FIRAZYR General Drug Use-Results Survey (Japan)
Conditions: Hereditary Angioedema (HAE)
Sponsor: Shire

Clinical Study Protocol 
NCT Number: NCT04057131 
Title: FIRAZYR® Subcutaneous Injection 30 mg Syringe General Drug Use-Results 
Survey 
Study Number: SHP667-401 
Document Version and Date: Version 9.0 / 21-Sep-2023 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 
A summary of changes to previous protocol versions is appended to the end of the 
document. 
Note; This document was translated into English as the language on original version 
was Japanese. 

For re-examination
FIRAZYR ® Subcutaneous Injection 30 mg Syringe 
General use-results survey
Protocol
Date of preparation: September 21, 2023 (Ver. 9.0) 
Takeda Pharmaceutical Company Limited. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

FIRAZYR ® Subcutaneous Injection 30 mg Syringe (Icatibant Acetate) 
General Drug Use-Results Survey Protocol SHP667-401 Ver.9.0  September 21, 2023 
Takeda 
1 
1.
Objectives of the survey
The main objectives of this survey are to investigate the following items in patients with hereditary
angioedema (Hereditary angioedema: Hereditary angioedema) who used Firazyr (hereinafter
referred to as this drug) in clinical practice.
(1)
Unknown adverse reactions
(2)
Incidence of adverse reactions under the actual use status of this drug
(3)
Factors that may affect the safety or efficacy
2.
Safety and efficacy specifications
(1)
Serious hypersensitivity and severe injection site reaction
(2)
Aggravation of cardiac function under ischemic conditions due to bradykinin antagonistic action
(3)
Blood pressure decreased
(4)
Immunogenicity
3.
Survey implementation plan
(1)
Number of patients to be surveyed and its rationale
Estimated number of patients to be surveyed: 75
Rationale for setting: There are 400 HAE patients in Japan, and approximately 2/3 of them are
assumed to receive treatment for acute attacks. Given the expected switch from existing products
to the use of this drug after the launch of this drug, the number of registrable cases will be
approximately 75 in 3 years. In the Japanese phase III clinical study (Study SHP FIR 301), the
incidence of severe injection site reaction was 12.5% (1/8 subjects), and the sample size of 75
subjects will enable to detect at least 3 cases of severe injection site reaction with a probability of
95%. To collect 75 cases, the survey period was determined to be approximately 4 years in
consideration of the registration period of 3 years and the period of 1 year until the collection of
survey forms and case fixation.
(2)
Scope of patients to be surveyed
To include HAE patients who are treated with this drug for the first time.
The indication and dosage and administration of this drug are as follows.
•
Indication: Acute attack of hereditary angioedema
•
Dosage and administration: The usual adult dosage is 30 mg of icatibant administered
subcutaneously. Additional doses of 30 mg may be administered at intervals of at least 6
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

FIRAZYR ® Subcutaneous Injection 30 mg Syringe (Icatibant Acetate) 
General Drug Use-Results Survey Protocol SHP667-401 Ver.9.0  September 21, 2023 
Takeda 
2 
hours if response is inadequate or if symptoms recur. No more than 3 doses may be 
administered within any 24 hours period. 
(3)
Planned number of sites by clinical department to be surveyed
Targeting all medical institutions to which this drug has been delivered: Approximately 20
institutions
(4)
Survey method
This surveillance will be conducted using an all-case surveillance system. Electrical Data Capture
(EDC) is used as a rule and data is collected based on the following procedures. If the EDC is not
acceptable at each site, an alternative method to the EDC will be used to conduct the same
investigation.
1)
Survey request/contract
At the time of requesting this survey, medical representatives, etc. shall request the survey at
all the following institutions.
•
Sites with physicians experienced in the treatment of HAE
•
Sites planning to administer this drug to patients to be surveyed
If the conduct of this survey is approved, a contract will be concluded in writing with the medical 
institution. 
2)
Patient Enrollment
Patients will be enrolled via a central registration system. Physicians in charge of surveillance
will register all patients who are prescribed this drug for the first time after approval in principle.
The investigator will enter the following information necessary for registration in the case
registration form and send it.
•
Patient identification number
•
Sex
•
Date of birth or age
•
Date this drug started or dispensed
3)
Collection of survey forms and observation period
•
Patients will be observed for up to 3 months after this drug administration.
However, as for the status of attack and its treatment status, the reporting period will be
the period until 3 months after the initial attack or until disappearance of up to the fifth
attack treated with this drug.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

FIRAZYR ® Subcutaneous Injection 30 mg Syringe (Icatibant Acetate) 
General Drug Use-Results Survey Protocol SHP667-401 Ver.9.0  September 21, 2023 
Takeda 
3 
The rationale for setting the observation period is set at 3 months from the prescription 
of this drug based on the results of a phase III clinical study (median number of months 
from the previous attack was 1.5 months). 
Adverse events occurring after the end of the observation period will be separately 
reported as spontaneous reports. 
•
The efficacy and safety variables to be collected in the survey were those that are
periodically observed in HAE patients in clinical practice.
•
Since the number of registered cases has reached the planned number, a request will be
made to prepare and submit CRFs for cases prescribed by June 30, 2020, and Patient
registration requiring no preparation and submission of CRFs will be implemented for
cases whose prescriptions have started on or after July 1, 2020, until the date of issuance
of the partial revision of the “Q & A on use-results surveys by the all-case surveillance
method for ethical drugs ” (Administrative Notice dated August 10, 2023).
Until the approval conditions for all-case surveillance are lifted, the system in which
survey forms can be collected as necessary to obtain appropriate information will be
maintained.
4)
Confirmation of All-case Registration
After shifting to the patient registration only period, we will confirm with the All-Case
Registration Confirmation Form that all patients for whom this drug was prescribed and who
require preparation and submission of CRF are registered.
(5)
Survey period
The investigation period is as follows.
•
Survey period: November 2018 to April 30, 2023
•
Registration period: November 2018 to August 10, 2023
•
Date of completion of investigation (date of completion of final analysis): January 2024
(planned)
*The survey and registration periods for patients whose prescriptions had been started by June
30, 2020, for whom preparation and submission of survey forms are required, are until April 30,
2023. Thereafter, only registration will be performed until August 10, 2023.
(6)
Items to be surveyed
1)
Patient characteristics: Patient identification number, sex, date of birth or age, and race
2)
Physical examination: weight, height
3)
HAE diagnosis: Year of onset of first symptom, year of HAE diagnosis, HAE type (Type I, II
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

FIRAZYR ® Subcutaneous Injection 30 mg Syringe (Icatibant Acetate) 
General Drug Use-Results Survey Protocol SHP667-401 Ver.9.0  September 21, 2023 
Takeda 
4 
or III), genetic mutation, other angioedema diagnosis, family history 
4)
Concomitant medications and therapies
5)
Past history and complications
6)
History of HAE attacks in the last 12 months before treatment with this drug: number of
attacks, location, treatment history
7)
HAE attack status during the observation period: number of attacks, site of onset, severity
of attacks, triggers of attack, prodromal symptoms, number of visits, details of treatment,
etc.
8)
Administration status of this drug: this drug Method of administration (self-administration or
administration by healthcare professionals), dose and frequency of administration, presence
or absence of other treatments, time from onset of attack to start of treatment, time to initial
symptom relief, time to symptom resolution
9)
Discontinued: Timing of and reason for discontinuation
10)
Laboratory tests: Clinically significant abnormal changes in routine laboratory parameters
arbitrarily measured at a medical institution before the start of prescription of this drug or
during the observation period, if any, will be collected as adverse events along with the time
course.
11)
Pregnancy and lactation status
12)
Adverse events: name of adverse event, date and time of onset, seriousness (classification
of serious), severity, presence or absence of treatment, details of treatment, outcome, date
and time of outcome, procedure, date and cause of death, presence or absence of autopsy
(if applicable), causal relationship with this drug
(7)
Items to be analyzed and methods
1)
Analysis Items
a. Patient Population
Number of patients enrolled, number of patients from whom survey forms were collected,
number of patients receiving this drug (safety analysis set), number of patients analyzed
for efficacy, number of discontinued patients, details of reason for discontinuation, etc.
b. Matters concerning safety
•
Adverse events/adverse drug reactions
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), and the incidence and number of ADRs will be tabulated by preferred term (PT) 
and system organ class (SOC), by treatment for angioedema, and other stratification as 
needed. Serious adverse events will be tabulated in the same manner. In addition, serious 
hypersensitivity and severe injection site reactions during or after this drug administration, 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

FIRAZYR ® Subcutaneous Injection 30 mg Syringe (Icatibant Acetate) 
General Drug Use-Results Survey Protocol SHP667-401 Ver.9.0  September 21, 2023 
Takeda 
5 
worsening of cardiac function under ischemic conditions due to bradykinin antagonism, 
decreases in blood pressure, and the development of symptoms suggestive of 
immunogenicity will be summarized. 
c. Items Related to Efficacy
To evaluate the efficacy of this drug in patients with HAE attacks.
•
Time from onset of attack to start of treatment: Time from onset of attack to first
dose
•
Time to initial symptom relief
•
Time to symptom resolution: time from first dose to complete resolution of all
symptoms
•
Duration of attack: time from the start of attack to resolution of all symptoms
2)
Analysis Methods
Mainly, frequencies will be tabulated for categorized data such as mean and standard
deviation of quantitative data and descriptive summaries. Additional details will be provided 
in the SAP. 
(8)
Organizational structure for implementation of the survey
See Attachment
(9)
If part of the operations related to the study is outsourced, the name and address of the
contractor of the operations and the scope of the outsourced operations
•
Entrustee of the operations [1]
Scope of operations 
Data management, statistical analysis, medical writing 
•
Contractor of the operations [2]
Scope of operations
Receipt of paper-based CRFs, etc. sent from sites, confirmation of the presence or
absence of descriptions of adverse events, transfer of original CRFs, etc. to Contractor 1,
storage of site contracts, etc.
•
Contractor of the operations (3)
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

FIRAZYR ® Subcutaneous Injection 30 mg Syringe (Icatibant Acetate) 
General Drug Use-Results Survey Protocol SHP667-401 Ver.9.0  September 21, 2023 
Takeda 
6 
 
Scope of operations
Operations related to monitoring
4.
ADDITIONAL MEASURES THAT MAY BE IMPLEMENTED BASED ON THE SURVEY RESULTS
AND CRITERIA FOR DETERMINING THE INITIATION
The Risk Management Plan including the following contents will be reviewed at milestones. 
•
Review the necessity for changes in risk minimization activities for the current safety
specifications.
•
Review the necessity for changing the contents of the plan of the post-marketing surveillance
(continuation of the surveillance, implementation of additional surveillance, etc.), including the
presence or absence of new safety specifications.
•
Review the necessity of formulating risk minimization measures for new safety specifications.
5.
Scheduled timing of milestones for evaluation of the implementation status of the survey
and obtained results, or reporting to the PMDA, and their rationales
•
At the time of preparation of periodic safety reports and at the time of application for
reexamination: To comprehensively examine safety information.
•
At the time of preparation of the final report: To evaluate the safety including the comparison
with the results of clinical studies and to examine the necessity of changing the plan such as
adding the number of subjects to be investigated.
6.
Other necessary matters
(1)
Revision of the protocol
The necessity of revision will be examined based on new findings obtained as the survey
progresses, and the protocol will be revised as necessary.
(2)
Actions to be taken if any problem or question is observed
In cases where the onset of a serious and unknown adverse reaction is suggested, a significant
increase in the frequency of adverse reactions is found, any problem is found in the efficacy and
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

FIRAZYR ® Subcutaneous Injection 30 mg Syringe (Icatibant Acetate) 
General Drug Use-Results Survey Protocol SHP667-401 Ver.9.0  September 21, 2023 
Takeda 
7 
safety compared to those until the time of approval, or the onset of a specific adverse reaction is 
suggested, etc., a hypothesis should be developed and implementation of a special drug use 
investigation to verify the hypothesis should be considered. 
< Attachment >
1)
Implementation guidelines
2)
Registration form
3)
Survey form
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Document History 
Version 
Date 
Comments 
original version 
2018/8/10 
New document 
2nd version 
2018/10/23 
2.
Safety 
and 
efficacy 
specifications 
and 
3. 
Survey
implementation plan
3rd version 
2019/3/27 
3. Survey implementation plan
4th version 
2020/10/1 
3. Survey implementation plan
5th version 
2020/11/1 
3. Survey implementation plan
6th version 
2021/1/15 
3. Survey implementation plan
7th version 
2021/11/8 
3. Survey implementation plan
8th version 
2022/5/12 
3. Survey implementation plan
9th version 
2023/9/21 
3. Survey implementation plan
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use