Clinical trial NCT04687137
Conditions: Hereditary Angioedema
Sponsor: Takeda
Start date: 2021-02-10; Completion date: 2022-06-18
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The expanded access program allows people to gain access to an unlicensed treatment on compassionate grounds. Lanadelumab, also known as TAK-743, is a medicine to help prevent hereditary angioedema attacks. Lanadelumab is not yet licensed for use in Japan.

The main aim of this study is to allow Japanese teenagers and adults with type I or type II hereditary angioedema to be treated with lanadelumab, through the expanded access program in Japan.

Participants can either have taken part in the previous study SHP643-302 or can be new participants. Participants just completing study SHP643-302 who reach the criteria can automatically take part in this study. However, for new participants, the study doctor will check who can take part at the first study visit.

For those who can take part, new participants will receive injections of lanadelumab just under the skin. Eventually, after training, some of these will be able to inject themselves with lanadelumab in the same way. Participants who injected themselves with lanadelumab in study SHP643-302 can continue to do so during this study.

The study doctors will decide if each participant will be treated with lanadelumab every 2 weeks or every 4 weeks. Treatment with lanadelumab will continue until lanadelumab is commercially available in Japan or the sponsor (Takeda) stops the study.

Participants can visit the clinic during treatment if needed. If treatment continues after 6 months, participants will visit the clinic every 12 weeks for a check-up. This will include noting any hereditary angioedema attacks and side effects from the treatment. After 7 months of treatment, the study staff will check-up with each participant every 2 weeks by telephone.

After treatment has finished, participants will visit the clinic for a final-check-up 4 weeks later.

Detailed description:
This study is Japan Expanded Access Program with TAK-743. The study drug in this study is called TAK-743. TAK-743 will be administered to people who have Type I or II hereditary angioedema (HAE).

Two types of participants will be enrolled into this study:

* Participants who rollover from Study SHP643-302 (NCT04180163).
* Participants who are non-rollovers (ie, were not participants in Study SHP643-302).

Participants who discontinue from Study SHP643-302 after providing informed consent are not eligible to enroll in this study.

All participants will be asked to administer TAK-743 300 mg with subcutaneous injection every 2 weeks throughout this study. Participants who is stable with over 6-month administration of 300mg every 2 weeks can be switched to 300mg every 4 weeks.

This multi-center trial will be conducted in Japan (approximately 15 sites). The overall time to participate in this study is over 182 days. Participants will make multiple visits to the clinic basically every 2 weeks until Day 182, and will be contacted by telephone every 2 weeks after Day 182 plus multiple visit every 12 weeks after Day 182 for a follow-up assessment until study completion.

Arms: arm 1: None
Interventions: intervention 1: TAK-743 300 mg
Intervention descriptions: intervention 1: TAK-743 300 mg, subcutaneous injection every 2 or 4 weeks

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
NCT Number: NCT04687137 
Title: Open-arm, Japan Expanded Access Program with Lanadelumab (TAK-743) for 
Japanese Patients with Hereditary Angioedema 
Study Number: TAK-743-5007 
Document Version and Date: Amendment 01 / 09-Feb-2021 
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. 


 
 
 
TAKEDA PHARMACEUTICALS 
PROTOCOL 
Title 
Open-arm, Japan Expanded Access Program with Lanadelumab (TAK-743) for Japanese 
Patients with Hereditary Angioedema 
Short Title 
Open-arm, Japan Expanded Access Program with Lanadelumab for Japanese Patients with 
Hereditary Angioedema 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Study Number: 
TAK-743-5007 
IND Number: 
Not Applicable  
EudraCT Number: 
Not Applicable 
Compound: 
Lanadelumab (TAK-743, formerly SHP643; DX-2930） 
Date: 
09 February 
2021 
Amendment 
Number: 
01 
Amendment History: 
Date 
Amendment Number 
Region 
06 October 2020 
Initial version 
Global 
09 February 2021 
01 
Global 
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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 
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1.3 
Protocol Amendment 01 Summary of Changes 
This document describes the changes in reference to the Protocol Incorporating Amendment No. 
01. 
The primary purpose of this amendment is to update the protocol regarding the list of clinical 
laboratory tests and errata of original protocol. Other minor changes in procedures are proposed. 
Minor editorial changes are included for clarification purposes only. Full details on changes of 
text are given in Protocol Annex 4, including detailed rationale. The following is a summary of 
the changes made in the amendment: 
•
Correction of contraception procedure and duration, and relevant inclusion criterion.
Justification: Inconsistencies within the original protocol is corrected according to acceptable
contraception in Japan. Also, the contraception duration for female subjects is the same as
Study SHP643-202.
•
Change of allowable duration of the short or long-term prophylactic therapy for hereditary
angioedema (HAE), eg, C1 inhibitor (C1-INH), attenuated androgens or anti-fibrinolytics
after starting the treatment period.
Justification: The allowable duration of therapy for HAE is extended like Study DX-2930-04.
•
Correction of number of prefilled syringe (PFS) supplied to subjects.
Justification: Considering the next visit, the required amount of study drug will be supplied
to the subject who self-administer study drug.
•
Medication history information of LTP will be recorded from 90 days prior to signing of
informed consent.
Justification: Medication history information will be recorded as with Study SHP643-302.
•
Addition of the action taken of study drug for adverse event (AE).
Justification: The action taken of study drug for AE includes dose reduced and dose
increased.
•
Addition of the list of clinical laboratory tests.
Justification: Clarification of the parameters of clinical laboratory tests.
•
Correction of the start date of the treatment duration.
•
Addition of the rationale for the study due to new approval of berotralstat.
•
Clarification of the informed consent of subjects aged 12 to 19.
•
Clarification of the prohibited duration of angiotensin-converting enzyme (ACE) inhibitors in
the excluded medication.
•
Correction of the items the site representative records on the label of the study drug.
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•
Correction of how to return the used and unused PFS to study site.
•
Correction of the person rollover subjects inform about an accidental overdose.
•
Correction of the contents assigned by Interactive Response Technology (IRT).
•
Clarification of the study procedure of rollover subjects and non-rollover subjects.
•
Clarification of the timepoint when subjects can self-administer the study drug.
•
Addition of the study visit of Study Day 266.
•
Clarification of the reporting of ongoing AE and concomitant medication from the previous
study.
•
Clarification of the study visit when clinical laboratory testing is not performed.
•
Correction of the study visits which can be done at local site or remotely (via phone or video)
at investigator’s discretion if approved by institutional review board (IRB).
•
Clarification of the study day on telephone visits after Study Visit 14 (Day 182).
•
Correction of the body temperature range on Grade 1 for fever oral in SYSTEMIC of
National Institute of Allergy and Infectious Diseases, Division of Microbiology and
Infectious Diseases (DMID) Adult Toxicity (Appendix E)
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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 .........................................................................................3 
1.3 
Protocol Amendment 01 Summary of Changes.............................................................4 
2.0 
STUDY SUMMARY.........................................................................................................11 
3.0 
LIST OF ABBREVIATIONS ............................................................................................15 
3.1 
Corporate Identification ...............................................................................................16 
4.0 
INTRODUCTION .............................................................................................................17 
4.1 
Background ..................................................................................................................17 
4.1.1 Indication and Current Treatment Options ............................................................18 
4.1.2 Non-clinical studies with Lanadelumab .................................................................18 
4.1.3 Clinical studies with Lanadelumab ........................................................................19 
4.2 
Rationale for the Proposed Study ................................................................................20 
4.3 
Benefit/Risk Profile .....................................................................................................21 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................22 
5.1 
Objectives ....................................................................................................................22 
5.1.1 Primary Objective ..................................................................................................22 
5.1.2 Secondary Objectives.............................................................................................22 
5.2 
Endpoints .....................................................................................................................22 
5.2.1 Safety Endpoints ....................................................................................................22 
5.2.2 Efficacy Endpoints .................................................................................................22 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................23 
6.1 
Study Design ................................................................................................................23 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................25 
6.2.1 Scientific rationale for study design ......................................................................25 
6.2.2 Justification for dose ..............................................................................................26 
6.3 
Premature Termination or Suspension of Study or Study Site ....................................27 
6.3.1 Criteria for Premature Termination or Suspension of the Study ...........................27 
6.3.2 Criteria for Premature Termination or Suspension of Study Sites ........................27 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s) .................................................................................27 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............28 
7.1 
Inclusion Criteria .........................................................................................................28 
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7.2 
Exclusion Criteria ........................................................................................................29 
7.3 
Excluded Medications ..................................................................................................30 
7.4 
Criteria for Discontinuation or Withdrawal of a Subject .............................................30 
7.5 
Procedures for Discontinuation or Withdrawal of a Subject .......................................31 
7.5.1 Individual Stopping Rules......................................................................................31 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT .......................................................32 
8.1 
Study Drug and Materials ............................................................................................32 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ......................................32 
8.1.2 Storage ...................................................................................................................33 
8.1.3 Dose and regimen ..................................................................................................34 
8.1.4 Overdose ................................................................................................................35 
8.2 
Study Drug Assignment and Dispensing Procedures ..................................................35 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs.......................................36 
9.0 
STUDY PLAN ...................................................................................................................38 
9.1 
Study Procedures .........................................................................................................38 
9.1.1 Informed Consent Procedure .................................................................................38 
9.1.2 Demographics, Medical History, and Medication History Procedure ...................38 
9.1.3 Physical Examination Procedure ...........................................................................39 
9.1.4 Vital Sign Procedure ..............................................................................................39 
9.1.5 Efficacy Measurement ...........................................................................................40 
9.1.6 Documentation of Concomitant Medications ........................................................40 
9.1.7 Documentation of Concurrent Medical Conditions ...............................................41 
9.1.8 Procedures for Clinical Laboratory Samples .........................................................41 
9.1.9 Contraception and Pregnancy Avoidance Procedure .............................................43 
9.1.10 Pregnancy ...............................................................................................................46 
9.1.11 Electrocardiogram ..................................................................................................47 
9.1.12 Documentation of Screen Failure ..........................................................................47 
9.1.13 Other Assessments .................................................................................................48 
9.2 
Monitoring Subject Treatment Compliance.................................................................49 
9.3 
Schedule of Assessments .............................................................................................49 
9.3.1 Screening................................................................................................................49 
9.3.2 Treatment Period ....................................................................................................50 
9.3.3 Study Visit post Visit 14 (Day 182) .......................................................................52 
9.3.4 Safety Follow-up Visit ...........................................................................................52 
9.3.5 Final Visit or Early Termination ............................................................................53 
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9.3.6 Post Study Care ......................................................................................................53 
10.0 
ADVERSE EVENTS .........................................................................................................54 
10.1 
Definitions....................................................................................................................54 
10.1.1 Adverse Events ......................................................................................................54 
10.1.2 Additional Points to Consider for Adverse Events ................................................54 
10.1.3 Serious Adverse Events .........................................................................................56 
10.1.4 Adverse Events of Special Interest ........................................................................57 
10.1.5 Intensity of Adverse Events ...................................................................................57 
10.1.6 Causality of Adverse Events ..................................................................................58 
10.1.7 Relationship to Study Procedures ..........................................................................58 
10.1.8 Start Date ...............................................................................................................58 
10.1.9 Stop Date ................................................................................................................59 
10.1.10 
Frequency .........................................................................................................59 
10.1.11 
Action Concerning Study Drug .......................................................................59 
10.1.12 
Outcome ...........................................................................................................59 
10.1.13 
Product Malfunctions .......................................................................................60 
10.2 
Procedures ....................................................................................................................60 
10.2.1 Collection and Reporting of Adverse Events.........................................................60 
10.2.2 Collection and Reporting of Serious Adverse Events............................................62 
10.3 
Follow-up of Serious Adverse Events .........................................................................63 
10.3.1 Safety Reporting to Investigators, Institutional Review Boards and Regulatory 
Authorities..............................................................................................................63 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................64 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................65 
12.1 
Case Report Forms (Electronic)...................................................................................65 
12.2 
Record Retention .........................................................................................................66 
13.0 
STATISTICAL METHODS ..............................................................................................67 
13.1 
Statistical and Analytical Plans ....................................................................................67 
13.1.1 Analysis Sets ..........................................................................................................67 
13.1.2 Subject disposition .................................................................................................67 
13.1.3 Analysis of Demographics and Other Baseline Characteristics ............................67 
13.1.4 Medical History .....................................................................................................67 
13.1.5 Treatment Exposure and Compliance ....................................................................67 
13.1.6 Prior and Concomitant Medications ......................................................................68 
13.1.7 Efficacy Analysis ...................................................................................................68 
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13.1.8 Safety Analysis ......................................................................................................68 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................69 
13.3 
Determination of Sample Size .....................................................................................69 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................70 
14.1 
Study-Site Monitoring Visits .......................................................................................70 
14.2 
Protocol Deviations ......................................................................................................70 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................70 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................71 
15.1 
Institutional Review Board Approval ..........................................................................71 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................72 
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 9.a 
Clinical Laboratory Tests .......................................................................................41 
Table 10.a 
Takeda Medically Significant Adverse Event List ................................................57 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ....................................................................................25 
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2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound: Lanadelumab (TAK-743) 
Title of Protocol: Open-arm, Japan Expanded Access 
Program with Lanadelumab (TAK-743) for Japanese 
Patients with Hereditary Angioedema. 
IND No.: Not applicable 
EudraCT No.: 
Not Applicable 
Study Number: TAK-743-5007 
Phase: Not applicable 
Study Design: 
Study TAK-743-5007 is an open-arm, Japan Expanded Access Program with Lanadelumab (TAK-743) for 
Japanese patients with Type I or II hereditary angioedema (HAE). Two types of subjects will be enrolled into 
this study: 
•
Subjects who rollover from Study SHP643-302.
•
Subjects who are non-rollovers (ie, were not participants in Study SHP643-302).
Subjects who discontinue from Study SHP643-302 after providing informed consent are not eligible to enroll in 
Study TAK-743-5007. 
Rollover subjects 
There is no screening period for rollover subjects. The first study visit for rollover subjects (Day 0) is to occur on 
the same day as the Study SHP643-302 Day 378 study visit. Rollover subjects will complete all Study 
SHP643-302 final study assessments (Day 378) at which time they will be discharged from that study. Results of 
the final SHP643-302 assessments on Day 378 will be used as the predose results for Day 0 of 
Study TAK-743-5007. 
Following informed consent and predose assessments, rollover subjects will continue with an open-label dose of 
300 mg lanadelumab administered subcutaneously (SC) on Day 0. Rollover subjects will receive SC 
administration of lanadelumab 300 mg every 2 weeks (q2w) or every 4 weeks (q4w) at the discretion of the 
Investigator, with optional consultation with the sponsor, if they have been well-controlled (eg, attack free for 
26 weeks). 
Non-rollover subjects 
Subjects with historical baseline HAE attack of at least 1 attack per 4 weeks in the recent 1 year who have not 
participated in Study SHP643-302 (non-rollovers) are permitted to enroll if they meet the eligibility requirements 
for expanded access. 
Screening of some subjects is allowed following discussion with the sponsor: ie, subjects who screen failed out 
of the run-in period for Study SHP643-302 when enrollment for that study closed. 
Once all screening assessments are completed and eligibility confirmed, non-rollover subjects will arrive at the 
study site and, following predose assessments, will receive an open-label dose of 300 mg lanadelumab 
administered SC on Day 0. Non-rollover subjects will receive SC administration lanadelumab 300 mg q2w or 
q4w if they have been well-controlled (eg, attack free for 26 weeks) and at the discretion of the Investigator with 
optional consultation with the sponsor. 
All doses are to fall within the accepted ±4 day window around study visits. From Day 0 to Day 182, visits will 
occur q2w. After Day 182, study visits will occur every 12 weeks, and site personnel are to call subjects q2w to 
collect adverse events (AEs), concomitant medications, and to ensure all attacks have been appropriately 
documented. 
The treatment period is to last up to lanadelumab manufacturing and sale, development discontinued or withdraw 
of new drug application. 
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Self-administration: 
All subjects who are considered suitable candidates will be allowed to self-administer treatment throughout the 
study. Subjects are required to complete appropriate training by the Investigator or designee and have their 
understanding of the procedures confirmed by the Investigator or designee. Subjects are allowed to initiate 
self-administration at the subject’s home or other agreed upon location after receiving the first 2 doses of 
lanadelumab at the study site. 
Adolescent subjects self-administering lanadelumab are to be supervised by a parent/legal guardian/caregiver. 
Alternatively, a parent/legal guardian/caregiver, after completing appropriate training, will be allowed to 
administer the study drug to an adolescent without study site personnel supervision. 
Primary Objectives: 
To ensure access to lanadelumab in Japanese subjects with HAE who meet the criteria for expanded access. 
Secondary Objectives: 
•
To evaluate the long-term safety of repeated SC administration of lanadelumab.
•
To evaluate the long-term efficacy of lanadelumab in preventing HAE attacks.
Subject Population: Japanese male/female HAE (Type I or II) subjects who are 12 years of age or older at the 
time of screening. 
Number of Subjects: 
Not applicable 
Number of Sites: 
Approximately 15 sites in Japan 
Dose Level(s): 
Lanadelumab 300 mg q2w 
Lanadelumab 300 mg q4w at the discretion of the 
Investigator, with optional consultation with the sponsor, 
if well-controlled (eg, attack free for 26 weeks) 
Route of Administration: 
Subcutaneous 
Duration of Treatment: 
First patient in: February 2021 to last patient last visit: 
November 2021 or until lanadelumab manufacturing and 
sale, development discontinued or withdraw of new drug 
application 
Period of Evaluation: 
Not applicable 
Main Criteria for Inclusion: 
Each subject has to meet the following criteria to be eligible for the study: 
1.
Be of Japanese descent, defined as born in Japan and having Japanese parents and Japanese maternal and
paternal grandparents.
2.
Male and female HAE subjects who are 12 years of age or older at the time of screening.
3.
Documented diagnosis of disease HAE (Type I or II) based on all of the following:
•
Documented clinical history consistent with HAE (SC or mucosal, nonpruritic swelling episodes
without accompanying urticaria).
•
Diagnostic testing results obtained during screening (or a prior lanadelumab study) that confirm HAE
Type I or II: C1 inhibitor (C1-INH) functional level <40% of the normal level. Subjects with functional
C1-INH level 40% to 50% of the normal level may be enrolled if they also have a C4 level below the
normal range. Subjects may be retested if results are incongruent with clinical history or believed by the
Investigator to be confounded by long-term prophylaxis (LTP) use. It is understood that C1-INH
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therapy may alter the lab results of C1-INH assessments; therefore, the Investigator's discretion in 
collaboration with sponsor is advised for proper documentation of eligibility. 
•
At least one of the following: Age at reported onset of first angioedema symptoms ≤ 30 years, a family
history consistent with HAE Type I or II, or C1q within normal range.
4.
Non-rollover subjects only: A historical baseline HAE attack rate of at least 1 attack per 4 weeks in the
recent 1 year. 
5.
Rollover subjects only: Subjects from Study SHP643-302 are permitted to rollover and enroll into this study
if: 
•
They completed the treatment period of Study SHP643-302; and
•
They consented to enter Study TAK-743-5007 on or before Day 350 of the SHP643-302 study (since
Day 378 of Study SHP643-302 is also Day 0 of Study TAK-743-5007, informed consent may be
completed on Day 364 or this visit, if not already provided).
Criteria for Exclusion: 
Patients who meet any of the following criteria are excluded from the study: 
1.
If rolling over from Study SHP643-302, presence of important safety concerns that would preclude
participation in this study.
2.
Concomitant diagnosis of another form of chronic, recurrent angioedema such as acquired angioedema,
HAE with normal C1-INH (also known as HAE Type III/normal C1-INH), idiopathic angioedema, or
recurrent angioedema associated with urticaria.
3.
Dosing with an investigational drug (not including lanadelumab or other HAE therapies) or exposure to an
investigational device within 4 weeks prior to screening.
4.
Exposure to angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to screening or any
newly initiated or dose modification of estrogen-containing medications with systemic absorption (such as
oral contraceptives or hormonal replacement therapy) 3 months prior to the screening visit.
5.
Unwilling to discontinue short or long-term prophylactic therapy for HAE, eg, C1-INH, attenuated
androgens or anti-fibrinolytics within 3 weeks after starting the treatment period. Short-term prophylaxis is
defined as C1-INH, attenuated androgens, or antifibrinolytic used to avoid angioedema complications from
medically indicated procedures.
6.
Any of the following liver function test abnormalities: alanine aminotransferase >3 × upper limit of normal
(ULN), or aspartate aminotransferase >3 × ULN, or total bilirubin >2 × ULN (unless the bilirubin elevation
is a result of Gilbert’s syndrome).
7.
Pregnancy or breast feeding.
8.
Have any uncontrolled underlying medical condition which would require treatment adjustment during the
study treatment period, that, in the opinion of the Investigator or sponsor, may confound the results of the
safety assessments or may place the subject at risk. Subjects with stable treatment for at least 3 months prior
to screening and NOT expecting any change to their treatment regimen for 6 months during the study
treatment period, will not be excluded.
9.
Subject has a known hypersensitivity to the study drug or its components.
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Criteria for Evaluation and Analyses: 
Safety measures: 
•
Number and percentage of subjects with treatment -emergent adverse events (TEAEs) including serious
adverse events (SAEs) and adverse event of special interest (AESI).
•
Number of subjects with clinically significant abnormal clinical laboratory testing (hematology, clinical
chemistry, coagulation, and urinalysis).
•
Number of subjects with clinically significant vital signs including blood pressure, heart rate, body
temperature, and respiratory rate.
Efficacy measure: 
•
Non-rollover Subjects: Time to first HAE attack after Day 0 for the efficacy evaluation period of Day 0
through Day 182.
Statistical Considerations: 
The Full Analysis Set (FAS) is defined as all subjects who received at least 1 dose of lanadelumab in this study. 
All safety and efficacy analyses will be based on the FAS. 
Interim summary may be produced during the study to support regulatory reporting if requested by the authority. 
Safety Analysis 
Adverse events are to be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary. No inferential statistics are planned. 
Adverse event of special interests for this study are hypersensitivity reactions and disordered coagulation 
(hypercoagulability events and bleeding events). 
The number and percentage of subjects with TEAEs will be displayed by system organ class and preferred term 
(PT) using MedDRA®. 
All AEs will be provided in subject listings. In addition, subject listings of AEs causing discontinuation of study 
medication, AEs leading to death, SAEs, related AEs, severe AEs, and Investigator-reported AESIs will be 
produced. 
Efficacy Analysis 
No statistical hypothesis testing will be performed. Time to the first Investigator-confirmed HAE attack will be 
analyzed using the Non-rollover subjects in FAS. 
Time to first Investigator-confirmed HAE attack is to be calculated from the time of first dose of lanadelumab in 
this study to the start time of the first Investigator-confirmed HAE attack. If a subject does not have an attack, 
the subject will be censored from the time of first dose of lanadelumab to the earlier of the early discontinuation 
date or end of treatment period date. The time to the first Investigator-confirmed HAE attack (days) will be 
summarized using Kaplan-Meier methods. 
Sample Size Justification: This study is designed to expand access of lanadelumab and evaluate the safety of 
open-label treatment with lanadelumab in subjects with HAE who participated in SHP643-302 (rollover subjects) 
and individuals who are not otherwise able to participate in SHP643-302 (non-rollover subjects). Therefore, no 
formal sample size calculation was performed. 
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3.0 
LIST OF ABBREVIATIONS 
ACE 
angiotensin-converting enzyme 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BP 
blood pressure 
B2 
bradykinin type 2 
CRF 
case report form 
eCRF 
electronic case report form 
C1-INH 
C1-inhibitor 
DMID 
Division of Microbiology and Infectious Diseases 
EDC 
electronic data capture 
ECG 
electrocardiogram 
EOS 
End of Study 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HAARP 
hereditary angioedema attack assessment and reporting procedures 
HAE 
hereditary angioedema 
hCG 
human chorionic gonadotropin 
HR 
heart rate 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
IgG1 
immunoglobulin G subclass 1 
IP 
investigational product 
IRB 
institutional review board 
IRT 
Interactive Response Technology 
IV 
intravenous 
KM 
Kaplan-Meier 
LTP 
long-term prophylaxis 
MedDRA 
Medical Dictionary for Regulatory Activities 
PFS 
prefilled syringe 
PK 
pharmacokinetic 
pKal 
active plasma kallikrein 
PT 
preferred term 
q2w 
every 2 weeks 
q4w 
every 4 weeks 
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RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SoA 
Schedule of Assessments 
SC 
subcutaneous 
SMQ 
Standardized MedDRA Queries 
SUSAR 
suspected unexpected serious adverse reactions 
TDC 
Takeda Development Center 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential 
3.1 
Corporate Identification 
TDC Japan 
Takeda Development Center Japan 
TDC Asia 
Takeda Development Center Asia, Pte Ltd 
TDC Europe 
Takeda Development Center Europe Ltd. 
TDC Americas 
Takeda Development Center Americas, Inc. 
TDC 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
Takeda 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
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4.0 
INTRODUCTION 
Lanadelumab (TAK-743), is a recombinant Chinese hamster ovary cell expressed, fully human 
immunoglobulin G subclass 1 (IgG1), kappa light chain, monoclonal antibody. Lanadelumab is a 
potent and specific inhibitor of the proteolytic activity of active plasma kallikrein (pKal). The 
drug is approved for prevention of angioedema attacks in patients with Type I or II hereditary 
angioedema (HAE), which is a rare and life-threatening disease. 
4.1 
Background 
Hereditary angioedema is a long-term, debilitating, and life-threatening disease caused by 
mutations in the C1-inhibitor (C1-INH) gene, resulting in deficiency or dysfunction of C1-INH 
protein. Hereditary angioedema manifests clinically as unpredictable, intermittent attacks of 
subcutaneous (SC) or submucosal edema of the face, larynx, gastrointestinal tract, limbs, and/or 
genitalia (Zuraw, 2008). Swelling may last up to 5 days; most patients suffer multiple attacks per 
year. The exact prevalence of HAE is unknown; however, current estimates range from 1 per 
10,000 to 1 per 150,000 persons, with many authors agreeing that 1 per 50000 as likely the 
closest estimate (Bygum, A. 2009; Goring et al., 1998; Lei et al., 2011; Lumry, 2013; Nordenfelt 
et al., 2014; Roche et al., 2005). Obstruction of airways due to swelling in larynx could result in 
death due to asphyxiation (Bork et al., 2000; Bork et al., 2012). Approximately 50% of all HAE 
patients will experience a laryngeal attack in their lifetime, and there is no way to predict which 
patients are at risk of a laryngeal attack (Bork et al., 2003; Bork et al., 2006). The incidence of 
death due to untreated laryngeal attacks is 30% to 40% and the risk of death is 3-fold greater in 
undiagnosed versus diagnosed patients (Bork et al., 2000; Bork et al., 2012; Bork et al., 2016). 
Abdominal attacks are often associated with nausea, vomiting, and severe pain; intestinal 
symptoms resembling abdominal emergencies may lead to unnecessary surgery (Agostoni and 
Cicardi, 1992; Zuraw, 2008). 
Approximately 85% of patients have Type I HAE, characterized by very low production of 
functionally normal C1-INH protein, while the remaining approximately 15% of patients have 
Type II HAE and produce normal or elevated levels of a functionally impaired C1-INH 
(Zuraw, 2008). Clinical suspicion of Type I and II HAE can be confirmed by available blood 
tests. In addition to abnormalities in C1-INH level and function, plasma C4 levels are markedly 
reduced at all times in blood from most patients. Acute treatments include purified, 
plasma-derived C1-INH, recombinant C1-INH, a pKal inhibitor (ecallantide), and a bradykinin 
type 2 (B2) receptor antagonist (icatibant). While acute treatments are effective at resolving the 
symptoms of acute attacks, they do not prevent attacks and thus leave patients at risk of 
developing debilitating and potentially life-threatening attacks. 
 
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4.1.1 Indication and Current Treatment Options 
Hereditary angioedema International Treatment Guidelines state that the goal of prophylactic 
treatment is to reduce the frequency and severity of attacks and thus to increase patients’ quality 
of life (Cicardi et al., 2012; Craig et al., 2012). These guidelines recommend C1-INH or 
attenuated androgens as the standard of care over anti-fibrinolytic agents (Cicardi et al., 2012; 
Craig et al., 2012). The most recent World Allergy Organization /European Academy of Allergy 
and Clinical Immunology guidelines (2017 revision and update) recommend C1-INH as first-line 
long-term prophylactic therapy (androgens as second-line). Anti-fibrinolytics are not 
recommended due to the lack of efficacy in long-term prophylaxis (LTP) (Maurer et al., 2018). A 
patient with HAE, regardless of age, is a candidate for a prophylactic regimen if a number of 
criteria are met which may include: events in life that are associated with increased disease 
activity, attack frequency or severity, history of laryngeal attacks, impact on quality of life 
including work and school performance, proximity to emergency care, physiological or 
psychological stress, etc. (Craig et al., 2009; Maurer et al., 2018). 
Currently, there are no approved therapies in Japan that are safe and effective for the long-term 
prevention of angioedema attacks in patients with Types I or II HAE. The only currently 
approved HAE therapies in Japan are Berinert, a human plasma-derived C1-INH concentrate for 
intravenous (IV) administration indicated for the treatment of acute attack and peri-procedural 
(short-term) prevention of acute attacks and, more recently, Firazyr, a SC B2-receptor antagonist 
indicated for the treatment of acute attacks. The Japan HAE guidelines recommend LTP in 
patients with a history of laryngeal edema and/or a high frequency of attacks (ie, symptoms at 
least once per month and/or more than 5 days/month) (Horiuchi et al., 2012). As there are no 
approved therapies in Japan for the long-term prevention of angioedema attacks in patients with 
Types I or II HAE, the Japan HAE guidelines currently recommend off-label use of attenuated 
androgens (eg, danazol) and the anti-fibrinolytic tranexamic acid as first-line long-term 
prevention strategies. 
Lanadelumab is expected to fulfill an unmet medical need in Japan for a long-term safe, effective 
and convenient intervention to prevent HAE attacks. Lanadelumab may provide significant 
benefit to Japanese HAE patients, given the demonstrated efficacy in preventing HAE attacks in 
an overseas population and the similarity in genetic characteristics, pathophysiology, and clinical 
presentation of HAE between the overseas population and Japanese HAE patients. The targeted 
indication of lanadelumab (SHP643, DX-2930) is for prophylaxis to prevent attacks of HAE in 
patients aged 12 years and older. 
4.1.2 Non-clinical studies with Lanadelumab 
The nonclinical program conducted to date indicated no safety signal or toxicity with SC 
administered lanadelumab at doses of up to and including the highest tested dose (50 mg/kg, 
once weekly) for 6 months in cynomolgus monkeys. Collectively, the nonclinical studies 
demonstrate that lanadelumab did not have adverse effects on vital functions or produce adverse 
target organ pathologies in rats or cynomolgus monkeys and support the safe use in patients with 
HAE as a prophylactic treatment by SC injection. 
 
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4.1.3 Clinical studies with Lanadelumab 
To date, the worldwide applications for marketing authorization of lanadelumab have been 
supported by 5 clinical studies. Results for all 5 clinical studies and summary of results in 
adolescent patients with HAE (in Studies DX-2930-03 and DX-2930-04) are briefly summarized 
below: 
•
Clinical study DX-2930-01 evaluated the safety, tolerability, and pharmacokinetic (PK) of a
single dose of lanadelumab (0.1, 0.3, 1.0, or 3.0 mg/kg) in healthy subjects. The data
demonstrated that lanadelumab was well tolerated by healthy subjects up to doses of
3.0 mg/kg without evidence of dose-limiting toxicity. The PK profile demonstrated linear,
dose-dependent exposure with a mean half-life of approximately 17 to 21 days across dose
groups. The exposure was dose proportional and the half-life was consistent across the dose
groups.
•
Clinical study DX-2930-02 evaluated the safety, tolerability, and PK of 2 doses of
lanadelumab (30, 100, 300, or 400 mg) separated by 14 days in HAE subjects and
demonstrated that lanadelumab was well tolerated following 2 doses up to 400 mg. There
were no deaths, serious adverse events (SAEs), discontinuations due to an adverse event
(AE), or safety signals following lanadelumab treatment. In a prespecified efficacy analysis,
a statistically significant finding of HAE attack prevention by lanadelumab was observed.
Specifically, in comparison to placebo, attack rate was reduced by 100% and 88% in the
300 mg and 400 mg lanadelumab treatment groups, respectively.
•
Study DX-2930-03 (HELP Study™) was a multicenter, randomized, double-blind,
placebo-controlled, parallel group efficacy and safety study to evaluate lanadelumab for LTP
against acute attacks of HAE. The primary objective of the study was to evaluate the efficacy
of lanadelumab in preventing HAE attacks.
Over the 26-week treatment period, all 3 lanadelumab dose regimens, 150 mg every 4 weeks
(q4w), 300 mg q4w, and 300 mg every 2 weeks (q2w), resulted in a highly statistically
significant percentage reduction in the least squares mean Investigator-confirmed HAE attack
rate compared with placebo of 76%, 73%, and 87% (adjusted p<0.001), respectively, for the
primary endpoint. Furthermore, all 3 lanadelumab regimens demonstrated highly statistically
significant attack rate reductions compared with placebo for all secondary efficacy analyses.
Notably, the magnitude of the treatment effect was consistently the largest across all
endpoints in the lanadelumab 300 mg q2w treatment arm compared with the lanadelumab
q4w arms. The evidence of prevention of HAE attacks was indicated by sustained decreased
frequency of attacks, decreased severity of attacks, reduced need for rescue medication (acute
treatment), and improved health-related quality of life (HRQoL). Lanadelumab was generally
well tolerated over the 26-week treatment period; no treatment-related SAEs or deaths were
reported.
•
Study DX-2930-04 (HELP Study ExtensionTM) is an open-label, long-term safety and
efficacy extension study of DX-2930-03 to evaluate the study drug, lanadelumab, in
preventing acute angioedema attacks in patients with Type I or II HAE. At the time of the
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interim analysis based on the data cutoff date of 31 August 2018, the safety profile in this 
study was consistent with the pivotal Study DX-2930-03 and previous interim analysis (data 
cutoff date of 01 September 2017) for the global marketing license or authorization 
applications for lanadelumab. No treatment-related SAEs or deaths were reported. 
Treatment-emergent AEs (TEAEs) for most subjects were mild or moderate in severity with 
few reported severe events considered related to lanadelumab treatment. Lanadelumab 
300 mg q2w remained highly effective during this extension study for rollover and 
non-rollover subjects. Efficacy was maintained and shown to be durable with over 12 months 
of lanadelumab exposure across Study DX-2930-03 and Study DX-2930-04 for rollover 
subjects. Improved HRQoL based on adverse event-quality of life scores were observed for 
rollover and non-rollover subjects. 
•
Study SHP643-101 was a Phase 1, open-label, matched-control, single dose, single-center
study. Its primary objective was to evaluate the PK properties of lanadelumab administered
as a single SC dose of 300 mg in healthy adult male and female volunteer subjects of
Japanese descent and matched non-Hispanic, Caucasian healthy volunteer subjects. All
32 subjects completed the study. Following single SC administration of 300 mg lanadelumab
in healthy Japanese subjects, peak and overall systemic exposure to lanadelumab (Cmax, area
under the concentration-time curve from time zero to the last measurable concentration
[AUC0-last] and area under the concentration-time curve from time zero extrapolated to
infinity [AUC0-∞]) was similar to that observed in healthy Caucasian subjects, as determined
from the 90% confidence intervals.
Adolescent clinical trial experience 
The Phase 3 clinical studies for lanadelumab, pivotal Study DX-2930-03 and open-label 
extension Study DX-2930-04 (ongoing), evaluated the adult and adolescent population; inclusion 
of adolescents in these studies was justified based on the similarity of the pathophysiology and 
clinical presentation of HAE in adults and adolescents, as well as by the lack of any safety signal 
identified in nonclinical and clinical studies to date. In the 23 unique adolescent subjects who 
participated across Phase 3 Studies DX-2930-03, no safety signals were identified in terms of 
clinical laboratory hematology or coagulation, laboratory test abnormalities, vital signs, physical 
examination, or electrocardiograms (ECGs). Overall, the safety and tolerability of lanadelumab 
were similar in the pediatric population (12 to <18 years old) and adults (≥18 years old). 
Based on analyses of PK parameters for adolescents and adults in Phase 3 studies, no influence 
of age was apparent on clearance of lanadelumab after correcting for body weight. Based on the 
evaluation of PK, efficacy and safety, no dosing regimen adjustment has been recommended for 
adolescents (12 to <18 years). 
4.2 
Rationale for the Proposed Study 
Lanadelumab was approved in the year 2018 in the United States, Canada, and the European 
Union, followed by multiple countries in 2019 for routine prophylaxis to prevent attacks of 
angioedema in HAE patients 12 years and older. Lanadelumab marketing licensing and 
 
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authorization packages are currently being reviewed in many other countries. Lanadelumab is a 
highly potent and specific inhibitor of pKal (Ki = 125 pM). As lanadelumab has a long half-life 
(approximately 14 days in HAE subjects), it was hypothesized that treatment with lanadelumab 
every 2 or 4 weeks would provide persistent suppression of pKal and thus prevention of HAE 
attacks. Lanadelumab is now approved for SC administration at the recommended dose 300 mg 
q2w. A dosing interval of 300 mg q4w may be considered in patients who are stable and attack 
free on treatment. 
There are no drugs that have been approved in Japan for LTP of HAE Type I and II at the time 
the study was planned. There is strong scientific rationale and high unmet medical need to 
expand the use of lanadelumab as a prophylactic therapy. In Japan, the sponsor is planning to file 
a marketing approval application based on the results of a Japanese Phase 3 study in Japanese 
HAE patients that is currently underway (study SHP643-302). By expanding access to subjects 
who rolled over from SHP643-302, and those who were not enrolled, the probability of benefit to 
the subjects with HAE will increase. The present study is an expanded access program that aims 
to provide access to lanadelumab in Japanese subjects with HAE and monitor the safety of SC 
lanadelumab administered every 2 or 4 weeks. 
4.3 
Benefit/Risk Profile 
Lanadelumab, a first-in-class monoclonal antibody against active pKal, represents a therapeutic 
innovation that will address the unmet medical needs within the HAE community and thus is 
expected to be of major public health interest. It is a fully human IgG1 monoclonal antibody 
inhibitor of active pKal with a long half-life, which allows for convenient, infrequent SC 
self-administration (eg, q2w). 
In the pivotal Phase 3 study, lanadelumab demonstrated highly statistically significant and 
clinically meaningful reductions in HAE attacks over the 26-week treatment period compared 
with placebo across primary and all secondary efficacy analyses. Evidence for prevention and 
control of HAE symptoms was indicated by sustained decreased frequency and severity of 
attacks, high proportion of attack-free subjects (eg, 77% attack free at steady state in 
lanadelumab 300 mg q2w), reduced number of high morbidity attacks, reduced need for rescue 
medication (acute treatment), and improved HRQoL (81% subjects achieving responder 
definition in lanadelumab 300 mg q2w treatment). The efficacy results observed with 
lanadelumab (particularly at the dose of 300 mg q2w) confirmed the expected significant benefit 
based on superior efficacy over existing treatments. 
From a benefit/risk perspective, lanadelumab is generally well tolerated and has not shown safety 
limitations (as compared with C1-INH or androgens) and thus provides significant improvement 
on the benefit/risk profile. In addition, importantly for patients, lanadelumab’s unique 
mechanism of action and properties allow reduced dosing frequency (eg, q2w) with SC 
self-administration (10 to 60 seconds), which significantly reduces the burden of treatment as 
compared with a daily oral or twice weekly IV or SC treatment experienced by patients; 
therefore, lanadelumab offers a more effective and convenient therapy for patients suffering from 
HAE. 
 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objective 
The primary objective is to ensure access to lanadelumab in Japanese subjects with HAE who 
meet the criteria for expanded access. 
5.1.2 Secondary Objectives 
•
To evaluate the long-term safety of repeated SC administration of lanadelumab.
•
To evaluate the long-term efficacy of lanadelumab in preventing HAE attacks.
5.2 
Endpoints 
5.2.1 Safety Endpoints 
The following safety endpoints are to be evaluated: 
•
Number and percentage of subjects with TEAEs, including SAEs and adverse events of
special interest (AESIs).
•
Number of subjects with clinically significant abnormal laboratory testing (hematology,
clinical chemistry, coagulation, and urinalysis).
•
Number of subjects with clinically significant vital signs including blood pressure (BP),
heart rate (HR), body temperature, and respiratory rate (RR).
5.2.2 Efficacy Endpoints 
The following efficacy endpoint is to be evaluated: 
•
Non-rollover Subjects: Time to first HAE attack after Day 0 for the efficacy evaluation
period of Day 0 through Day 182.
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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is an open-label, Japan Expanded Access Program with lanadelumab (TAK-743) for 
Japanese patients with Type I or II HAE. Two types of subjects will be enrolled into this study: 
•
Subjects who rollover from Study SHP643-302.
•
Subjects who are non-rollovers (ie, were not participants in Study SHP643-302).
Rollovers from Study SHP643-302 
Subjects from Study SHP643-302 are permitted to rollover and enroll into this study if: 
1. They have completed the treatment period of Study SHP643-302; and
2. They have consented to enter Study TAK-743-5007 on or before Day 350 of the
SHP643-302 study (since Day 378 of Study SHP643-302 is also Day 0 of
Study TAK-743-5007, informed consent may be completed on Day 364 or this visit, if not
already provided).
Subjects who discontinue from Study SHP643-302 after providing informed consent are not 
eligible to enroll in Study TAK-743-5007. 
There is no screening period for rollover subjects. The first study visit for rollover subjects 
(Day 0) is to occur on the same day as the Study SHP643-302 Day 378 study visit. Rollover 
subjects will complete all Study SHP643-302 final study assessments (Day 378) at which time 
they will be discharged from that study. Results of the final SHP643-302 assessments on 
Day 378 will be used as the predose results for Day 0 of Study TAK-743-5007. 
Following informed consent and predose assessments, rollover subjects will continue with an 
open-label dose of 300 mg lanadelumab administered SC on Day 0. Rollover subjects will 
receive SC administration of lanadelumab 300 mg q2w or q4w at the discretion of the 
Investigator, with optional consultation with the sponsor, if they have been well-controlled 
(eg, attack free for 26 weeks). Rollovers from Study SHP643-302 who have been 
self-administering the study drug at the time of screening will be permitted to continue 
self-administration of lanadelumab. 
Non-rollover subjects 
Subjects with historical baseline HAE attack of at least 1 attack per 4 weeks in the recent year 
who have not participated in Study SHP643-302 (non-rollovers) are permitted to enroll if they 
meet the eligibility requirements for expanded access. 
Screening of some subjects is allowed following discussion with the sponsor: ie, subjects who 
screen failed out of the run-in period for Study SHP643-302 when enrollment for that study 
closed. 
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Once all screening assessments are completed and eligibility confirmed, non-rollover subjects 
will arrive at the study site and, following predose assessments, will receive an open-label dose 
of 300 mg lanadelumab administered SC on Day 0. Non-rollover subjects will receive SC 
administration lanadelumab 300 mg q2w or q4w if they have been well-controlled (eg, attack 
free for 26 weeks) and at the discretion of the Investigator with optional consultation with the 
sponsor. 
All doses are to fall within the accepted ± 4 days window around study visits. From Day 0 to 
Day 182, visits will occur q2w. After Day 182, study visits will occur every 12 weeks, and site 
personnel are to call subjects q2w to collect AEs, concomitant medications, and to ensure all 
attacks have been appropriately documented. 
All subjects who are considered suitable candidates will be allowed to self-administer treatment 
throughout the study. Subjects are required to complete appropriate training by the Investigator 
or designee and have their understanding of the procedures confirmed by the Investigator or 
designee (refer Section 9.1.13.1 for more details). 
The treatment period is to last up to lanadelumab manufacturing and sale, discontinued 
development, or withdrawal of new drug application. 
If a subject experiences an acute angioedema attack at any time during the study that in the 
opinion of the Investigator requires medical intervention, standard of care therapy is to be 
provided based on subject’s medical history and per locally approved product information. 
Administration of lanadelumab and study procedures is to continue without alteration to 
 even if a subject receives treatment for a breakthrough angioedema attack on the 
day of a scheduled dose of study drug (if self-administering) or scheduled study visit. 
An overview of the study design scheme is provided in Figure 6.a. All study procedures are 
detailed in the schedule of assessments 
 
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Figure 6.a 
Schematic of Study Design 
LTP = long-term prophylaxis 
6.2 
Justification for Study Design, Dose, and Endpoints 
6.2.1 Scientific rationale for study design 
The current study is designed in view of Japan HA regulations and intends to ensure access to 
lanadelumab in Japanese subjects with HAE who meet the criteria for expanded access. 
An open-label design selected to ensure maximum and expanded access to the patients as it is the 
primary objective of the study and norm for expanded access programs. 
 
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The eligibility criteria are identical to those in Study SHP643-302 with respect to subject age, 
diagnosis, and clinical presentation of HAE at study entry. 
Non-rollover, they need to have historical baseline HAE attack of at least 1 attack per 4 weeks. 
No separate screening procedures for rollover patients to lessen the patient burden. 
6.2.2 Justification for dose 
In all the countries where lanadelumab have been approved, the recommended dose regimen is 
300 mg q2w. A dosing interval of 300 mg q4w may be considered in patients who are stably 
attack free on treatment. 
Based on the totality of efficacy, PK and pharmacodynamic, and safety data from the pivotal 
overseas study in adolescent and adult subjects with HAE (Study DX-2930-03), the 300 mg q2w 
dose regimen was considered the recommended dose as it consistently demonstrated the greatest 
treatment effect compared with placebo and had an optimal benefit-risk profile during the 
26 weeks of treatment period. Lanadelumab treatment resulted in a high proportion of subjects 
being attack free on all dosing regimens evaluated (300 mg q2w, 300 mg q4w, and 150 mg q4w), 
with the 300 mg q2w dosing regimen having the highest percentage of subjects (44%) who were 
attack free for the entire 26-week treatment period, and approximately 77% of subjects attack 
free after achieving steady state. 
The ongoing open-label Phase 3 HELP Study ExtensionTM (Study DX-2930-04) in adolescent 
and adult subjects with HAE demonstrated that the prevention of HAE attacks for lanadelumab 
300 mg q2w was consistent with a substantially longer treatment duration. The safety profile in 
this study was consistent with the pivotal Study DX-2930-03. No treatment-related SAEs or 
deaths were reported. Treatment-emergent AEs for most subjects were mild or moderate in 
severity with few severe events were considered related to lanadelumab treatment. 
Lanadelumab 300 mg q2w provides exposure approximately above the maximal inhibitory 
concentration (IC90) of cHMWK, EAUC90 for clinical response in the majority of subjects 
across a large range of body weight (46.8 to 150 kg), and the safety profile supports lanadelumab 
300 mg q2w as the recommended fixed-dose regimen, including adolescent population. 
Meanwhile, understanding the need for clinicians to individualize therapy, including an 
opportunity for flexible dosing regimen, and thus, extending the dosing interval beyond q2w to 
q4w represents a substantial quality of life benefit for patients and could be considered if the 
subjects are well-controlled (eg, attack free for 26 weeks) on the recommended dose. 
A Phase 1 clinical study (Study SHP643-101), the data indicated that the peak and systemic 
exposure to lanadelumab (Cmax, AUC0-last, and AUC0-∞) in healthy Japanese subjects was similar 
to that observed in healthy Caucasian subjects. Lanadelumab was generally safe and well 
tolerated by both ethnic groups. 
 
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The present study is an expanded access program that aims to provide access to lanadelumab in 
Japanese subjects with HAE and monitor the safety of SC lanadelumab administered every 2 or 
4 weeks. 
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 TAK-743, 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 Site(s) 
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 
7.1 
Inclusion Criteria 
Each subject has to meet the following criteria to be eligible for the study: 
1. In the opinion of the Investigator, the subject is capable of understanding and complying with
protocol requirements.
2. Be of Japanese descent, defined as born in Japan and having Japanese parents and Japanese
maternal and paternal grandparents.
3. Male and female HAE subjects who are 12 years of age or older at the time of screening.
4. Documented diagnosis of disease HAE (Type I or II) based on all of the following:
•
Documented clinical history consistent with HAE (SC or mucosal, nonpruritic swelling
episodes without accompanying urticaria).
•
Diagnostic testing results obtained during screening (or a prior lanadelumab study) that
confirm HAE Type I or II: C1-INH functional level <40% of the normal level. Subjects
with functional C1-INH level 40% to 50% of the normal level may be enrolled if they
also have a C4 level below the normal range. Subjects may be retested if results are
incongruent with clinical history or believed by the Investigator to be confounded by LTP
use. It is understood that C1-INH therapy may alter the lab results of C1-INH
assessments; therefore, the Investigator's discretion in collaboration with sponsor is
advised for proper documentation of eligibility.
•
At least one of the following: Age at reported onset of first angioedema symptoms
≤30 years, a family history consistent with HAE Type I or II, or C1q within normal
range.
5. Non-rollover subjects only: A historical baseline HAE attack rate of at least 1 attack per
4 weeks in the recent 1 year.
6. Rollover subjects only: Subjects from Study SHP643-302 are permitted to rollover and enroll
into this study if: 
•
They completed the treatment period of Study SHP643-302; and
•
They consented to enter Study TAK-743-5007 on or before Day 350 of the SHP643-302
study (since Day 378 of Study SHP643-302 is also Day 0 of Study TAK-743-5007,
informed consent may be completed on Day 364 or this visit, if not already provided).
7. Adult subjects and caregivers of subjects under the age of 20 are willing and able to read,
understand, and sign an informed consent form. Subjects aged 12 to 19, whose caregiver has
provided informed consent, are willing and able to read, understand and sign an informed
consent form (an assent form, if applicable) as much as possible.
8. Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
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9. Males and females who are fertile and sexually active must adhere to contraception
requirements for the duration of the study as follows:
•
Females* of childbearing potential must agree to be abstinent or it is recommended to use
highly effective forms of contraception from the screening period through 70 days after
the final study visit. Notes: 1) A female whose male partner has had a vasectomy must
agree to use 1 additional form of medically acceptable contraception. 2) Use of a male
condom with or without spermicide or cervical cap diaphragm or sponge with spermicide
or a combination (double-barrier methods) are not considered highly effective.
•
Females of nonchildbearing potential, defined as surgically sterile (status
post-hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or postmenopausal
for at least 12 months do not require contraception during the study.
•
Males, including males who are surgically sterile (post-vasectomy), with female partners
of childbearing potential must agree to be abstinent or else use a medically acceptable
form of contraception from the screening period through 70 days after the final study
visit.
*Note: Female rollover subjects (those who previously participated in Study SHP643-302) of childbearing potential
may continue to use the birth control method used during Study TAK-743-5007. 
7.2 
Exclusion Criteria 
Subjects who meet any of the following criteria are excluded from the study: 
1. If rolling over from Study SHP643-302, presence of important safety concerns that would
preclude participation in this study.
2. Concomitant diagnosis of another form of chronic, recurrent angioedema such as acquired
angioedema, HAE with normal C1-INH (also known as HAE Type III/normal C1-INH),
idiopathic angioedema, or recurrent angioedema associated with urticaria.
3. Dosing with an investigational drug (not including lanadelumab or other HAE therapies) or
exposure to an investigational device within 4 weeks prior to screening.
4. Exposure to angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to
screening or any newly initiated or dose modification of estrogen-containing medications
with systemic absorption (such as oral contraceptives or hormonal replacement therapy)
3 months prior to the screening visit.
5. Unwilling to discontinue short or long-term prophylactic therapy for HAE, eg, C1-INH,
attenuated androgens or anti-fibrinolytics within 3 weeks after starting the treatment period.
Short-term prophylaxis is defined as C1-INH, attenuated androgens, or antifibrinolytic used
to avoid angioedema complications from medically indicated procedures.
6. Any of the following liver function test abnormalities: alanine aminotransferase (ALT)
>3 × upper limit of normal (ULN), or aspartate aminotransferase (AST) >3 × ULN, or total
bilirubin >2 × ULN (unless the bilirubin elevation is a result of Gilbert’s syndrome).
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7. Pregnancy or breast feeding.
8. Have any uncontrolled underlying medical condition which would require treatment
adjustment during the study treatment period, that, in the opinion of the Investigator or
sponsor, may confound the results of the safety assessments or may place the subject at risk.
Subjects with stable treatment for at least 3 months prior to screening and NOT expecting
any change to their treatment regimen for 6 months during the study treatment period, will
not be excluded.
9. Subject has a known hypersensitivity to the study drug or its components.
7.3 
Excluded Medications 
Use of the following treatments will not be permitted during the study: 
•
LTP for HAE (eg, use of C1-INH for LTP, attenuated androgens, or antifibrinolytics) once
LTP is discontinued (within 3 weeks following the first dose of lanadelumab).
•
ACE inhibitors within 4 weeks prior to screening and during the study.
•
Estrogen-containing medications with systemic absorption within 3 months prior to
screening and during the study.
•
Use of androgens (eg, stanozolol, danazol, oxandrolone, methyltestosterone, and
testosterone) for non-HAE related medical conditions or for HAE after discontinuation
during the first 2 weeks during the treatment period.
•
Any other investigational drug or device.
7.4 
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 electronic case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.12. 
1. Adverse event. 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.
2. 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.
3. 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.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) 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]). 
5. Study termination. The sponsor, IRB, or regulatory agency terminates the study.
6. 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 9.1.10.
7. 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.
8. Death.
9. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.5 
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 7.4. 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. Discontinued or withdrawn subjects will not 
be replaced. 
7.5.1 Individual Stopping Rules 
Dosing for any individual subject will be discontinued or interrupted if the subject experienced a 
lanadelumab-related SAE (or a lanadelumab-related, clinically significant non-serious AE) that, 
in the assessment of the Investigator, warranted discontinuation from further dosing for that 
subject’s wellbeing. The Investigator has the ability to contact and consult with the sponsor on 
such matters. Subjects are to continue to be followed through the completion of all scheduled 
nondosing visits, unless they requested to be discontinued from the study. 
 
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8.0 
CLINICAL STUDY MATERIAL MANAGEMENT 
8.1 
Study Drug and Materials 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
8.1.1.1 Study Drug 
The study drug is lanadelumab, which will be provided as a sterile, preservative free, 
ready-to-use solution at a concentration of 150 mg/mL. The study drug will be provided in a 
prefilled syringe (PFS) at a dosage strength of 300 mg (300 mg/2 mL). Prefilled syringe is filled 
to deliver a nominal volume of 2 mL of lanadelumab SC. 
Labels containing study information and pack identification are applied to the study drug 
container. 
All study drug is labeled with a minimum of the following: protocol number, MedID number, lot 
number, expiry date, dosage form, directions for use, storage conditions, the sponsor's name and 
address, and the statements “For clinical trial use only” and "Keep out of sight and reach of 
children". The label will comply with Japanese GCP. 
Space is allocated on the label so that the site representative can record a subject number and 
Investigator name. 
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the study drug in order to satisfy local or institutional requirements, but must 
not: 
•
Contradict the clinical study label.
•
Obscure the clinical study label.
•
Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement. 
The open-label lanadelumab will be supplied by the sponsor and pre-packaged in a study kit for 
the study. Each study kit will contain 1 PFS of study drug. Both the PFS and carton (kit) will be 
appropriately labeled according to local regulations and bear the unique study drug kit number. 
The investigative site will provide ancillary supplies to the subjects. The site has the option of 
using needles of a different gauge to aid subject comfort with each SC injection. 
Detailed instructions on preparation and administration of study drug will be provided to the 
clinical sites in a Pharmacy Manual. 
 
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Subjects (or parents/caregivers) who elect to self-administer study drug, where permitted per 
protocol (see Section 9.1.13.1) will be provided the following supplies as applicable: 
•
Required number of PFS.
•
Ancillary supplies, and a container for sharps disposal.
•
Subject accountability form to record study drug administration details.
All used and unused PFS should be returned to the study kit cartons/boxes for drug 
accountability. Written instructions on lanadelumab handling and self-administration procedures 
will be provided to trained subjects (and their parent/caregiver) prior to initiating self-
administration. Refer to the Pharmacy Manual for additional details on lanadelumab and its 
administration. 
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor. 
8.1.1.2 Rescue Medication 
Hereditary angioedema attacks occurring during the run-in period and study treatment periods 
will be treated according to the local standard of care. In case of insufficient response to the first 
dose, additional rescue medications will be allowed. Administration of lanadelumab and study 
procedures will continue without alteration to the protocol-specified study schedule, even if the 
subject has symptoms of an HAE attack on the day of lanadelumab administration and/or 
receives treatment for an HAE attack. 
8.1.1.3 Sponsor-Supplied Drug 
Sponsor-supplied drugs referenced in other sections of the protocol includes the study drug 
(lanadelumab). 
8.1.2 Storage 
The Investigator has overall responsibility for ensuring that study drug is stored in a secure, 
limited-access location. Limited responsibility may be delegated to the pharmacy or member of 
the study team, but this delegation must be documented. Study drug is distributed by the 
pharmacy or nominated member of the study team. The pharmacist/nominated team member will 
enter the unique subject identifier on the PFS labels as they are distributed. 
Lanadelumab should be stored in a refrigerator at 2°C to 8°C. Prefilled syringes should be 
removed from refrigeration and allowed to get to room temperature before administration. Do 
not freeze. The PFS should be protected from light in the original carton. Refer to the latest 
version of the Investigator’s Brochure for current stability data. 
Before use, each PFS of study drug should be inspected for appearance. Any PFS containing 
visible particles or discoloration should not be used. Avoid shaking or vigorous agitation of the 
PFS. 
 
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Any unused contents of a PFS of study medication should be discarded in accordance with local 
requirements for investigational materials. Intact PFS of study medication that are not used 
during the course of the clinical study should be returned according to direction from the 
sponsor. 
Study drug must be stored in accordance with labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained within 
an established temperature range. The Investigator is responsible for ensuring that the 
temperature is monitored throughout the duration of the study and that records are maintained; 
the temperature should be monitored continuously by using either an in-house system, a 
mechanical recording device such as a calibrated chart recorder, or by manual means, such that 
both minimum and maximum thermometric values over a specific time period can be recorded 
and retrieved as required. Such a device (ie, certified min/max thermometer) would require 
manual resetting upon each recording. The sponsor must be notified immediately upon discovery 
of any excursion from the established range. Temperature excursions will require site 
investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the study drug and will provide supportive documentation as necessary. Under no 
circumstances should the product be dispensed to subjects until the impact has been determined 
and the product is deemed appropriate for use by the sponsor. 
The sponsor should be notified immediately if there are any changes to the storage area of the 
study drug that could affect the integrity of the product(s), eg, fumigation of a storage room. 
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. 
8.1.3 Dose and regimen 
This is an open-label study. There are 2 sets of subjects-rollovers (from the previous study) and 
non-rollover subjects who will be enrolled to receive lanadelumab after fulfilling the inclusion 
criteria. 
Lanadelumab will be administered by SC injection in the abdominal area, thigh, or upper arm. 
Rollovers from Study SHP643-302 who have been self-administering the study drug at the time 
of screening will be permitted to continue self-administration of lanadelumab. Upper arm 
location is not recommended for self-administration but rather an additional injection site when 
administered by a parent/caregiver or health care provider. 
Subjects will receive SC administration of lanadelumab 300 mg q2w or q4w at the discretion of 
the Investigator, with optional consultation with the sponsor, if they have been well-controlled 
(eg, attack free for 26 weeks). 
 
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Dose Modification 
•
Dose modification may be considered for individual subjects based on benefit-risk
assessment (See Section 4.3).
•
Subjects may receive 300 mg q4w at the discretion of the Investigator, with optional
consultation with the sponsor, if they have been well-controlled (eg, attack free for
26 weeks).
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 documented on an Overdose page 
of the 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. Adverse 
events associated with an overdose will be documented on AE case report forms (CRFs) 
according to Section 10.0. 
Serious adverse events associated with overdose should be reported according to the procedure 
outlined in Section 10.2.2. 
In case of accidental overdose the rollover subjects (who self-administered the study drug) 
should inform it to site. In the event of drug overdose, the subject should be treated 
symptomatically. 
8.2 
Study Drug Assignment and Dispensing Procedures 
An Interactive Response Technology (IRT) vendor will be used for this study to manage 
packaged Investigational product (IP) supply, IP shipments, receipt of IP at clinical sites, 
randomization of IP to subjects, expiry tracking, IP returns, and IP accountability. 
Subjects will receive treatment according to the study schedule. The Enrollment Number will be 
entered onto the eCRF. 
This is an open-label study. Subject numbers are assigned to all subjects as they consent to take 
part in the study. Within each site (numbered uniquely within a study), the subject number is 
assigned to subjects according to the sequence of presentation for study participation. 
The subject number represents a unique number corresponding to study drug allocated to the 
subject, once eligibility has been determined. 
Subjects will be assigned to receive the next available medication ID number allocated to each 
study site. The medication ID number will be entered onto the eCRF. 
 
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8.3 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee. 
The Investigator has overall responsibility for administering and dispensing study drug (for 
dosing by site personnel and self-administration, respectively). The Investigator or designee must 
ensure that the sponsor-supplied drug is used in accordance with the protocol and is dispensed 
only to subjects enrolled in the study. To document appropriate use of sponsor-supplied drug, the 
Investigator or designee must maintain records of all sponsor-supplied drug delivery to the site, 
site inventory, dispensation and use by each subject, and return to the sponsor or designee. 
•
Upon Continuously monitoring expiration dates.
•
Frequently verifying that actual inventory matches documented inventory.
•
Verifying that all containers used are documented accurately on the log.
•
Verifying that required fields are completed accurately and legibly.
Upon receipt of sponsor-supplied drug, the Investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, and 
the medication is in good condition. If quantity and conditions are acceptable, Investigator or 
designee should acknowledge the receipt of the shipment by signing bottom half of the packing 
list and faxing per instructions provided on the form/by recording in IRT. If there are any 
discrepancies between the packing list versus the actual product received, Takeda must be 
contacted to resolve the issue. The packing list should be filed in the Investigator’s essential 
document file. 
The Investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to: 
•
Continuously monitoring expiration dates if expiry date/retest date is provided to the
investigator or designee.
•
Frequently verifying that actual inventory matches documented inventory.
•
Verifying that the log is completed for the drug lot used to prepare each dose.
•
Verifying that all containers used are documented accurately on the log.
•
Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
The IRT will include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed. 
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All study drug not returned to the site by a subject must be investigated by the site and 
appropriately documented on the drug accountability log. 
Self-administering subjects will either return their IP to site for accountability. 
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The Investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, 
and/or destruction, and originals will be sent to the sponsor or designee. 
The Investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction. 
In the event of expiry date extension of sponsor-supplied drug already at the study site, 
sponsor-supplied drugs may be relabeled with the new expiry date at that site. In such cases, 
Takeda or its designee will prepare additional labels, certificates of analyses, and all necessary 
documentation for completion of the procedure at the sites. 
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 from the subject as well as return of 
them to the sponsor or destruction of them. 
 
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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 Assessments (SoA) is located in 
 
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent and assent forms must be approved for use by the reviewing IRB. Informed 
consent must be obtained prior to the subject entering into the study (or their parent/caregiver, as 
applicable), and before any protocol-directed procedures are performed. Assent will also be 
obtained from each subject, where required in accordance with IRB and local regulations, prior 
to performing any study-related activities. Subjects and their parent(s)/caregiver(s) may 
withdraw consent at any time. Participation in the study may be terminated at any time without 
the consent/assent of the subject (or their parent/caregiver, as applicable) as determined by the 
Investigator. 
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained, which will be used throughout the study. 
9.1.2 Demographics, Medical History, and Medication History Procedure 
Subject demographic information including gender, age, and race will be collected prior to the 
subject receiving the first dose of IP. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved within 1 year prior to 
signing of informed consent. Ongoing conditions are considered concurrent medical conditions 
(see Section 9.1.7). 
For rollover subjects, demography data from SHP643-302 will be re-entered for TAK-743-5007. 
However, medical history reported in the SHP643-302 study will not be re-entered into the eCRF 
for TAK-743-5007; only new medical history data will be entered. 
For non-rollover subjects, medication history information to be obtained includes any medication 
relevant to eligibility criteria (efficacy/safety evaluation) stopped at or within 4 weeks prior to 
signing of informed consent. The information of LTP administration will be recorded from 90 
days prior to signing of informed consent. 
 
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9.1.3 Physical Examination Procedure 
A complete physical examination will be performed by the Investigator or his/her qualified 
designee according to the SoA 
 The date and time of examination, and any 
findings, will be recorded on the source documents and eCRF. 
Adverse events emerging from any physical examination will be recorded on the source 
document and eCRF. 
The physical examination will be performed in accordance with standards at the site. The 
physical examination will include, at a minimum, assessments of the body systems listed below: 
•
General appearance.
•
Ears, nose, and throat.
•
Head and Neck.
•
Ophthalmological.
•
Respiratory.
•
Cardiovascular.
•
Abdomen.
•
Neurological.
•
Extremities.
•
Dermatological.
•
Lymphatic.
In addition, height and weight will be measured at the screening visit only in accordance with 
standards of the site. 
9.1.4 Vital Sign Procedure 
Vital signs will be assessed by the Investigator or his/her qualified designee according to the 
SoA 
 Vital signs will include body temperature, RR, BP (systolic and diastolic, 
resting more than 5 minutes), and HR (bpm). For HR measurement, it is acceptable to use 
sphygmomanometers to measure pulse rate instead of using ECG or stethoscope for HR. Vital 
signs will be obtained prior to dosing and 1 hour after dosing with a ±15 minutes window. 
Routine vital sign assessments will be taken with the subject in the sitting or supine position after 
5 minutes at rest. Blood pressure should be determined using the same arm and the same 
equipment, and the same position for each assessment throughout the study. 
During the study, additional vital signs measurements will be performed if clinically indicated. 
Every effort should be made to measure and record vital signs prior to any blood sample 
collection. 
 
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The Investigator will assess whether a change from baseline (ie, the predose measurement at 
Visit 1/Day 0) in vital signs may be deemed clinically significant and whether the change should 
be considered and recorded as an AE. 
9.1.5 Efficacy Measurement 
9.1.5.1 Collection of Hereditary Angioedema Attacks 
Historical HAE attack information will be collected at screening for non-rollover subjects. 
Throughout the study (ie, from screening through follow-up), HAE attack information will be 
solicited by site personnel during scheduled study visits and site check-ins, as shown in SoA 
 In addition, study subjects (or parent/caregivers, in the event the subject is 
<18 years old or is incapacitated) will be instructed to report details of the HAE attack to the 
study site within 72 hours of the onset of the attack. 
The collection, reporting and assessment of HAE attacks in this study will be done in accordance 
with the hereditary angioedema attack assessment and reporting procedures (HAARP) provided 
in 
 of this protocol. Site personnel will be trained on HAARP prior to screening 
subjects at their site. 
9.1.5.2 Management of Acute Angioedema Attacks 
Acute HAE attacks during the study are to be managed in accordance with the Investigator’s 
usual care of their subjects, including use of acute attack therapies that the Investigator deemed 
medically appropriate. Use of C1-INH is permitted as an acute attack therapy but not as an LTP 
therapy. Administration of lanadelumab and study procedures is to continue without alteration to 
the protocol-specified study schedule, even if the subject had symptoms of an HAE attack the 
day of lanadelumab administration and/or received treatment for an HAE attack. The 
administration of lanadelumab can also be re-scheduled as long as the minimum and maximum 
timeframe between doses is met based on patient preference or physician discretion. 
9.1.6 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug including the rescue 
medications. These may be prescribed by a physician or obtained by the subject 
over-the-counter. Concomitant medication is not provided by the sponsor. At each study visit, 
subjects will be asked whether they have taken any medication other than the study drug (used 
from signing of informed consent through the end of the study), and all medication including 
vitamin supplements, over-the-counter medications, and oral herbal preparations, must be 
recorded in the eCRF. For rollover subjects, any medications that are ongoing at the end of the 
previous study and that are still present at the time of enrollment into this study will be recorded 
in the eCRF for Study TAK-743-5007. 
 
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9.1.7 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at screening examination, according to the judgment of 
the Investigator. The condition (ie, diagnosis) should be described. 
9.1.8 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with standard laboratory procedures using 
established and validated methods according to the SoA 
 Reference ranges will be 
supplied by the laboratory and used to assess the results for clinical significance and out-of-range 
changes which may be associated with, or constitute, an AE. The Investigator should assess 
out-of-range clinical laboratory values for clinical significance, indicating if the value(s) is/are 
not clinically significant or clinically significant. Abnormal clinical laboratory values, which are 
unexpected or not explained by the subject’s clinical condition, may, at the discretion of the 
Investigator or sponsor, be repeated as soon as possible until confirmed, explained, or resolved. 
9.1.8.1 Laboratory testing and blood volume to be collected 
Laboratory testing includes general safety parameters (hematology, serum chemistry, 
coagulation, and urinalysis), pregnancy tests, C1-INH functional assay, C4 assay, and C1q assay 
using established and validated methods. All laboratory tests will be performed using established 
and validated methods. Table 9.a lists the tests that will be obtained for each laboratory 
specimen. 
Table 9.a 
Clinical Laboratory Tests 
Chemistry 
•
Albumin
•
Alkaline phosphatase
•
Alanine aminotransferase (ALT; SGPT)
•
Aspartate aminotransferase (AST; SGOT)
•
Bilirubin (total and direct)
•
Blood urea nitrogen (BUN)
•
Calcium
•
Bicarbonate
•
Chloride
•
Creatinine
•
Creatine phosphokinase (CPK)
•
Glucose
•
Phosphate
•
Magnesium
•
Potassium
•
Sodium
•
Total protein
•
Uric acid
Hematology
•
Hemoglobin
•
Hematocrit
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•
Red blood cell (RBC) count
•
White blood cell (WBC) count with differential
•
Mean corpuscular volume (MCV)
•
Mean corpuscular hemoglobin (MCH)
•
Mean corpuscular hemoglobin concentration (MCHC)
•
Absolute platelet count
Coagulation
•
Prothrombin time
•
Activated partial thromboplastin time (aPTT)
•
International Normalized Ratio (INR)
Urinalysis
•
Bilirubin
•
Glucose
•
Ketones
•
Blood
•
Nitrite
•
pH
•
Protein
•
Specific gravity
•
Microscopy (if indicated by macroscopic findings)
Virology (at screening only for rollover subjects)
•
Hepatitis B Surface Antigen (HbsAg)
•
Hepatitis C Virus (HCV)
•
Human Immunodeficiency Virus (HIV)
When multiple sample collection types are performed at the same assessment time point, the 
samples will be drawn in the following order of safety assessment (hematology, coagulation, and 
serum chemistry) and eligibility assessment (C1-INH functional assay, C4 assay, and C1q 
assay). Subjects will be seated in a supine position during blood collection. 
The maximum volume of blood to be collected at any single visit and the approximate total 
volume of blood for the study will be specified in the Lab Manual. Note: The amount of blood to 
be drawn for each assessment is an estimate. The amount of blood to be drawn may vary 
according to the instructions provided by the manufacturer or laboratory for an individual 
assessment. 
 
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9.1.8.2 Blood Sample Collection, Storage and Shipping 
Blood samples for laboratory assessments will be collected at the site by a trained site staff 
designated and/or approved by the study Investigator. Details for the collection, processing, 
storage, and shipment of samples for all laboratory determinations will be provided in the 
Laboratory Manual. Biological material will be stored and secured in a manner that assures that 
unauthorized access is prohibited, and the samples are not lost, allowed to deteriorate, or 
accidentally or illegally destroyed. 
9.1.9 Contraception and Pregnancy Avoidance Procedure 
Lanadelumab has not been studied in pregnant women, and there are limited data from its use in 
pregnant women. However, a risk to the pregnant woman or developing fetus cannot be 
excluded. No evidence of testicular toxicity or adverse effects on male fertility or teratogenicity 
transferable to a fetus/embryo from animal studies were observed. 
9.1.9.1 Male subjects and their Female Partners 
Males, including males who are surgically sterile (post-vasectomy), with female partners of 
childbearing potential must agree to be abstinent or else use a medically acceptable form of 
contraception from screening through 70 days after the final study visit. Females of childbearing 
potential who are partners of male subjects are also advised to use additional contraception as 
shown in the list containing highly effective/effective contraception below. 
9.1.9.2 Female subjects and their Male Partners 
Females* of childbearing potential who are sexually active with a nonsterilized male partner 
must agree to be abstinent or it is recommended to use highly effective forms of contraception 
from the screening period through 70 days after the final study visit. If used, hormonal 
contraceptives should be administered according to the package insert. Any female of 
childbearing potential who is not currently sexually active must agree to use acceptable 
contraception, as defined below, if she becomes sexually active during the study and for 70 days 
following the last dose of IP.  
•
A female whose male partner, including males who have had a vasectomy, must agree to
be abstinent or else use a medically acceptable form of contraception from screening
through 70 days after the final study visit.
•
Use of a male condom with or without spermicide or cervical cap diaphragm or sponge
with spermicide or a combination (double-barrier methods) are not considered highly
effective.
Females of nonchildbearing potential, defined as surgically sterile (status post-hysterectomy, 
bilateral oophorectomy, or bilateral tubal ligation) or postmenopausal for at least 12 months do 
not require contraception during the study. 
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*Note: Female rollover subjects (those who previously participated in Study SHP643-302) of childbearing potential
may continue to use the birth control method used during Study SHP643-302.
9.1.9.3 
Definitions and Procedures for Contraception and Pregnancy Avoidance 
The following definitions apply for contraception and pregnancy avoidance procedures. 
A woman is considered a woman of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as 
no menses for 12 months without an alternative medical cause. A high follicle stimulating 
hormone (FSH) level in the postmenopausal range (FSH >40 IU/L) may be used to confirm a 
postmenopausal state in younger women (eg, those <45 year old) or women who are not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient. 
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. 
The following procedures apply for contraception and pregnancy avoidance. 
1. Highly effective methods of contraception are defined as those, alone or in combination, that
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and
correctly). In this study, the acceptable methods of contraception are:
•
Non-Hormonal Methods:
•
Intrauterine device.
•
Bilateral tubal occlusion.
•
Hormonal Methods:
•
Combined (estrogen and progestogen) hormonal contraception associated with
inhibition of ovulation initiated at least 3 months prior to the first dose of study
drug OR combined with a barrier method (male condom, female condom or
diaphragm) if for shorter duration until she has been on contraceptive for
3 months;
•
Oral.
•
Intravaginal (eg, ring)*.
•
Transdermal*.
•
Progestogen-only hormonal contraception associated with inhibition of ovulation
initiated at least 3 months prior to the first dose of study drug OR combined with
a barrier method (male condom, female condom or diaphragm) if shorter till she
has been on contraceptive for 3 months;
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•
Oral*.
•
Injectable*.
•
Implantable*.
•
Double-barrier method (contraceptive sponge, diaphragm or cervical cap* with
spermicidal jellies* or creams* PLUS male condom).
2. Unacceptable methods of contraception includes:
•
Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).
•
Spermicides* only.
•
Withdrawal.
•
No method at all.
•
Use of female and male condoms together.
•
Cap*/diaphragm/sponge without spermicide* and without condom.
Note:*These contraception methods and pregnancy avoidance procedures are not approved in Japan.
3. Subjects will be provided with information on highly effective/effective methods of
contraception as part of the subject informed consent process and will be asked to sign a
consent form stating that they understand the requirements for avoidance of pregnancy,
donation of ova, and sperm donation during the course of the study.
4. During the course of the study, regular serum/urine human chorionic gonadotropin (hCG)
pregnancy tests will be performed only for women of childbearing potential and all subjects
(male and female) will receive continued guidance with respect to the avoidance of
pregnancy and sperm donation as part of the study procedures. Such guidance should include
a reminder of the following:
a.
Contraceptive requirements of the study.
b. Reasons for use of barrier methods (ie, condom) in males with pregnant partners.
c.
Assessment of subject compliance through questions such as:
i.
Have you used the contraception consistently and correctly since the last visit?
ii.
Have you forgotten to use contraception since the last visit?
iii.
Are your menses late (even in women with irregular or infrequent menstrual
cycles a pregnancy test must be performed if the answer is “yes”)
iv.
Is there a chance you could be pregnant?
5. In addition to a negative urine hCG pregnancy test at screening, female subjects of
childbearing potential must also have confirmed menses in the month before first dosing (no
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delayed menses), a negative serum/urine hCG pregnancy test prior to receiving any dose of 
study medication. 
9.1.9.4 
General Guidance With Respect to the Avoidance of Pregnancy 
From signing of informed consent and throughout the duration of the study and for 70 days after 
the last dose, female subjects of childbearing potential (ie, nonsterilized, premenopausal female 
subjects) who are sexually active must use acceptable methods of contraception. Also from 
signing of informed consent, throughout the duration of the study, and for 70 days after last dose, 
nonsterilized male subjects who are sexually active with a female partner of childbearing 
potential must use contraception. Such subjects will be provided with information on acceptable 
methods of contraception as part of the subject informed consent process, and will be asked to 
sign a consent form stating that they understand the requirements for avoidance of pregnancy 
during the course of the study. During the course of the study, regular urine hCG pregnancy tests 
will be performed, and subjects will receive continued guidance with respect to avoiding 
pregnancy as part of the study procedures
 
In addition to a negative urine hCG pregnancy test at screening, subjects also must have a 
negative serum/urine hCG pregnancy test on the day of the first dose of study drug (predose), 
prior to receiving any dose of study drug. 
The contraceptive methods available in Japan are shown below. 
Nonsterilized males with female partners of childbearing potential must use condoms (with or 
without spermicide). Females of childbearing potential with male partners who are participating 
in this study and female subjects of childbearing potential with nonsterilized male partners must 
use the following contraceptive methods. 
•
Intrauterine device (IUD).
•
Bilateral tubal occlusion.
•
Vasectomized partner* (provided that partner is the sole sexual partner of the trial
participant and that the vasectomized partner has received medical assessment of the
surgical success).
Note: *must agree to be abstinent or else use a medically acceptable form of contraception from screening 
through 70 days after the final study visit. 
•
Combined (estrogen and progestogen) hormonal contraception associated with inhibition
of ovulation. (Not used for female subjects).
9.1.10 Pregnancy 
For all females, pregnancy testing will be performed at the time points specified in SoA 
 if pregnancy is suspected; or on withdrawal (early termination visit) of the subject 
from the study. Pregnancy testing at Day 0 will be urine-based. All other pregnancy testing in 
this study may be urine- or serum-based. 
 
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If any subject is found to be pregnant during the study, she should be withdrawn and any 
sponsor-supplied study drug should be immediately discontinued. In addition, any pregnancies in 
the partner of a male subject during the study or for 160 days after the last dose, should also be 
recorded following authorization from the subject’s partner. 
All pregnancies are reported from the time informed consent is signed until the defined 
follow-up period. The pregnancy should be reported immediately, using a pregnancy notification 
form, to the contact listed in Section 1.0/Annex 1. 
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the Investigator should notify the primary care physician that the female 
subject/female partner of the 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, including female partners of male subjects, in subjects on 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. 
9.1.11 Electrocardiogram 
A standard 12-lead ECG (single recording) will be performed at screening visit, final visit/ early 
termination, and when clinically indicated. The date and time of each ECG and its results will be 
documented in the source documents and eCRF. 
9.1.12 Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent. A screen failure is a 
subject who has given informed consent and failed to meet all inclusion criteria and/or has met at 
least 1 of the exclusion criteria and has not been administered study drug. Once a subject has 
been designated as a screen failure, the subject may be rescreened at the discretion of the 
Investigator and following discussion with the sponsor medical monitor. 
If the subject is withdrawn at the screening visit, the Investigator should complete the eCRF. 
Screening of some subjects is allowed to have following discussion with the sponsor: ie, subjects 
who screen fail out of the run-in period for Study SHP643-302 when enrollment for that study 
closed. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
•
AE.
•
Did not meet inclusion criteria or did meet exclusion criteria.
•
Significant protocol deviation.
•
Lost to follow-up.
•
Voluntary withdrawal.
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•
Other.
Subject identification numbers assigned to subjects who fail screening should not be reused. 
9.1.13 Other Assessments 
9.1.13.1 Self-administration of Lanadelumab 
All subjects who are considered suitable candidates will be allowed to self-administer treatment 
throughout the study. 
Self-administration will be permitted after a subject (and/or their parent/caregiver) has received 
appropriate training by the Investigator or designee and has demonstrated their understanding of 
self-administration. Subjects are allowed to initiate self-administration at the subject’s home or 
other agreed upon location after receiving the first 2 doses of lanadelumab at the study site. 
Subjects can also self-administer lanadelumab for Dose 3 thereafter. The first dose of self-
administration is required to be administered at the study site. Once initiated, subjects can self-
administer subsequent doses of lanadelumab at the study site (when visits are scheduled study 
site visits) or the subject’s home (or other agreed upon location, when the study permitted off-
site dosing). 
Rollover subjects from Study SHP643-302 who were self-administrating the study drug at the 
time of screening will be permitted to continue self-administrating. 
Adolescent subjects self-administering lanadelumab are to be supervised by a parent/legal 
guardian/caregiver. Alternatively, a parent/legal guardian/caregiver, after completing appropriate 
training, will be allowed to administer the study drug to an adolescent without study site 
personnel supervision. 
The Investigator or designee will train subjects (and/or parents/caregivers) who elect to 
self-administer lanadelumab on the following: 
•
The subject’s (or parent/caregiver’s) transportation of study drug using a
sponsor-provided cooler, and the recommended storage conditions of study drug when
stored at an off-site location.
•
Maintenance of accurate records regarding each administration of study drug including
supply identification (ie, lot/kit number), date and time of injection, injection site
location, infusion time, and if applicable, any reason the self-administration could not be
completed as instructed.
•
Retention of all used and unused PFS of study drug for drug accountability purposes.
•
Additional information, as provided in the Pharmacy Manual.
Site personnel are to call subjects within approximately 3 days after the planned off-site 
self-administrations to ensure the administration occurred, to collect AEs, concomitant 
medications, and to ensure all attacks have been appropriately documented. Throughout the 
study, study site personnel are to document information in source documents (ie, the subject’s 
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medical record) and eCRF regarding the subject’s experience with self-administration and SC 
administration of lanadelumab. 
9.1.13.2 Injection Report 
An Injection Report will be completed by the subject (or parent/caregiver) following each dose 
of lanadelumab, according to the SoA 
 The Injection Report will collect 
information on the subject’s experience with SC injection and self-administration of 
lanadelumab. 
Study personnel will document the subject’s responses in the subjects’ medical record and eCRF. 
9.1.13.3 Biomarkers (C1-INH, C1q, and C4) 
For non-rollover subjects, one blood sample will be obtained at the screening visit for evaluation 
of C1-INH, C4, and C1q to confirm a diagnosis of HAE. Diagnostic testing will be performed by 
a sponsor-approved central laboratory. Results of a C1-INH functional assay are required for 
eligibility assessment in all subjects. Results of the C4 assay are required for eligibility in 
subjects with a C1-INH level of 40 to 50%, and results of C1q assay are required for eligibility in 
subjects without a documented family history consistent with HAE Type I or II. With prior 
sponsor approval, subjects may be retested for C1-INH or C4 if results are incongruent with 
clinical history or believed by the Investigator to be confounded by recent LTP use. Note: 
Because C1-INH therapy may alter the laboratory results of C1-INH functional assay, the 
Investigator's discretion in collaboration with the medical monitor is advised for proper 
documentation of eligibility. No blood sampling is needed for rollover subjects. 
9.2 
Monitoring Subject Treatment Compliance 
Treatment compliance and the extent of exposure to study drug will be described by the 
percentage of planned doses received by the subject, total number of doses received by the 
subject, and the number and percentage of subjects that received at least 80% of planned doses, 
summarized for each analysis population. All supplies used to administer study drug to the 
subject will be recorded on the eCRFs. 
9.3 
Schedule of Assessments 
The schedule for all study-related procedures for all evaluations is shown in SoA 
 
9.3.1 Screening 
Rollover subjects: For subjects rolling over from the SHP643-302 study, no screening visit is 
required. The first study visit for rollover subjects (Day 0) is to occur on the same day as the 
Study SHP643-302 Day 378 study visit.  
Non-rollover Subjects: For subjects not rolling over from Study SHP643-302, subjects are 
required to provide informed consent and have screening assessments completed within 28 days 
prior to firs dose administration. Screened non-rollover subjects (adults and adolescents) who are 
 
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on LTP therapy for HAE can continue their current LTP until 3 weeks following the first dose of 
lanadelumab. It is understood that C1-INH therapy can alter the laboratory results of C1-INH 
assessments; therefore, the Investigator's discretion in collaboration with sponsor is advised for 
proper documentation of eligibility.  
Procedures to be completed at screening include: 
•
Informed consent for non-rollover subjects.
•
Eligibility review.
•
Long-term prophylactic therapy.
•
Demographics, medical history, and medication history.
•
Pregnancy test (for female subjects).
•
Complete physical examination, including documentation of height and weight.
•
Vital signs.
•
Prior and concomitant therapy (including medications and procedures).
•
Concurrent medical conditions.
•
Screening clinical laboratory tests.
•
12-lead ECG.
•
Collection of historical HAE attack data 
•
Functional C1-INH, C4, and C1q testing.
•
Adverse events.
9.3.2 Treatment Period 
9.3.2.1 Study Visit 1; Study Day 0 
Visit 1 on Day 0 will be a scheduled on-site visit. The following procedures and assessments are 
to be performed on Day 0 prior to the first dose administration. 
•
Informed consent after site check-in with rollover subjects
Informed consent may be completed on Day 364 of Study SHP643-302 or this visit, if not
already provided.
•
Confirmation of eligibility.
•
Long-term prophylactic therapy details (tapered) for non-rollover subjects.
•
Pregnancy test (for female subjects).
•
Vital signs including body temperature, HR (pulse), BP, and RR.
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•
All clinical laboratory testing including hematology, coagulation, serum chemistry, and
urinalysis.
•
Prior or concomitant therapy (including medications and procedures).
•
HAE attack data
The following post-treatment procedures and assessments will be performed: 
•
Lanadelumab injection report.
•
Vital signs including body temperature, HR (pulse), BP, and RR at 1 hour post-dose.
•
Concomitant therapy (including medications and procedures).
•
Adverse events collection, including SAEs and AESIs.
For rollover subjects, study site personnel will contact the subjects approximately every 7 days 
following the first dose of open-label lanadelumab solicit for any HAE attacks not already 
reported. Site check-in with rollover subjects will continue until the subject receives their second 
open-label dose. 
9.3.2.2 Study Visit 2 (Study Day 14) to Study Visit 14 (Study Day 182) 
The assessment and other procedures that will take place from Study Visit 2 (Study Day 14) to 
Study Visit 14 (Study Day 182) are: 
•
Concomitant therapy (including medications and procedures).
•
Adverse events collection, including SAEs and AESIs.
•
HAE attack data 
•
Lanadelumab injection report.
As indicated in SoA, the following procedures will be performed on Study Visits 2, 3, 5, 8, 11, 
and 14 (Study Day 14, 28, 56, 98, 140, and 182 respectively) are: 
•
Long-term prophylactic therapy details at Visit 2 and Visit 3 for non-rollover subjects.
•
Vital signs including body temperature, HR (pulse), BP, and RR (both prior and 1 hour
post-dose).
•
Pregnancy test.
•
Clinical laboratory testing (not performed on Visit 2 for all subjects, and not performed
on Visit 5 and Visit 11 for rollover subjects).
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Self-administration: 
Subjects can also self-administer lanadelumab for Dose 3 thereafter. The first dose of self-
administration is required to be administered at the study site. Once initiated, subjects can self-
administer subsequent doses of lanadelumab at the study site (when visits are scheduled study 
site visits) or the subject’s home (or other agreed upon location, when the study permitted off-
site dosing). 
Vital signs, pregnancy test and clinical laboratory testing at Study Visits 3, 5, and 11 (Study Day 
28, 56, and 140 respectively) can be done at local site at investigator’s discretion if approved by 
IRB. 
Prior and concomitant therapy, adverse events collection, including SAEs and AESIs, HAE 
attack data and lanadelumab injection report from Study Visit 3 (Study Day 28) to Study Visit 13 
(Study Day 168) except for Visit 8 (Study Day 98) can be done remotely (via phone or video) at 
investigator’s discretion if approved by IRB. 
9.3.3 Study Visit post Visit 14 (Day 182) 
After Study Day 182, study visits will occur every 12 weeks, and site personnel are to make 
telephone calls to each subject q2w after Study Day 182 (except for in-clinic visits every 12 
weeks) to collect AEs, concomitant medications, and to ensure all HAE attacks have been 
appropriately documented. 
The treatment period is to last up to lanadelumab manufacturing and sale, development 
discontinued, or withdraw of new drug application. Administration of lanadelumab and study 
procedures is to continue without alteration to SoA, even if a subject receives treatment for a 
breakthrough angioedema attack on the day of a scheduled dose of study drug (if 
self-administering) or scheduled study visit. 
Vital sings, pregnancy test, and clinical laboratory testing can be done at local site at 
Investigator’s discretion if approved by IRB. 
Prior and concomitant therapy, adverse events collection, including SAEs and AESIs, HAE 
attack data, and lanadelumab injection report can be done remotely (via phone or video) at 
Investigator’s discretion if approved by IRB. 
For Study Day 266, subjects should visit the study site for dispensing and/or administering study 
drug. 
9.3.4 Safety Follow-up Visit 
After completion of the treatment period, all subjects are to undergo safety evaluations during a 
4-week follow-up period.
At the end of the follow-up period there will be a scheduled on-site end of study (EOS) visit, at 
which the following assessments and procedures will be performed: 
•
Vital signs including body temperature, HR (pulse), BP, and RR.
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•
Clinical laboratory testing, including hematology, serum chemistry, coagulation, and
urinalysis.
•
Pregnancy test (for female subjects).
•
HAE attack data (Note: Subjects must report details of an HAE attack to the study site
within 72 hours of onset of the attack, in accordance with HAARP 
•
Prior and concomitant therapy (including medications and procedures).
•
Adverse events collection, including SAEs and AESIs. Note: All AEs and SAEs that are
not resolved at the time of this contact will be followed to closure.
9.3.5 Final Visit or Early Termination 
All procedures and assessments scheduled for the EOS visit will be followed for the early 
termination visit 
•
Vital signs including body temperature, HR (pulse), BP, and RR.
•
Clinical laboratory testing, including hematology, serum chemistry, coagulation, and
urinalysis.
•
Pregnancy test (for female subjects).
•
12-Lead ECG.
•
HAE attack data (Note: Subjects must report details of an HAE attack to the study site
within 72 hours of onset of the attack, in accordance with HAARP 
•
Prior and concomitant therapy (including medications and procedures).
•
Adverse events collection, including SAEs and AESIs. Note: All AEs and SAEs that are
not resolved at the time of this contact will be followed to closure.
•
Discharge from study.
9.3.6 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 Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent and administered a drug; it does not necessarily have to have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
In addition, drug-device AEs related to product malfunctions will be collected. 
10.1.2 Additional Points to Consider for Adverse Events 
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.)
•
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.
Adverse events 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 retest and/or continued monitoring of an abnormal value or finding
are not considered an intervention. In addition, repeated or additional noninvasive testing
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for verification, evaluation or monitoring of an abnormality is not considered an 
intervention. 
•
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, the worsening or complication
should be recorded appropriately as an AE (worsening or complication occurs after start
of study drug). 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 from Baseline (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 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 Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose: 
10. Results in DEATH.
11. 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.
12. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
13. Results in persistent or significant DISABILITY/INCAPACITY.
14. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
15. 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 Adverse Event 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 adverse event List represent the broad medical concepts to be 
considered as “Important Medical Events” satisfying serious adverse event reporting requirements. 
10.1.4 Adverse Events of Special Interest 
An AESI (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. 
Adverse events of special interest include hypersensitivity reactions and events of disordered 
coagulation (bleeding AESIs and hypercoagulable AESIs). 
10.1.5 Intensity of Adverse Events 
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 Adverse Events 
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 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
Investigator. 
AEs 
Start Date 
Any signs/symptoms/diseases 
(diagnosis) 
The date that the first signs/symptoms/diseases were noted by the subject 
and/or the Investigator should be recorded. 
Asymptomatic diseases 
The date when examination was performed for diagnosis and diagnosis 
was confirmed should be recorded. 
The date 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 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 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 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. 
AE = adverse event 
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10.1.9 
Stop Date 
The stop date of the AE is the date 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.
•
Dose Reduced – the dose interval was extended due to the particular AE.
•
Dose Increased – the dose interval was returned to the original setting 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.
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•
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.
10.1.13 Product Malfunctions 
Malfunction means the failure of a drug product and/or medical device (eg, prefilled syringe) to 
meet its performance specifications or otherwise perform as intended. Performance 
specifications include all claims made in the labeling for the product. The intended performance 
of a product refers to the intended use for which the product is labeled or marketed. 
An Investigator who is made aware of or identifies a potential product malfunctions should 
immediately report the event to the sponsor. Whenever possible, the associated product should 
be maintained in accordance with the instructions pending further guidance from the sponsor. 
10.2 
Procedures 
10.2.1 
Collection and Reporting of Adverse Events 
10.2.1.1 Adverse Event Collection Period 
Collection of AEs will commence from the time the subject signs the informed consent to 
participate in the study. For rollover subject, ongoing AEs (including HAE attacks) at the end of 
the previous study is required to be followed-up in the study. Routine collection of AEs will 
continue until final visit/ early termination. 
10.2.1.2 Adverse Events 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 an 
SAE 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-serious AEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol. 
In this study, HAE attacks are to be captured as AEs. All AEs, regardless of seriousness, 
severity, or causal relationship to lanadelumab, are to be recorded on the AE page of the eCRF 
(with the exception of HAE attacks as indicated below). Any AE reported to the site meeting 
criteria for a SAE is required to be reported to the sponsor using the SAE Reporting Form in the 
electronic data capture (EDC) system within 3 working days of becoming aware of the event. 
•
Non-HAE attack AEs will be reported on the AE page of the eCRF. The severity of these
AEs will be assessed according to the Division of Microbiology and Infectious Diseases
(DMID) Adult Toxicity Table 
 and the DMID Pediatric Toxicity Table
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•
These HAE attack AEs will be reported on the designated angioedema attack page of the
eCRF. Severity of the angioedema attack will be assessed in accordance with HAARP,
which includes an assessment using HAARP criteria 
 and an assessment
using DMID criteria.
For all AEs that are reported as HAE attacks, the Investigator or physician designee is to review 
the event within 3 days of initial notification and, in accordance with HAARP, evaluate if it 
represents a confirmed HAE attack. If necessary for the evaluation, the Investigator or designee 
can contact the subject to receive additional information. Any subject-reported attack not 
confirmed by the Investigator or physician designee is required to have an alternate AE diagnosis 
recorded. 
Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
are to be captured. 
All subjects experiencing AEs, 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.
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.
10.2.1.3 Adverse Events of Special Interest 
If the AESI that occurs during the treatment period or the follow-up period is considered to be 
clinically significant based on the criteria below, it should be reported by the Investigator to the 
sponsor/the Emergency Reception Center for Safety Information (see Annex 1) immediately or 
within 24 hours of/after the first onset or subject’s notification of the event. Reporting urgency 
depends on the level of emergency. An AESI Form or an SAE form should be completed, 
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signed, or signed and sealed by the Investigator and reported to the sponsor/the Emergency 
Reception Center for Safety Information (see Annex) within 10 calendar days. 
The Investigator should submit the original copy of the AESI Form or the SAE form to the 
sponsor. Adverse events of special interest have to be recorded as AEs in the eCRF. An 
evaluation form along with all other required documentation must be submitted to the sponsor. 
The following describe the AESI and the criteria for reporting AESI. 
Hypersensitivity Reactions 
As hypersensitivity reactions have been observed for monoclonal antibodies as a class, these 
events are considered AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with hypersensitivity 
reactions, regardless of causality, within 24 hours from the time of study drug administration. 
Investigators will report hypersensitivity reactions that occur after 24 hours, only if the reactions 
are suspected to be related to study drug. 
Events of Disordered Coagulation 
Bleeding AESI 
Although activated partial thromboplastin time (aPTT) prolongation due to pKal inhibition is an 
artifactual in vitro phenomenon, as a precautionary measure in evaluating the safety of 
lanadelumab, bleeding events will be reported as AESI for this study. Investigators will report all 
diagnoses, or signs and symptoms when diagnoses cannot be determined, that are consistent with 
a clinical event of bleeding. Coagulation testing (aPTT, prothrombin time, and international 
normalized ratio) should be performed when possible, and when temporally reasonable, with any 
reports of bleeding or for clinical conditions possibly indicative of bleeding. 
Hypercoagulable AESI 
Investigators will report all diagnoses, or signs and symptoms when diagnoses cannot be 
determined, that are consistent with a thrombotic or embolic etiology. 
10.2.2 
Collection and Reporting of Serious Adverse Events 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
An SAE should be reported by the Investigator to the sponsor/the Emergency Reception Center 
for Safety Information (see annex 1) within 24 hours of the SAE occurrence, along with any 
relevant information. The Investigator should submit the detailed SAE form to the sponsor/the 
Emergency Reception Center for Safety Information appropriate personnel (see annex 1) within 
10 calendar days. 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.
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•
Investigator’s name.
•
Name of the study drug(s).
•
Causality assessment.
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. 
10.3 
Follow-up of Serious Adverse Events 
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, Institutional Review Boards 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 or the 
head of the study site, as applicable. 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 3 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. Adverse Events, 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/Japanese Drug Dictionary. 
12.1 
Case Report Forms (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. Electronic CRFs must be completed in English/Japanese. Data are transcribed 
directly onto eCRFs. 
All corrections must be initialed and dated. 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. Reasons for significant 
corrections should additionally be included. All new additions are to be made with the date and 
sign. 
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.
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF. 
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/CRFs (Data Clarification Form) provided by the sponsor. The Principal Investigator must 
review the data change for completeness and accuracy, and must sign and date. 
Electronic CRFs 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. 
 
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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 identification log of all participating subjects, medical records, all original signed 
and dated informed consent forms, copies of all query responses/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. 
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 prepared prior to the first subject enrolled and finalized 
prior to database lock to preserve the integrity of the statistical analysis and study conclusions. 
The SAP will provide the statistical methods and definitions for the analysis of the clinical 
outcomes and safety data, as well as describe the approaches to be taken for summarizing other 
study information such as subject disposition, demographics and baseline characteristics, study 
drug exposure, and prior and concomitant medications. The SAP will also include a description 
of how missing, unused and spurious data will be addressed. 
All statistical analyses will be performed using SAS Version 9.4 or higher (SAS Institute, Cary, 
NC 27513). 
13.1.1 
Analysis Sets 
Full Analysis Set (FAS) is defined as all subjects who received at least 1 dose of lanadelumab. 
All safety and efficacy analyses will be based on the FAS and each subset in FAS defined below. 
Unless otherwise specified, summary tabulations conducted using FAS will be presented by the 
each subset and overall. 
•
Rollover subjects in FAS: the subset of subjects who participated in Study SHP643-302
and received any study drug after entering Study TAK-743-5007.
•
Non-rollover subjects in FAS: the subset of subjects who entered Study TAK-743-5007
directly and received any study drug after entering Study TAK-743-5007.
13.1.2 
Subject disposition 
The numbers of subjects treated with study drug, completed the study, and discontinued 
prematurely by reason will be summarized for FAS. 
13.1.3 
Analysis of Demographics and Other Baseline Characteristics 
Baseline HAE characteristics and demographic variables will be summarized for FAS. 
13.1.4 
Medical History 
Medical history will be coded using the MedDRA and summarized by system organ class and 
preferred term (PT) for FAS. 
13.1.5 
Treatment Exposure and Compliance 
Treatment compliance and the extent of exposure to study drug will be described by the 
percentage of planned doses received by the subject, total number of doses received by the 
subject, and the number and percentage of subjects that received at least 80% of planned doses, 
summarized for FAS. 
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13.1.6 
Prior and Concomitant Medications 
Concomitant medications will be coded using the WHO-Drug Dictionary. The number and 
percentage of subjects with prior or concomitant medications will be summarized by therapeutic 
class and PT for FAS. A separate, similar table will be provided for the subset of concomitant 
medications classified as rescue medications. 
13.1.7 
Efficacy Analysis 
No statistical hypothesis testing will be performed. 
Time to the first Investigator-confirmed HAE attack will be analyzed using the Non-rollover 
subjects for FAS. 
Time to first Investigator-confirmed HAE attack is to be calculated from the time of first dose of 
lanadelumab in this study to the start time of the first Investigator-confirmed HAE attack. If a 
subject does not have an attack, the subject will be censored from the time of first dose of 
lanadelumab to the earlier of the early discontinuation date or end of treatment period date. The 
time to the first Investigator-confirmed HAE attack (days) will be summarized using 
Kaplan-Meier (KM) methods. Summaries will include 25th, 50th (median), and 75th percentiles, 
if estimable, and the corresponding 95% confidence intervals. In addition, KM plots detailing 
each subject’s contribution to the analysis will be provided. 
All efficacy data, including derived data, will be presented in subject data listings. 
13.1.8 
Safety Analysis 
13.1.8.1 Adverse events 
Adverse events are to be coded using the MedDRA coding dictionary. No inferential statistics 
are planned. 
Treatment-emergent AEs are defined as AEs with onset at the time of or following the first 
exposure to lanadelumab in this study, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. 
The number and percentage of subjects with TEAEs will be displayed by system organ class and 
PT using MedDRA for FAS. This tabulation will be repeated for related AEs, SAEs, related 
SAEs, severe AEs, related severe AEs, and Investigator-reported AESIs. 
All AEs will be provided in subject listings. In addition, subject listings of AEs causing 
discontinuation of study medication, AEs leading to death, SAEs, related AEs, severe AEs, and 
Investigator-reported AESIs will be produced. 
Adverse events of special interests for this study are hypersensitivity reactions and disordered 
coagulation (hypercoagulability events and bleeding events). Standardized MedDRA Queries 
 
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(SMQ) for each AESI will be performed using the study data. A listing detailing the PT within 
the SMQ will be provided. 
Injection site reaction AEs will be identified by AEs with the PTs starting with “Injection site,” 
“Application site,” or “Administration site.” A listing of injection site reaction AEs will be 
provided. 
13.1.8.2 Clinical laboratory evaluation 
Laboratory test results will be summarized for FAS. All laboratory test results will be listed. 
Subjects with clinically significant abnormal laboratory test results will be listed. This listing will 
include all results of the laboratory parameter that was abnormal and determined to be clinically 
significant by the Investigator for a subject across study visit to identify any trends. 
13.1.8.3 Vital signs 
Vital signs will be summarized for FAS. All vital signs will be listed. 
Subjects with clinically significant vital sign values will be listed. This listing will include all 
results of the vital sign parameters that were determined by the Investigator to be clinically 
significant for a subject across study time points to identify any trends. 
13.2 
Interim Analysis and Criteria for Early Termination 
Interim summary may be produced during the study to support regulatory reporting if requested 
by the authority. 
13.3 
Determination of Sample Size 
This study is designed to expand access of lanadelumab and evaluate the safety of open-label 
treatment with lanadelumab in subjects with HAE who participated in SHP643-302 (rollover 
subjects) and individuals who are not otherwise able to participate in SHP643-302 (non-rollover 
subjects). Therefore, no formal sample size calculation was performed. 
 
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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 the study site/head of the study site guarantee access to source documents 
by the sponsor or its designee (contract research organization) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information, 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 can deviate and change from the protocol for any medically unavoidable reason, 
for eg, 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, 
including those of foreign governments (eg, the Food and Drug Administration [FDA], the 
United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The Investigator and study 
site/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 International Council for Harmonisation (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 
 The principles of Helsinki 
are addressed through the protocol and through appendices containing requirements for informed 
consent and Investigator responsibilities. 
15.1 
Institutional Review Board Approval 
Institutional Review Boards must be constituted according to the applicable state and 
federal/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, 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 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/signing a contract for the clinical study). 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) reviewed; and state the approval date. The sponsor will ship 
drug/notify site once the sponsor has confirmed the adequacy of site regulatory documentation. 
Until the site receives drug/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, 
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 incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor. 
 
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15.2 
Subject Information, Informed Consent, 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. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe 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 and the subject information sheet 
(if applicable) further explain 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 form and if applicable, the subject authorization form. The informed consent form, 
subject authorization form (if applicable), and subject information sheet (if applicable) must be 
approved by both the IRB and the sponsor prior to use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the Investigator to explain the detailed elements of the informed 
consent form, subject authorization form (if applicable), and subject information sheet (if 
applicable) to the subject. 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, or the subject’s legally acceptable representative, 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, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject 
or the subject’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The Investigator must also sign and date 
the informed consent form and subject authorization (if applicable) at the time of consent and 
prior to subject entering into the study. 
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the Investigator’s site file. The 
Investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
form (if applicable), and subject information sheet (if applicable) shall be given to the subject. 
 
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent 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, 
Pharmaceuticals and Medical Devices Agency), 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 as part of the informed consent 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, other 
than study recruitment materials and/or advertisements, 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. 
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. 
 
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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 names, Investigator’s city, country, and recruiting status 
will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the Investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive Investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any Investigator who objects to the sponsor providing this information to callers must provide 
the sponsor with a written notice requesting that their information not be listed on the registry 
site. 
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 
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Craig, T., Pursun, E. A., Bork, K., Bowen, T., Boysen, H., Farkas, H., Grumach, A., Katelaris, C. 
H., Lockey, R., Longhurst, H., Lumry, W., Magerl, M., Martinez-Saguer, I., Ritchie, B., Nast, 
A., Pawankar, R., Zuraw, B. and Maurer, M. 2012. WAO Guideline for the Management of 
Hereditary Angioedema. World Allergy Organ J, 5, 182-199. 
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publication. Allergology international : official journal of the Japanese Society of Allergology, 
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Lumry, W., Martinez-Saguer, I., Moldovan, D., Nast, A., Pawankar, R., Potter, P., Riedl, M., 
Ritchie, B., Rosenwasser, L., Sanchez-Borges, M., Zhi, Y., Zuraw, B. and Craig, T. 2018. The 
international WAO/EAACI guideline for the management of hereditary angioedema - the 2017 
revision and update. Allergy. 
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Zuraw, B. L. 2008. Clinical practice. Hereditary angioedema. N Engl J Med, 359, 1027-36.
 
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SAP_001.pdf: 
Statistical Analysis Plan 
NCT Number: NCT04687137 
Title: Open-arm, Japan Expanded Access Program with Lanadelumab (TAK-743) for 
Japanese Patients with Hereditary Angioedema 
Study Number: TAK-743-5007 
Document Version and Date: Original version/ 01-Feb-2021 
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. 


 
 
 
STATISTICAL ANALYSIS PLAN 
Study Number: TAK-743-5007 
Study Title: Open-arm, Japan Expanded Access Program with Lanadelumab (TAK-743) for 
Japanese Patients with Hereditary Angioedema 
Phase: Japan Expanded Access Program 
Version: 1.0 
Date: 01-Feb-2021 
 
 
 
 
Based on: 
Protocol Version: Original 
Protocol Date: 06-Oct-2020 
 
 
 
 
 
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REVISION HISTORY 
Version  
Approval Date 
Primary Rationale for Revision 
Original version 
01-Feb-2021 
Not Applicable 
 
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TABLE OF CONTENTS 
 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................7 
1.1 
Objectives ......................................................................................................................7 
1.1.1 
Primary Objective ..................................................................................................7 
1.1.2 
Secondary Objectives ............................................................................................7 
1.2 
Endpoints .......................................................................................................................7 
1.2.1 
Safety Endpoints ....................................................................................................7 
1.2.2 
Efficacy Endpoints ................................................................................................7 
1.3 
Estimand ........................................................................................................................7 
2.0 
STUDY DESIGN.................................................................................................................7 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES .............................................11 
3.1 
Statistical Hypotheses ..................................................................................................11 
3.2 
Statistical Decision Rules ............................................................................................11 
3.3 
Multiplicity Adjustment ...............................................................................................11 
4.0 
SAMPLE-SIZE DETERMINATION ................................................................................11 
5.0 
ANALYSIS SETS .............................................................................................................11 
5.1 
Screened Set .................................................................................................................11 
5.2 
Enrolled Set ..................................................................................................................11 
5.3 
Full Analysis Set ..........................................................................................................11 
6.0 
STATISTICAL ANALYSIS .............................................................................................12 
6.1 
General Considerations ................................................................................................12 
6.1.1 
Analysis Approach for Continuous Variables .....................................................12 
6.1.2 
Analysis Approach for Binary Variables ............................................................12 
6.1.3 
Analysis Approach for Time-to-Event Variables ................................................12 
6.2 
Disposition of Subjects ................................................................................................12 
6.2.1 
Disposition of Subjects ........................................................................................12 
6.2.2 
Protocol Deviations .............................................................................................12 
6.3 
Demographic and Other Baseline Characteristics .......................................................13 
6.3.1 
Demographics and Other Baseline Characteristics .............................................13 
6.3.2 
Medical History and Concurrent Medical Conditions .........................................14 
6.4 
Medication History and Concomitant Medications .....................................................14 
6.4.1 
Prior Medications ................................................................................................14 
6.4.2 
Concomitant Medications ....................................................................................15 
6.5 
Efficacy Analysis .........................................................................................................15 
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6.5.1 
Time to First HAE Attack ...................................................................................15 
6.5.2 
Achievement of Attack-free Status by interval (1 month, 2 months, 3 
months, …,  until the Day 182 Visit) ..................................................................16 
6.5.3 
Number of investigator-confirmed HAE attacks during Day 0 through Day 
182 .......................................................................................................................16 
6.6 
Safety Analysis ............................................................................................................18 
6.6.1 
Adverse Events ....................................................................................................18 
6.6.2 
Adverse Events of Special Interest ......................................................................19 
6.6.3 
Injection Site Reaction AEs .................................................................................20 
6.6.3.1 
Duration of Injection Site Reaction AEs .....................................................20 
6.6.4 
Clinical Laboratory Data .....................................................................................21 
6.6.5 
Vital Signs ...........................................................................................................22 
6.6.6 
Electrocardiogram (ECG) ....................................................................................23 
6.6.7 
Other Safety Analysis ..........................................................................................23 
6.6.7.1 
Biomarker Test ............................................................................................23 
6.6.7.2 
Pregnancy Test ............................................................................................24 
6.6.7.3 
Physical Examination ..................................................................................24 
6.6.8 
Extent of Exposure and Compliance ...................................................................24 
6.6.8.1 
Exposure to Investigational Product (IP) ....................................................24 
6.6.8.2 
Measurements of Treatment Compliance ...................................................24 
6.6.8.3 
Study Drug Administration and Injection Report .......................................25 
6.7 
Interim Analyses ..........................................................................................................25 
7.0 
REFERENCES ..................................................................................................................25 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................25 
9.0 
APPENDIX ........................................................................................................................25 
9.1 
Changes From the Previous Version of the Statistical Analysis Plan (SAP) ..............25 
9.2 
Data Handling Conventions .........................................................................................25 
9.2.1 
General Data Reporting Conventions ..................................................................25 
9.2.2 
Definition of Baseline ..........................................................................................26 
9.2.3 
Definition of Visit Windows ...............................................................................26 
9.2.3.1 
Analysis Periods ..........................................................................................26 
9.2.4 
Derived Efficacy Endpoints ................................................................................27 
9.2.4.1 
Unique HAE Attacks...................................................................................27 
9.2.5 
Repeated or Unscheduled assessments of Safety Parameters .............................27 
9.2.6 
Handling of Missing, Unused, and Spurious Data ..............................................27 
9.2.6.1 
Missing Start or End Date and Time for HAE Attacks ...............................28 
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9.2.6.2 
Missing Date/Time Information for Prior or Concomitant 
Medications/Therapies/Procedures .............................................................29 
9.2.6.3 
Missing Date/Time Information for Adverse Events ..................................30 
9.2.6.4 
Missing Severity assessment for Adverse Events .......................................31 
9.2.6.5 
Missing Relationship to IP for Adverse Events ..........................................31 
9.2.6.6 
Character Values of Clinical Laboratory Variables ....................................31 
9.3 
Analysis Software ........................................................................................................31 
 
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ABBREVIATIONS 
 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical 
BILI 
Total bilirubin 
BP 
blood pressure 
C1-INH 
C1 esterase inhibitor 
C1q 
complement component 1q  
C4 
complement component 4 
CI 
confidence interval 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
HAAARP 
HAE Attack Assessment and Reporting Procedures 
HAE 
hereditary angioedema 
HR 
heart rate 
IP 
investigational product 
ISR 
injection site reaction 
KM 
Kaplan-Meier 
LLN 
lower limit of normal  
LTP 
long-term prophylaxis 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
Preferred Term (MedDRA) 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SD 
standard deviation 
SMQ 
Standardized MedDRA Queries 
SOC 
System Organ Class 
TEAE  
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Primary Objective 
The primary objective is to ensure access to lanadelumab in Japanese subjects with hereditary 
angioedema (HAE) who meet the criteria for expanded access. 
1.1.2 
Secondary Objectives 
• To evaluate the long-term safety of repeated subcutaneous (SC) administration of 
lanadelumab. 
• To evaluate the long-term efficacy of lanadelumab in preventing HAE attacks. 
1.2 
Endpoints 
1.2.1 Safety Endpoints 
The following safety endpoints are to be evaluated: 
• Number and percentage of subjects with treatment-emergent adverse events (AEs), 
including serious adverse event (SAE)s and adverse events of special interest (AESIs). 
• Number of subjects with clinically significant abnormal laboratory testing (hematology, 
clinical chemistry, coagulation, and urinalysis). 
• Number of subjects with clinically significant vital signs including blood pressure (BP), 
heart rate (HR), body temperature, and respiratory rate (RR). 
1.2.2 Efficacy Endpoints 
The following efficacy endpoint is to be evaluated: 
• Non-rollover Subjects: Time to first HAE attack after Day 0 for the efficacy evaluation 
period of Day 0 through Day 182. 
1.3 
Estimand 
Not Applicable. 
2.0 
STUDY DESIGN 
This is an open-label, Japan Expanded Access Program with lanadelumab (TAK-743) for 
Japanese patients with Type I or II HAE. Two types of subjects will be enrolled into this study: 
• Subjects who rollover from Study SHP643-302. 
• Subjects who are non-rollovers (ie, were not participants in Study SHP643-302). 
Rollovers from Study SHP643-302 
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Subjects from Study SHP643-302 are permitted to rollover and enroll into this study if: 
1. They have completed the treatment period of Study SHP643-302; and 
2. They have consented to enter Study TAK-743-5007 on or before Day 350 of the SHP643-302 
study (since Day 378 of Study SHP643-302 is also Day 0 of Study TAK-743-5007, informed 
consent may be completed on Day 364 or this visit, if not already provided). 
Subjects who discontinue from Study SHP643-302 after providing informed consent are not 
eligible to enroll in Study TAK-743-5007. 
There is no screening period for rollover subjects. The first study visit for rollover subjects 
(Day 0) is to occur on the same day as the Study SHP643-302 Day 378 study visit. Rollover 
subjects will complete all Study SHP643-302 final study assessments (Day 378) at which time 
they will be discharged from that study. Results of the final SHP643-302 assessments on Day 378 
will be used as the predose results for Day 0 of Study TAK-743-5007. 
Following informed consent and predose assessments, rollover subjects will continue with an 
open-label dose of 300 mg lanadelumab administered SC on Day 0. Rollover subjects will 
receive SC administration of lanadelumab 300 mg q2w or q4w at the discretion of the 
Investigator, with optional consultation with the sponsor, if they have been well-controlled 
(eg, attack free for 26 weeks). Rollovers from Study SHP643-302 who have been 
self-administering the study drug at the time of screening will be permitted to continue 
self-administration of lanadelumab. 
Non-rollover subjects 
Subjects with historical baseline HAE attack of at least 1 attack per 4 weeks in the recent year 
who have not participated in Study SHP643-302 (non-rollovers) are permitted to enroll if they 
meet the eligibility requirements for expanded access. 
Screening of some subjects is allowed following discussion with the sponsor: ie, subjects who 
screen failed out of the run-in period for Study SHP643-302 when enrollment for that study 
closed. 
Once all screening assessments are completed and eligibility confirmed, non-rollover subjects 
will arrive at the study site and, following predose assessments, will receive an open-label dose 
of 300 mg lanadelumab administered SC on Day 0. Non-rollover subjects will receive SC 
administration lanadelumab 300 mg q2w or q4w if they have been well-controlled (eg, attack 
free for 26 weeks) and at the discretion of the Investigator with optional consultation with the 
sponsor. 
All doses are to fall within the accepted ± 4 days window around study visits. From Day 0 to 
Day 182, visits will occur q2w. After Day 182, study visits will occur every 12 weeks, and site 
personnel are to call subjects q2w to collect AEs, concomitant medications, and to ensure all 
attacks have been appropriately documented. 
All subjects who are considered suitable candidates will be allowed to self-administer treatment 
throughout the study. Subjects are required to complete appropriate training by the Investigator 
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or designee and have their understanding of the procedures confirmed by the Investigator or 
designee. 
The treatment period is to last up to lanadelumab manufacturing and sale, discontinued 
development, or withdrawal of new drug application. 
If a subject experiences an acute angioedema attack at any time during the study that in the 
opinion of the Investigator requires medical intervention, standard of care therapy is to be 
provided based on subject’s medical history and per locally approved product information. 
Administration of lanadelumab and study procedures is to continue without alteration to 
Appendix A in the protocol, even if a subject receives treatment for a breakthrough angioedema 
attack on the day of a scheduled dose of study drug (if self-administering) or scheduled study 
visit. 
An overview of the study design scheme is provided in Figure 1. All study procedures are 
detailed in the schedule of assessments (Appendix A in the protocol). 
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Figure 1 Schematic of Study Design 
 
LTP = long-term prophylaxis 
 
 
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3.0 
STATISTICAL HYPOTHESES AND DECISION RULES  
3.1 
Statistical Hypotheses 
Not Applicable. 
3.2 
Statistical Decision Rules 
Not Applicable. 
3.3 
Multiplicity Adjustment 
Not Applicable. 
4.0 
SAMPLE-SIZE DETERMINATION 
This study is designed to expand access of lanadelumab and evaluate the safety of open-label 
treatment with lanadelumab in subjects with HAE who participated in SHP643-302 (rollover 
subjects) and individuals who are not otherwise able to participate in SHP643-302 (non-rollover 
subjects). Therefore, no formal sample size calculation was performed. 
5.0 
ANALYSIS SETS 
5.1 
Screened Set 
The Screened Set is defined as all subjects who have signed informed consent. 
5.2 
Enrolled Set 
The Enrolled Set is defined as all subjects who have signed informed consent and also passed 
inclusion/exclusion criteria, i.e., the subjects not identified as screen failure on the study 
completion/early termination electronic case report form (eCRF). 
5.3 
Full Analysis Set 
Full Analysis Set (FAS) is defined as all subjects who received at least 1 dose of lanadelumab. 
All safety and efficacy analyses will be based on the FAS and each subset in FAS defined below. 
Unless otherwise specified, summary tabulations conducted using FAS will be presented by each 
subset and overall. 
• Rollover subjects in FAS: the subset of subjects who participated in Study SHP643-302 
and received any study drug after entering Study TAK-743-5007. 
• Non-rollover subjects in FAS: the subset of subjects who entered Study TAK-743-5007 
directly and received any study drug after entering Study TAK-743-5007. 
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6.0 
STATISTICAL ANALYSIS  
6.1 
General Considerations 
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. 
6.1.3 
Analysis Approach for Time-to-Event Variables 
Time-to-event variables will be summarized using Kaplan-Meier (KM) estimates of the 25th, 
50th (median), and 75th percentiles with associated two-sided 95% confidence interval (CI), as 
well as percentage of events and censored observations unless stated otherwise in the section 
specific to an endpoint. 
In addition, KM plots detailing each subject’s contribution to the analysis will be provided. 
6.2 
Disposition of Subjects 
6.2.1 
Disposition of Subjects 
The number of subjects who were included in each defined analysis set (i.e., Screened, Enrolled, 
and FAS) will be summarized for the Screened Set by rollover, non-rollover and overall. 
The number and percentage of subjects who completed or prematurely discontinued the study 
will be presented for FAS. Reasons for premature discontinuation from study will be 
summarized (number and percentage) for the FAS.  
Disposition of all subjects, including screen failures, will be presented in a listing for the 
Screened Set. Inclusion criteria not met and exclusion criteria met will be listed.   
6.2.2 
Protocol Deviations 
Protocol deviations as obtained from a clinical trial management system (CTMS) will be 
assessed throughout the study. All identified deviations will be reported in the CTMS. Protocol 
deviations from the CTMS will be coded to severity categories (“critical”, “major” and “minor”) 
and provided as part of the CTMS transfer to Biostatistics.  
Protocol deviations will be summarized by deviation type and severity for the FAS. All protocol 
deviations will be included in a subject listing. In particular, protocol deviations identified as 
related to the impact of COVID-19 will be flagged in the subject listings. 
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6.3 
Demographic and Other Baseline Characteristics 
6.3.1 
Demographics and Other Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented for FAS. 
The following demographic characteristics will be summarized:  
• Age at informed consent date (years),  
• Age category (<18, 18 to <40, 40 to <65, ≥65 years),  
• Sex (Male, Female),  
• Weight (kg),  
• Weight category (<50, 50 to <75, 75 to <100, ≥100 kg),  
• Height (cm),  
• Body mass index (BMI) (kg/m2), calculated as 10000*weight (kg)/ height (cm)2,  
• BMI group for subjects ≥ 18 years of age (<18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2),  
• BMI percentile group for subjects < 18 years of age based on growth charts from the Centers 
for Disease Control and Prevention (CDC) (Underweight: <5th percentile, Healthy or 
Overweight: 5th to <95th percentile, Obese: >=95th percentile),  
o Official and validated SAS programs created by CDC will be used to calculate the 
percentile of BMI. For more information on the CDC SAS programs, see 
http://www.cdc.gov/growthcharts/computer_programs.htm. 
The following baseline HAE characteristics will be summarized in a separate table:  
• Age at onset of HAE symptoms (years),  
• HAE type (Type I, Type II, Unspecified- Type I or Type II), 
• History of laryngeal attacks,  
• Primary attack location, 
• Number of attacks in the last 1 and 12 months prior to screening, 
• Average attack duration (in days) in the last 12 months prior to screening, 
• Average severity of HAE attacks in the last 12 months prior to screening, 
• LTP therapy use before entering the run-in or treatment period of study (yes or no) as 
recorded on the LTP Therapy Discontinuation eCRF, 
• Type of LTP therapy before entering the run-in or treatment period (C1-INH, Androgens, 
Anti-fibrinolytics, or not on LTP)  
 
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For rollover subjects, the data of the LTP (C1-INH, Androgens, or Anti-fibrinolytics) treatment a 
subject was on prior to the run-in period in SHP643-302 study will be used. For non-rollover 
subjects, the LTP treatment a subject was on prior to the treatment period will be determined by 
applying the algorithm below to prior medications (i.e., medications with start and stop date prior 
to the start date of the treatment period, imputing partial dates as described in Section 9.2.6.2) 
reported for that subject that lasted for ≥4 days: 
LTP 
Algorithm to Identify Medications 
C1-INH 
ATC level 4 in (‘B06AC’) and preferred drug name not in 
(‘icatibant’, ‘ecallantide’, ‘icatibant acetate’) 
Androgens 
ATC level 4 in (‘G03BA’, ‘G03BB’, ‘A14AA’) or 
preferred drug name in (‘danazol’, ‘oxandrolone’)  
Anti-fibrinolytics 
ATC level 4 in (‘B02AA’, ‘B02AB’) 
All baseline and demographic data will be presented in subject listings. 
6.3.2 
Medical History and Concurrent Medical Conditions 
This section will be applied to non-rollover subjects in FAS only. 
Medical history will be collected at the Screening Visit and will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) Version 23.0 or newer. 
The medical history will be summarized by system organ class (SOC) and preferred term (PT) 
for non-rollover subjects in FAS. Tabulations will be presented sorted by SOC in alphabetical 
order and by PT within each SOC by descending frequency.   
All medical history will be presented in subject listings for non-rollover subjects in FAS. 
6.4 
Medication History and Concomitant Medications  
6.4.1 
Prior Medications 
This section will be applied to non-rollover subjects in FAS only. 
Prior medications will be coded using the World Health Organization Drug Dictionary dated 
(WHO-DD) Mar 2020. Prior therapies and procedures will be coded using MedDRA Version 
23.0 or newer. 
Prior medication/therapy/procedure is defined as any medication/therapy/procedure with the start 
date and time prior to the date and time of the first dose of investigational product (IP).  
Partial date imputation for medications is described in Section 9.2.6.2.  
The prior medications will be summarized by the number and proportion of subjects within each 
Anatomical Therapeutic Chemical (ATC) Level 2 therapeutic class and PT for non-rollover 
subjects in FAS. The prior therapies and procedures will be summarized by the number and 
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proportion of subjects within each SOC and PT for non-rollover subjects in FAS. Tabulations 
will be presented sorted by therapeutic class in alphabetical order and by PT within each 
therapeutic class by descending frequency. Multiple medication usage by a subject in the same 
category (i.e., therapeutic class or PT) will be counted only once.  
All prior therapies, procedures and medication will be listed for non-rollover subjects in FAS. 
6.4.2 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug Dictionary dated Mar 2020. 
Concomitant therapies and procedures will be coded using MedDRA Version 23.0 or newer. 
Concomitant medication/therapy is defined as any medication/therapy with a start date and time 
prior to the date and time of the first dose of IP and continuing after the first dose of IP or with a 
start date and time between the dates and times of the first dose of IP and end of the treatment, 
inclusive. Concomitant procedure is defined as any procedure with a start date and time between 
the dates and times of the first dose of IP and end of the treatment, inclusive. 
Any medication/therapy/procedure with a start date after the end of the treatment will not be 
considered a concomitant medication/therapy/procedure. Partial date imputation for medications 
is described in Section 9.2.6.2.  
The summaries of concomitant medication/therapy/procedure will be presented separately for: 
• Concomitant Medications/therapies/procedures (excluding those taken for an HAE Attack) 
• Concomitant Medications/therapies/procedures taken for an HAE Attack 
The concomitant medications will be summarized by the number and proportion of subjects 
within each ATC Level 2 therapeutic class and PT for FAS. Tabulations will be presented sorted 
by therapeutic class in alphabetical order and by PT within each therapeutic class by descending 
frequency. The concomitant therapies and procedure will be summarized by the number and 
proportion of subjects within each SOC and PT for FAS. Tabulations will be presented sorted by 
therapeutic class in SOC and by PT within each SOC by descending frequency. Multiple 
medication usage by a subject in the same category (i.e., therapeutic class or PT) will be counted 
only once.   
All concomitant therapies, procedures and medication will be listed for FAS. 
6.5 
Efficacy Analysis 
All efficacy data, including derived data, will be presented in subject data listings. 
6.5.1 
Time to First HAE Attack 
This analysis will be conducted in non-rollover subjects in FAS only.  
The time to the first investigator-confirmed HAE attack (days) after Day 0 for the efficacy 
evaluation period of Day 0 through Day 182 will be calculated from the date and time of the first 
dose of lanadelumab for that efficacy evaluation period to the date and time of the first 
investigator-confirmed HAE attack after the first dose for that efficacy evaluation period.  
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Subjects who do not experience any attacks during the efficacy evaluation period will be 
censored at the date and time of the end of the period, i.e., visit date of Day 182 visit and time of 
23:59. Subjects who discontinue the study during the efficacy evaluation period prior to 
experiencing their first on-study investigator-confirmed HAE attack will be censored at the date 
of study discontinuation and time of 23:59.  
Time to the first investigator-confirmed HAE attack will be summarized using Kaplan-Meier 
(KM) estimates of the 25th, 50th (median), and 75th percentiles with associated two-sided 95% 
CI, as well as percentage of events and censored observations.  
In addition, KM plots detailing each subject’s contribution to the analysis will be provided.  
6.5.2 
Achievement of Attack-free Status by interval (1 month, 2 months, 3 months, …,  
until the Day 182 Visit) 
This analysis will be conducted in non-rollover subjects in FAS only.  
The definition of attack free is given in Section 6.5.3.  
The number and percentage of subjects achieving attack-free status will be summarized for the 
following intervals: 1 month (i.e., Day 0 to Day 28 visit date minus one day), 2 months (Day 0 to 
Day 56 visit date minus one day), 3 months (i.e., Day 0 to Day 84 visit date minus one day), …,  
Day 0 through Day 182 (as defined in Section 9.2.3.1) A two-sided 95% CI for the proportion of 
subjects achieving attack-free will be derived using the exact method. 
A subject is considered as attack free during an interval if the subject has no investigator-
confirmed HAE attacks during that interval. For subjects who discontinue the study during an 
interval, the evaluation period will end at the date of study discontinuation with time 23:59 and 
attack-free status will be evaluated for the period of time that the subject was in the evaluation 
period. 
The number and percentage of subjects achieving attack-free status after Day 182 will be only 
listed for the following intervals: 266 days (i.e., Day 0 to Day 266 visit date minus one day), 350 
days (Day 0 to Day 350 visit date minus one day). 
6.5.3 
Number of investigator-confirmed HAE attacks during Day 0 through Day 182 
The total number of investigator-confirmed HAE attacks reported and subject-time in months 
that each subject contributed during Day 0 through Day 182 will be summarized in rollover 
subjects in FAS and non-rollover subjects in FAS (not be summarized in FAS). 
A listing of all investigator confirmed HAE attacks will be presented. 
Normalized Number of Investigator-confirmed Hereditary Angioedema Attacks (NNA) 
The investigator-confirmed NNA per 4 weeks during Day 0 through Day 182 will be expressed 
as a monthly (4 weeks, i.e., 28 days) HAE attack rate for each subject. In what follows, for 
conciseness, HAE attack rate refers to NNA per 4 weeks.  
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For Rollover subjects in FAS, the data of the baseline investigator-confirmed HAE attack rate in 
SHP643-302 study will be used.  
For non-rollover subjects in FAS, the number of HAE attacks in last 1 month prior to screening 
collected by CRF divided by the number of days of the month prior to screening multiplied by 28 
days will be used as baseline. As a note, this HAE attacks prior to screening are not investigator-
confirmed. 
The treatment period investigator-confirmed HAE attack rate will be calculated as the number of 
HAE attacks occurring during that treatment period divided by number of days the subject 
contributed to that treatment period multiplied by 28 days.  
The treatment period HAE attack rate percentage change from baseline will be calculated for 
each subject as the difference in attack rates, treatment period attack rate minus run-in period 
attack rate, divided by the run-in period attack rate or prior screening attack rate. 
The baseline attack rate, as well as the treatment period investigator-confirmed attack rate, 
change from baseline, and percent change from baseline will be summarized using descriptive 
statistics.  
In addition, the number of investigator-confirmed HAE attacks per month (defined as 28 days) 
will be summarized by study month (per 28-day interval). The summary will include descriptive 
statistics for run-in period investigator-confirmed attack rate or prior screening attack rate, as 
well as monthly treatment period investigator-confirmed attack rates, monthly change from 
baseline, and monthly percent change from baseline. Investigator-confirmed HAE attacks will be 
grouped into 28-day intervals using the start date of the HAE attack. In particular, if a HAE 
attack starts during an interval and is ongoing at the start of the next interval, that HAE attack 
will be counted only once for the interval during which it started. The first study drug 
administration date and time in this study will be used as the start of the first interval and end of 
the interval will be the first study drug administration date and time in this study plus 28 days. 
Each successive interval will start the last day of the prior interval plus 1 day (24 hours) and end 
28 days later. 
Similar summary tables except the summary of attack rate per month will be presented for the 
following clinical outcome measures: 
• Number of investigator-confirmed HAE attacks requiring acute treatment:  
Investigator-confirmed HAE attacks requiring acute treatment are defined as those attacks 
with ‘Has the subject received any of the following acute HAE therapy treatment for this 
reported attack?’ marked as ‘Yes’ on the CRF.  
• Number of moderate or severe investigator-confirmed HAE attacks: 
Moderate and severe investigator-confirmed HAE attacks are defined as those attacks that 
were classified as of moderate or severe according to the HAE Attack Assessment and 
Reporting Procedures (HAARP) defined severity and reported as such on the CRF.  
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• Number of high-morbidity investigator-confirmed HAE attacks:  
High morbidity HAE attack is defined as any attack that has at least 1 of the following 
characteristics as reported on the HAE acute attack CRF: severe based on HAARP, results in 
hospitalization (except hospitalization for observation <24 hours), hemodynamically 
significant (systolic blood pressure <90, requires IV hydration, or associated with syncope or 
near syncope) or laryngeal (based on primary or secondary HAE attack location). 
If the length of hospitalization cannot be determined due to missing dates and times, then that 
hospitalization will be conservatively counted as being greater than 24 hours. 
6.6 
Safety Analysis 
No statistical hypothesis testing will be performed. All safety summaries will be based on the 
FAS. Safety endpoints include AEs, clinical laboratory variables, vital signs, and 
electrocardiogram (ECG) variables. 
The definition of baseline is provided in Section 9.2.2.  
All safety data, including derived data, will be presented in subject data listings. 
6.6.1 
Adverse Events 
AEs will be coded using MedDRA Version 23.0 or newer. 
Treatment-emergent AEs (TEAEs) are defined as AEs with onset at the time of or following the 
first exposure to lanadelumab in this study, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. For AEs with partial onset times, non-missing date parts will be used to determine if 
the AE is treatment-emergent or not. If a determination cannot be made using the non-missing 
date as to when the AE occurred relative to study drug administration, then the AE will be 
classified as treatment-emergent. Partial date imputation for AE is described in Section 9.2.6.3.  
The analyses described in this section will be based on TEAEs only; plainly referred to as AEs in 
this section for brevity. All AEs (TEAEs and non-TEAEs) will be provided in the AE subject 
listing. 
Related AEs are AEs classified as related to study drug by the investigator. Missing relationship 
to study drug imputation is described in Section 9.2.6.5.  
Severe AEs are AEs classified as severe (grade 3) or life threatening (grade 4) by the 
investigator. Missing severity imputation is described in Section 9.2.6.4.  
The collection of tabulations described in this section (with the exception of the analyses of 
AESI and injection site reaction [ISR]) will be produced for 2 mutually exclusive subgroups of 
AEs based on whether the AE was identified in EDC as a subject-reported HAE attack or not, 
and defined as follows:  
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Non-HAE attack reported AEs will include the subset of AEs identified in EDC as not a reported 
HAE attack. Essentially, this will be all AEs excluding HAE attack reported events.  
HAE reported AEs will include the subset of AEs identified in EDC as a reported HAE attack. 
Note that this includes investigator-confirmed HAE attacks; all investigator-confirmed HAE 
attacks will be coded to the PT of angioedema. 
The number and percentage of subjects with any AE, any related AE, any SAE, any related SAE, 
any severe AE, any related severe AE, and any investigator-reported AESI, as well as the total 
number of events for each category will be summarized. The number of deaths due to an AE, 
hospitalization due to an AE and study discontinuation due to an AE will be summarized. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by SOC, and PT. This tabulation will be repeated for related AEs, SAEs, related 
SAEs, severe AEs, related severe AEs, and investigator-reported AESI. Tabulations will be 
presented sorted by SOC in alphabetical order and by PT within each SOC by descending 
frequency.  
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by PT. This tabulation will be repeated for related AEs and serious AEs. 
Tabulations will be presented sorted by PT by descending frequency.  
All AEs will be provided in subject listings. In addition, subject listings of AEs causing 
discontinuation of study medication, AEs leading to death, SAEs, related AEs, severe AEs, and 
investigator-reported AESIs will be produced. 
6.6.2 
Adverse Events of Special Interest 
AESI for this study are hypersensitivity reactions and disordered coagulation (hypercoagulability 
events and bleeding events). The preferred terms from MedDRA 23.0 Standardized MedDRA 
Queries (SMQ) will be used to identify an SMQ-defined AESI. Table 1 shows the SMQs used to 
identify AESI of hypersensitivity, hypercoagulable, and bleeding.  
Table 1. SMQ Used to Identify AESI 
AESI 
SMQ 
Hypersensitivity 
Hypersensitivity 
Hypercoagulable 
Embolic and thrombotic events, arterial 
Embolic and thrombotic events, venous 
Embolic and thrombotic events, vessel type unspecified and mixed 
arterial and venous 
Bleeding 
Haemorrhage laboratory terms 
Haemorrhage terms (excl laboratory terms) 
 
The number and percentage of subjects with any AESI, any related AESI, any serious AESI, any 
related serious AESI, any severe AESI, and any related severe AESI, as well as the total number 
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of events for each category will be summarized. The number of deaths due to an AESI, 
hospitalization due to an AESI and study discontinuation due to an AESI will be summarized. 
The number and percentage of subjects with SMQ-defined AESI, as well as the total number of 
SMQ-defined AESIs, will be summarized by SOC and PT. Separate summary tables will be 
created for each AESI category and for those events with the SMQ-defined AESIs classified as 
related, serious, related serious, severe, and related severe. Tabulations will be presented sorted 
by SOC in alphabetical order and by PT within each SOC by descending frequency. A listing 
detailing the PT within the SMQ will be provided. 
6.6.3 
Injection Site Reaction AEs 
ISR AEs will be identified by adverse events with the preferred terms starting with ‘Injection 
site’, ‘Application site’, or ‘Administration site’.  
The number and percentage of subjects with any ISR AE, any related ISR AE, any serious ISR 
AE, any related serious ISR AE, any severe ISR AE, and any related severe ISR AE, as well as 
the total number of events for each category will be summarized. The number of deaths due to an 
ISR AE, hospitalization due to an ISR AE and study discontinuation due to an ISR AE will be 
summarized. 
The number and percentage of subjects with an ISR AE, as well as the total number of ISR AEs, 
will be summarized by SOC, and PT.   
The number and percentage of subjects with an ISR AE will be summarized by SOC, PT and 
maximum severity.   
The number of ISR events and the percentage of ISR events calculated based on total number of 
injections, will be summarized by PT and overall. Descriptive statistics (n, mean, SD, minimum, 
median, and maximum) will be presented to describe the ISR duration (hours). ISR duration will 
also be summarized by category (0-0.5 hour, >0.5 - 1 hour, >1 – 12 hour, >12 – 24 hour, <= 1 
Day - Unclear, > 1 Day: >1-14 Days, >14 Days).   
A listing of ISR AEs will be provided. 
6.6.3.1 
Duration of Injection Site Reaction AEs 
Duration of ISR AEs is calculated as ‘stop date/time – start date/time’ for the ISR AEs with non-
missing start and stop date/time.  
The missing start or stop date/time for ISR AEs will not be imputed. ISR AEs with missing start 
or stop date/time will be excluded from the summary statistics analysis and reported as number 
missing in the continuous analysis of ISR AE duration. For the categorical analyses on ISR AE 
duration, the following rules will be applied: 
• ISR AE with non-missing start and stop date/time: duration of the AE will be calculated as 
‘stop date/time – start date/time’ and mapped to a duration category. 
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• ISR AE with non-missing start and stop dates and missing time: duration of the AE will be 
calculated as ‘stop date – start date +1’. If the calculated duration is 1 day, then the duration 
category for this AE is <= 1 day - unclear. If the calculated duration is greater than 1 day, 
then it will be mapped to a >1 day category. 
• ISR AE with missing start or stop date: The ISR AE will be excluded from the categorical 
analyses on duration and will be listed in the missing category. 
6.6.4 
Clinical Laboratory Data 
Laboratory evaluations that are done at study site visits will be collected and processed via a 
central laboratory, and presented in conventional units.  
Clinical laboratory parameters to be evaluated include the following: 
Hematology 
Hemoglobin, hematocrit, red blood cells (RBC), white blood cells (WBC) 
count total and differential - neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), absolute platelet count. 
Chemistry 
Albumin, alkaline phosphatase, alanine transaminase (ALT), aspartate 
transaminase (AST), bilirubin (total and direct), blood urea nitrogen 
(BUN), calcium, carbon dioxide (CO2), chloride, creatinine, creatine 
phosphokinase (CPK), glucose, phosphate, magnesium, potassium, 
sodium, total protein. 
Coagulation 
Prothrombin time, activated partial thromboplastin time (aPTT), 
international normalized ratio (INR) 
Urinalysis 
Bilirubin, glucose, ketones, blood, nitrite, potential hydrogen (pH), 
protein, specific gravity, microscopy (if indicated by macroscopic 
findings). 
Virology 
Hepatitis B Surface Antigen (HbsAg); Hepatitis C Virus (HCV); Human 
Immunodeficiency Virus (HIV) 
Hematology, Chemistry, Coagulation, and Urinalysis results will be summarized as described 
below. Virology results will be listed only. 
Actual values and change from baseline in clinical laboratory tests will be summarized by study 
visit. If more than one laboratory result is reported per study visit per parameter, the last non-
missing result will be selected for analysis. 
Categorical laboratory test results (urinalysis excluding pH) will be summarized by study visit. If 
more than one laboratory result is reported per study visit per parameter, the result yielding the 
most severe classification will be selected for analysis. 
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Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the investigator. The number of subjects with a non-missing result, 
and the number and percentage of subjects with a clinically significant result less than the lower 
limit of normal (LLN), non-clinically significant result less than the LLN, within the normal 
range, non-clinically significant result more than the upper limit of normal (ULN), and clinically 
significant result more than the ULN will be summarized by study visit. If more than one 
laboratory result is reported per study visit per parameter, the result yielding the most severe 
classification will be selected for analysis.  
Among chemistry parameters, additional analyses in Table 1 will be conducted on liver function 
tests for the FAS using the highest pre-treatment and highest overall treatment period 
measurements. The number and percentage of subjects with highest results falling into the 
categories of normal (<=1 x ULN), >1 – <=3 x ULN, >3 – <=5 x ULN, and greater than >5 x 
ULN on the liver function tests for ALT/AST will be summarized for all pre-treatment 
measurements and overall treatment period measurements. Total bilirubin (BILI) will be 
summarized by the number and percentage of subjects with highest results falling into the 
categories of <=2 x ULN and >2 x ULN for all pre-treatment measurements and overall 
treatment period measurements. Additionally, for the FAS, a shift table summarizing the shift in 
categories from highest pre-treatment measurements to the highest overall treatment period 
measurements will be created for the liver function tests including ALT, AST and BILI.  
Table 1. Lab Parameter Criteria Categories 
Parameter 
Criteria Categories 
Liver Function Tests 
ALT (U/L) 
Normal (<=1 x ULN) 
>1 – <=3 x ULN 
>3 – <=5 x ULN 
>5 x ULN 
AST (U/L) 
Normal (<=1 x ULN) 
>1 – <=3 x ULN 
>3 – <=5 x ULN 
>5 x ULN 
Bilirubin (umol/L) 
- 
<=2.0 x ULN 
>2 x ULN 
- 
 
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis due 
to, for example, that a character string is reported for a numerical variable (e.g., “<X”), a coded 
value will be used in the analysis instead as specified in Section 9.2.6.6. However, the actual 
values as reported in the database will be presented in data listings. 
All laboratory test results will be presented in subject listings. Subjects with clinically significant 
abnormal laboratory test results will be listed. This listing will include all results of the 
laboratory parameter that was abnormal and determined to be clinically significant by the 
investigator for a subject across study visit to identify any trends. 
6.6.5 
Vital Signs 
The following vital signs will be measured:   
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
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• HR (beats per minute) 
• Body temperature (°C) 
• RR (breaths per minute) 
Actual values and changes from baseline in vital signs will be summarized by study visit and 
study time point. If more than one vital sign result is reported per study visit and study time point 
per parameter, the last non-missing result will be selected for analysis. 
Vital sign values will be classified according to clinical significance as determined by the 
investigator. The number of subjects with a non-missing result, and the number and percentage 
of subjects with a non-clinically significant result and clinically significant result will be 
summarized by study visit and study time point. If more than one vital sign result is reported per 
study visit and study time point per parameter, the result yielding the most severe classification 
will be selected for analysis. 
All vital sign data will be presented in subject listings. Subjects with clinically significant vital 
sign values will be listed. This listing will include all results of the vital sign parameter that was 
determined by the investigator to be clinically significant for a subject across study time points to 
identify any trends. 
6.6.6 
Electrocardiogram (ECG) 
A standard 12-lead ECG (single recording) will be performed at screening visit, final visit/early 
termination, and when clinically indicated.  
The following ECG variables will be measured: 
• HR (beats per minute) 
• RR duration (millisecond [msec]) 
• PR duration (msec) 
• QRS duration (msec) 
• QT duration (msec) 
All ECG data will be presented in subject listings.  
6.6.7 
Other Safety Analysis 
6.6.7.1 
Biomarker Test 
C1 esterase inhibitor (C1-INH), complement component 4 (C4), and complement component 1q 
(C1q) assays will be obtained at screening for eligibility assessment. Samples need not be 
obtained at screening for eligibility assessment if they were already collected as part of Study 
SHP643-302. 
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The C1-INH, C1q, and C4 testing results at screening will be listed for non-rollover subjects in 
FAS. The corresponding reference ranges will be provided in the same listing. 
6.6.7.2 
Pregnancy Test 
Pregnancy test results will be listed by study visit.  
6.6.7.3 
Physical Examination 
Physical examination will be listed by study visit. 
6.6.8 
Extent of Exposure and Compliance 
6.6.8.1 
Exposure to Investigational Product (IP) 
Exposure to IP for the FAS will be summarized and overall in terms of time on treatment 
(month) and total dose received (mg). 
Time on treatment (month) will be calculated as (number of days from the date of the first dose 
to the earliest of the data cut date, early discontinuation date, or the date of the end of the 
treatment, inclusively)/28.  
Total dose received (mg) will be calculated as the sum of subject’s dose (mg) received at each 
visit, i.e., 150 mg/mL*study drug volume (mL) administered at the visit. 
For the summaries, these quantities will be calculated from the first dose to the earliest of the 
data cut date, early discontinuation date, or the date of the end of the treatment. 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) will be presented for time 
on treatment and total dose received. In addition, time on treatment will be summarized by 
category (<1 Month, 1 -< 3 Months, 3 -< 6 Months, 6 -< 9 Months, 9 -< 12 Months, >= 12 
Months). 
A listing of study drug administration, injection report and dose frequency modifications will be 
provided.  
6.6.8.2 
Measurements of Treatment Compliance 
Treatment compliance is defined as the percentage of planned doses received by the subject and 
will be calculated as follows: 
Treatment compliance (%) = number of doses received / number of planned doses * 100.  
The number of planned doses is the number of doses planned to be administered up to study 
completion or early termination, i.e., the number of records entered using the study drug 
administration CRF regardless of whether the study drug was indicated to be administered or not. 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) of total number of doses 
received by the subject, treatment compliance, and the number and percentage of subjects that 
received at least 80% of planned doses will be presented for FAS.  
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6.6.8.3 
Study Drug Administration and Injection Report 
All subjects who are considered suitable candidates will be allowed to self-administer treatment 
throughout the study.  
An Injection Report will be completed by the subject (or parent/caregiver) following each dose 
of IP, according to the assessment schedule in protocol Appendix A. The Injection Report will 
collect information on the subject’s experience with SC injection and self-administration of IP. 
The number and percentage of subjects who performed study drug administration via study staff 
administration in-clinic, self-administration in-clinic (including “Self-administration in the study 
clinic under supervision by study staff” and “Parent/ caregiver administration in the study clinic 
under supervision by study staff”), or self-administration at home (including “Self-administration 
at home or other outside clinic location” and “Parent/ caregiver administration at home or other 
outside clinic location”), as well as the total number of injections in each category and in each 
category by study visit, will be tabulated for the FAS. 
Additionally, the number and percentage of subjects who received 0, 1-5, 6-10, 11-20, or >20 
study staff administration in-clinic, self-administration in-clinic, or self-administration at home 
will be summarized for the FAS. 
A listing of study drug administration and injection report will be provided. 
6.7 
Interim Analyses 
Interim summary may be produced during the study to support regulatory reporting if requested 
by the authority. 
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 Statistical Analysis Plan (SAP) 
Not Applicable. 
9.2 
Data Handling Conventions  
9.2.1 
General Data Reporting Conventions  
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, SD, minimum, and maximum values will be 
presented. 
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For the summary statistics of all numerical variables, unless otherwise specified, minimum and 
maximum will be displayed to the same level of precision as reported. Mean and median will be 
displayed to one level of precision greater than the data collected. SD will be displayed to two 
levels of precision greater than the data collected. 
Percentages shall be reported to 1 decimal place, except when the percentage equals exactly 100 
where it shall be displayed as an integer (100). For zero, only count and no percentage will be 
displayed. The denominator for all percentages will be the number of subjects within the 
population of interest, unless otherwise specified. 
BMI will be rounded to 1 decimal place and normalized number of HAE attacks will be rounded 
to 2 decimal places for reporting. 
Listings will be sorted by subject ID, visit (when available), assessment/event start date (when 
available), assessment/event end date (when available) and alphabetically by preferred 
term/name (when available), unless otherwise specified. 
9.2.2 
Definition of Baseline  
For safety analyses, baseline is defined as the last non-missing value prior to first exposure to 
study drug (based on date or date/time) in this study. 
For efficacy analyses, refer to baseline attack rate defined in Section 6.5.4. 
9.2.3 
Definition of Visit Windows  
Although there is a visit window of ± 4 days around the expected visit date, nominal visits will 
be used for the per-visit analyses. Therefore, no windowing of visits by study day will be done 
for data obtained at the scheduled visits.  
For the analysis, study day will be calculated as follows: 
If the assessment date is on or after the date of first dose of IP:  
Study day = assessment date – first dosing date + 1 
If the assessment date is before the date of first dose of IP: 
Study day = assessment date – first dosing date 
9.2.3.1 
Analysis Periods 
The efficacy evaluation period of Day 0 through Day 182 is defined as the interval of time:     
[date/time of first exposure to study drug, date of Day 182 visit at 23:59] 
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9.2.4 
Derived Efficacy Endpoints 
9.2.4.1 
Unique HAE Attacks 
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms.   
Specifically, there must be at least 24 hours between the stop date/time of the first event and the 
start date/time of the next event, for the attacks to be considered distinct. If there is less than 24 
hours between the stop date/time of the first event and the start date/time of the next event, the 
events will be counted as one attack.  
When two or more attacks are combined for efficacy analysis, the parameters of the attacks will 
be conservatively chosen. The start date and time of the combined attack will take the earliest 
start date and time from the individual attacks; and the end date and time of the combined attack 
will take the latest end date and time of the individual attacks. If there are two attacks within 24 
hours, but the start date of the later attack occurs after the end of the efficacy evaluation period, 
the attacks will be combined and counted as one attack that occurs within the efficacy evaluation 
period of the start time. The severity of the combined attack will take the highest severity from 
the individual attacks. The primary location of the combined attack will be determined by the 
primary location of the individual attacks, and by following the hierarchy of laryngeal attack, 
abdominal attack, and peripheral attack. One primary location will be taken; and all the other 
primary location(s) and secondary locations will be considered as secondary location for the 
combined attack. The rescue medications and supportive treatment for the combined attack will 
include all the records from individual attacks. Also, the combined attack will be considered as 
an investigator-confirmed attack if any of the individual attack being combined is an 
investigator-confirmed attack.  
The duration of an HAE attack is calculated as stop date/time – start date/time. 
The imputation rules for partial start or end date and time for HAE attacks date/time is described 
in Section 9.2.6.1. 
9.2.5 
Repeated or Unscheduled assessments of Safety Parameters 
Unscheduled measurements will not be included in by-visit summaries, however if a subject has 
repeated assessments before the start of IP, then the results from the final assessment made prior 
to the start of IP will be used as baseline. If EOS/ET assessments are repeated or unscheduled, 
the last post-baseline assessment will be used as the EOS/ET assessment for generating 
descriptive statistics. All post-baseline assessments will be presented in the data listings. 
9.2.6 
Handling of Missing, Unused, and Spurious Data 
All subjects in the analysis sets defined in Section 5.0 will be included in the associated analyses. 
No imputation for missing data (e.g., last observation carried forward) will be applied except for 
the missing date/time for HAE attacks, the partial dates for AEs and prior/concomitant 
medications, the missing severity for AEs and the missing relationship to IP for AEs. 
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Imputed dates will not be presented in the listings. The original missing date/time will be 
presented in the listings.  
9.2.6.1 
Missing Start or End Date and Time for HAE Attacks 
The following rules apply to the handling of HAE attack data for efficacy analyses only.  
In general, missing start date/time and end date/time will be imputed as described in Section 
9.2.6.3.  However, the following rules will be applied for the attacks satisfying the corresponding 
conditions, in order to conservatively classify the attacks as separate, distinct attacks with at least 
24 hours in-between: 
• For HAE attacks with a missing start time and a non-missing start date one calendar day after 
the end date of the previous attack, the start time will be imputed using the end time of the 
previous HAE attack to ensure there are 24 hours in between the two attacks.  
• For HAE attacks with a missing start time and a non-missing end date/time within 24 hours 
from the end date/time of the previous attack, the attack should be considered as one attack 
with the previous attack (see Section 9.2.4.1 for details on combining HAE attacks)  
• For HAE attacks with missing end time and a non-missing end date one calendar day before 
the start date of the next attack, the end time will be imputed as the start time of the next 
HAE attack to ensure there are 24 hours in between the two attacks.  
• For HAE attacks with a missing end time and non-missing start date/time within 24 hours 
from the start date/time of the next attack, the attack should be considered as one attack with 
the next attack (see Section 9.2.4.1 for details on combining HAE attacks)  
For HAE attacks with a non-missing start date and time and a missing stop date and time: 
• If the event is not indicated as ongoing, the stop date and time will be imputed as start date 
and time + 48 hours or 24 hours before the start date and time of the next attack, whichever is 
earlier. 
• If the event is indicated as ongoing, the stop date and time will be imputed as the earliest of 
the following two date and time: 
 Start date and time + 48 hours or study completion date and the stop time of 
23:59, whichever is later. 
 24 hours before the start date and time of the next attack. 
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9.2.6.2 
Missing Date/Time Information for Prior or Concomitant 
Medications/Therapies/Procedures 
For prior or concomitant medications (and/or therapies/procedures), including rescue 
medications, incomplete (i.e., partially missing) start date/time and/or stop date/time will be 
imputed. When the start date/time and the stop date/time are both incomplete for a subject, 
impute the start date/time first. 
9.2.6.2.1 
Incomplete Start Date/Time 
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
9.2.6.2.1.1 
Missing Time 
• 
If the start time is missing and the start date is equal to the date of first study drug 
administration (before or after imputation), then the time of first study drug administration 
will be assigned to the missing time. 
• 
For any other cases, the missing time will be imputed as 0:00. 
9.2.6.2.1.2 
Missing Day and Month 
• If the year of the incomplete start date is the same as the year of the date of the first dose of 
IP, then the day and month of the date of the first dose of IP will be assigned to the missing 
fields 
• If the year of the incomplete start date is before the year of the date of the first dose of IP, 
then December 31 will be assigned to the missing fields 
• If the year of the incomplete start date is after the year of the date of the first dose of IP, then 
01 January will be assigned to the missing fields. 
9.2.6.2.1.3 
Missing Month only 
• The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
9.2.6.2.1.4 
Missing Day only 
• If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of IP, then the day of the date of the first dose of IP will be assigned to 
the missing day 
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• If either the year is before the year of the date of the first dose of IP or if both years are the 
same but the month is before the month of the date of the first dose of IP, then the last day of 
the month will be assigned to the missing day 
• If either the year is after the year of the date of the first dose of IP or if both years are the 
same but the month is after the month of the date of the first dose of IP, then the first day of 
the month will be assigned to the missing day. 
9.2.6.2.2 
Incomplete Stop Date/Time 
The following rules will be applied to impute the missing numerical fields. If the imputed stop 
date is before the start date (imputed or non-imputed start date), then the imputed stop date will 
be equal to the start date.  
9.2.6.2.2.1 
Missing Time 
If the stop time is missing, the missing time will be imputed as 23:59. 
9.2.6.2.2.2 
Missing Day and Month 
31 December will be assigned to the missing fields 
9.2.6.2.2.3 
Missing Month only 
The day will be treated as missing and both month and day will be replaced according to the 
above procedure. 
9.2.6.2.2.4 
Missing Day only 
The last day of the month will be assigned to the missing day 
9.2.6.3 
Missing Date/Time Information for Adverse Events 
For AEs with partial start date/time, non-missing date/time parts will be used to determine if the 
AE is treatment-emergent or not. If a determination cannot be made using the non-missing 
date/time parts as to when the AE occurred relative to study drug administration, e.g. AE start 
year and month are the same as the year and month of the first dose of IP, then the AE will be 
classified as treatment-emergent. 
To facilitate categorization of AEs as treatment emergent, imputation of start date/time will be 
used. Stop date/time will not be imputed. 
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9.2.6.3.1 
Incomplete Start Date/Time 
Follow the same rules as in Section 9.2.6.2.1. 
9.2.6.3.2 
Incomplete Stop Date/Time 
Not applicable.  
9.2.6.4 
Missing Severity assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of IP, then a severity of 
“Mild” will be assigned. If the severity is missing for an AE starting on or after the date of the 
first dose of IP, then the worst severity will be assigned, i.e., “life threatening (grade 4)”. The 
imputed values for severity assessment will be used for incidence summaries, while the actual 
values will be used in data listings. 
This rule applies also to HAARP severity for HAE attacks for which the worst severity is 
“Severe”. 
9.2.6.5 
Missing Relationship to IP for Adverse Events 
If the relationship to IP is missing for an AE starting on or after the date of the first dose of IP, a 
causality of “Related” will be assigned. The imputed values for relationship to double-blind IP 
will be used for incidence summaries, while the actual values will be presented in data listings. 
9.2.6.6 
Character Values of Clinical Laboratory Variables 
The non-standard laboratory results will be converted to numeric values using the rules shown in 
Table 4. 
Table 2. Convention for Converting Non-Standard Laboratory Results 
Non-Standard Lab Values 
Standardized Numeric Values 
<0.2 
Deduct 0.01 from the reference value. i.e., 0.19 
<0.1 
Deduct 0.01 from the reference value. i.e., 0.09 
>1.045 
Add 0.001 to the reference value. i.e., 1.046 
<3 
Deduct 0.1 from the reference value, i.e., 2.9 
<2 
Deduct 0.1 from the reference value, i.e., 1.9 
 
9.3 
Analysis Software  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS® on a suitably 
qualified environment. 
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