head of the study site guarantee access for quality 
assurance auditors to all study documents as described in Section 14.1. 
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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
15.1 
IRB Approval 
IRBs must be constituted according to the applicable local requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of members 
who make up the respective IRB. If any member of the IRB has direct participation in this study, 
written notification regarding his or her abstinence from voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent form/assent form, and, if applicable, subject recruitment materials and/or 
advertisements and other documents required by all applicable laws and regulations, must be 
submitted to a central or local IRB for approval. The IRB’s written approval of the protocol and 
subject informed consent/assent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB approval must refer to the study by exact protocol title, number, and 
version date; identify versions of other documents (eg, informed consent form /assen form) 
reviewed; and state the approval date. The sponsor will notify site once the sponsor has confirmed 
the adequacy of site regulatory documentation. Until the site receives notification no protocol 
activities, including screening may occur. 
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent 
form/assent form, recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals specified 
by the respective IRB, and submission of the investigator’s final status report to IRB. All IRB 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee. 
Subject/parent/legal guardian incentives should not exert undue influence for participation. 
Payments to subjects must be approved by the IRB and sponsor. 
15.2 
Subject Information, Informed Consent/Assent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. An assent document describes the study, using a language 
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appropriate to the subject’s age and development, to potential subjects with enough mental 
capacity to understand what it means to participate in a clinical study, and is used to obtain the 
subject’s assent (a pediatric subject’s consent, which is not a regulatory requirement) separately 
from the subject’s parent’s, or the subject’s legal guardian’s consent. The informed consent form 
describes the planned and permitted uses, transfers, and disclosures of the subject’s personal and 
personal health information for purposes of conducting the study. The informed consent form 
further explains the nature of the study, its objectives, and potential risks and benefits, as well as 
the date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the informed 
consent and assent forms. The informed consent and assent forms must be approved by both of the 
IRB and sponsor prior to use. 
The subject assent form must be written in a language appropriate to the potential subject’s age and 
development. The informed consent form must be written in a language fully comprehensible to a 
subject’s parent or the subjects’ legal guardian. It is the responsibility of the investigator or 
subinvestigator to explain the subject assent form to the subject using a language and terms 
comprehensible and to explain the detailed elements of the informed consent form to the subject’s 
parent, or the subject’s legal guardian. Information should be given in both oral and written form 
whenever possible and in the manner deemed appropriate by the IRB. In the event the subject is 
not capable of rendering adequate written informed consent, then the subject’s legally acceptable 
representative may provide such consent for the subject in accordance with applicable laws and 
regulations. 
The subject and the subject’s parent, or the subject’s legal guardian must be given ample 
opportunity to: (1) inquire about details of the study and (2) decide whether or not to participate in 
the study. If the subject’s parent or the subject’s legal guardian determines the subject will 
participate in the study, then the informed consent form must be signed and dated by the subject’s 
parent or the subject’s legal guardian at the time of consent and prior to the subject entering into 
the study. 
Whenever possible, the subject’s own assent should be obtained in addition to the subject’s 
parent’s or the subject’s legal guardian’s consent. The subject’s assent will be preferably obtained 
in writing, if he/she is a junior high school student or of a higher age. Whenever a written assent is 
not provided, though preferable also for subjects aged below junior high school students, the 
subject’s oral assent must be documented in the informed consent form signed by the subject’s 
parent or the subject’s legal guardian. The subject’s parent or the subject’s legal guardian should 
be instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. The 
investigator or subinvestigator must also sign and date the informed consent form and subject 
assent form at the time of consent and prior to subject entering into the study. 
Once signed, the original informed consent form, and the subject assent form (if applicable, the 
same hereinafter) will be stored in the investigator’s site file. The investigator or subinvestigator 
must document the dates the subject’s parent or the subject’s legal guardian signs the informed 
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consent form and the date the subject signs the subject assent form in the subject’s medical record. 
Copies of the signed informed consent form and the signed subject assent form shall be given to 
the subject, the subject’s parent, or the subject’s legal guardian. 
All revised informed consent/assent forms must be reviewed and signed by relevant subjects, the 
relevant subject’s parent or the subject’s legal guardian in the same manner as the original 
informed consent/assent. The date the revised consent/assent was obtained should be recorded in 
the subject’s medical record, and the subject, the subject’s parent, or legal guardian should receive 
a copy of the revised informed consent/assent form. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit the monitor or the sponsor’s designee, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, PMDA), 
the sponsor’s designated auditors, and the appropriate IRBs to review the subject’s original 
medical records (source data or documents), including, but not limited to, laboratory test result 
reports, ECG reports, admission and discharge summaries for hospital admissions occurring 
during a subject’s study participation, and autopsy reports. Access to a subject’s original medical 
records requires the specific authorization of the subject, the subject’s parent, or the subject’s legal 
guardian as part of the informed consent /assent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 
Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results is the sole 
responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. 
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The investigator needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association.  
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail. 
15.4.2 
Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with facility name, investigator’s site city, state (for Americas 
investigators), country, and recruiting status will be registered and available for public viewing.  
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee. 
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16.0 
REFERENCES 
1. Zuraw B. L. Clinical practice. Hereditary angioedema. N Engl J Med. 2008 Sep 
4;359(10):1027-36. 
2. Yamamoto T, Horiuchi T, Miyahara H, Yoshizawa S, Maehara J, Shono E, et al. Hereditary 
Angioedema in Japan: Genetic Analysis of 13 Unrelated Cases. The American Journal of the 
Medical Sciences. 2012 Mar; 343(3):210-14. 
3. Ohsawa I, Honda D, Nagamachi S, Hisada A, Shimamoto M, Inoshita H, et al. Clinical 
manifestations, diagnosis, and treatment of hereditary angioedema: survey data from 94 
physicians in Japan. Ann Allergy Asthma Immunol. 2015 Jun;114(6):492-8. 
4. The Japanese Association for Complement Research. HAE guideline planning committee. 
Hereditary Angioedema (HAE) guideline (2019 revision). 
5. Farkas H, Martinez-Saguer I, Bork K, Bowen T, Craig T, Frank M, et al. International 
consensus on the diagnosis and management of pediatric patients with hereditary angioedema 
with C1 inhibitor deficiency. Allergy. 2017 Feb;72(2):300-13. 
6. Maurer M, Magerl M, Ansotegui I, Aygoren-Pursun E, Betschel S, Bork K, et al. The 
international WAO/EAACI guideline for the management of hereditary angioedema—The 
2017 revision and update. Allergy. 2018;73:1575–96. 
7. Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for 
scoring postoperative pain in young children. Pediatr Nurs. 1997;23 (3):293–7. 
 
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CCI
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Appendix B 
 
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Appendix D 
 
CCI
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Appendix F 
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SAP_001.pdf: 
Title: A Multicenter, Open-Label, Non-randomized Phase 3 Study to Assess the Safety, 
Efficacy and Pharmacokinetics of Subcutaneous Administration of Icatibant (TAK-667) 
in Japanese Children and Adolescents with Acute Attacks of Hereditary Angioedema 
NCT Number: NCT04654351 
Statistical analysis plan Approve Date: 03-SEP-2021 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered
confidential information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners,
personal information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


 
 
 
STATISTICAL ANALYSIS PLAN 
Study Number: TAK-667-3001 
Study Title: A Multicenter, Open-Label, Non-randomized Phase 3 Study to Assess the Safety, 
Efficacy and Pharmacokinetics of Subcutaneous Administration of Icatibant (TAK-667) in 
Japanese Children and Adolescents with Acute Attacks of Hereditary Angioedema 
Phase: 3 
Version: 2.0 
Date: 03-Sep-2021 
 
 
 
Prepared by: 
 
Based on: 
Protocol Version: Amendment 1 
Protocol Date: 21-Dec-2020 
 
 
 
 
PPD
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Statistical Analysis Plan Amendment 1 
03-Sep-2021
 
REVISION HISTORY 
Version  
Approval Date 
Primary Rationale for Revision 
[Original version] 
15-Jan-2021 
[Not Applicable] 
[Amendment 1] 
03-Sep-2021 
To add listings for off-study HAE attacks in section 6.5.1.6.  
 
 
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TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .......................................................... 6 
1.1 
Objectives .................................................................................................................. 6 
1.2 
Endpoints................................................................................................................... 6 
1.2.1 
Primary Endpoint(s)........................................................................................... 6 
1.2.2 
Secondary Endpoint(s) ....................................................................................... 6 
1.3 
Estimand(s)................................................................................................................ 7 
2.0 
STUDY DESIGN ............................................................................................................ 7 
3.0 
THESES AND DECISION RULES .............................................................................. 10 
3.1 
Multiplicity Adjustment ........................................................................................... 10 
4.0 
SAMPLE-SIZE DETERMINATION............................................................................. 10 
5.0 
ANALYSIS SETS ......................................................................................................... 10 
5.1 
Safety Analysis Set .................................................................................................. 10 
5.2 
Full Analysis Set ...................................................................................................... 10 
6.0 
STATISTICAL ANALYSIS .......................................................................................... 10 
6.1 
General Considerations ............................................................................................ 10 
6.1.1 
Analysis Approach for Continuous Variables ................................................... 11 
6.1.2 
Analysis Approach for Binary Variables .......................................................... 11 
6.2 
Disposition of Subjects ............................................................................................ 11 
6.2.1 
Study Information ............................................................................................ 11 
6.2.2 
Screen Failures ................................................................................................ 11 
6.2.3 
Subject Eligibility ............................................................................................ 12 
6.2.4 
Number of Subjects Who Entered the Treatment Period by Site ....................... 12 
6.2.5 
Disposition of Subjects .................................................................................... 12 
6.2.6 
Protocol Deviations and Analysis Sets ............................................................. 13 
6.2.6.1 
Protocol Deviations ................................................................................. 13 
6.2.6.2 
Analysis Sets ........................................................................................... 13 
6.3 
Demographic and Other Baseline Characteristics ..................................................... 14 
6.3.1 
Demographics and Other Baseline Characteristics ........................................... 14 
6.3.2 
Medical History and Concurrent Medical Conditions ....................................... 16 
6.4 
Medication History and Concomitant Medications ................................................... 16 
6.4.1 
Prior Medications ............................................................................................ 16 
6.4.2 
Concomitant Medications ................................................................................ 17 
6.5 
Efficacy Analysis ..................................................................................................... 17 
6.5.1 
Secondary Endpoint(s) Analysis ...................................................................... 17 
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6.5.1.1 
Derivation of Endpoint(s) ........................................................................ 17 
6.5.1.2 
Main Analytical Approach for Time-to-Event Variables .......................... 18 
6.5.1.3 
Main Analytical Approach for Other Variables ........................................ 18 
6.5.1.4 
Supplementary Analyses 1 ....................................................................... 19 
6.5.1.5 
Supplementary Analyses 2 ....................................................................... 20 
6.5.1.6 
Supplementary Analyses 3 ....................................................................... 20 
6.6 
Safety Analysis ........................................................................................................ 21 
6.6.1 
Adverse Events ................................................................................................ 21 
6.6.1.1 
Overview of Treatment-Emergent Adverse Events .................................. 21 
6.6.1.2 
Displays of Treatment-Emergent Adverse events ..................................... 22 
6.6.1.3 
Displays of Pretreatment Events .............................................................. 24 
6.6.2 
Adverse Events of Special Interest ................................................................... 24 
6.6.2.1 
Injection Site Reaction ............................................................................. 24 
6.6.3 
Clinical Laboratory Evaluations ....................................................................... 25 
6.6.3.1 
Hematology and Serum Chemistry .......................................................... 25 
6.6.3.2 
Urinalysis ................................................................................................ 26 
6.6.4 
Vital Signs ....................................................................................................... 27 
6.6.5 
12-Lead ECGs ................................................................................................. 28 
6.6.6 
Other Safety Analysis ...................................................................................... 29 
6.6.6.1 
Reproductive hormone levels ................................................................... 29 
6.6.6.2 
Immunogenicity (presence of anti-Icatibant antibodies) ........................... 30 
6.6.7 
Extent of Exposure and Compliance ................................................................ 30 
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses ................................ 30 
6.7.1 
Pharmacokinetic Analysis ................................................................................ 30 
6.8 
Other Analyses ........................................................................................................ 31 
6.8.1 
Self-administration Assessment ....................................................................... 31 
6.9 
Interim Analyses ...................................................................................................... 32 
7.0 
REFERENCES .............................................................................................................. 32 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ................................................ 32 
9.0 
APPENDIX ................................................................................................................... 32 
9.1 
Changes From the Previous Version of the SAP....................................................... 32 
9.2 
Data Handling Conventions ..................................................................................... 37 
9.2.1 
Definition of Visit Windows ............................................................................ 37 
9.3 
Analysis Software .................................................................................................... 37 
 
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ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
BMI 
body mass index 
BUN 
Blood urea nitrogen 
COVID-19 
coronavirus disease 2019  
CO2 
Carbon dioxide 
C1-INH 
C1 esterase inhibitor 
ECG 
electrocardiogram 
FAS 
full analysis set 
FLACC 
Faces, Legs, Activity, Cry, and Consolability 
FPS-R 
Faces Pain Scale-Revised 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
GGT 
Gamma-Glutamyl transferase 
HAE 
hereditary angioedema 
LDH 
Lactate dehydrogenase 
LH 
luteinizing hormone 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic 
PT 
Preferred Term (MedDRA) 
PTE 
pretreatment event 
RBC 
Red blood cells 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
Subcutaneous 
SD 
Stable Disease 
SOC 
System Organ Class 
TEAE  
treatment-emergent adverse event] 
WBC 
White blood cells 
WHO 
World Health Organization 
 
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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
To evaluate the safety, efficacy and PK of Icatibant for the treatment of acute attacks in 
Japanese children and adolescents with type I or type II HAE. 
1.2 
Endpoints 
1.2.1 
Primary Endpoint(s) 
Safety: 
• Frequency and severity of treatment-emergent adverse events (TEAEs), including injection 
site reactions 
1.2.2 
Secondary Endpoint(s)  
Safety: 
• Resting 12-lead electrocardiogram parameters in comparison to baseline 
• Vital sign measurements in comparison to baseline 
• Clinical laboratory parameters (serum chemistry, hematology and urinalysis) in comparison 
to baseline 
• Reproductive hormone levels in comparison to baseline 
• Immunogenicity (presence of anti-Icatibant antibodies) in comparison to baseline 
Efficacy: 
• Time to onset of symptom relief and time to minimal symptom, 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 symptom relief, defined as the duration of time in hours from the 
time of Icatibant administration to the earliest time at which at least a 20% 
improvement is observed in the average post-treatment score with no worsening of 
any single component score. 
 The time to minimal symptoms, defined as the duration of time in hours from the time 
of Icatibant administration to the earliest time post-treatment when all symptoms are 
either mild or absent based on the investigator-rated symptom score. 
 For subjects ≥4 to <18 years of age only: subject self-assessment of HAE-related pain 
using the Faces Pain Scale-Revised (FPS-R). 
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 The time to onset of symptom relief, defined as the duration of time in hours from the 
time of Icatibant administration to the earliest time at which the post-treatment score 
improved by at least 1 level. 
 The time to minimal symptoms, defined as the duration of time in hours from the time 
of Icatibant administration to the earliest time at which the post-treatment score 
improved to 0. 
 For subjects 2 to <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 symptom relief, defined as the earliest time at which a 20% 
improvement is observed in the total post-treatment score. 
 The time to minimal symptoms, defined as the duration of time in hours from the time 
of Icatibant administration to the earliest time at which the total post-treatment score 
improved to 0. 
• 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. 
• Time to initial symptom improvement reported by investigator or subject 
 Time to initial symptom improvement reported by investigator, defined as the 
duration of time in hours from Icatibant administration until the time when overall 
subject improvement was first noted by investigator.  
 Time to initial symptom improvement reported by subject, defined as the duration of 
time in hours from Icatibant administration until the time when overall subject 
improvement was first noted by subject, subject’s parent or subject’s legal guardian. 
Pharmacokinetics: 
Plasma concentrations of Icatibant and its major metabolites (M-I and M-II) at 0.5, 1.0, 2.0, and 
4.0 hours after the first SC injection for an initial attack. 
1.3 
Estimand(s) 
Not applicable. 
2.0 
STUDY DESIGN 
This is a multicenter, open-label, phase 3 study to evaluate the safety, efficacy and PK of SC 
administration of Icatibant in Japanese children and adolescents from 2 to less than 18 years of 
age with acute attacks of HAE. 
Once informed consent is obtained and subject eligibility is established at screening, subjects 
will begin to receive treatment with Icatibant after they present with an acute attack of 
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cutaneous, abdominal, or laryngeal edema. The region and severity of the attack is assessed by 
investigators. 
Subjects eligible at pre-treatment physical examination and assessment will receive treatment 
with single-dose SC administration of Icatibant per attack according to the subject’s body weight 
within 12 hours after the onset of symptom. Up to 2 additional injections are permitted per 
attack with a time interval of at least 6 hours within 48 hours of the initial injection if there is 
insufficient relief or worsening of symptoms. If symptoms get worse or recur after more than 48 
hours of the initial administration, it will be considered as a new attack. Icatibant will be 
administered by a healthcare professional, or be self-administered by the subject or the subject’s 
caregiver, e.g. the subject’s family, at the study site under the supervision of a healthcare 
professional. In the case that Icatibant is administered by whom other than healthcare 
professionals, if the subject and his/her legal guardian agree and the investigator considers it 
appropriate after the subject receive education and training, the subject or his/her caregiver, 
e.g. the subject’s family, will be allowed to self-administer Icatibant under the supervision of a 
healthcare professional. 
Subjects will be closely monitored in the hospital/study center for at least 8 hours after 
administration and receive physical examination and assessment to evaluate safety, efficacy and 
PK. Hospitalization may be prolonged until, in the opinion of the investigator, the subject is 
clinically stable and onset of HAE attack is completely resolved. 
After discharge, follow-up to assess the subject’s condition at >24-48 hours after final 
administration (Day 2) will be conducted via a telephone call by investigators and follow-up of 
safety assessment will be conducted 7 days after initial administration of Icatibant (Day 8) at the 
study site. 
After having received initial treatment with Icatibant, subjects who subsequently experience an 
acute attack may continue to receive treatment with Icatibant for a total of 3 eligible Icatibant-
treated attacks if the subject and the subject’s parent or the subject’s legal guardian consent to 
further treatment. Further treatment with Icatibant is contingent upon presentation of an acute 
cutaneous, abdominal, or laryngeal edema attack of HAE at least 7 days after first treatment for 
a prior attack. The new attack of within less than 7 days after first treatment for a prior attack 
should be treated in accordance with standard of care for HAE without being administrated 
Icatibant. Except for PK assessment, all outcomes are to be measured after each attack as with 
the initial attack. 
The period of active participation in the study may depend on the number of subsequent 
treatment and could be a maximum of approximately 25 days. 
Sites will employ all efforts to see subjects in the hospital/study center for assessments. In 
unavoidable circumstances (eg, a widespread disease outbreak such as the coronavirus disease 
2019 (COVID-19) pandemic or natural disaster), exceptions may be consulted for alternative 
visits or assessments for conducting subject visits with approval by the Medical Monitor and/or 
sponsor. Such instances will be documented in the study records as related to COVID-19. 
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A schematic of the study design is included as Figure 1. A schedule of assessments is listed in 
Appendix A in the protocol. 
Figure 1 
Schematic of Study Design 
 
a) Hospitalization may be prolonged until the investigator determines that the clinical condition is stable and the 
subject’s HAE symptoms is resolved. In this case, as a general rule, the efficacy evaluation (investigator-rated 
symptom score, FPS-R, FLACC scale) and injection site reaction evaluation are performed every 2 hours 
including 8 hours after administration, until discharge. Initial symptom improvement (investigator and subject), 
adverse events, and concomitant medications will be continuously evaluated until discharge. Physical 
examination, vital signs, ECG, clinical laboratory tests and reproductive hormone assessments are performed 
only at discharge.  
b) A contact via telephone is scheduled at >24-48 hours after final administration. If hospitalization continues 48 
hours after the last dose, assessments are performed at the hospital. 
c) Investigator-rated symptom score, FPS-R, FLACC scale will be performed within 1 hour prior to treatment. 
Other assessments are performed within the acceptable range up to 3 hours before administration. 
d) Administration of Icatibant will consist of 1 SC injection of Icatibant. However, a maximum of 3 SC injections 
of Icatibant with at least 6 hours intervals can be given for treatment of an attack if, within 48 hours of the 
initial injection, there is insufficient relief or worsening of symptoms. 
e) The vomiting and diarrhea assessments will be performed every 2 hours and, therefore, are excluded from the 
investigator-rated symptom score at the time points indicated. 
f) 
In the event that a subsequent attack occurs at least 7 days after first treatment for a prior attack, but within the 
window (+1 day) allowed for performance of follow-up (Day 8) assessments associated with a prior attack, the 
follow-up (Day 8) assessments may also serve as the pretreatment (baseline) assessments for the subsequent 
attack. 
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3.0 
THESES AND DECISION RULES  
Not applicable. 
3.1 
Multiplicity Adjustment 
Not applicable. 
4.0 
SAMPLE-SIZE DETERMINATION 
Total of at least 3 subjects*  
* The enrollment will be continued until the end of the enrollment period and the sample size 
may exceed 3 subjects. 
[Justification for Determination of Sample Size] 
The planned sample size chosen of 3 subjects administered Icatibant in this study is based on the 
feasibility and is not statistically determined. 
Although there have been no accurate reports regarding the number of pediatric HAE patients in 
Japan, it is estimated approximately 30 to 50 patients based on the population estimate and the 
percentage of children among Japanese HAE patients confirmed in the latest Japanese HAE 
survey. However, comprehensivefeasibility assessment for medical institutions across Japan 
found much less candidate subjects and only few clinical sites possible to conduct the study due 
to some hurdles in implementation. In addition, considering a difficulty to obtain informed 
consent in a pediatric study, the number of patients to be enrolled was assumed to be 3. 
5.0 
ANALYSIS SETS 
5.1 
Safety Analysis Set 
The safety analysis set will be defined as all subjects who received at least 1 dose of study drug. 
5.2 
Full Analysis Set 
The full analysis set will be defined as all subjects who received at least 1 dose of study drug. 
The definition of full analysis set is the same as the safety analysis set in this study. 
6.0 
STATISTICAL ANALYSIS  
6.1 
General Considerations 
In case of 2 subjects who received at least 1 dose of study drug, no tables and figures will be 
produced except for 6.5.1.2 (2), 6.6.1.1, 6.6.1.2 (1), and 6.6.2.1. In case of only one subject who 
received at least 1 dose of study drug, no tables and figures will be produced. 
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6.1.1 
Analysis Approach for Continuous Variables 
Continuous variables will be summarized using the descriptive statistics (n, mean, standard 
deviation [SD], minimum, median, and maximum) unless stated otherwise in the section specific 
to an endpoint. 
6.1.2 
Analysis Approach for Binary Variables 
Binary and categorical variables will be summarized using the number and percentage of 
subjects unless stated otherwise in the section specific to an endpoint 
6.2 
Disposition of Subjects 
6.2.1 
Study Information 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variables: 
Date of First Subject Signed Informed Consent Form 
Date of Last Subject’s Last Visit/Contact 
MedDRA Version 
WHO Drug Version 
SAS Version Used for Creating the Datasets 
Analytical Methods: 
(1) Study Information 
Study information shown in the analysis variables section will be provided. 
6.2.2 Screen Failures 
Analysis Set: 
All Subjects Who Did Not Enter the Treatment Period 
Analysis Variables: 
Age (years) [<6 years, 6-11 years, >11 years] 
Gender 
[Male, Female] 
Analytical Methods: 
(1) Screen Failures 
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided. 
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6.2.3 Subject Eligibility 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variables: 
Eligibility Status 
[Eligible for Entrance into the Treatment Period, Not Eligible for 
Entrance into the Treatment Period] 
Primary Reason for Subject Not Being Eligible 
[Death, Adverse Event, Screen 
Failure, Protocol Deviation, Lost to Follow-up, Withdrawal by Subject, Withdrawal by 
Parent or Guardian, Study Terminated by Sponsor, Pregnancy, The study is closed 
prior to the subject’s eligible attack, Other] 
Analytical Methods: 
(1) Eligibility for Entrance into the Treatment Period 
Frequency distributions will be provided. When calculating percentages for the 
primary reasons for subject not being eligible, the total number of ineligible subjects 
will be used as the denominator. 
6.2.4 Number of Subjects Who Entered the Treatment Period by Site 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variables: 
Status of Entrance into the Treatment Period 
[Entered] 
Category: 
Site 
[Site numbers will be used as categories] 
Analytical Methods: 
(1) Number of Subjects Who Entered the Treatment Period by Site 
Frequency distribution will be provided by site. 
6.2.5 Disposition of Subjects 
Analysis Set: 
All Subjects Who administered the Study Drug 
Analysis Variables: 
Study Status 
[Completed, Discontinued] 
Reason for Discontinuation of Study 
[Death, Adverse Event, Significant Protocol 
Deviation, Lost to Follow-up, Voluntary Withdrawal by the Subject, Voluntary 
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Withdrawal by Subject’s Parent/Subject’s Legal Guardian, Study Termination, 
Pregnancy, Lack of Efficacy, Other] 
Analytical Methods: 
(1) Disposition of Subjects 
Frequency distributions will be provided. When calculating percentages for the reasons 
for not being treated, the total number of subjects not treated by the study drug will be 
used as the denominator. When calculating percentages for the reasons for 
discontinuation, the total number of subjects who prematurely discontinued will be 
used as the denominator. 
6.2.6 Protocol Deviations and Analysis Sets 
6.2.6.1 Protocol Deviations 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variables: 
Significant Protocol Deviation 
[Entry Criteria, Concomitant Medication, Procedure 
Not Performed Per Protocol, Study Medication, Withdrawal Criteria, Major GCP 
Violations] 
Analytical Methods: 
(1) Protocol Deviations 
Frequency distribution will be provided for each deviation category. A subject who has 
several deviations will be counted once in each appropriate category. A subject who 
has several deviations that can be classified into the same category will be counted 
only once. 
6.2.6.2 Analysis Sets 
Analysis Set: 
All Subjects Who Administered the Study Drug 
Analysis Variables: 
Handling of Subjects 
[Subject Evaluability List] 
Analysis Sets 
Full Analysis Set 
[Included] 
 
 
 
Safety Analysis Set 
[Included] 
Analytical Methods: 
(1) Subjects Excluded from Analysis Sets 
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(2) Analysis Sets 
Frequency distributions will be provided. For (1), a subject who has several reasons for 
exclusion will be counted once in each appropriate category. A subject who has several 
reasons for exclusion that can be classified into the same category will be counted only 
once. 
6.3 
Demographic and Other Baseline Characteristics 
6.3.1 
Demographics and Other Baseline Characteristics 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Age at Informed Consent (years) [<6 years, 6-11 years, >11 years]  
Age at First Treatment (years) 
[<6 years, 6-11 years, >11 years]  
Gender 
[Male, Female] 
Height at First Treatment (cm) 
Height Percentile at First Treatment 
Weight at First Treatment (kg) 
Weight Percentile at First Treatment 
BMI at First Treatment (kg/m2) 
BMI Percentile at First Treatment 
Pubertal Status 
[Prepubertal, Pubertal/Postpubertal] 
 
Prior Icatibant Treatment [Yes, No] 
Time Since Diagnosis at First Treatment (years) 
Time Since First Symptom at First Treatment (years) 
Type of HAE [I, II, Unclassified] 
Amount of C1-INH protein (mg/dL) 
Activity of C1-INH (%) 
Genetic Mutation [Yes, No] 
Family history of HAE 
[Yes, No, No Answer] 
Number of Attacks During Last 12 Months 
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Number of Attacks with Any Medical Intervention During Last 12 Months 
Number of Attacks with Icatibant Treatment During Last 12 Months 
Number of Abdominal Attacks During Last 12 Months 
Number of Cutaneous Attacks During Last 12 Months 
Number of Cutaneous and Abdominal Attacks During Last 12 Months 
Number of Laryngeal Attacks During Last 12 Months 
 
Time Since Last Attack at First Treatment (months) 
Type of Last Attack  
[Cutaneous, Abdominal, Cutaneous and Abdominal, 
Laryngeal] 
Existence of Trigger of Last Attack 
[Yes, No] 
Prodromal Symptoms of Last Attack 
[Yes, No] 
Severity of Last Attack 
[Mild, Moderate, Severe, Very Severe] 
Time to Onset of Relief from Last Attack (hours) 
Time to Complete Relief from Last Attack (hours) 
Medical Intervention 
[Yes, No] 
HAE Medication 
[Yes] 
Intubation 
[Yes] 
Other 
[Yes] 
Analytical Methods: 
(1) Summary of Demographics  
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided.  
For weight percentile and height percentile, a category which apply to the sex and age 
(year and month) of a subject will be identified based on the attached table 2 in the 
Japanese Society for Pediatric Endocrinology1, such as “3 -< 10 percentile”. 
Below variables will be derived and listed. 
Average Time from HAE Onset to Relief for Cutaneous Attacks (hours) 
Average Time from HAE Onset to Relief for Abdominal Attacks (hours) 
 
1 http://jspe.umin.jp/medical/taikaku.html 
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Average Time from HAE Onset to Relief for Cutaneous and Abdominal Attacks 
(hours) 
Average Time from HAE Onset to Relief for Laryngeal Attacks (hours) 
Most Frequent Severity for Previous Cutaneous Attacks [Mild, Moderate, Severe, 
Very Severe] 
Most Frequent Severity for Previous Abdominal Attacks 
[Mild, Moderate, 
Severe, Very Severe] 
Most Frequent Severity for Previous Cutaneous and Abdominal Attacks 
[Mild, 
Moderate, Severe, Very Severe] 
Most Frequent Severity for Previous Laryngeal Attacks [Mild, Moderate, Severe, 
Very Severe] 
6.3.2 
Medical History and Concurrent Medical Conditions 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Medical History 
Concurrent Medical Conditions 
Analytical Methods: 
Medical History and Concurrent Medical Conditions coded by MedDRA dictionary 
will be listed. 
6.4 
Medication History and Concomitant Medications  
6.4.1 
Prior Medications 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Prior HAE Medications 
Analytical Methods: 
(1) Prior HAE Medications by Preferred Medication Name 
Frequency distributions will be provided. WHO Drug dictionary will be used for 
coding. Summaries will be provided using preferred medication name and sorted in 
decreasing frequency based on the number of reports. A subject who has been 
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administered several medications with the same preferred medication name will be 
counted only once for that preferred medication name. 
6.4.2 
Concomitant Medications 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Concomitant HAE Medications 
Rescue Medications 
Analytical Methods: 
(1) Concomitant HAE Medications by Preferred Medication Name 
(2) Rescue Medications by Preferred Medication Name 
Frequency distributions will be provided. WHO Drug dictionary will be used for 
coding. Summaries will be provided using preferred medication names and sorted in 
decreasing frequency based on the number of reports. A subject who has been 
administered several medications with the same preferred medication name will be 
counted only once for that preferred medication name. 
6.5 
Efficacy Analysis 
Due to the small sample size, no statistical inferences (statistical test nor confidence interval) 
will be performed. 
6.5.1 
Secondary Endpoint(s) Analysis 
6.5.1.1 
Derivation of Endpoint(s) 
The definitions of the events of time-to-event endpoints are referred to 1.2.2. The definitions 
of the censors are the duration of time in hours from the time of Icatibant administration to 
the latest observed time in the score or the record in subjects without events. 
Composite investigator-assessed symptom score is calculated by taking an average of 8 
(abdominal or cutaneous attack) or 13 (laryngeal attack) individual symptom scores 
(0=None, 1=Mild, 2=Moderate, 3=Severe, 4=Very Severe), excluding missing scores. 
Assessments on vomiting and diarrhea symptom severity follow a less frequent schedule than 
the other symptoms. On time points that these two symptom scores were not assessed, the 
composite symptom scores will be calculated by taking the average of the other symptom 
scores. 
The subjects with worsened intensity of clinical HAE symptoms between 2 and 4 hours after 
treatment with SC Icatibant using investigator-rated symptom scores is defined as subjects 
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who one or more symptom score(s) in 4 hours after treatment worsen from 2 hours after 
treatment. 
FLACC total score is calculated by sum of all FLACC scores. 
6.5.1.2 
Main Analytical Approach for Time-to-Event Variables 
Analysis Set: 
Full Analysis Set 
Analysis Variables: 
Time to onset of symptom relief by an investigator-rated symptom score 
Time to minimal symptoms by an investigator-rated symptom score 
Time to onset of symptom relief by FPS-R for subjects ≥4 to <18 years of age only 
Time to minimal symptoms by FPS-R for subjects ≥4 to <18 years of age only 
Time to onset of symptom relief by FLACC scale for subjects 2 to <4 years of age 
only 
Time to minimal symptoms by FLACC scale for subjects 2 to <4 years of age only 
Time to initial symptom improvement reported by investigator 
Time to initial symptom improvement reported by subject 
Analytical Methods: 
(1) The survival function (e.g. proportion of subjects not achieving symptom relief) for 
each assessment time will be calculate by Kaplan-Meier method using the first 
Icatibant-treated attacks within each subject. In case of 2 or less subjects in an 
analysis variable, no tables and figures will be produced for the analysis variable. 
(2) Assuming independency in recurrent events within a subject, the survival function 
for each assessment time will be also calculated by Kaplan-Meier method using all 
Icatibant-treated attacks. In case of 2 or less events of Icatibant-treated attacks in 
an analysis variable, no tables and figures will be produced for the analysis 
variable. 
Analysis variables in the second and third Icatibant-treated attacks will be listed.  
6.5.1.3 
Main Analytical Approach for Other Variables 
Analysis Set: 
Full Analysis Set 
Analysis Variables: 
The incidence of rescue medication use 
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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 
Categories: 
Icatibant Exposure 
[#1, #2, #3] 
Analytical Methods: 
(1) The incidence of rescue medication use 
Refer to 6.4.2 (2). 
(2) 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 by Icatibant exposure. 
Frequency distributions will be provided by Icatibant exposure 
6.5.1.4 
Supplementary Analyses 1 
Analysis Set: 
Full Analysis Set 
Analysis Variables: 
Composite investigator-assessed symptom score 
FPS-R 
FLACC total score 
Categories: 
Icatibant Exposure 
[#1, #2, #3] 
Visit: 
Pretreatment (0 Hour), 1, 2, 3, 4, 6, 8 Hour Post-treatment in Icatibant exposure #1 
Pretreatment (0 Hour), 1, 2, 4, 6, 8 Hour Post-treatment in Icatibant exposure #2 and 
#3 
Analytical Methods: 
(1) Composite investigator-assessed symptom score by visit in each Icatibant 
Exposure 
Descriptive statistics for composite investigator-assessed symptom score and 
changes from pretreatment will be provided by visit in each Icatibant exposure. 
The changes from pretreatment will be calculated in each Icatibant exposure.  
Plots of composite investigator-assessed symptom score and subscores over time in 
each Icatibant exposure for each subject will be presented. 
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(2) FPS-R by visit in each Icatibant Exposure 
Descriptive statistics for FPS-R and changes from pretreatment will be provided by 
visit in each Icatibant exposure. The changes from pretreatment will be calculated 
in each Icatibant exposure. 
Plots of FPS-R over time in each Icatibant exposure for each subject will be 
presented. 
(3) FLACC total score by visit in each Icatibant Exposure 
Descriptive statistics for FLACC total score and changes from pretreatment will be 
provided by visit in each Icatibant exposure. The changes from pretreatment will 
be calculated in each Icatibant exposure. 
Plots of FLACC total score over time in each Icatibant exposure for each subject 
will be presented. 
6.5.1.5 
Supplementary Analyses 2 
Analysis Set: 
Full Analysis Set 
Analysis Variables: 
Type of On-study HAE Attack 
[Cutaneous, Abdominal, Cutaneous and Abdominal, 
Laryngeal] 
Time from On-study HAE Attack to Study Drug Administration (hours) 
Categories: 
Icatibant Exposure 
[#1, #2, #3] 
Analytical Methods: 
(1) Type of On-study HAE Attack by Icatibant Exposure 
Frequency distributions will be provided by Icatibant exposure. 
(2) Time from On-study HAE Attack to Study Drug Administration (hours) by 
Icatibant Exposure 
Descriptive statistics will be provided by Icatibant exposure. 
6.5.1.6 
Supplementary Analyses 3 
Analysis Set: 
Full Analysis Set 
Analysis Variables: 
Time to onset of relief from HAE medication in off-study HAE attack 
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Time to complete relief from HAE medication in off-study HAE attack 
Analytical Methods: 
Time to onset of relief and complete relief from HAE medication in off-study HAE 
attack will be listed. 
6.6 
Safety Analysis 
6.6.1 
Adverse Events 
6.6.1.1 
Overview of Treatment-Emergent Adverse Events 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
TEAE 
Categories: 
Relationship to Study Drug [Related, Not Related] 
Intensity 
[Mild, Moderate, Severe] 
Analytical Methods: 
TEAE is defined as an AE that occurs on or after administration of Icatibant for each 
attack and until the end of follow-up period (Day 8). 
The following summaries will be provided. 
Overview of Treatment-Emergent Adverse Events 
1) All Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects)  
2) Relationship of Treatment-Emergent Adverse Events to study drug (number of 
events, number and percentage of subjects) 
3) Intensity of Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects) 
4) Treatment-Emergent Adverse Events leading to study drug discontinuation 
(number of events, number and percentage of subjects) 
5) Serious Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects) 
6) Relationship of Serious Treatment-Emergent Adverse Events to study drug 
(number of events, number and percentage of subjects) 
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7) Serious Treatment-Emergent Adverse Events leading to study drug 
discontinuation (number of events, number and percentage of subjects) 
8) Treatment-Emergent Adverse Events resulting in death (number of events, 
number and percentage of subjects) 
9) Injection Site Reaction Meeting SAE Criteria 
 
TEAEs will be counted according to the rules below. 
Number of subjects 
• Summaries for 2) and 6)  
A subject with occurrences of TEAE in both categories (i.e., Related and Not Related) 
will be counted once in the Related category. 
• Summary for 3)  
A subject with multiple occurrences of TEAE will be counted once for the TEAE with 
the maximum toxicity grade. 
• Summaries other than 2) , 3) , and 6)  
A subject with multiple occurrences of TEAE will be counted only once. 
Number of events 
For each summary, the total number of events will be calculated. 
6.6.1.2 
Displays of Treatment-Emergent Adverse events 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
Icatibant Exposure 
[#1, #2, #3] 
Analytical Methods: 
The following summaries will be provided using frequency distribution. 
TEAEs will be coded using the MedDRA and will be summarized using SOC and PT. 
SOC will be sorted alphabetically and PT will be sorted in decreasing frequency for 
tables provided by SOC and PT. SOC and PT will be sorted in decreasing frequency 
for tables provided by System Organ Class only or PT only. 
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(1) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
(2) Treatment-Emergent Adverse Events by System Organ Class 
(3) Treatment-Emergent Adverse Events by Preferred Term 
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
(5) Intensity of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class, and Preferred Term 
(7) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term 
(8) Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 
(9) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by 
Icatibant Exposure 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
• Summary tables other than (5) and (6) 
A subject with multiple occurrences of TEAE within a SOC will be counted only once 
in that SOC. A subject with multiple occurrences of TEAE within a PT will be counted 
only once in that PT. Percentages will be based on the number of subjects in the safety 
analysis set. 
• Summary tables for (5), (6) and (9) 
A subject with multiple occurrences of TEAE within a SOC or a PT will be counted 
only once for the TEAE with the maximum intensity. Percentages will be based on the 
number of subjects in the safety analysis set. 
• Summary table for (9)  
TEAEs in Icatibant Exposure #1 are defined as TEAEs occurred on or after 
administration of the first Icatibant (until administration of the second Icatibant if the 
subject received the second Icatibant treatment). 
TEAEs in Icatibant Exposure #2 are defined as TEAEs occurred on or after 
administration of the second Icatibant (until administration of the third Icatibant if the 
subject received the third Icatibant treatment). 
TEAEs in Icatibant Exposure #3 are defined as TEAEs occurred on or after 
administration of the third Icatibant. 
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A subject with a TEAE that occurs in more than one category (#1, #2, #3) is counted in 
all the intervals that the TEAE occurs. For each category, a subject with multiple 
occurrences of TEAE within a SOC or a PT will be counted only once in that SOC or 
PT. 
When calculating percentages for each category, the number of subjects at risk (i.e., 
subjects who received the number of Icatibant) will be used as the denominator. The 
number of subjects whose onset of any one of the TEAEs is within the category will be 
used as the numerator. 
6.6.1.3 
Displays of Pretreatment Events 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variables: 
PTE 
Analytical Methods: 
PTE is defined as an AE that occurs before the first administration of Icatibant. 
The following summaries will be provided using frequency distribution. 
PTEs will be coded using the MedDRA and will be summarized using SOC and PT. 
SOC will be sorted alphabetically and PT will be sorted in decreasing frequency. 
(1) Pretreatment Events by System Organ Class and Preferred Term 
(2) Serious Pretreatment Events by System Organ Class and Preferred Term 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
A subject with multiple occurrences of PTE within a SOC will be counted only once in 
that SOC. A subject with multiple occurrences of PTE within a PT will be counted 
only once in that PT. 
<Number of events 
For each summary, the total number of events will be calculated.> 
6.6.2 
Adverse Events of Special Interest 
6.6.2.1 Injection Site Reaction 
Analysis Set: 
Safety Analysis Set 
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Analysis Variables: 
Erythema 
[Absent, Mild, Moderate, Severe] 
Swelling 
[Absent, Mild, Moderate, Severe] 
Cutaneous Pain 
[Absent, Mild, Moderate, Severe] 
Burning Sensation [Absent, Mild, Moderate, Severe] 
Itching/Pruritis 
[Absent, Mild, Moderate, Severe] 
Warm Sensation 
[Absent, Mild, Moderate, Severe] 
Categories: 
Icatibant Exposure 
[#1, #2, #3] 
Visit: 
At Any Time Point1 hour Post Treatment, 4 hours Post Treatment, 8 hours Post 
Treatment, Day 2, Follow-up 
Analytical Methods: 
(1) Proportion of Subjects with Any Injection Site Reaction by each Icatibant Exposure 
Frequency distributions will be provided by each Icatibant exposure.  
(2) Proportion of Subjects with Severe Injection Site Reaction by each Icatibant 
Exposure 
Frequency distributions will be provided by each Icatibant exposure.  
(3) Summary of Injection Site Reaction by Severity by Visit in each Icatibant Exposure 
Frequency distributions will be provided by visit in each Icatibant exposure.  
6.6.3 
Clinical Laboratory Evaluations 
6.6.3.1 
Hematology and Serum Chemistry 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Hematology 
Red blood cells (RBC), White blood cells (WBC) count with differential (%) 
(neutrophil, basophil, eosinophil, lymphocyte, monocyte), Hemoglobin, Hematocrit, 
Platelets, Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin 
concentration (MCHC), Mean corpuscular volume (MCV) 
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Serum Chemistry 
ALT, Albumin, Alkaline phosphatase, AST, Total bilirubin, Creatinine, Creatine 
kinase, Gamma-Glutamyl transferase (GGT), Chloride, Potassium, Sodium, 
Calcium, Glucose, Lactate dehydrogenase (LDH), Carbon dioxide (CO2), 
Phosphorus, Blood urea nitrogen (BUN), Magnesium, Total protein, Uric acid 
Categories: 
Icatibant Exposure 
[#1, #2, #3] 
Results of determination based on normal reference range 
[Low, Normal, High] 
Visit: 
Baseline, Post Treatment, Follow-up 
Analytical Methods: 
The following summaries will be provided. 
(1) Summary of Laboratory Test Results and Change from Baseline by Visit in each 
Icatibant Exposure 
Descriptive statistics for observed values and changes from baseline will be provided 
by visit in each Icatibant Exposure. The changes from baseline will be calculated in 
each Icatibant Exposure. 
Values below the lower limit of quantification will be treated as zero when calculating 
the descriptive statistics. Values above the upper limit of quantification will be treated 
as the upper limit value when calculating the descriptive statistics. 
(2) Summary of Shifts of Laboratory Test Results by Visit in each Icatibant Exposure 
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit will be provided. 
For each laboratory test, the laboratory values will be classified as “Low”, “Normal” or 
“High” relative to the normal reference range. The shift tables will be based on these 
classifications. 
6.6.3.2 
Urinalysis 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Specific gravity 
Glucose 
[-,  +-,  1+,  2+,  3+,  4+,  5+] 
pH [Min <= - <= 8.0, 8.0 < - <= Max] 
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Protein 
[-,  +-,  1+,  2+,  3+,  4+,  5+] 
Occult blood 
[-,  +-,  1+,  2+,  3+,  4+,  5+] 
Ketones 
[-,  +-,  1+,  2+,  3+,  4+,  5+] 
Bilirubin 
[-,  +-,  1+,  2+,  3+,  4+,  5+] 
Nitrites 
[-,  +-,  1+,  2+,  3+,  4+,  5+] 
Categories: 
Icatibant Exposure 
[#1, #2, #3] 
Visit: 
Baseline, Post Treatment, Follow-up 
Analytical Methods: 
For specific gravity, summaries (1) and (2) will be provided. 
For each variable other than specific gravity, summaries (3) will be provided. 
(1) Summary of Laboratory Test Results and Change from Baseline by Visit in each 
Icatibant Exposure 
Descriptive statistics for observed values and changes from baseline will be provided 
by visit in each Icatibant Exposure. The changes from baseline will be calculated in 
each Icatibant Exposure. 
(2) Summary of Shifts of Laboratory Test Results by Visit in each Icatibant Exposure 
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit in each Icatibant exposure will be provided. 
For each laboratory test, the laboratory values will be classified as “Low”, “Normal” or 
“High” relative to the normal reference range. The shift tables will be based on these 
classifications. 
(3) Number of Subjects in Categories of Urine Laboratory Test Results by Visit in each 
Icatibant Exposure 
Shift tables showing the number of subjects in each category at baseline and each post-
baseline visit in each Icatibant exposure will be provided. 
6.6.4 
Vital Signs 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Body Temperature 
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Respiratory Rate 
Sitting Systolic Blood Pressure 
Sitting Diastolic Blood Pressure 
Pulse Rate 
Categories: 
Icatibant Exposure 
[#1, #2, #3] 
Visit: 
Baseline, 0.5 hour Post Treatment, 1 hour Post Treatment, 8 hours Post Treatment, 
Follow-up in Icatibant Exposure #1 
Baseline, 1 hour Post Treatment, 8 hours Post Treatment, Follow-up in Icatibant 
Exposure #2 and #3 
Analytical Methods: 
The following summaries will be provided. 
(1) Summary of Vital Signs and Change from Baseline by Visit in each Icatibant 
Exposure 
Descriptive statistics for observed values and changes from baseline will be provided 
by visit in each Icatibant Exposure. The changes from baseline will be calculated in 
each Icatibant exposure. 
6.6.5 
12-Lead ECGs 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Heart Rate 
RR Interval 
PR Interval 
QT Interval 
QRS Interval 
QTcF Interval 
Interpretation 
[Within Normal Limits, Abnormal but not Clinically Significant, 
Abnormal and Clinically Significant] 
Categories: 
Icatibant Exposure 
[#1, #2, #3] 
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Visit: 
Baseline, 0.75 hour Post Treatment, 8 hours Post Treatment, Follow-up in Icatibant 
Exposure #1 
Baseline, 1 hour Post Treatment, 8 hours Post Treatment, Follow-up in Icatibant 
Exposure #2 and #3 
Analytical Methods: 
For each variable other than 12-lead ECG interpretations, summaries (1) and (2) will 
be provided. 
For 12-lead ECG interpretation, summary (3) will be provided. 
(1) Summary of ECG Parameters and Change from Baseline by Visit in each Icatibant 
Exposure 
Descriptive statistics for observed values and changes from baseline will be provided 
by visit in each Icatibant Exposure. The changes from baseline will be calculated in 
each Icatibant exposure. 
(2) Summary of Shift of 12-lead ECG Interpretation by Visit in each Icatibant Exposure 
Shift table showing the number of subjects in each category at baseline and each post-
baseline visit in each Icatibant exposure will be provided. 
6.6.6 
Other Safety Analysis 
6.6.6.1 
Reproductive hormone levels 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Reproductive hormone levels 
FSH, LH, estradiol, and progesterone in females 
FSH, LH, and testosterone in males 
Categories: 
Icatibant Exposure 
[#1, #2, #3] 
Results of determination based on normal reference range 
[Low, Normal, High] 
Visit: 
Baseline, Post Treatment, Follow-up 
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Analytical Methods: 
Reproductive hormone levels and classified values as “Low”, “Normal” or “High” 
relative to the normal reference range will be listed. 
6.6.6.2 
Immunogenicity (presence of anti-Icatibant antibodies) 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Immunogenicity (presence of anti-Icatibant antibodies) 
Categories: 
Icatibant Exposure 
[#1, #2, #3] 
Anti-Icatibant Antibody [Positive, Negative] 
Visit: 
Baseline, Follow-up 
Analytical Methods: 
The following summaries will be provided. 
(1) Frequency Distributions by Visit in each Icatibant Exposure 
Frequency distributions of Anti-Icatibant Antibody by visit in each Icatibant exposure 
will be provided. 
6.6.7 
Extent of Exposure and Compliance 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Number of Icatibant Exposure 
[1, 2, 3] 
Analytical Methods: 
(1) Study Drug Exposure and Compliance 
Frequency distributions for categorical variables will be provided. 
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses 
6.7.1 
Pharmacokinetic Analysis 
Analysis Set: 
Safety Analysis Set 
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Analysis Variable(s): 
Plasma Concentrations of Icatibant Analyte (Icatibant, M-I and M-II) 
Visit: 
Predose, 0.5, 1.0, 2.0, and 4.0 hours after the first Icatibant administration 
Analytical Method(s): 
The following summaries will be provided. 
(1) Summary of Plasma Concentrations by Visit 
Descriptive statistics will be provided by visit. 
6.8 
Other Analyses 
6.8.1 
Self-administration Assessment 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Do you consider the training materials sufficient to explain the method of self-
administration? 
[1 - not at all sufficient, 2 - not sufficient, 3 - neither sufficient nor 
insufficient, 4 - sufficient, 5 - very sufficient] 
How stressful did you find the idea of self-injecting this medication during an HAE 
attack? 
[1 - very stressful, 2 - stressful, 3 - indifferent, 4 - not stressful, 5 - not at 
all stressful] 
Was it difficult to prepare the injection site before self-injection? [1 - very difficult, 2 - 
difficult, 3 - neither difficult nor easy, 4 - easy, 5 - very easy] 
Was it difficult to adjust the dose using a graduated syringe and connector? 
[1 - 
very difficult, 2 - difficult, 3 - neither difficult nor easy, 4 - easy, 5 - very easy] 
Did you find it difficult to assemble and handle the syringe? 
[1 - very difficult, 2 - 
difficult, 3 - neither difficult nor easy, 4 - easy, 5 - very easy] 
How difficult was it to actually self-inject the study medication? [1 - very difficult, 2 - 
difficult, 3 - neither difficult nor easy, 4 - easy, 5 - very easy] 
Visit: 
Icatibant Exposure [#1, #2, #3] 
Analytical Method(s): 
The frequency distributions by Icatibant exposure will be provided. 
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6.9 
Interim Analyses 
Not applicable. 
7.0 
REFERENCES 
Not applicable. 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
Not applicable. 
9.0 
APPENDIX  
9.1 
Changes From the Previous Version of the SAP 
 
Original version in section 6.1 
In case of 2 subjects who received at least 1 dose of study drug, no tables and figures will be 
produced except for 6.5.1.2 (2), 6.6.1.1, 6.6.1.2 (1), and 6.6.2.1. 
 
Amendment 1 
In case of 2 subjects who received at least 1 dose of study drug, no tables and figures will be 
produced except for 6.6.1.1, 6.6.1.2 (1), and 6.6.2.1. 
 
Reason for the amendment 
Correction, to follow the specification in 6.5.1.2 (2), “In case of 2 or less events of Icatibant-
treated attacks in an analysis variable, no tables and figures will be produced for the analysis 
variable.” 
 
 
Original version in section 6.2.5.1 
6.2.5.1 Treatment of Subjects 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variables: 
Study Drug Administration Status 
[Eligible but Not Treated] 
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Reason for Not Being Treated 
[Death, Adverse Event, Significant Protocol Deviation, 
Lost to Follow-up, Voluntary Withdrawal by the Subject, Voluntary Withdrawal by Subject’s 
Parent/Subject’s Legal Guardian, Study Termination, Pregnancy, Other]  
Analytical Methods: 
(1) 
Disposition of Subjects 
Frequency distributions will be provided. When calculating percentages for the reasons for not 
being treated, the total number of subjects not treated by the study drug will be used as the 
denominator. When calculating percentages for the reasons for discontinuation, the total number 
of subjects who prematurely discontinued will be used as the denominator. 
 
Amendment 1 
Deleting this section. 
 
Reason for the amendment 
The same results will be obtained as the analysis of 6.2.5.2. 
 
 
Original version in section 6.3.1 
Age (years) 
[<6 years, 6-11 years, >11 years]  
Gender [Male, Female] 
Height (cm) 
Height percentile 
Weight (kg) 
Weight percentile 
BMI (kg/m2) 
BMI percentile 
 
Amendment 1 
Age at Informed Consent (years) 
[<6 years, 6-11 years, >11 years]  
Age at First Treatment (years) 
[<6 years, 6-11 years, >11 years]  
Gender [Male, Female] 
Height at First Treatment (cm) 
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Height Percentile at First Treatment 
Weight at First Treatment (kg) 
Weight Percentile at First Treatment 
BMI at First Treatment (kg/m2) 
BMI Percentile at First Treatment 
 
Reason for the amendment 
To ad age at informed consent and to clarify the timing of analyses. 
 
Original version in section 6.3.1 
Average Duration of Previous Cutaneous Attacks (days) 
Average Duration of Previous Abdominal Attacks (days) 
Average Duration of Previous Cutaneous and Abdominal Attacks (days) 
Average Duration of Previous Laryngeal Attacks (days) 
 
Amendment 1 
Deleting above them. 
 
Reason for the amendment 
These cannot be calculated. 
 
 
Original version in section 6.3.1 
Most Frequent Severity for Previous Cutaneous Attacks 
[Mild, Moderate, Severe] 
Most Frequent Severity for Previous Abdominal Attacks 
[Mild, Moderate, Severe] 
Most Frequent Severity for Previous Cutaneous and Abdominal Attacks 
[Mild, Moderate, 
Severe] 
Most Frequent Severity for Previous Laryngeal Attacks 
[Mild, Moderate, Severe] 
 
Amendment 1 
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Most Frequent Severity for Previous Cutaneous Attacks 
[Mild, Moderate, Severe, Very 
Severe] 
Most Frequent Severity for Previous Abdominal Attacks 
[Mild, Moderate, Severe, Very 
Severe] 
Most Frequent Severity for Previous Cutaneous and Abdominal Attacks 
[Mild, Moderate, 
Severe, Very Severe] 
Most Frequent Severity for Previous Laryngeal Attacks 
[Mild, Moderate, Severe, Very 
Severe] 
 
Reason for the amendment 
To add “Very Severe” per CRF. 
 
 
Original version  
None 
 
Amendment 1 
6.5.1.6 Supplementary Analyses 3 
Analysis Set: 
Full Analysis Set 
Analysis Variables: 
Time to onset of relief from HAE medication in off-study HAE attack 
Time to complete relief from HAE medication in off-study HAE attack 
Analytical Methods: 
Time to onset of relief and complete relief from HAE medication in off-study HAE attack will be 
listed. 
 
Reason for the amendment 
To add this listing. 
 
 
Original version in section 6.6.2 
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Visit: 
Baseline, 1 hour Post Treatment, 4 hours Post Treatment, 8 hours Post Treatment, Day 2, 
Follow-up 
 
Amendment 1 
Visit: 
At Any Time Point, 1 hour Post Treatment, 4 hours Post Treatment, 8 hours Post Treatment, Day 
2, Follow-up 
 
Reason for the amendment 
Correction 
 
 
Original version in section 6.6.3.2 
Glucose 
[-,  +-,  1+,  2+,  3+,  4+] 
pH 
[Min <= - <= 8.0, 8.0 < - <= Max] 
Protein [-,  +-,  1+,  2+,  3+,  4+] 
Occult blood [-,  +-,  1+,  2+,  3+,  4+] 
Ketones 
[-,  +-,  1+,  2+,  3+,  4+] 
Bilirubin 
[-,  +-,  1+,  2+,  3+,  4+] 
Nitrites[-,  +-,  1+,  2+,  3+,  4+] 
 
Amendment 1 
Glucose 
[-,  +-,  1+,  2+,  3+,  4+,  5+] 
pH 
[Min <= - <= 8.0, 8.0 < - <= Max] 
Protein [-,  +-,  1+,  2+,  3+,  4+,  5+] 
Occult blood [-,  +-,  1+,  2+,  3+,  4+,  5+] 
Ketones 
[-,  +-,  1+,  2+,  3+,  4+,  5+] 
Bilirubin 
[-,  +-,  1+,  2+,  3+,  4+,  5+] 
Nitrites[-,  +-,  1+,  2+,  3+,  4+,  5+] 
 
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Reason for the amendment 
Correction 
 
 
Original version in section 6.6.5 
Visit: 
Baseline, 0.75 hour Post Treatment, 1 hour Post Treatment, 8 hours Post Treatment, Follow-up 
in Icatibant Exposure #1 
 
Amendment 1 
Visit: 
Baseline, 0.75 hour Post Treatment, 8 hours Post Treatment, Follow-up in Icatibant Exposure #1 
 
Reason for the amendment 
Correction 
 
9.2 
Data Handling Conventions  
9.2.1 
Definition of Visit Windows  
No windowing of visits and time points will be done for data obtained at the scheduled visits and 
time points.  
9.3 
Analysis Software  
Statistical analyses will be performed using
on a suitably 
qualified environment. 
CCI
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