A Phase 3 Multi-center, Open-label Study to Evaluate the Efficacy and Safety of Lanadelumab (SHP643) in Japanese Subjects With Hereditary Angioedema
Phase: PHASE3
Conditions: Hereditary Angioedema (HAE)
Sponsor: Shire

Title: A Phase 3 Multi-center, Open-label Study to Evaluate the Efficacy and Safety of 
Lanadelumab (SHP643) in Japanese Subjects with Hereditary Angioedema
NCT Number: NCT04180163
Protocol Approve Date: 05-Oct-2020
Certain information within this protocol has been redacted (ie, specific content is masked
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information.
This may include, but is not limited to, redaction of the following:
z
Named persons or organizations associated with the study.
z
Patient identifiers within the text, tables, or figures or in by-patient data listings.
z
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder.
z
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae).

PROTOCOL: SHP643-302
TITLE:
A Phase 3 Multi-center, Open-label Study to Evaluate the Efficacy and 
Safety of Lanadelumab (SHP643) in Japanese Subjects with Hereditary
Angioedema
SHORT TITLE:
Efficacy and Safety of Lanadelumab (SHP643) in Japanese Subjects with 
Hereditary Angioedema 
STUDY PHASE:
Phase 3
DRUG:
Lanadelumab; TAK-743 (formerly SHP643, DX-2930)
IND NUMBER:
Non-IND
EUDRACT 
NUMBER:
Non-EUDRACT
SPONSOR:
Dyax Corp., (a wholly-owned, indirect subsidiary of Shire plc) (Shire plc, 
a wholly-owned subsidiary of Takeda Pharmaceutical Company Limited) 
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR: Multicenter study
PROTOCOL 
HISTORY:
Original Protocol: 03 Apr 2019
Amendment 1.0: 29 Jul 2019
Amendment 2.0: 05 Oct 2020
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
ry
ry
Subjects 
ubject
43, DX
, DX-2
owned, 
wned, 
sidiary
idiary o
y
Lexington
xingt
enter stud
ter stu
Original 
igina
Amen
Am
A
ument co
ment c
non
non-discl
dis
nd should
nd shou

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 3
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
AMENDMENT SUMMARY
Noteworthy changes to the protocol are captured in the table below including corrections for 
consistency. Additionally, any minor revisions in grammar, spelling, punctuation, and format are 
not reflected in the summary of changes.
Summary of Changes from Amendment 1 to Amendment 2:
Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected 
by Change
Revised Sponsor approval to 
. 
Protocol Signature 
Page
Added that subjects may elect to roll over into an expanded access 
study (Study TAK-743-5007). Provided clarification that subjects 
continuing to Study TAK-743-5007 will have their EOS visit on Day
378. All other subjects will continue the study as originally planned and
have their EOS visit on Day 392. A site check-in will occur at Day 371
for subjects participating in Study TAK-743-5007.
Section 1.1 Synopsis 
Section 1.2 Schema
Table 2
Section 4.1 Overall 
Design 
Section 8.1.3 Follow-
up Period
Revised the interim analysis to include 2 interim analyses: the first
analysis will be performed when the first 6 subjects enrolled in the 
study have reached Day 182 or discontinued in Treatment Period A (26 
weeks of treatment) and the second analysis will be performed when 
the first 4 subjects enrolled in the study have reached Day 364 or 
discontinued. Two interim clinical study reports along with a final 
clinical study report will be prepared.
Section 1.1 Synopsis 
Section 1.2 Schema 
Section 4.1 Overall 
Design
Section 9.2 Planned 
Interim Analysis, 
Adaptive Design, and 
Data Monitoring 
Committee 
Updated interim results from Study DX-2930-04 with final results as 
the study is now complete. The safety profile observed from the interim 
analysis is consistent with the final analysis. 
Section 2.4.3.4
Clinical 
Study DX-2930-04
Section 2.4.3.6
Adolescent Clinical 
PPD
Property y of
Up
Up
f
thth
f
o T
pd
Takeda: 
T
For 
po
non-commercia
clude
ude 2
en the f
the f
2 or dis
or dis
the sec
he sec
rolled in
led in
ial 
interim
nterim
ort wi
rt wi
ial use only 
7.
and 
nall
ally
ill occu
l occu
subject 
ess s 
bjects
bjects
visit on D
isit on 
ly pla
y p
t to 
to the
Pro
Pr
P
th
applicable 
ction(s) 
ion(s)
by C
by
a
oto
a
Terms 
T
of Use

Shire
Page 4
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected 
by Change
Trial Experience 
Section 2.6
Benefit/Risk 
Assessment
Corrected error that screening visit is also Visit 1. 
Section 6.6 Prior and 
Concomitant Therapy 
Corrected error on collection of prior treatment: prior treatments should 
be collected prior to screening visit. 
Section 6.6.1 Prior 
Treatment 
Corrected investigator-confirmed HAE attacks to state: 3 or more than 
3 investigator-confirmed HAE attacks. 
Section 8.1.1.2 Run-
in Period (up to 8 
weeks)
Removed body weight from physical exams at Visit 26 and Visit 27. 
Section 8.1.2.4 Study
Visit 26 (Study Day
350)
Section 8.1.2.5 Final 
Treatment Period 
Visit at Study Visit 
27 (Study Day 364)
Removed pregnancy tests at Visit 26 and Visit 27. 
Section 8.1.2.4 Study
Visit 26 (Study Day
350)
Section 8.1.2.5 Final 
Treatment Period 
Visit at Study Visit 
27 (Study Day 364)
Removed the following sentence: Overall attack rates will be estimated 
using a Poisson general linear model adjusting for run-in period attack 
rate and accounting for potential overdispersion. 
Section 9.6 Efficacy
Analyses
Added if applicable to analysis of efficacy endpoints at 4 efficacy
evaluation periods. 
Section 9.6 Efficacy
Analyses
Property y of 
Re
R
usi
us
o Ta
Remo
Remo
Takeda: 
Ta
For non-commercial 
s at Vi
at V
m
use only 
sitit
and 
t 26 a
26 
an
subject 
more tha
more th
ec to 
uld
the 
h
d
S
he
th
applicable 
k k
entnt
tion
on 6.6
6
Concom
oncom
lic
Terms s
ms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 6
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the “Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol” within 24 hours to the Shire Global Drug Safety Department. The fax 
number and e-mail address are provided on the form (sent under separate cover). A copy of this 
form must also be sent to the contract research organization (CRO)/Shire medical monitor using 
the details below.
For protocol- or safety-related questions or concerns during normal business hours, the 
investigator must contact the IQVIA medical monitor:
For protocol- or safety-related questions or concerns outside of normal business hours, the 
investigator must contact the IQVIA medical monitor:
PPD
PPD
PPD
Property of Takeda: For non-commercial use only and 
r:r:
subject 
tside of
side o
su
to the applicable 
ness hou
ess ho
pp
Terms 
is 
using
using
of Use

Shire
Page 7
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Shire within 24 hours.  If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis.
A product quality complaint includes any instances where there is an allegation or report relating 
to Shire  licensed or investigational products, received in writing, electronically, or orally, which 
indicates an impact to a product’s strength, identity, safety, purity, or quality, or which suggests 
that a product did not meet the criteria defined in the regulatory applications, licenses, or 
marketing authorizations for the product. Examples of investigational product quality complaints 
include, but are not limited to, the following:
Unit issues
•
Capsule fill empty or overage
•
Bottle/vial fill shortage or overage
•
Capsule/tablet damaged/broken
•
Syringe/vial cracked/broken
•
Syringe leakage
•
Missing components
•
Product discoloration
•
Device malfunction
Labeling
•
Label missing
•
Leaflet or Instructions For Use
(IFU) missing
•
Label illegible
•
Incomplete, inaccurate, or
misleading labeling
•
Lot number or serial number missing
Packaging
•
Damaged packaging (e.g., 
secondary, primary, bag/pouch)
•
Tampered seals
•
Inadequate or faulty closure
•
Missing components within package
Foreign
material
•
Contaminated product
•
Particulate in bottle/vial
•
Particulate in packaging
Please report the product quality complaint using the “Product Complaint Data Collection Form” 
via the email address:
For instructions on reporting AEs related to product complaints, see Appendix 3.4.
PPD
PPD
PPD
Property 
F
of
of Takeda:
da: 
Taked
T
For 
Fo
F
non-commercial 
clo
clo
oduct
duct
bottle/v
ottle/v
in pack
n pack
al
mm
uct qua
uct qu
ss:
use 
osure
osur
only 
uch)
ch)
y and 
•
subject 
ct d
t 
vice ma
vice m
Incomp
com
misl
mis
L
bje
to 
com
om
disc
disc
the 
kage
kage
mpo
mpo
e applicable
y, 
h sugge
h sugg
es, or 
s, or 
uality
ality co
c
y
a
Terms 
ating
ating
which
which
of Use

Shire
Page 8
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
AMENDMENT SUMMARY..........................................................................................................3
EMERGENCY CONTACT INFORMATION................................................................................6
PRODUCT QUALITY COMPLAINTS..........................................................................................7
TABLE OF CONTENTS.................................................................................................................8
LIST OF TABLES.........................................................................................................................12
LIST OF FIGURES .......................................................................................................................12
1.
PROTOCOL SUMMARY......................................................................................................13
1.1
Synopsis................................................................................................................13
1.2
Schema..................................................................................................................21
1.3
Schedule of Activities...........................................................................................22
2.
INTRODUCTION ..................................................................................................................28
2.1
Disease Etiology and Pathophysiology ................................................................28
2.2
Epidemiology in Japanese Patients with Hereditary Angioedema .......................29
2.3
Indication and Current Treatment Options ...........................................................30
2.4
Product Background and Clinical Information.....................................................31
Drug Information ...................................................................................................31
2.4.1
Nonclinical Studies with Lanadelumab .................................................................33
2.4.2
Clinical Studies with Lanadelumab .......................................................................33
2.4.3
2.5
Study Rationale.....................................................................................................39
2.6
Benefit/Risk Assessment ......................................................................................39
2.7
Compliance Statement..........................................................................................42
3.
OBJECTIVES AND ENDPOINTS........................................................................................43
3.1
Study Objectives...................................................................................................43
3.2
Study Endpoints....................................................................................................43
4.
STUDY DESIGN ...................................................................................................................46
4.1
Overall Design......................................................................................................46
4.2
Scientific Rationale for Study Design ..................................................................47
4.3
Justification for Dose............................................................................................49
4.4
Duration of Subject Participation and Study Completion Definition ...................50
4.5
Sites and Regions..................................................................................................50
5.
STUDY POPULATION.........................................................................................................51
5.1
Inclusion Criteria ..................................................................................................51
5.2
Exclusion Criteria .................................................................................................52
5.3
Restrictions ...........................................................................................................53
Medical Interventions ............................................................................................53
5.3.1
Property 
5
of Takeda: 
3
4.4
4.4
4
For 
ESIG
SI
Ov
Ov
non-commercial 
........
........
essmen
smen
Stateme
ateme
ENDPO
NDP
Objecti
Objecti
udy End
End
y
GN
GN
use 
ade
ad
delum
delum
only 
nf
.........
.......
elum
elu
and 
ions
ons ....
forma
orma
subject 
........
......
..........
.......
ereditar
redita
to
.......
......
the 
.
........
......
applicable 
.
..........
.......
.........
........
..........
....
......
......
Terms 
6
.......7
......
of Use

Shire
Page 9
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
Fluid and Food Intake ............................................................................................53
5.3.2
Activity ..................................................................................................................53
5.3.3
5.4
Reproductive Potential..........................................................................................53
Female Contraception ............................................................................................53
5.4.1
Male Contraception................................................................................................54
5.4.2
6.
STUDY INTERVENTION ....................................................................................................55
6.1
Investigational Product .........................................................................................55
Identity of Investigational Product.........................................................................55
6.1.1
Blinding the Treatment Assignment ......................................................................55
6.1.2
6.2
Administration of Investigational Product............................................................55
Interactive Response Technology for Investigational Product Management ........55
6.2.1
Allocation of Subjects to Treatment ......................................................................55
6.2.2
Dosing....................................................................................................................55
6.2.3
Unblinding the Treatment Assignment..................................................................56
6.2.4
Dose Modification .................................................................................................56
6.2.5
6.3
Labeling, Packaging, Storage, and Handling of Investigational Product .............56
Labeling .................................................................................................................56
6.3.1
Packaging...............................................................................................................57
6.3.2
Storage and Handling.............................................................................................58
6.3.3
6.4
Drug Accountability .............................................................................................59
6.5
Subject Compliance..............................................................................................60
6.6
Prior and Concomitant Therapy............................................................................60
Prior Treatment ......................................................................................................61
6.6.1
Concomitant Treatment .........................................................................................61
6.6.2
Permitted Treatment...............................................................................................61
6.6.3
Prohibited Treatment .............................................................................................61
6.6.4
7.
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT
DISCONTINUATION/WITHDRAWAL.....................................................................62
7.1
Discontinuation of Study Treatment.....................................................................62
7.2
Reasons for Discontinuation.................................................................................62
7.3
Withdrawal from the Study ..................................................................................62
7.4
Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit ..........................63
7.5
Stopping Rules......................................................................................................63
Study Level Stopping Rules...................................................................................63
7.5.1
Individual Stopping Rules......................................................................................63
7.5.2
Follow-Up for Subjects Meeting Stopping Criteria...............................................63
7.5.3
8.
STUDY ASSESSMENTS AND PROCEDURES..................................................................64
8.1
Study Periods........................................................................................................64
of Takeda: 
.3
7.4
7.4
For
CONT
ON
Di
D
non-commercial 
...
tant Th
nt Th
.......
.....
Treatm
reatm
Treatm
reatm
ited Tr
ted Tr
UATIO
UATI
TI
TI
use 
......
....
....
...
only 
......
.....
..........
.....
and 
linin
........
....
subject 
..........
......
............
.........
ng of In
g of 
to 
.....
.....
the 
uct M
t M
......
.....
applicable 
........
.........
....
..........
........
..........
......
Mana
Mana
Terms 
54
.....
.....55
55
.
of Use

Shire
Page 10
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
Screening, Washout, and Run-in Period................................................................64
8.1.1
Treatment Period....................................................................................................65
8.1.2
Follow-up Period ...................................................................................................71
8.1.3
Early Termination ..................................................................................................72
8.1.4
Additional Care of Subjects after the Study ..........................................................72
8.1.5
8.2
Study Assessments ..........................................................................................................72
Informed Consent...................................................................................................72
8.2.1
Eligibility Review ..................................................................................................73
8.2.2
Demographic and Other Baseline Characteristics .................................................73
8.2.3
Efficacy..................................................................................................................73
8.2.4
Safety .....................................................................................................................73
8.2.5
Other Study Assessments.......................................................................................77
8.2.6
Volume of Blood to Be Drawn from Each Subject ...............................................79
8.2.7
Blood Sample Collection, Storage, and Shipping..................................................80
8.2.8
9.
STATISTICAL CONSIDERATIONS ...................................................................................81
9.1
Statistical Analysis Process .............................................................................................81
General Considerations..........................................................................................81
9.1.1
9.2
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee .............81
9.3
Sample Size and Power Considerations ..........................................................................81
9.4
Statistical Analysis Set(s) ................................................................................................81
9.5
Disposition, Demographics and Baseline Characteristics, and Exposure .......................82
Subject Disposition................................................................................................82
9.5.1
Demographics and Other Baseline Characteristics................................................82
9.5.2
Medical History .....................................................................................................82
9.5.3
Treatment Exposure and Compliance....................................................................82
9.5.4
Prior and Concomitant Medications ......................................................................82
9.5.5
9.6
Efficacy Analyses............................................................................................................82
Primary Efficacy Endpoint ....................................................................................83
9.6.1
Other Efficacy Endpoints.......................................................................................83
9.6.2
Exploratory Endpoints ...........................................................................................87
9.6.3
9.7
Safety Analyses ...............................................................................................................87
Adverse Events ......................................................................................................88
9.7.1
Laboratory Test Results .........................................................................................89
9.7.2
Vital Signs..............................................................................................................90
9.7.3
9.8
Other Analyses ................................................................................................................90
Health-related Quality of Life Analyses ................................................................90
9.8.1
Pharmacokinetic/Pharmacodynamic Analyses ......................................................90
9.8.2
Immunogenicity Analyses .....................................................................................91
9.8.3
Property of Takeda: 
2
9.6.3
6.3
.7
S
For
Prima
Prim
Ot
O
non-commercial 
nd d
........
......
nd Othe
Othe
ory
ry .....
t Exp
Expos
os
nd Con
d Con
Anal
Analy
use 
......
....
Base
Base
only
ign, a
ign,
ns ......
...
and 
...
........
....
an
an
subject 
g..........
......
..........
........
.....
..
to 
.....
.....
the 
.......
......
.....
applicable 
........
.........
....
.........
........
..........
......
..
Terms 
72
.....
.....72
72
.
of Use

Shire
Page 11
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
9.9
Statistical/Analytic Considerations .................................................................................91
Multiplicity Adjustment.........................................................................................91
9.9.1
Control of Type I Error..........................................................................................91
9.9.2
Handling of Missing Data......................................................................................91
9.9.3
Multicenter Studies ................................................................................................91
9.9.4
Subgroup Analyses ................................................................................................91
9.9.5
9.10 Sensitivity Analyses ........................................................................................................91
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .........93
11. REFERENCES .....................................................................................................................158
CCI
Property of Takeda: For non-comme
........
......
ercial use only and subject to the 
able 
........
ONS
NS ..
applicab
Terms 
91
.....
.....91
91
.
of Use

Shire
Page 12
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
LIST OF TABLES
Table 1:
Study Activity Schedule-Screening, Run-in and Treatment Period A ............22
Table 2:
Study Activity Schedule - Treatment Period B and Follow-up Period............25
Table 3
Statistical Analysis of Lanadelumab Plasma Pharmacokinetic 
Parameters Using ANOVA (Pharmacokinetic Set).........................................37
Table 4:
Objectives and Endpoints ................................................................................44
Table 5:
Volume of Blood to Be Drawn from Each Subject .........................................80
Table 6:
Sensitivity Analysis for Other Efficacy Endpoints..........................................92
LIST OF FIGURES
Figure 1:
Study Design....................................................................................................21
Figure 2:
Lanadelumab Specifically Inhibits Plasma Kallikrein (pKal) .........................32
Property of Takeda: For non-commercial use only and subject 
kr
to
rein (
ein 
the 
........
.......
applicable 
.........
.......
............
........
Terms 
...37
37
.......4
.......4
of Use

Shire
Page 13
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
1. PROTOCOL SUMMARY
1.1
Synopsis
Protocol number: SHP643-302
Drug: Lanadelumab
Title of the study: A Phase 3 Multi-center, Open-label Study to Evaluate the Efficacy and Safety of Lanadelumab 
(SHP643) in Japanese Subjects with Hereditary Angioedema 
Short title: Efficacy and Safety of Lanadelumab (SHP643) in Japanese Subjects with Hereditary Angioedema 
Study phase: Phase 3
Number of subjects (total and per treatment arm):
A sufficient number of subjects will be enrolled to ensure that at least 8 subjects enter Treatment Period A, after 
having successfully completed the washout period (if applicable) and run-in period. 
Investigator(s): This is a multicenter study.
Site(s) and Region(s): 
Up to 15 sites in Japan will participate.
Study period (planned): 
Nov 2019 to Dec 2021
Clinical phase:
3
Objectives:
The objectives of the study are:
•
To evaluate the efficacy of repeated subcutaneous (SC) administrations of lanadelumab in Japanese subjects
with hereditary angioedema (HAE).
•
To evaluate the safety of repeated SC administrations of lanadelumab in Japanese subjects with HAE.
•
To evaluate the pharmacokinetics (PK) of repeated SC administrations of lanadelumab in Japanese subjects
with HAE.
•
To evaluate the effect of repeated SC administrations of lanadelumab on health-related quality of life (HRQoL)
in Japanese subjects with HAE.
•
To evaluate the pharmacodynamics (PD) of repeated SC administrations of lanadelumab in Japanese subjects
with HAE.
•
To evaluate the immunogenicity of repeated SC administration of lanadelumab and the effect on lanadelumab
PK, PD, efficacy, and safety in Japanese subjects with HAE.
of Takeda: For
imm
m
cacy, an
cacy, a
F
non-commercial 
inin
K) of rep
of rep
ted SC a
ed SC
AE.
E.
acodyna
dyna
mun
mun
use 
strati
strati
only 
(SC) adm
SC) ad
and 
d subject 
bje
to 
o the 
he
t
applicable 
dema
ema
ble
mentnt Peri
Pe
ca
Terms s
ab
s
ms
a
Te
of Use

Shire
Page 14
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
Rationale:
HAE 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.
The United States (US) Food and Drug Administration (FDA) approved the first monoclonal antibody, lanadelumab 
(Takhzyro, SHP643), for the treatment of types I and II HAE in patients aged 12 years and older on 23 August 2018. 
Also, European Medicines Agency (EMA) approved Lanadelumab (Takhzyro, SHP643), for preventing attacks of 
hereditary angioedema in patients aged 12 years and over on 22 November 2018.
There are currently 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. Lanadelumab is expected to fulfill this unmet medical need. 
The current study will bridge the global lanadelumab efficacy, safety, PK, HRQoL, PD and immunogenicity data to 
Japanese HAE subjects.
Investigational product, dose, and mode of administration:
Treatment will consist of SC injection of lanadelumab. A single dose regimen of 300 mg q2wks lanadelumab will be 
evaluated in Treatment Period A. In Treatment Period B, a subject may continue to receive lanadelumab 
300 mg q2wks or, if the subject has been well-controlled (eg., attack free) for 26 consecutive weeks of lanadelumab 
treatment in the study, the subject may switch to a dose of 300 mg q4wks at the discretion of the investigator and 
following approval by the sponsor’s medical monitor.
In Treatment Period A, all doses of lanadelumab will be administered by site personnel. Self-administration of 
lanadelumab will be permitted in Treatment Period B. All subjects (adolescent or adult) who are considered suitable 
candidates (ie, those with a physical and mental capability of learning and willing to be trained) may be allowed to 
self-administer treatment. Subjects (and/or their parent/caregiver) must complete appropriate training by the 
investigator or designee and understanding of the training must be confirmed by the investigator or designee. 
Subjects (or their parent/caregiver) are allowed to initiate self-administration under the investigator supervision; 
once initiated, subjects (or their parent/caregiver) may self-administer subsequent doses of lanadelumab at the 
investigational site or an offsite location.
The drug product is a sterile, preservative-free, ready-to-use solution of lanadelumab at a concentration of 
150 mg/mL. For Treatment Period A, lanadelumab will be provided in a single-use 5 mL glass vial (2 mL fill). For 
all subjects, a 2 mL (300 mg) dose will be withdrawn from the vial and administered to the subject. For Treatment 
Period B, lanadelumab will be provided in similar single-use glass vials and may also be provided in pre-filled 
syringes (PFS) if available and permitted per local regulations. Lanadelumab will be administered by SC injection in 
the upper arm, thigh, or abdominal area. The upper arm location is not recommended for self-administration but 
rather as an additional injection site when administered by a parent/caregiver or healthcare provider. 
Methodology:
This open-label Phase 3 study will enroll approximately 8 Japanese subjects with HAE Type I or II. Following 
signing of informed consent, subjects will undergo screening assessments; eligible subjects who are on long-term
prophylaxis (LTP) for HAE are required to undergo a minimum 2-week washout period prior to entering the run-in 
period. This LTP washout period is permitted as long as the investigator determines that doing so would not place 
the subject in any undue safety risk, and that the subject is at least 18 years of age. 
Eligible subjects who are not on LTP therapy for HAE, or who have completed the required washout period, will 
enroll and enter a run-in period of 4 weeks to determine their baseline attack rate. Only subjects meeting a minimum 
baseline attack rate of at least 1 investigator-confirmed attack per 4 weeks will be eligible for treatment. Subjects 
who experience 3 or more investigator-confirmed attacks before the end of the 4-week run-in period may exit the 
run-in period early and proceed to Treatment Period A. Subjects without at least 1 Investigator-confirmed attack 
after 4 weeks of run-in may have their run-in period extended for another 4 weeks. Subjects who have their run-in 
extended must complete the full 8-week run-in period and must have at least 2 investigator-confirmed attacks during 
this time to be eligible to enter Treatment Period A. Subjects who do not meet the minimum attack rate during the 
run-in period, or are otherwise determined to be ineligible based on screening assessments, will be considered a 
Property
b
y of 
Eligi
Elig
enro
enro
Takeda:
form
rm
s (LTP)
(LTP
This LT
is LT
ubject in
bject in
giblbl
For 
Phase 3
Phase 3
med c
med
non-commercial 
e, rea
re
delumab
elumab
be withd
e withd
ded in si
ed in si
rmitted 
mitted 
inal area
nal area
ion site 
n site
on
use 
ady
ady
only
must b
st
self
elf-f adm
ad
self
elf-f adm
adm
and
ning a
ng a
er) must
r) must
be c
be c
subject 
e disc
dis
y site per
site pe
dole
olescen
sce
nd w
d
to
onsec
onsec
cret
cret
the
mg q2w
q2w
ceive l
ceive 
t
applicable 
n of 
of 
medical n
medical
ogenicity 
enicit
ks
k
pli
Terms 
8. 
of 
ms of Use

Shire
Page 15
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
screen failure and will not be allowed to enter the treatment phase of the study; they will be replaced with new HAE 
subjects, until at least 8 subjects have entered Treatment Period A.
•
Treatment Period A:
Subjects who enter Treatment Period A will receive lanadelumab 300 mg q2wks for 26 weeks.
After completion of the first 26-week treatment period, subjects will immediately continue into
Treatment Period B.
•
Treatment Period B:
Subjects who enter the Treatment Period B will receive lanadelumab for an additional 26 weeks (total of
52 weeks). During these additional 26 weeks, an individual subject may remain on the same dose regimen as
Treatment Period A or may consider lanadelumab 300 mg q4wks if they have been well-controlled (eg, attack
free) for 26 consecutive weeks with lanadelumab treatment. The dose frequency change will be based on the
investigator’s discretion and approval by the sponsor’s medical monitor.
After completion of the second 26-week treatment period (Treatment Period B), subjects may roll over into an 
expanded access study, Study TAK-743-5007. Subjects that elect to rollover to Study TAK-743-5007 will return on 
Day 378 to complete EOS assessments and will be discharged from this study. All other subjects will continue the 
study as originally planned and will be discharged from the study on Day 392 following completion of all EOS visit 
procedures.
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.
Individual subject participation from screening through the completion of safety follow-up visit will be 
approximately 68 weeks (see below for duration of each study period). Subjects participating in Study TAK-743-
5007 will be discharged from this study 2-weeks early on Day 378.
Inclusion and Exclusion Criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the criteria below.
1.
Be of Japanese descent, defined as born in Japan and having Japanese parents and Japanese maternal and
paternal grandparents.
2.
The subject is male or female and ≥12 years of age at the time of informed consent.
3.
Documented diagnosis of HAE (Type I or II) based upon all of the following:
•
Documented clinical history consistent with HAE (subcutaneous or mucosal, nonpruritic swelling episodes
without accompanying urticaria).
•
Diagnostic testing results obtained during screening that confirm HAE Type I or II: C1 inhibitor (C1-INH)
functional level <40% of the normal level. Subjects with functional C1-INH level 40-50% of the normal
level may be enrolled if they also have a C4 level below the normal range. With prior sponsor approval,
subjects may be retested during the run-in period if results are incongruent with clinical history or believed
by the investigator to be confounded by recent C1 inhibitor use.
•
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.
Attack rate:
•
Subjects must experience at least 1 investigator-confirmed HAE attack per 4 weeks during the run-in period
to enter the lanadelumab treatment period.
Property y of Takeda: 
hout a
out a
Diagno
Diagno
func
func
lele
For 
agn
gn
ented c
ented 
acc
ac
non-commercial 
gible fo
ible fo
fined as 
ned as 
or fema
r fem
nosis 
osis
use
rly on
rly on
us
only 
he comp
e comp
h study 
stud
D
and
ponse t
onse 
subject 
All
All
follow
ollow
d study t
study
o t
to 
dy T
y T
l other
othe
the 
cts may
cts may
TAK
TAK
applicable 
otal of
otal of
se regime
regim
trolled (eg
rolled (
will be bas
l be b
Terms 
ms of Use

Shire
Page 16
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
5.
The subject (or the subject’s parent/legally authorized representative, if applicable) has provided written
informed consent approved by the Institutional Review Board/Independent Ethics Committee (IRB/IEC).
If the subject is an adult, be informed of the nature of the study and provide written informed consent 
before any study-specific procedures are performed.
OR
If the subject is a minor (ie, below the age of majority), have a parent/legally authorized representative who 
is informed of the nature of the study provide written informed consent (ie, permission) for the minor to 
participate in the study before any study-specific procedures are performed. Assent will be obtained from 
minor subjects.
6.
Males, or nonpregnant, nonlactating females who are fertile and sexually active and who agree to be abstinent
or agree to comply with the applicable contraceptive requirements of this protocol for the duration of the study,
or females of nonchildbearing potential, defined as surgically sterile (status post hysterectomy, bilateral
oophorectomy, or bilateral tubal ligation) or postmenopausal for at least 12 months.
7.
Agree to adhere to the protocol-defined schedule of assessments and procedures.
Exclusion Criteria:
The subject will be excluded from the study if any of the following exclusion criteria are met. 
1.
Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE),
HAE with normal C1-INH (also known as HAE Type 3), idiopathic angioedema, or recurrent angioedema
associated with urticaria.
2.
Participation in a prior lanadelumab study.
3.
Dosing with investigational drug or exposure to an investigational device within 4 weeks prior to entering to
screening.
4.
Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with
systematic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to
screening.
5.
Exposure to androgens (eg, danazol, methyltestosterone, testosterone) within 2 weeks prior to entering the run-
in period.
6.
Use of long-term prophylactic therapy for HAE (C1-INH, attenuated androgens, or anti-fibrinolytics) within 2
weeks prior to entering the run in period.
7.
Use of short-term prophylaxis for HAE 7 days prior to entering the run-in period. Short-term prophylaxis is
defined as C1-INH, attenuated androgens, or anti-fibrinolytics used to avoid angioedema complications from
medically indicated procedures.
8.
Any of the following liver function abnormalities: alanine aminotransferase (ALT) >3x upper limit of normal,
or aspartate aminotransferase (AST) >3x upper limit of normal or bilirubin >2x upper limit of normal (unless
the bilirubin is a result of Gilbert’s syndrome).
9.
Pregnancy or breast feeding.
10. Subject has any condition that in the opinion of the investigator or sponsor, may compromise their safety or
compliance, preclude successful conduct of the study, or interfere with interpretation of the results (eg, history
of substance abuse, or dependence, significant pre-existing illnesses or major comorbidity the investigator
considers may confound the interpretation of the study results).
11. Subject has a known hypersensitivity to the investigational drug or its components.
Maximum duration of subject participation in the study:
•
Planned duration of screening period: up to 4 weeks (Note: Eligible subjects on LTP must complete a 2-week
Property y of 
0
Takeda:
rtate am
ate a
ilirubin 
rubin
Pregnan
regnan
Sub
Sub
For 
cated
te
followi
follow
non-commercial 
cep
ce
l, methy
methy
tic thera
c thera
he run in
e run i
ophylax
phyla
H, attenu
, attenu
d pr
d pr
use
ACE) i
CE) 
ptives
ptives
only 
nvestigat
vestiga
and subject 
criteria
riteri
edema, su
ema, s
hic angio
ic ang
to the applicable 
ed 
to be abs
o be ab
uration of
ration 
tomy, bil
omy, b
Terms
who 
who 
r to
r to
from
from
ms 
ms of Use

Shire
Page 17
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
washout prior to entering the run-in period.)
o
Planned duration of enrollment period: up to 4 weeks. An enrolled subject will have signed the
informed consent form and met the inclusion criteria (and no exclusion criteria) for the screening visit.
•
Planned duration of run-in period: up to 8 weeks. The run-in period will be at least 4 weeks except for those
subjects who report ≥3 investigator-confirmed HAE attacks before the end of the 4 weeks. The run-in period
may be extended to 8 weeks in subjects without at least 1 investigator-confirmed attack after 4 weeks.
•
Planned duration of treatment period (Treatment Periods A and B): 52 weeks
•
Planned duration of follow-up period: 4 weeks
Statistical analysis:
Analysis Sets
Analysis of study data will be based on the following analysis sets:
•
Full analysis set (FAS): All subjects who received at least 1 dose of lanadelumab (investigational
product). All safety, efficacy, and HRQoL analyses will be based on the FAS.
•
Pharmacokinetic set (PK Set): All subjects in the FAS who have at least 1 evaluable post dose PK
concentration value. All PK analyses will be based on the PK set.
•
Pharmacodynamic set (PD Set): All subjects in the FAS who have at least 1 evaluable post dose PD
value. All PD analyses will be based on the PD set.
Efficacy Endpoints and Analyses
Efficacy Evaluation Periods
There will be a total of 4 efficacy evaluation periods:
•
Day 0 (after study drug administration) through Day 182 (the end of Treatment Period A)
•
Day 0 (after study drug administration) through Day 364 (the end of Treatment Period B)
•
Presumed steady-state period from Day 70 through Day 182
•
Presumed steady-state period from Day 70 through Day 364
Efficacy Endpoints
The primary efficacy endpoint is achievement of attack-free status for the efficacy evaluation period of Day 0 
through Day 182.
Other efficacy endpoints are: 
•
Number of investigator-confirmed HAE attacks during each of the efficacy evaluation periods.
•
Number of investigator-confirmed HAE attacks requiring acute treatment during each of the efficacy
evaluation periods.
•
Number of investigator-confirmed moderate or severe HAE attacks during the each of efficacy
evaluation periods.
•
Maximum attack severity during each of the efficacy evaluations periods.
•
Number of investigator-confirmed high-morbidity attacks during each of the efficacy evaluation
periods; a high morbidity HAE attack is defined as any attack that has at least 1 of the following
characteristics: severe, results in hospitalization (except hospitalization for observation <24 hours),
Property y of Takeda: 
cacy end
acy end
•
For 
cy end
y en
2.2.
non-commercial
istratio
stratio
dmi
ministr
nistr
te period
period
y state p
state p
dp
dp
use 
ds:
ds:
only and subject 
ve at leas
e at lea
K set.
K set.
who hav
who h
to
nad
the F
the F
the 
delum
delum
applicable 
ble Terms 
ms of Use

Shire
Page 18
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
hemodynamically significant (systolic blood pressure <90, requires IV hydration, or associated with 
syncope or near syncope) or laryngeal.
•
Time to first HAE attack after Day 0 for the efficacy evaluation period of Day 0 through Day 182.
•
Time to first HAE attack after Day 0 for the efficacy evaluation period of Day 70 through Day 182.
•
Achievement of at least a 50%, 70% and 90% reduction in the investigator-confirmed normalized
number of attacks (NNA) per 4 weeks relative to the run-in period NNA for each of the efficacy
evaluation periods.
•
Achievement of an efficacy evaluation period NNA <1.0 per 4 weeks, <0.75 per 4 weeks, <0.50 per 4
weeks, and <0.25 per 4 weeks for each of the efficacy evaluations periods.
•
Achievement of attack-free status for each of the efficacy evaluation period of Day 0 through Day 364,
Day 70 through Day 182, and Day 70 through Day 364.
•
Percentage of attack free days during each of the efficacy evaluation periods.
Efficacy Analyses
No statistical hypothesis testing will be performed. The totality of results across all efficacy endpoints will be the 
measure of overall treatment benefit, with the primary goal of demonstrating consistency across the endpoints, 
especially the primary efficacy endpoint, with the pivotal overseas study (DX-2930-03). 
•
Continuous efficacy endpoints will be summarized using number of subjects (n), mean, SD, median,
minimum, and maximum. Whenever appropriate, raw (actual) values and changes from baseline will
be summarized at each scheduled time point. Overall attack rates will be estimated using a Poisson
general linear model adjusting for run-in period attack rate and accounting for potential overdispersion.
Additionally, the attack rates will be calculated using the number of attacks divided by the duration of
time for each subject for each efficacy evaluation period.
•
Categorical efficacy endpoints (eg, attack severity) will be summarized in terms of the number and
percentage of subjects in each category of the efficacy endpoint.
•
Time-to-event endpoint (eg, time to the first HAE attack) will be summarized using Kaplan-Meier
(KM) estimates. Summaries will include 25th, 50th (median), and 75% 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 summaries will be based on the FAS. Efficacy data, including derived data, will be presented in subject 
data listings.
A subject is considered as attack free during an efficacy evaluation period if the subject has no 
investigator-confirmed HAE attacks during that efficacy evaluation period. For subjects who discontinue treatment 
during an efficacy evaluation period, the evaluation period will end at the time of treatment discontinuation and 
attack-free status will be evaluated for the period of time that the subject was in the evaluation period.
The treatment period HAE attack rate percentage change from the run-in period 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. The attack rates for each period (run-in period and each efficacy evaluation period) will be 
calculated for each subject using the number of attacks for that period divided by the duration of time the subject 
spent in the period.
Property 
sp
y of
s
perio
peri
cal
cal
Takeda:
ficacy
cacy
e status 
status
treatme
treatme
the dif
the dif
d
For
dered a
ered 
firmed 
firmed
ev
e
non-commercial 
atego
tego
, time to
time to
ries will
es wi
% confid
confid
analysi
nalysi
l be bas
be ba
use 
val
attack s
attack 
ory
ory
only 
od atta
od att
lated usin
ated usi
luation
uati
and
ing
ng
aw (act
(act
w
erall att
all at
subject 
ss all 
 all 
g consist
g consi
(DX
(DX-293
29
g numb
num
to 
eff
ef
the 
s.
applicable 
<0.50 p
0.50 
0 through
0 throu
Terms
ms 
ms of Use

Shire
Page 19
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
Safety Endpoints and Analyses
Safety Endpoints
The safety measures will include:
•
Treatment emergent adverse events (TEAEs), including adverse events of special interest (AESI) and
serious adverse events (SAEs).
•
Clinical laboratory testing (hematology, clinical chemistry, coagulation, and urinalysis).
•
Vital signs including blood pressure (BP), heart rate (HR), body temperature, and respiratory rate.
•
12 lead-Electrocardiogram (ECG)
Safety Analyses
No statistical hypothesis testing will be performed. 
•
Continuous safety endpoints (eg, change in laboratory parameter) will be summarized using number of
subjects (n), mean, standard deviation (SD), median, minimum value, and maximum value. As
appropriate, raw (actual) values and changes from baseline will be summarized overall and at each
scheduled time point.
•
Categorical endpoints (eg, presence or absence of an outcome measure) will be summarized using
counts and percentages. Summaries will include but are not limited to: number and percentage of
subjects with an outcome measure, and laboratory shift tables (categorical change from baseline).
•
Only treatment-emergent AEs (TEAEs) will be analyzed. The number and percentage of subjects
reporting any TEAEs, SAEs, TEAEs related to the investigational product, TEAEs leading to
withdrawal, severe TEAEs and absolute count of events will be summarized by PT and SOC.
•
Clinical laboratory tests and vital signs will be summarized by visit. Potentially clinically important
findings will also be summarized or listed).
Other Study Endpoints and Analyses
Pharmacokinetics and pharmacodynamics: The PK endpoints include plasma concentrations of lanadelumab. The 
PD endpoints include plasma kallikrein (pKal) activity as measured by cleaved high molecular weight kininogen 
(cHMWK) level (ie, plasma concentrations of cHMWK). No formal statistical hypothesis will be tested. Individual
PK concentrations and cHMWK levels will be provided in subject data listing(s) and summarized using descriptive 
statistics (number of subjects, arithmetic mean, standard deviation [SD], coefficient of variation [CV%], median, 
minimum, maximum, geometric mean, and %CV of geometric mean). Figures of individual and mean (± SD) 
concentration-time profiles plasma lanadelumab will be generated. Tabular and graphical summaries will be 
analyzed based on the PK set and PD set, as appropriate.
Health-related quality of life (HRQoL): HRQoL will be measured by the angioedema quality of life (AE-QoL) 
questionnaire, which consists of 17 disease-specific quality-of-life items, to produce a total AE-QoL score and 
4 domain scores (functioning, fatigue/mood, fear/shame, and nutrition). The AE-QoL total score and domain scores 
will be summarized using descriptive statistics by scheduled visit. Change in total AE-QoL score and 4 domain 
scores from baseline (Day 0) to Day 182 and Day 364 will be reported.
Immunogenicity: Immunogenicity will be measured by the presence or absence of anti-drug antibody (ADA) in 
plasma (neutralizing or non-neutralizing antibody in plasma). Immunogenicity data will be summarized using 
descriptive statistics, and the effect on lanadelumab plasma concentrations, cHMWK, and the number of 
Property 
w
y of 
ques
que
4 do
do
Takeda:
axim
on
on-tim
time
d based 
based 
alth
alth-rel
rel
Ta
stioio
For 
and c
d 
r of sub
r of sub
mum,
mum
non-commercial 
vital
vital sisi
marized o
rized 
yses
es
macodyn
codyn
c
sma kal
ma ka
asma co
sma c
cHM
cHM
use
)
Es
Es rere
olute c
lute c
only
ud
ratory sh
atory 
will
will b
t
and 
of f an
an o
e but
but
subject 
er) will
will
inimum
imum
line will
will
to the applicable 
ratory rat
atory r
Terms
and
and
ms 
ms of Use

Shire
Page 20
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
investigator-confirmed HAE attacks during the efficacy evaluation periods will be evaluated.
Interim Analysis
Two interim data analyses to support the Japanese New Drug Application (JNDA) submission will be performed. 
Both will summarize the efficacy, safety, PK, HRQoL, PD and immunogenicity of treatment with lanadelumab in 
Japanese subjects with HAE. The first interim analysis will be conducted when the first 6 subjects enrolled in the 
study have reached Day 182 or discontinued in Treatment Period A (26 weeks of treatment); enabling comparison to 
the Study DX-2930-03 pivotal overseas study data. The second interim analysis will be done when the first 4 
subjects enrolled in the study have reached Day 364 or discontinued. An interim clinical study report summarizing 
data will be prepared for both analyses. 
A final data analysis will summarize the efficacy, long-term safety, PK, HRQoL, PD and immunogenicity of 
52 weeks of treatment with lanadelumab in Japanese subjects with HAE (Treatment Periods A and B) and additional 
4 weeks follow-up and will be submitted to further support the JNDA during the review period.
Sample Size 
The planned total sample size for this study is 8 subjects. No formal sample size calculation was performed for this 
study. The sample size of 8 is based on study feasibility.
Property of Takeda: For non-commercial use only and subject 
bje
to
alcula
alcula
the applicable 
mmariz
mmari
genicity o
genicity
and B) an
nd B) a
od.d.
Terms
son to 
son to 
4
zin
ms 
ms of Use

Shire
Page 21
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
05 Oct 2020
1.2
Schema
Figure 1:
Study Design
Screening Period
Informed consent, screening (up to 4 weeks, including 
washout; see below)
Washout (if needed)
2 weeks
Run-in Period
Assess attack rate
4 weeks (and up to 8 weeks)
Treatment Period A
lanadelumab 300 mg q2wks
26 weeks
Treatment Period B
lanadelumab 300 mg q2wks or 
300 mg q4wksa
26 weeks 
(total 52 weeks)
Safety Follow-up Periodb
4 weeks
a During Treatment Period B, a subject may continue to receive lanadelumab 300 mg q2wks or, if the subject has been well-
controlled (attack free) for 26 consecutive weeks with lanadelumab treatment, the subject may switch to a dose of 300 mg q4wks 
at the investigator’s discretion and following approval by the sponsor’s medical monitor. 
b Subjects that complete the second 26-week treatment (Treatment B) period and choose to roll over into Study TAK-743-5007 
will return on Day 378. All other subjects will continue the study as originally planned and will return on Day 392.  
Final analysis
Two interim 
analyses 
Property of 
wil
wil
Takeda:
atment 
atment 
(attack 
ttack 
nvestigat
vestigat
ubjects th
ubjects t
ll retur
ll retur
For non-commercial 
(
ial
me
om
use 
0 m
0 m
26 
26 
(tot
(tot
only 
t Perio
Per
300 mg
300 mg
mg q4
mg q
and 
a
subject 
wks
ks
ec to 
to the 
he applicable Terms of Use

Shire
Page 22
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK743/SHP643)
05 Oct 2020
1.3
Schedule of Activities
Table 1:
Study Activity Schedule-Screening, Run-in and Treatment Period A
Procedures
Screening
Run-in 
Perioda
Treatment Period Ab
See protocol 
section 
below for 
details 
Visit 
1
Day 
0
Visit 
2
Day 
14
Visit 
3
Day 
28
Visit 
4
Day 
42
Visit 
5
Day 
56
Visit 
6
Day 
70
Visit 
7
Day 
84
Visit 
8
Day 
98
Visit 
9
Day 
112
Visit 
10
Day 
126
Visit 
11
Day 
140
Visit 
12
Day 
154
Visit 
13
Day 
168
Visit 
14
Day 
182
Informed consent 
X
Section 8.2.1
Eligibility review
X
Xm
Section
8.2.2
Prior/current 
medications, 
therapies, and 
procedures
X
X
Xn
Section
6.6
LTP washoutc
X
Section
8.1.1.2
Lanadelumab 
300 mg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section
6.2.3
Site check-ind
Between scheduled study visits
Demographic and 
medical history
X
Section
8.2.3
C1-INH, C1q, and 
C4 testinge
X
Section
8.2.6.4
Pregnancy test 
(females)f
X
X
X
Section
8.2.5.6
Vital signsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section
8.2.5.4
Physical 
examination
X
X
X
X
X
X
X
Section
8.2.5.1
Height and weight
X
Section
8.2.5.1
12-lead ECG
X
X
X
X
X
Section
8.2.5.7
Clinical laboratory 
testingh
X
X
X
X
X
X
X
Section
8.2.5.5
Serologies: 
HBsAg, HCV, and 
HIV
X
Section
8.2.5.5
Property of f Tak
Takeda: 
ed
ak
For 
X
r
F
non-commercial lal
rc
me
X
m
co
m
co
co
co
o
co
on
no
use 
e
u
only y
X
ly
Be
B
o
and 
nd
a
subject t
jec
jejeje
s
je
to 
2
o
to the 
10
Day 
Day 
12
1
t
applicable 
ica
it
Visi
Visi
pp
ap
Terms of Use

Shire
Page 23
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK743/SHP643)
05 Oct 2020
Table 1:
Study Activity Schedule-Screening, Run-in and Treatment Period A
Procedures
Screening
Run-in 
Perioda
Treatment Period Ab
See protocol 
section 
below for 
details 
Visit 
1
Day 
0
Visit 
2
Day 
14
Visit 
3
Day 
28
Visit 
4
Day 
42
Visit 
5
Day 
56
Visit 
6
Day 
70
Visit 
7
Day 
84
Visit 
8
Day 
98
Visit 
9
Day 
112
Visit 
10
Day 
126
Visit 
11
Day 
140
Visit 
12
Day 
154
Visit 
13
Day 
168
Visit 
14
Day 
182
Concomitant 
therapy 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section
6.6
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section
8.2.5.2
HAE attack datai
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section
8.2.4.1
Quality of life 
assessmentsj
X
X
X
X
X
X
X
Section
8.2.6.5
PK blood samplek
X
X
X
X
X
Section
8.2.6.1
PD blood samplek
X
X
X
X
X
Section
8.2.6.2
Plasma anti-drug 
antibody testingk
X
X
X
X
X
Section
8.2.6.3
Injection Reportl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section
8.2.6.8
BP=blood pressure; C1-INH=C1 inhibitor; ECG=electrocardiogram; EOS=End of Study; ET=Early Termination; HAE=hereditary angioedema; HAARP=HAE Attack Assessment 
and Reporting Procedures; HbsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HR=heart rate; LTP=long-term prophylaxis; 
IMP=investigational medicinal product; PD=pharmacodynamic; PK=pharmacokinetic; RR=resting rate
a Subjects will undergo a run-in period to determine their baseline HAE attack rate. Only subjects meeting a minimum baseline attack rate of at least 1 investigator-confirmed 
attack per 4 weeks will be eligible for treatment. Subjects who experience 3 or more investigator-confirmed attacks before the end of the 4-week run-in period may exit the run-in 
period early and proceed to Treatment Period A. The run-in period may be extended to 8 weeks if the minimum baseline attack rate is not achieved in the first 4 weeks of the run-in 
period. Subjects who have their run-in extended must complete the full 8-week run-in period and must have at least 2 investigator-confirmed attacks during this time to be eligible 
to enter Treatment Period A. Subjects who do not meet the minimum attack rate during run-in or were otherwise determined to be ineligible due to screening assessments will be 
considered a screen fail.
b Treatment period visits will have a ±3 day window, with a maximum of 17 days or a minimum of 11 days between any 2 doses, starting with Dose 2, Day 14 through end of 
treatment.
c Subjects who are receiving LTP for HAE will be required to undergo a minimum 2-week washout period prior to the start of the run-in period. This LTP washout is permitted as 
long as the investigator determines that doing so will not place the subject at any undue safety risk and the subject is at least 18 years of age. The investigator will confirm that the 
subject has successfully completed the 2-week washout period before they may enter the run-in period.
d Site personnel will contact the subject once between scheduled site visits (or approximately 7 days after last contact with subject) to solicit for any attacks not already reported by 
the subject (see also footnote i) and to collect information on AEs and concomitant medications. The preferred method of site contact is a telephone call; however, alternate 
methods of contact may be considered as site policies permit.
Property of 
be co
e c
Takeda:
AE w
E 
hat doing
at doing
d the 2-
the 2-w
e subjec
subjec
e i) and 
e i) and 
onsi
ns
For 
indow
do
will b
will
non-commercial
=End o
=End o
hepatitis 
patitis 
=pharma
pharma
e HAE a
HAE a
o experie
experie
n period 
period 
omplete t
plete t
et the m
the m
w w
w w
use 
e
X
e
u
only y
nly and
a
 
an
a
subject 
X
t
jec
X
bjejeje
s
je
s
to
X
o
t
the 
2
X
e
th
applicable 
le
6
isit
sit 
11
11
Day 
Day
14
1
Vi
V
a
ap
ca
a
Terms of Use

Shire
Page 24
SHP643-302 Protocol Amendment 2
Lanadelumab (TAK743/SHP643)
05 Oct 2020
Table 1:
Study Activity Schedule-Screening, Run-in and Treatment Period A
Procedures
Screening
Run-in 
Perioda
Treatment Period Ab
See protocol 
section 
below for 
details 
Visit 
1
Day 
0
Visit 
2
Day 
14
Visit 
3
Day 
28
Visit 
4
Day 
42
Visit 
5
Day 
56
Visit 
6
Day 
70
Visit 
7
Day 
84
Visit 
8
Day 
98
Visit 
9
Day 
112
Visit 
10
Day 
126
Visit 
11
Day 
140
Visit 
12
Day 
154
Visit 
13
Day 
168
Visit 
14
Day 
182
e Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment. Testing will be performed by a Sponsor-approved central laboratory.
f Pregnancy testing is required for all female subjects; the test will be urine-based on Day 0 and may be serum-or urine-based at other visits.
g There will be a ±15 minute window for all vital signs. At study visits in which IMP will be administered, vital signs including sitting or supine BP, HR, body temperature, and 
RR, are to be obtained prior to dosing, 1 hour after dosing, and 2 hours after dosing for the first 4 doses with the ability to eliminate the 2-hour vitals for the remaining doses based 
on the discretion of the investigator and the absence of safety signals.
h Clinical laboratory testing will include hematology, coagulation, serum chemistry, and urinalysis. 
i Historical attack information will be collected at screening. During the study the subjects (or their parents/caregivers, in the event the subject is <18 years old or is incapacitated) 
are instructed to report details of the attack to the study site within 72 hours of the onset of the attack, in accordance with HAARP. Site personnel will also contact the subject once 
a week or at approximately 7 days after last contact with the subject during the run-in period and once between study visits or approximately 7 days after last contact with the 
subject during the treatment period in order to solicit for any attack that may have occurred. In addition, during study visits, site personnel will solicit for any new HAE attack 
information that was not given through prior subject contact with the site.
j Quality of life data will be obtained using the Angioedema Quality of Life Questionnaire (AE-QoL). 
k Blood samples for testing PK, PD and formation of antibodies to lanadelumab will be obtained predose (ie, within 2 hours prior to dosing). 
l Collect the injection reports assessing the subject’s experience with SC lanadelumab administration. An injection report must be completed by the subject after each dose of
lanadelumab.
m Post run-in eligibility review must take place before Day 0 dosing.
n Includes medications, therapies, and procedures administered/occurring prior to the first dose of lanadelumab
Note: In the event a subject prematurely discontinues from treatment and/or the study, EOS/ET procedures will be performed as soon as possible (see Table 2). 
Note: Investigators are to report all SAEs to Shire Drug Safety through 30 days after the last dose of investigational product and SAEs considered related to investigational product 
>30 days after the last dose of investigational product.
Property of Takeda: For non-commercial 
urring pr
ing pr
ment and
ent an
ty throug
throug
use
l be o
l be o
umab a
umab 
only 
In a
n 
aire (AE
re (AE
bta
and
ar
ack, in 
k, in 
nd once b
d once b
addit
ddit
subject 
gn
gn
e ab
ability
ilit
ents/car
nts/ca
acc
to 
e-ba
s inclu
s inclu
the
2
med by 
med by
ased 
ased
e applicable 
le
6
isit
sit 
11
11
Day 
Day
14
1
Vi
V
a
ap
ca
a
Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 29
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
genitalia (Zuraw, 2008; Zuraw et al., 2013). Frequency of recurrences varies between patients 
and within the same patient. Swelling may last up to 5 or more days; patients can range from 
asymptomatic to suffering 3 attacks per week. Mortality related to upper airway attacks is 
significant at 30% and is considerably higher (almost 3-fold to 9-fold) in patients who remain 
undiagnosed (Bork et al., 2012). Triggers of angioedema attacks in patients with HAE can 
include stress, physical trauma, medical or dental procedures, and estrogen exposure, although 
most attacks appear to occur spontaneously (Bork, 2014a; Bork, 2014b).
Hereditary angioedema is an orphan disorder and its exact prevalence is unknown, but current 
estimates range from 1 per 10,000 to 1 per 50,000 persons (Bygum, 2009; Goring et al., 1998; 
Lei et al., 2011; Lumry, 2013; Nordenfelt et al., 2014; Roche et al., 2005). HAE affects all ethnic 
populations, adults and children, and both genders (Nzeako et al., 2001). Symptoms often begin 
in childhood and typically worsen during puberty. The unpredictability of attacks results in 
significant decrements in vocational and school achievement (Caballero et al., 2014). 
Additionally, due to the chronic, recurrent nature of HAE attacks and the ever present risk of 
death from asphyxiation, HAE considerably affects patient quality of life (Caballero et al., 2014; 
Fouche et al., 2014a; Lumry et al., 2014; Fouche et al., 2014b).
2.2
Epidemiology in Japanese Patients with Hereditary Angioedema
In Japan, the number of identified patients with HAE has been reported as 52 patients with type I 
or type II HAE (Iwamoto et al., 2012), 132 unique Japanese patients with HAE (Yamamoto et 
al., 2012), 171 HAE patients (Ohsawa et al., 2015), and 350 HAE patients (Ohi et al., 2017). 
HAE may have been historically under reported in Japan due to the medical community’s lack of 
recognition of disease characteristics and/or misdiagnosis of symptoms given the similarity with 
many other more common angioedemas. Publication of the Japan HAE guidelines and other 
educational interventions have contributed to a recent rise in HAE diagnosis. 
The genetic characteristics, pathophysiology, and clinical presentation of HAE appear to be 
similar between Japanese HAE patients and the overseas HAE population. Worldwide, over 
400 different mutations in the SERPING1 gene have been identified. Two studies in Japanese 
HAE patients have shown that gene mutations are widely distributed across the C1-INH gene 
and conclude that the genetic characteristics of Japanese HAE patients are likely to be similar to 
those of HAE patients in Western populations (Yamamoto et al., 2012; Gordon et al., 1981). The 
pathophysiology of HAE is linked to the kallikrein-kinin pathway and is not known to differ 
between ethnic groups. Levels of plasma prekallikrein and high-molecular kininogen were 
reported to be similar in Oriental and Caucasian healthy subjects (Gordon et al., 1981), and 
Phase 1 studies with lanadelumab and another small molecule pKal inhibitor showed similar 
kallikrein activity profiles in Japanese and non-Japanese healthy subjects (Cornpropst et al., 
2016; lanadelumab investigator’s brochure). Data from a Phase 1 clinical study conducted by the 
Sponsor (SHP643-101) 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. Clinical manifestations in Japanese HAE patients are similar to those of the 
overseas population, consistent with the common genetic characteristics and disease 
pathophysiology of HAE. In the largest survey of HAE status in Japan, the onset of HAE was 
reported to be delayed in Japan compared to Western countries (24 years vs. 10-15 years) 
Property 
S
A
of
201
201
Sp
S
Ta
a
Takeda:
ethnic
ethnic
ed to be
d to be
se 1 stu
e 1 stu
llikrei
llikre
6
For
atien
atien
ogy
ogy of
of
y
non-commercial 
as. P
s. 
tributed
ibuted
athoph
hoph
HAE pa
AE p
in the S
n the 
hown th
wn th
he gen
he gen
nts
nts
use
ted
or mis
or mi
Pub
Pub
only 
e Jap
e Ja
015), an
), an
ed in J
d in
and 
E has be
has b
pan
pan
subject 
y of
o
tary An
ary A
to 
d the
the
f life
f life
the
at
et al.,
et al.
e ev
e ev
applicable
curren
curre
t al., 199
al., 19
affects a
affects
mptoms o
toms 
tacks r
acks 
2
Terms of Use

Shire
Page 30
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
(Ohsawa et al., 2015). The authors suggested that this finding was hindered by low 
representation of younger HAE patients in the survey (8% younger than 20 years and 5% 
pediatrics), and low awareness of HAE among Japanese physicians, which ultimately results in a 
diagnostic delay. In addition, a high incidence of laryngeal edema was observed in Japanese 
subjects (10%), which the authors hypothesized may be due to the lack of HAE-specific 
prophylactic drugs in Japan and the lack of timely recognition of HAE symptoms that would 
permit early administration of acute treatment to prevent the worsening of attacks.
2.3
Indication and Current Treatment Options 
Management of HAE has evolved over the last 10 years from underdiagnosed disability and 
higher risk of death from asphyxiation if undiagnosed, towards self-administration and 
independence from inpatient treatment. Effective management of HAE, including optimization 
of therapy, may reduce the clinical burden and have an overall favorable impact on the quality of 
life for individual HAE patients and their families (Banerji, 2013; Caballero et al., 2014).
HAE 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 [WAO]/European Academy of Allergy and Clinical 
Immunology [EAACI] 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 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 that is indicated for the treatment of acute attack and 
peri-procedural (short-term) prevention of acute attacks and, more recently, Firazyr, a 
subcutaneous B2-receptor antagonist that is 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 
Property 
r
of
of a
of a
re
Takeda:
ous B
us B
HAE gu
AE gu
h freque
frequ
Horiuc
Horiuc
For
V) adm
ad
al (sho
al (sh
2
non-commercial 
ocia
ci
ks, impa
, impa
gency
ency
).
approve
prove
dema a
ema a
rapies 
apies 
mi
m
use
LT
phylylac
ac
ated
ate
only 
and 
and
second
econd-l
TP (
P (M
and 
t al.,
al.
n Acad
Acad
up
up
subject 
oph
phylylac
a
ients’ qu
ents’ 
INH or
INH or
, 201
20
to 
bal
the
clu
e impa
impa
llero
llero
applicable 
sability
ability a
y
ation and
ion an
uding o
ding o
ct
Terms of Use

Shire
Page 31
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
an overseas population (Section 2.4.3.3 and Section 2.4.3.4) and the similarity in genetic 
characteristics, pathophysiology, and clinical presentation of HAE between the overseas 
population and Japanese HAE patients. In the overseas population, lanadelumab has a convenient 
dosing schedule with a recommended starting dose of 300 mg every 2 weeks (q2wks) and a 
dosing interval of every 4 weeks (q4wks) if the patient is well controlled or stably attack free (eg, 
for more than 6 months) in adolescent and adults. A similar convenient dosing interval of q2wks 
or q4wks is being proposed for the Japanese HAE patient population in this study. In addition, 
lanadelumab has a favorable route of administration (SC).
The targeted indication of lanadelumab (SHP643, DX-2930) is for prophylaxis to prevent attacks 
of HAE in patients aged 12 years and older.
2.4
Product Background and Clinical Information
Drug Information
2.4.1
Mechanism of Action
Lanadelumab is a fully human, immunoglobulin G1 kappa light chain monoclonal antibody
expressed in Chinese hamster ovary cells. It is a potent (inhibition constant=125 pM) and 
specific inhibitor of active pKal activity that binds both soluble and membrane-bound forms of 
the enzyme (Kenniston et al., 2014). Lanadelumab was designed to specifically bind active pKal 
as opposed to prekallikrein, the zymogen form of the enzyme mainly present in plasma. This 
specificity of lanadelumab for active pKal indicates that the main form of the antibody in the 
circulation is free to inhibit the excess amount of pKal generated during an attack enabling near 
normal levels of enzyme activity prior to reversible inhibition by the antibody. Nonclinical data 
demonstrates that the specific inhibition of pKal by lanadelumab prevents the release of 
bradykinin from HMWK. Inhibition of bradykinin generation prevents the vascular leak and 
swelling during an angioedema attack initiated when bradykinin binds to the B2 receptor (Figure 
1). The pharmacokinetic (PK) properties of lanadelumab offer the potential for a long-acting and 
sustained therapeutic effect (administration q2wks or q4wks) through the control of pKal 
activity, limiting both contact system activation as well as the generation of bradykinin in 
patients with HAE.
Property of Takeda: For non-commercial
ion of
ion o
n of br
of b
attack 
attack
K) prop
prop
ct (adm
(adm
contact
ntact
use
unt o
nt o
revers
revers
f p
f
only 
f the e
the 
icates th
cates th
of pK
of
and
h solu
olu
was de
as de
en
subject 
ight chai
ght cha
hibition
hibitio
uble
b
to the applicable 
revent a
vent 
Terms 
ks s 
on,
on,
of Use

Shire
Page 32
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Figure 2:
Lanadelumab Specifically Inhibits Plasma Kallikrein (pKal)
The kallikrein-kinin system (KKS or contact system) is initiated by the autoactivation of the Factor XII zymogen to XIIa 
following contact with a negatively charged surface (1), leading to the conversion of prekallikrein to active pKal (2), which 
cleaves HWMK to generate cleaved HMWK (2-chain or cleaved HMWK) and bradykinin (3). In addition, pKal will activate 
more FXII (dotted arrow) and FXIIa can initiate coagulation via the intrinsic pathway (dashed arrow). Bradykinin binds and 
activates the bradykinin B2 receptor (4) and following plasma exoprotease generation of des-Arg9 bradykinin (5), the bradykinin 
B1 receptor. The KKS is dysregulated in HAE patients that are deficient in C1-INH (6), an endogenous inhibitor of active pKal 
and FXIIa. Lanadelumab (7) is a potent and specific, fully human antibody inhibitor of pKal engineered to restore normalized 
pKal regulation in HAE due to C1-INH through the lack of binding to prekallikrein, which is expected to permit low levels of 
pKal activity prior to being reversibly inhibited (Adapted from Kenniston et al., 2014).
Dosage Form 
The drug product is a sterile, preservative-free, ready-to-use solution at a lanadelumab 
concentration of 150 mg/mL, provided in a single-use 5 mL glass vial (300 mg in 2 mL fill).
For Japanese patients with HAE, the same formulation and presentation used in the overseas 
population of adolescents and adults aged 12 years and above are planned. In this study, the 
proposed presentation is a solution in a vial, where 2 mL (300 mg) will be withdrawn from the 
vial and administered to the subject. In addition, for Treatment Period B only, the proposed 
presentation may include a pre-filled syringe, if available and permitted per local regulations.
Route of Administration
Lanadelumab is formulated as a liquid for injection and is intended for SC administration in the 
abdomen, thigh, or upper arm. The upper arm location is not recommended for 
p
of 
prop
pro
via
via
Takeda:
ion o
on o
apanes
apanes
opulatio
opulati
opo
po
For 
duct is 
duct is 
of
of
non-commercial
(1
(
chain or
chain o
te coagu
e coagu
d followi
followi
n HAE pa
HAE p
nt and sp
t and s
INH thr
NH thr
ersibly in
ibly in
use 
initiate
initiate
), lead
), lead
on
only and 
an
t
ubject 
sub
to 
t
he 
the
ble 
ble
plicable
appl
Terms 
T
of Use

Shire
Page 33
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
self-administration but rather as an additional injection site when administered by a 
parent/caregiver or healthcare provider.
Nonclinical Studies with Lanadelumab
2.4.2
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. At the no-observed-adverse-effect-level in 
the 6-month cynomolgus monkey study, exposure margins based on maximum observed 
concentration (Cmax) occurring at time to reach maximum observed plasma concentration (tmax) 
and area under the drug concentration-time curve (AUC) were approximately 22- and 23-fold 
higher, respectively, than those observed at the clinical dosage of 300 mg q2wks (Study DX-
2930-03).
The battery of genotoxicity studies routinely conducted for pharmaceuticals is not applicable to 
biotechnology-derived pharmaceuticals and therefore was not conducted. Carcinogenicity studies 
were not conducted. A weight-of-evidence approach indicates a low risk for carcinogenicity in 
humans as lanadelumab is a fully human immunoglobulin molecule that does not target any 
hormonal or cell proliferation pathways; the pharmacologic mechanism of action does not pose 
an increased risk for carcinogenicity, nor is there evidence from any of the preclinical studies for 
an increased risk of hyperplasia, preneoplasia, or neoplastic lesions.
Nonclinical juvenile toxicology studies were not performed. However, the range of ages of 
cynomolgus monkeys used in the completed repeat-dose toxicity studies correspond to 
juvenile/adolescents to adults in human (Baldrick, 2010; Morford et al., 2011). Furthermore, no 
effects on development parameters were noted in an enhanced pre-and post-natal development 
(ePPND) study conducted in cynomolgus monkeys. In the ePPND study in pregnant cynomolgus 
monkeys administered once weekly SC doses, there were no lanadelumab-related effects on 
pregnancy and parturition or embryo-fetal development. In the infants maintained for 3 months 
post-partum, exposure to lanadelumab was dose-proportional to maternal dose and no 
lanadelumab-related defects on survival, growth, and/or postnatal development were noted. It is 
expected that the exposure of infants to lanadelumab during the fetal period and during the first 3 
to 6 months of postnatal life covers many critical periods relevant to human development (Martin 
and Weinbauer, 2010).
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 subcutaneous 
injection.
Clinical Studies with Lanadelumab
2.4.3
To date, the worldwide applications for marketing authorization of lanadelumab have been 
supported by 4 clinical studies. The proposed indication of lanadelumab for routine prophylaxis 
to prevent attacks of HAE in patients 12 years and older is primarily supported by the efficacy
results from a double-blind, placebo-controlled Phase 3 study (DX-2930-03). Supportive data, 
including durability of response and long-term safety, are provided from the open-label, Phase 3 
Property 
T
of
2.4.
2.4
Takeda:
y, tht
functio
unctio
upport 
upport 
ection.
ection.
For 
201
0
he n
he
non-commercial
olgus 
olgus 
y SC d
y SC d
mbry
bryo-
o-
nadelum
delum
cts on 
s on 
sure of
ure of
natal li
atal li
10
10).)
use
ldric
ldri
noted
noted
only 
perfor
perfo
epeat
peat-d
ck
and
ce
ce
plastic
lastic
subject
ow ri
w ri
ecule th
ecule t
mechan
mecha
from 
from
l
to
cted.
cted
risk
isk
the 
cals is
cals is
C
applicable 
ation (t
ion (tm
and 23-
nd 23 f
ks (Study
(Stud
Terms 
el in
el in
of Use

Shire
Page 34
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
study (DX-2930-04) and the proof of concept, Phase 1b, multiple ascending dose study
(DX-2930-02). Prior to evaluating lanadelumab in subjects with HAE, a randomized, double-
blind, placebo-controlled, Phase 1a, single ascending dose study evaluated the safety, 
tolerability, and PK of a single dose of lanadelumab in healthy adult subjects (DX-2930-01). In 
addition, in support of the intended application for marketing authorization of lanadelumab in 
Japan, the Sponsor recently completed a Phase 1 study (SHP643-101) comparing the PK, safety, 
tolerability, and PD of a single 300 mg subcutaneous dose of lanadelumab in healthy adult 
Japanese subjects and matched non-Hispanic Caucasian adult subjects. Results for all 5 clinical 
studies are briefly summarized below. A summary of results in adolescent patients with HAE (in 
Studies DX-2930-03 and DX-2930-04) is also provided below.
Refer to the latest version of the lanadelumab IB for details.
2.4.3.1
Clinical Study DX-2930-01
Clinical study DX-2930-01 evaluated the safety, tolerability, and 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 17-21 days across dose groups. The exposure was dose 
proportional and the half-life was consistent across the dose groups.
2.4.3.2
Clinical Study DX-2930-02
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. One SAE of pneumonia was reported in a placebo-treated 
subject. Two subjects treated with lanadelumab tested positive for anti-drug antibodies (ADAs), 
which were not classified as neutralizing. The PK profile of lanadelumab is consistent and 
predictable, with a half-life of approximately 14 days in HAE subjects. Pharmacodynamic (PD) 
activity of lanadelumab was associated with plasma drug levels. Doses of 300 mg and 400 mg
suppressed pKal activity and reduced kininogen cleavage to the levels observed in healthy 
subjects. 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 and 400 mg lanadelumab treatment groups, respectively. 
The effects on HAE attacks were associated with drug exposure. Safety results from the 
multiple-ascending dose study in HAE patients, in conjunction with results from the 
single-ascending dose study in healthy subjects and the current nonclinical data package, 
supported the continued clinical development of lanadelumab in patients with HAE.
2.4.3.3
Clinical Study DX-2930-03
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. Adolescent and adult patients with Type I or Type II HAE who 
experienced at least 1 attack per 4 weeks during the run-in period were included in this study. 
Property 
2
of
supp
sup
Takeda:
y
y 100
y 100
fects on
ects on
tiple
iple-as
a
ngle
ngle-a
For
respe
espe
lanad
lanad
%
non-commercial
wing
ng
tions d
ons d
t. One 
One 
with la
with la
as neutr
neut
life of a
fe of 
ab was
b was
ctivity
tivity
cic
use
t
days 
days
g 2 d
g 2 d
only 
ty, tole
y, to
and
gr
g
e dose
dose
subject
 data
data
s of 3.0 
s of 3.
dose-
ose-dep
d
roups. T
oups
to
K of a
of a
a d
a d
the 
a s
applicable
clin
th HAE
th HA
Terms 
ty, , 
nical
nical
of Use

Shire
Page 35
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Based on PD bioactivity, PK, safety, and efficacy of lanadelumab from the Phase 1 clinical 
studies and nonclinical studies, the dosing regimens identified for this study were: 300 mg 
q2wks, 300 mg q4wks, and 150 mg q4wks. The 3 proposed dose-regimen combinations provide 
a 6-fold range of steady-state trough concentrations and leverage both the biomarker and efficacy
data generated in study DX-2930-02. Evaluation of the lanadelumab plasma concentrations at the 
time of attacks reported by lanadelumab-treated subjects in DX-2930-02 suggested that the 3 
planned dosing regimens would provide a meaningful range of clinical response. 
The primary objective of the study was to evaluate the efficacy of lanadelumab in preventing 
HAE attacks. The secondary objective was evaluation of the safety of repeated SC administration 
of lanadelumab. Each subject underwent a treatment period consisting of 13 doses of blinded 
investigational medicinal product (IMP) for a period of 26 weeks from the date of the first dose 
on Day 0 through 2 weeks after the final dose (for the 150 mg q4wks and 300 mg q4wks 
regimens, every second dose was placebo). Over the 26-week treatment period, all 
3 lanadelumab dose regimens, 150 mg q4wks, 300 mg q4wks, and 300 mg q2wks, 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. During the estimated steady-state 16-week period (Day 70 
through Day 182), the percentage reduction in the mean monthly HAE attack rates for 
lanadelumab-treated subjects compared with placebo was 78% in the 150 mg q4wks arm, 81% in 
the 300 mg q4wks arm, and 91% in the 300 mg q2wks arm. Furthermore, all 3 lanadelumab 
regimens demonstrated highly statistically significant attack rate reductions compared with 
placebo for all secondary efficacy analyses (adjusted p<.001 for all comparisons): attacks 
requiring acute treatment (74-87%), moderate or severe attacks (70-83%), and attacks from Day
14 through Day 182 (75-89%). The mean reduction in HAE attack rate was consistently higher 
across the lanadelumab treatment arms compared with placebo regardless of the baseline history
of LTP therapy, laryngeal attacks, or attack rate during the run-in period. Notably, the magnitude 
of the treatment effect was consistently the largest across all endpoints in the lanadelumab 
300 mg q2wks treatment arm compared with the lanadelumab q4wks arms. Lanadelumab 
treatment resulted in a high proportion of subjects being attack free during the 26-week treatment 
period and it is notable that once steady state was achieved, especially for the 300 mg q2wks 
group, 77% of subjects were attack free for 16 weeks. 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) based on angioedema quality of life (AE-QoL) scores. Lower cleaved high molecular 
weight kininogen (cHMWK) levels corresponded with higher lanadelumab plasma 
concentrations and lower investigator-confirmed HAE attack rate (attacks/month/4 weeks), thus 
corroborating the outcome of the primary efficacy analysis. Lanadelumab was generally well 
tolerated over the 26-week treatment period; no treatment-related SAEs or deaths were reported. 
No discernible dose-response pattern or dose-related toxicity was observed for any related 
treatment-emergent AE (TEAE). Two subjects (1 lanadelumab treated and 1 placebo) 
discontinued the study due to a TEAE. The overall incidence of ADA in the pivotal study was 
11.9% in lanadelumab-treated subjects and 4.9% in placebo-treated subjects. No subject 
discontinued treatment due to the presence of ADA. All ADA-positive samples were of low titer 
(range: 20-1280), and a few (3.2%; 2 subjects in lanadelumab 150 mg q4wks treatment arm) 
Property 
tr
of 
tolol
No 
No 
Takeda:
ase
kininog
ninog
ntratio
ntratio
rrobora
rrobora
lerate
lerate
For
at
for res
for res
ed on
ed o
non-commercial
ms com
s co
or attac
or attac
sistently
stently
m comp
comp
gh prop
h prop
that on
at on
ects wer
ts we
ed b
ed by
use
te o
e o
n reduc
reduc
mp
m
only 
icant a
cant
djusted p
usted p
or se
or s
and
was 7
as 7
ks arm
ks arm
at
subject
uare
ar
%, and 
%, and 
steady
steady
monthly
onthly
8%
8%
to 
00 m
0 m
res m
es m
the
300
period
perio
mg q
mg
applicable
venting
ventin
administ
dmini
es of blin
s of bl
e of the
of th
0 mg q
 mg
Terms of Use

Shire
Page 36
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
tested positive for antibodies classified as neutralizing. The development of ADA including 
neutralizing antibodies did not appear to impact PK, PD, efficacy, or safety profiles.
2.4.3.4
Clinical Study DX-2930-04
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 IMP, lanadelumab, in preventing acute 
angioedema attacks in patients with Type I or Type II HAE. 
The open-label extension study DX-2930-04 has been completed. The study enrolled 212 total 
subjects, including 109 who rolled over from DX-2930-03 and 103 nonrollover subjects. The 
safety profile of this study is consistent with the pivotal Study DX-2930-03 and previous interim 
analysis (data cutoff date of 01 Sep 2017) for the global marketing license or authorization 
applications for lanadelumab. No treatment-related SAEs or deaths were reported. Treatment-
emergent AEs for most subjects were mild or moderate in severity with few reported severe 
events considered related to lanadelumab treatment. Lanadelumab 300 mg q2wks remained 
highly effective during this extension study for rollover and nonrollover 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 AE-QoL
scores were observed for rollover and nonrollover subjects.
2.4.3.5
Clinical Study SHP643-101
Study SHP643-101 was a Phase 1, open-label, matched-control, single dose, single-center study. 
Its primary objective was to evaluate the pharmacokinetic (PK) properties of lanadelumab 
administered as a single subcutaneous (SC) dose of 300 mg in healthy adult male and female 
volunteer subjects of Japanese descent and matched non-Hispanic, Caucasian healthy volunteer 
subjects. The secondary objective was to assess the safety and tolerability of lanadelumab 
administered as a single SC dose of 300 mg. The study duration was comprised of a 28-day
screening period, followed by a 5-day in-house confinement treatment period, and then 8 out-
patient visits up to a total of 112 days follow-up after the single dose of investigational product 
was administered. 
A total of 32 male and female subjects between the ages of 18-55 years, inclusive, were planned 
to be enrolled: 16 non-Hispanic, Caucasian subjects and 16 subjects of Japanese descent.
Of the 32 subjects enrolled, all 32 subjects completed the study.
Following a single SC administration of 300 mg lanadelumab in healthy adult Japanese and 
matched-control healthy adult Caucasian subjects, peak exposures to lanadelumab of 21.9 μg/mL 
and 21.4 μg/mL (Cmax, geometric mean estimates) were attained (tmax) at approximately
114 and 120 hours postdose (median estimates), respectively; thereafter, plasma concentrations 
of lanadelumab declined in a monophasic manner with a geometric mean t½ of 15.5 and 15.8 
days for Japanese and Caucasian subjects, respectively.
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 
Property 
o
of 
and
and
114
114
Takeda:
subje
ubje
owing a
wing a
atched
atched
d 21
2
For 
6 no
n
ect
ec
non-commercial
an
an
was to a
as to a
 of 300
of 300
a 5-da
da
f 112 d
112 
and fem
nd fe
on
on
use
rm
) dos
) dos
nd m
d m
only 
matched
matche
macok
maco
and 
cts
subject
ollov
llov
anadelum
nadelu
mprove
mprov
s
to
00 m
00 m
ver
ver
the 
repo
po
few re
few re
mg
applicable 
212 tot
212 to
bjects.
bjects. T
previou
previo
r authori
author
orted
rted
Terms of Use

Shire
Page 37
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
concentration-time curve from time zero extrapolated to infinity [AUC0-∞]) was similar to that 
observed in healthy Caucasian subjects, as determined from the 90% CIs. As is shown in Table 
3, the 90% CIs of the geometric mean ratios (Japanese vs Caucasian) were contained within 
bioequivalence limits (0.80, 1.25).
Table 3
Statistical Analysis of Lanadelumab Plasma Pharmacokinetic Parameters Using 
ANOVA (Pharmacokinetic Set)
Parameter
Ethnic 
Group
N
n
Geometric
LS Means
Ethnic 
Group 
Comparison
Ratio of
Geometric
LS Means
90% CI of 
the
Ratio
Cmax
(ng/mL)
Japanese
Caucasian
16
16
16
16
21.91
21.42
Japanese vs 
Caucasian
1.0229
(0.8473, 
1.2349)
AUC(0-last)
(h*ng/mL)
Japanese
Caucasian
16
16
16
16
510.6
547.6
Japanese vs 
Caucasian
0.9324
(0.8016, 
1.0846)
AUC(0-∞)
(h*ng/mL)
Japanese
Caucasian
16
16
16
16
515.0
552.7
Japanese vs 
Caucasian
0.9318
(0.8005, 
1.0846)
CI = confidence interval; CV%=coefficient of variation; LS = least squares; N = number of subjects in the PK Set, defined as all 
subjects in the Safety Analysis Set (all subjects dosed) who have at least 1 evaluable postdose PK concentration value; n=number 
of subjects with evaluable PK parameter values.
Note: An ANOVA-based analysis was performed with the ln transformed pharmacokinetic parameters as the dependent variable 
and ethnic group as a fixed effect independent variable.
Lanadelumab was generally safe and well tolerated by both ethnic groups when administered as 
a single 300 mg dose. There were no deaths, serious TEAEs, severe TEAEs, TEAEs considered 
related to lanadelumab, or any TEAEs leading to discontinuation of lanadelumab treatment. 
Overall, there were no notable differences between ethnic groups in the number of subjects who 
has TEAEs.
Raw means and mean changes from baseline in biochemistry, hematology, and urinalysis values 
at all time points were generally similar between ethnic groups, with the majority of results 
normal at all time points. The number of results flagged as potentially clinically important were 
low for biochemistry, hematology and urinalysis. None of the results were reported as TEAEs by
the investigator.
Raw values and mean changes from baseline in vital signs, including pulse rate, systolic blood 
pressure, and diastolic blood pressure, were generally similar between ethnic groups with no 
clinically meaningful differences between ethnic groups. 
There were no notable mean changes from baseline in ECG results. No ECG results were 
considered clinically significant and reported as TEAEs.
One subject in the Caucasian ethnic group had positive ADA at Day 112; the subject did not 
have a positive result at any previous time point during the study. The positive ADA sample was 
low titer and negative for neutralizing antibodies and did not impact the exposure profile. 
Property 
T
of
clin
clin
Takeda:
igator
igator
values
value
essure
essure
nic
For
me po
e p
emistr
emist
non-commercial 
well
el
o death
o death
EAEs l
EAEs 
e differ
differ
cha
chang
ng
were ge
ere ge
oin
oin
use 
n tr
l tol
l tol
only 
at leas
at lea
ransfo
rans
and 
uares; N
ares; N
t 1
t 1
nd subject 
ese vs
se vs 
ucasian
casian
to the applicable 
90% C
90% 
t
229
29
lic
Terms 
ng g
T
of Use

Shire
Page 38
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
2.4.3.6
Adolescent Clinical Trial Experience
The Phase 3 clinical studies for lanadelumab, pivotal Study DX-2930-03 and open-label 
extension Study DX-2930-04, 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. As of the data cut for the global marketing 
license or authorization application for lanadelumab, the 23 unique adolescent subjects across the 
2 Phase 3 studies received a total of 413 doses of lanadelumab, most of which were 300 mg
Both Phase 3 studies demonstrated superior efficacy compared to placebo or baseline and 
well-tolerated safety profiles in both adolescent and adult populations. In the pivotal Study
DX-2930-03, although the number of adolescent subjects was low (150 mg q4wks=1; 300 mg
q4wks=3; 300 mg q2wks=2, placebo = 4), overall, a lower mean (SD) HAE attack rate during
the treatment period was observed in the 6 lanadelumab-treated pediatric subjects (0.254 [0.284])
compared to the mean (SD) HAE attack rate in the 4 placebo-treated pediatric subjects (0.917
[0.992]), and the results were consistent with the results observed in the well-represented age
groups ≥18 to <40 and ≥40 to <65 years. A similar observation was made for <18 years of age
(N=8) in the rollover population in Study DX-2930-04 and for the nonrollover subjects who
were <18 years of age (N=13). All pediatric subjects had >50% reduction in HAE attack rate
relative to the run-in period or the pretreatment baseline.
Lanadelumab was generally well-tolerated by subjects across the clinical development program. 
The pediatric study in patients with HAE, <12 years of age, is being initiated after the 
completion of the 26-week long pivotal Phase 3 study and a mean (SD) duration of exposure of 
19.98 (4.942) months with a maximum of 33 months of data from the Phase 3 long-term safety 
clinical study in patients with HAE, including adolescents (Study DX-2930-04).
In the 23 unique adolescent subjects who participated across Phase 3 Studies DX-2930-03 and 
DX-2930-04, no relevant differences between the TEAE profile for pediatric subjects and that
reported for adult subjects were identified. The most frequently reported treatment-related TEAE
was injection site pain. No adolescent subjects had reported investigator-confirmed AESIs in
Study DX-2930-03 or in Study DX-2930-04. One adolescent subject in the lanadelumab
treatment arms in Study DX-2930-03 had 1 unrelated severe, serious TEAE of catheter site
infection. One rollover adolescent subject in Study DX-2930-04 had 1 unrelated severe, serious
TEAE of suicidal ideation. There were no deaths or discontinuations in adolescent subjects due
to TEAEs during the treatment period in the pivotal Phase 3 study or its open-label extension
study.
No safety signals were identified in terms of clinical laboratory hematology or coagulation, 
laboratory test abnormalities, vital signs, physical examination or 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 (CL/F) of lanadelumab after correcting for body weight. Based 
Property
to
of 
No
No
labo
labo
Takeda: 
uicid
c
Es durin
durin
y.
o saf
o sa
For
n S
e rollov
e rollov
dal
da
non-commercial
includ
nclud
bjects w
ects w
fferenc
ferenc
s were 
were
. No ad
No ad
or in S
r in S
Study
tudy
use
ase 3
ase 3
f f 33 m
33
i
only
ubjects 
bject
years o
years
st
and 
d >
ine.e.
subject 
d in th
in th
n was m
was m
for the n
for the
>50% 
50%
to
d pedi
ped
he
h
the
AE at
E a
c subj
c subj
i
applicable 
mg
mg
line and 
ine and
votal St
otal S
q4wks=1
4wks=
attack
ttack
Terms 
al
ng 
oss the
oss the
of Use

Shire
Page 39
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
on the evaluation of PK, efficacy and safety, no dosing regimen adjustment has been 
recommended for adolescents (12 to <18 years). 
2.5
Study Rationale
There is an unmet medical need in Japan for a long-term safe, effective and convenient 
intervention to prevent HAE attacks (see Section 2.3). The current study is being conducted to 
bridge the global lanadelumab efficacy, safety, PK, HRQoL, PD and immunogenicity data to 
Japanese HAE subjects.
2.6
Benefit/Risk Assessment 
Clinical studies with lanadelumab demonstrated the improved efficacy and safety for routine 
prophylaxis to prevent and control symptoms of HAE in an overseas population of patients 
12 years and older (Section 2.4.3; refer to the latest version of the lanadelumab IB).
From a benefit/risk perspective, lanadelumab was generally well tolerated by subjects with HAE 
across the clinical program and has not shown safety limitations. There were no deaths and few 
subjects withdrew due to TEAEs. There were no discontinuations of treatment due to TEAEs in 
adolescent subjects in any of the Phase 3 studies. 
In the pivotal study (DX-2930-03), lanadelumab was generally well tolerated over the 26-week 
treatment period. No treatment-related SAEs or deaths were reported. No discernible dose-
response pattern or dose-dependent or limiting toxicity was observed for any related TEAEs. 
Hypersensitivity reactions occurred in few patients and were generally mild, transient, did not 
lead to discontinuation and did not need further treatment. The most frequent TEAE was 
injection site reaction, a majority of which were generally mild, lasted <0.5 hours in duration, 
and did not lead to study discontinuation. The safety profile of the completed Phase 3 open-label 
study (DX-2930-04) is consistent with the pivotal study. 
As of the data cutoff on 24 July 2020 (IB Edition 8.0), the most frequently reported AEs in the 
lanadelumab-treated population across Study DX-2930-03 and Study DX-2930-04 were injection 
site pain (53.6%), viral upper respiratory tract infection (43.2%), headache (27.7%), upper 
respiratory tract infection (25.9%), injection site erythema (18.2%), and injection site bruising 
(13.6%).
Overall, 63.6% (140/220) of lanadelumab-treated subjects reported a total of 2541 related 
TEAEs across Study DX-2930-03 and Study DX-2930-04. The vast majority of related TEAEs 
were injection site reactions (ISRs), eg: injection site pain (50.0%, 110/220), injection site 
erythema (17.3%, 38/220), injection site bruising (10.9%, 24/220), injection site swelling (6.4%, 
14/220), and injection site pruritus (5.9%, 13/220) in ≥5.0% of lanadelumab-treated population. 
The most frequently occurring non-ISR related AE was headache, reported by 4.5% (10/220) of 
lanadelumab-treated population. Other related non-ISR AEs reported by ≥2 subjects included 
hypersensitivity (2.3%, 5/220), ALT increased (1.4%, 3/220), aspartate aminotransferase (AST) 
increased (1.4%, 3/220), dizziness, (1.4%, 3/220), dysgeusia (0.9%, 2/220), and nausea (0.9%, 
2/220).
Property
T
of 
erery
14
14/2/
Takeda: 
63.6
3.6%
Es acro
Es acro
ere inje
ere inje
ythem
he
For 
infe
nf
non-commercial
d 
which
which
nuation
uation
ent wit
nt wit
4 Jul
July
opulati
pulati
viral upp
al up
fectio
ectio
use
patie
patie
furthe
furth
only
was
deaths
death
g toxici
toxic
nt
and 
s gene
gen
subject 
tolera
oler
ns. Ther
s. The
uations o
ations 
to 
ad
rat
the
ulatio
lati
eluma
elum
applicable 
afet
fety fo
y f
on o
Terms 
to 
toto
of Use

Shire
Page 40
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Across both Phase 3 studies, 8.6% (19/220) of lanadelumab-treated subjects reported SAEs, and 
none of them were related to lanadelumab treatment. There was no discernible pattern or 
commonality to the events reported as SAEs.
Across both Phase 3 studies, changes in hematology, coagulation, and chemistry laboratory
parameters over time were small and no clinically relevant trends were observed, especially in 
adolescent subjects. Overall, there were no clinically meaningful changes in vital signs and 
physical findings. No subject receiving treatment with lanadelumab had an abnormal, clinically 
significant ECG result.
Prespecified identified risks associated with the use of lanadelumab or other monoclonal 
antibodies include ISRs(identified risk) and hypersensitivity (important identified risk).
In the pivotal Study DX-2930-03, 84 lanadelumab-treated subjects received 2118 injections of 
investigational product. Approximately half (52.4%) of the lanadelumab treated subjects 
experienced 398 ISRs, most of which were considered related to investigational product (98.2%) 
and were mild in intensity (97%), and none of which were serious or severe. No subject 
discontinued due to an ISR. The majority of ISRs were ≤0.5 hours duration, with over 90% of all 
ISRs resolving within 1 day of onset.
For Study DX-2930-04, 117 (55.2%) subjects had a total of 2287 injection site reaction TEAEs 
during the treatment period. These ISRs occurred across a collective 11899 doses, equivalent to a 
mean of 56.1 doses per subject. Most of the ISRs were related to lanadelumab (2083 of 2287 ISR 
TEAEs). None of the ISRs were serious or severe. Most ISRs were mild in severity (98.8% 
[2260 of 2287 ISR TEAEs]) and reports of moderate ISRs were infrequent; the most frequent 
single event, injection site pain, had a maximum severity of mild in 98 (46.2%) subjects and 
moderate in 2 (0.9%) subjects. The majority of ISRs (92.6%) resolved within a day, while 70.2% 
resolved within an hour. Similar frequencies of ISRs were reported by subjects regardless of 
administration type (self-administered at home, self-administered in-clinic, and study staff 
administration in-clinic).
An important identified risk was hypersensitivity. Hypersensitivity reactions were prespecified 
AESIs due to the theoretical risk associated with monoclonal antibodies, including anaphylactoid 
events or anaphylaxis. At the time of the global marketing and authorization application, the 
incidence of hypersensitivity was low (1.8%) in lanadelumab-treated population and there were 
no events of anaphylaxis observed in both Phase 3 studies. Few investigator-defined AESIs were 
reported in the pivotal Study DX-2930-03: 1 subject in the 300 mg q2wks arm had 2 related 
events reported as hypersensitivity reactions (1 mild and 1 moderate in severity), which included 
symptoms of tingling, itchiness, and discomfort of the tongue, dry cough, and mild headache and 
3 lanadelumab-treated subjects from 1 clinical site (1 in each dosing arm) had a total of 5 related 
events (all mild in severity) that were investigator-defined AESI, with the PTs of ISR, erythema, 
or induration (all “delayed or recall ISR” according to the principal investigator). No anaphylaxis 
or anaphylactoid events were reported and none of the subjects with these AESIs developed 
ADAs. No investigator-defined AESI of hypersensitivity were reported in the placebo group. 
Property of
3 la
3 la
ev
ev
Takeda:
of an
of an
d in the
in the
nts repo
s repo
mptom
mptom
ana
For 
ylaxi
ax
hyp
ypers
ers
ap
a
non-commercial
ma
ma
majori
majori
frequen
freque
inistere
nistere
ed risk 
d risk 
heoretic
eoreti
isis
use
v
f mod
f mod
xim
xim
only 
acro
cr
Rs were
s wer
vere. M
ere. 
and 
otal of
tal of
ross 
oss
subject
nv
us or s
s or s
hours du
hours 
to
mab
estig
estig
the
ved 2
ved 2
b trea
b trea
applicable 
ni
noclonal
oclona
fied risk
ed ris
118
11
Terms 
call
cally
of Use

Shire
Page 41
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
In Study DX-2930-04, there were 9 investigator-reported hypersensitivity AESIs: 4 events in 
rollover subjects and 5 events in nonrollover subjects. Four of the AESIs were hypersensitivity
reactions (all occurring in nonrollover subjects); there were also 6 ISRs that were classified as 
hypersensitivity. All of the hypersensitivity AESIs were classified as related to lanadelumab. 
None of the events were serious. Three of the subjects discontinued due to the hypersensitivity
AESIs. One of these AESIs of hypersensitivity was classified as related and severe because it 
coincided with an HAE attack and ongoing disease under study. However, no anaphylaxis and no 
anaphylactoid reactions were observed and none of the subjects with these AESIs developed 
ADA. 
Besides hypersensitivity, disordered coagulation (bleeding events or hypercoagulable events 
potentially associated with the mechanism of action of lanadelumab, an active pKal inhibitor) 
was a prespecified AESI. One adult subject in Study DX-2930-03 diagnosed with 
gastroesophageal reflux had an investigator-reported AESI, 1 mild event of microcytic anemia, 
although screening hemoglobin and hematocrit were below the normal range and there was no 
actual event of “bleeding” reported. Two subjects had 4 investigator-reported AESIs of vaginal 
bleeding in Study DX-2930-04 (1 subject had uncontrolled hypothyroidism and the other subject 
had comorbidity of uterine adenomyosis). None of these 4 events were related to lanadelumab 
treatments or required dosing interruption. 
An important potential risk associated with the use of lanadelumab or other monoclonal 
antibodies includes immunogenicity. The overall incidence of ADA in the pivotal study was 
11.9% in lanadelumab-treated subjects and 4.9% in placebo-treated subjects. Pre-existing ADA 
of low titer was observed in 3 lanadelumab-treated subjects and 1 placebo-treated subject at 
baseline. No subject discontinued treatment due to the presence of ADA. All ADA-positive 
samples were of low titer (range: 20-1280), and 2/84 or 2.4% lanadelumab-treated subjects tested 
positive for antibodies classified as neutralizing. The overall prevalence of ADAs in treated 
subjects in Study DX-2930-04 was 9.9% (21/212 subjects), which included 13 rollover and 8 
nonrollover subjects. A total of 6 subjects on the study developed ADAs classified as 
neutralizing; therefore, the prevalence of neutralizing antibody was 2.8% (6/212). Except for 1 
subject at one time point, all other ADA-positive samples were consistent with the low titer 
range (20-1280) observed in the prior interim analysis data and in Study DX-2930-03. 
Overall, the formation of ADAs or neutralizing antibodies had no observable effect on the PK, 
PD, efficacy or safety profiles. 
In summary, safety signals have not emerged from all available clinical and nonclinical data to 
date for systemically administered lanadelumab. The proposed study in Japanese HAE patients is 
being initiated after completion of a 26-week pivotal study in an overseas population of 
adolescent and adult HAE patients, with further safety data available from the completed long-
term safety study in this population. The Japanese HAE patients enrolled in the current study will 
have a similar baseline clinical presentation to the population in the pivotal overseas study, as the 
eligibility criteria for this study will be identical (confirm) to those of the pivotal study. 
Additionally, the type and frequency of safety assessments will be comparable to the pivotal 
overseas study (see Schedule of Activities, Table 1 and Table 2).
Property 
t
h
of
ado
ado
ter
t
Takeda: 
y
mary, s
mary, s
for s
for sy
eing in
eing in
l
For
rmatio
rmati
or safe
or saf
non-commercial 
1280
280
s neutra
neutra
was 9.9
as 9.9
of 6 su
f 6 su
e preval
preva
nt, all o
all o
erved i
rved
use 
rea
rea
nt due
nt due
0) a
0) a
only 
incid
inci
9% in pla
% in pl
ated 
ate
and 
f lanad
f lanad
den
de
subject
or
or
othy
othyroi
ro
y
vents we
ents w
to 
al ra
l ra
-repo
-repo
the
d
t of m
t of m
rang
ang
applicable 
pe
lable ev
able e
e pKal in
pKal 
with
with
Terms 
nd no 
nd no 
ed 
ed
of Use

Shire
Page 42
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Always refer to the latest version of the lanadelumab IB for the overall benefit/risk assessment 
and the most accurate and current information regarding drug metabolism, pharmacokinetics, 
efficacy, and safety of lanadelumab. 
2.7
Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (Integrated Addendum to ICH E6[R1]: 
Guideline for Good Clinical Practice E6[R2] Current Step 4 version, 9 November 2016), Title 21 
of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 2005/28/EC), 
and applicable national and local regulatory requirements.
CCI
Property of Takeda: For non-commercial use only and subject to the applicable 
6), Titl
), Ti
2005/28
005/2
app
Terms 
R1]:
R1]:
l
of Use

Shire
Page 43
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
3. OBJECTIVES AND ENDPOINTS
3.1
Study Objectives
The objectives of the study are:
•
To evaluate the efficacy of repeated SC administrations of lanadelumab in Japanese
subjects with HAE.
•
To evaluate the safety of repeated SC administrations of lanadelumab in Japanese
subjects with HAE.
•
To evaluate the PK of repeated SC administrations of lanadelumab in Japanese subjects
with HAE.
•
To evaluate the effect of repeated SC administrations of lanadelumab on health-related
quality of life (HRQoL) in Japanese subjects with HAE.
•
To evaluate the pharmacodynamics (PD) of repeated SC administrations of lanadelumab
in Japanese subjects with HAE.
•
To evaluate the immunogenicity of repeated SC administration of lanadelumab and the
effect on lanadelumab PK, PD, efficacy, and safety in Japanese subjects with HAE
3.2
Study Endpoints
A list of endpoints which support the study objectives are tabulated below. A detailed description 
of endpoints and the planned statistical analysis are provided in Section 9.
Property of Takeda: For non-commercial use
obje
obje
nal
nalys
ysisi
only 
ectiv
ect
and
ad
afety
fety i
y
subject
 admin
admin
dminist
minis
to the 
umab o
umab 
applicable 
nese
ese
Japanese
apanes
Terms of Use

Shire
Page 44
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Table 4:
Objectives and Endpoints
Objective
Endpoint(s)
1.
To evaluate the efficacy of
repeated SC administrations of
lanadelumab in Japanese
subjects with HAE.
Primary efficacy measure is:
•
Achievement of attack-free status for the efficacy evaluation period of
Day 0 through Day 182
Other efficacy measures include:
•
Number of investigator-confirmed HAE attacks during each of the
efficacy evaluation periods.
•
Number of investigator-confirmed HAE attacks requiring acute
treatment during each of the efficacy evaluation periods.
•
Number of investigator-confirmed moderate or severe HAE attacks
during the each of efficacy evaluation periods.
•
Maximum attack severity during each of the efficacy evaluations
periods.
•
Number of investigator-confirmed high-morbidity attacks during each
of the efficacy evaluation periods; a high morbidity HAE attack is
defined as any attack that has at least 1 of the following characteristics:
severe, 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.
•
Time to first HAE attack after Day 0 for the efficacy evaluation period
of Day 0 through Day 182.
•
Time to first HAE attack after Day 0 for the efficacy evaluation period
of Day 70 through Day 182.
•
Achievement of at least a 50%, 70% and 90% reduction in the
investigator-confirmed NNA per 4 weeks relative to the run-in period
NNA for each of the efficacy evaluation periods.
•
Achievement of an efficacy evaluation period NNA <1.0 per 4 weeks,
<0.75 per 4 weeks, <0.50 per 4 weeks, and <0.25 per 4 weeks for each
of the efficacy evaluations periods.
•
Achievement of attack-free status for each of the efficacy evaluation
period of Day 0 through Day 364, Day 70 through Day 182, and Day 70
through Day 364.
•
Percentage of attack free days during each of the efficacy evaluation
periods.
2.
To evaluate the safety of
repeated SC administrations of
lanadelumab in Japanese
subjects with HAE.
•
Treatment emergent adverse events (TEAEs), including adverse events
of special interest (AESI) and serious adverse events (SAEs)
•
Clinical laboratory testing (hematology, clinical chemistry, coagulation,
and urinalysis)
•
Vital signs including blood pressure (BP), heart rate (HR), body
temperature, and respiratory rate
•
12 lead-electrocardiogram (ECG)
3.
To evaluate the PK of repeated
SC administrations of
lanadelumab in Japanese
subjects with HAE.
•
Plasma concentrations of lanadelumab
Property y of Takeda: 
aluate th
luate t
peated S
peated S
lanadelu
lanadelu
subje
subje
For 
F
non-commercial
chihi
invest
invest
NN
NN
•
mm
use
irs
y 70 th
70 th
evem
evem
only 
HAE at
AE a
rough Da
ough D
st HAE
t H
and
n, or as
or a
tttt
subject
hig
hig
ds; a high
; a hig
at least 1
at least
zation (ex
ation (e
cally sig
ally s
so
to 
gh
gh-mo
mo
the
he effic
he effi
applicable 
f th
ng acute
g acute
ods.
ods.
evere HA
vere H
Terms
he
h
ms 
ms of Use

Shire
Page 45
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Table 4:
Objectives and Endpoints
Objective
Endpoint(s)
4.
To evaluate the effect of
repeated SC administrations of
lanadelumab on health-related
quality of life (HRQoL) in
Japanese subjects with HAE.
•
Measured by the AE-QoL questionnaire, which consists of 17 disease-
specific quality-of-life items, to produce a total AE-QoL score and
4 domain scores (functioning, fatigue/mood, fear/shame, and nutrition).
Change in total and domain AE-QoL scores from baseline (Day 0) to
Day 182 and Day 364 will be reported.
5.
To evaluate the
pharmacodynamics (PD) of
repeated SC administrations of
lanadelumab in Japanese
subjects with HAE.
•
Plasma kallikrein activity as measured by cHMWK level (ie, plasma
concentrations of cHMWK).
6.
To evaluate the immunogenicity
of repeated SC administration of
lanadelumab and the effect on
lanadelumab PK, PD, efficacy,
and safety in Japanese subjects
with HAE.
•
Measured by the presence or absence of anti-drug antibody (ADA) in
plasma (neutralizing or non-neutralizing antibody in plasma).
AE-QoL= angioedema quality of life; HAE=hereditary angioedema; cHMWK=cleaved high molecular weight kininogen; 
IV=intravenous; NNA=normalized number of attacks
Property of Takeda: For non-commercial use only and subject 
=cleaved h
cleaved 
bje
to the
dru
ntibody
ntibod
applicable 
, plasm
, plas
ug anti
g ant
i
ap
Terms 
).
to
ms
ma
T
of Use

Shire
Page 46
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
4. STUDY DESIGN
4.1
Overall Design
This open-label Phase 3 study will enroll approximately 8 Japanese subjects with HAE Type I or 
II. Following signing of informed consent, subjects will undergo screening assessments; eligible
subjects who are on long-term prophylaxis (LTP) for HAE are required to undergo a minimum
2-week washout period prior to entering the run-in period. This LTP washout period is permitted
as long as the investigator determines that doing so would not place the subject in any undue
safety risk, and that the subject is at least 18 years of age.
Eligible subjects who are not on LTP therapy for HAE, or who have completed the required 
washout period, will enroll and enter a run-in period of 4 weeks to determine their baseline 
attack rate. Only subjects meeting a minimum baseline attack rate of at least 1 investigator-
confirmed attack per 4 weeks will be eligible for treatment. Subjects who experience 3 or more 
investigator-confirmed attacks before the end of the 4-week run-in period may exit the run-in 
period early and proceed to Treatment Period A. Subjects without at least 1 Investigator-
confirmed attack after 4 weeks of run-in may have their run-in period extended for another 
4 weeks. Subjects who have their run-in extended must complete the full 8-week run-in period 
and must have at least 2 investigator-confirmed attacks during this time to be eligible to enter 
Treatment Period A. Subjects who do not meet the minimum attack rate during the run-in period, 
or are otherwise determined to be ineligible based on screening assessments, will be considered a 
screen failure and will not be allowed to enter the treatment phase of the study; they will be 
replaced with new HAE subjects, until at least 8 subjects have entered Treatment Period A.
•
Treatment Period A:
Subjects who enter Treatment Period A will receive lanadelumab 300 mg q2wks for 26
weeks.
After completion of the first 26-week treatment period, subjects will immediately
continue into Treatment Period B.
•
Treatment Period B:
Subjects who enter the Treatment Period B will receive lanadelumab for an additional
26 weeks (total of 52 weeks). During these additional 26 weeks, an individual subject
may remain on the same dose regimen as Treatment Period A or may consider
lanadelumab 300 mg q4wks if they have been well-controlled (eg, attack free) for 26
consecutive weeks with lanadelumab treatment. The dose frequency change will be based
on the investigator’s discretion and approval by the sponsor’s medical monitor.
Section 4.3 provides justification for the dosing regimen proposed for this study. All doses of 
lanadelumab will be administered by SC injection (Section 2.4.1). Further details on dosing and 
self-administration of lanadelumab are provided in Section 6.2.3 and Section 8.2.6.7, 
respectively.
After completion of the second 26-week treatment (Treatment B) period, subjects may roll over 
into an expanded access study, Study TAK-743-5007. Subjects that elect to rollover to Study
Property 
la
of 
Sec
Se
Takeda:
ay rem
 rem
y
lanade
anade
con
con
For
 who
wh
eks (to
eks (to
ma
m
non-commercial 
ment Per
nt Per
f the fir
the fir
atment
tmen
Period
eriod
o e
o e
use 
st 
only 
d on 
d on
the treat
he trea
8 sub
8 su
and 
duri
dur
minimum
inimum
scr
scr
subject
p
ut at le
t at l
n period
n peri
mplete t
mplete t
ring t
ing
to
wh
eriod
eriod
the
east 1
east 1
ho exp
o ex
applicable 
undue
undu
d the req
the re
e their b
their b
ini
Terms 
e
um
mitted
mitted
of Use

Shire
Page 47
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
TAK-743-5007 will return on Day 378 to complete EOS assessments and will be discharged 
from this study. All other subjects will continue the study as originally planned and will be 
discharged from the study on Day 392 following completion of all EOS / ET visit procedures.
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.
Two interim clinical study reports along with a final clinical study report will be prepared. The 
first interim analysis will be conducted when the first 6 subjects enrolled in the study have 
reached Day 182 or discontinued in Treatment Period A (26 weeks of treatment); enabling 
comparison to the DX-2930-03 pivotal overseas study data. The second interim analysis will be 
done when the first 4 subjects enrolled in the study have reached Day 364 or discontinued. The 
final clinical study report will summarize data from all subjects for the entire study duration.
Individual subject participation from screening through the completion of safety follow-up visit 
will be approximately 68 weeks (up to 4-week screening visit [including a 2-week washout 
period, if applicable], up to 8-week run-in period, 52-week treatment period, and 4-week safety 
follow-up visit [Day 392]). Subjects participating in Study TAK-743-5007 will be discharged 
from this study 2-weeks early on Day 378. An overview of the study design scheme is provided 
in Figure 1. All study procedures are detailed in the schedule of assessments (Table 1 and Table 
2). 
4.2
Scientific Rationale for Study Design
The current study is intended to bridge the overseas clinical data to Japanese HAE subjects. 
Therefore, the study design for SHP643-302 is similar to that of the pivotal overseas study 
(DX-2930-03).
The eligibility criteria for SHP643-302 are identical to those in Study DX-2930-03 with respect 
to subject age, diagnosis, and clinical presentation of HAE at study entry. To further ensure the 
similarity in baseline clinical presentation of the respective study populations, the subjects in the 
current study (like those in DX-2930-03) will undergo a 2-week washout from LTP after which 
they will complete a run-in period of 4 weeks (up to 8 weeks) to ensure a robust evaluation of 
baseline attack rate, and must have a baseline attack rate of at least 1 attack per 4 weeks to be 
eligible to enter the treatment period. 
The planned sample size of 8 subjects is driven by feasibility, given the low estimates of the 
prevalence of HAE in Japan (refer to Section 2.2) and the enrollment in this study of only those 
patients with severe HAE. In a recent survey including data collected from 94 physicians on 
171 HAE patients in Japan, the percent of patients experiencing frequent attacks that would 
potentially qualify them for enrollment in the proposed study was less than 21% (Yamamoto et 
al., 2012). Of these patients with severe HAE, not all patients will have access to study sites, 
attrition during screening and run-in period is likely, either because HAE attacks (which do not 
typically present regularly) may not be experienced during the run-in period or because other 
eligibility criteria are not met, and not every eligible HAE patient will choose to enroll and 
comply with the protocol requirements.
CCI
Property 
p
of 
pati
pat
171
171
Takeda:
enter
ente
planned
lanned
evalenc
evalen
tien
en
For 
ete a
e 
k rate, 
k rate,
r th
r
non-commercial
thth
643
643-3
HP643
P643
, and cl
and cl
clinical
inica
those in
hose in
a ru
a ru
use 
gn
e ov
e ov
only
n
ly and 
w of 
of
schedu
chedu
an
subject
eti
ncludin
cludi
eatment 
eatme
y TAK
TAK-7
f the 
f th
to
on of
on o
the
r
ntire s
ntire 
applicable 
red.d. T
y have
have
y
; enablin
enabl
m anal
analy
discon
discon
t
Terms 
st 
h
of Use

Shire
Page 48
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Study SHP643-302 will be an open-label single-arm study. Unlike DX-2930-03, the current 
study will not include a parallel placebo control group. Prior to the conduct of the overseas 
Phase 3 program there were insufficient data to support the clinical use of lanadelumab in HAE; 
therefore, a randomized, placebo-controlled study was necessary to support the development 
goal of demonstrating that lanadelumab was safe and effective for the prevention of angioedema 
attacks in patients with HAE. Study DX-2930-03 and an ongoing overseas open-label extension 
study (DX-2930-04), which are the largest and longest ever conducted in HAE patients, provide 
compelling results that lanadelumab is both safe and effective for the prevention of angioedema 
attacks in Western populations, and served as the basis for multiple global submissions and 
initial major regulatory approvals. At this time the objective of the Japanese development 
program, and Study SHP643-302 specifically, is to demonstrate similar lanadelumab treatment 
effects in Japanese HAE patients, using the most ethical and effective approach. Therefore, 
SHP643-302 will administer lanadelumab at the most effective dose regimen observed in the 
overseas clinical development, which is also the dose assessed in the open-label extension study
(300 mg q2wks) (refer to Section 4.3 for further dose justification). Given the severity of the 
patients’ disease at enrollment and the established efficacy and safety profile of lanadelumab in 
the overseas population, it was considered unethical to expose the Japanese HAE subjects to 
26 weeks of placebo treatment. Moreover, inclusion of a parallel placebo arm could jeopardize 
the reproducibility and reliability of study outcomes given that the planned sample size of 8 
subjects, which is driven by feasibility, would lead to small cohorts (approximately 4 subjects), 
and a patient assigned to placebo might discontinue prior to completing the 26-week treatment 
period, leading to missing data and potentially uninterpretable results. A cross-over design with 
placebo, while overcoming the problem of extremely small cohorts, was not feasible due to the 
very long half-life of lanadelumab and would not overcome the ethical challenge of 26 weeks of 
placebo treatment in patients with severe HAE.
The objectives of Study SHP643-302 are identical to those of the overseas Phase 3 studies, and 
similar endpoints will be used to evaluate the effect of lanadelumab in Japanese HAE patients. 
The primary treatment period will be 26 weeks (Treatment Period A), the same duration as the 
pivotal overseas study. Additional data on long-term safety and efficacy will be collected during 
a further 26 weeks of treatment (Treatment Period B). Overall treatment benefit will be based on 
the totality of results across all efficacy endpoints, with the primary goal of demonstrating 
consistency across the endpoints (especially the primary efficacy endpoint) with the pivotal 
overseas study (DX-2930-03). The primary efficacy endpoint in the current study, as agreed in 
the Sponsor’s discussions with PMDA, will be achievement of attack-free status for the efficacy
evaluation period from Day 0 through Day 182 (Treatment Period A). Similar analysis methods 
for estimating attack rates will enable comparison across studies for the 300 mg q2wks treatment 
group with respect to unadjusted attack rates for the run-in period, treatment period, and 
treatment period change from run-in period, as well as, model-based estimates of adjusted 
treatment period attack rates.
Data from Treatment Period A (26 weeks) will be submitted at the Japanese New Drug 
Application (JNDA), enabling comparison to the DX-2930-03 pivotal overseas study data. Final 
study data, including Treatment Periods A and B (52 weeks) and safety follow-up (4 weeks) will 
be submitted to further support the JNDA during the review period.
Property of 
trea
re
trea
trea
Takeda:
r s 
on peri
n peri
timatin
timatin
oup wit
oup wit
eatme
eatme
For
ss 
y (DX
y (DX-
disc
disc
non-commercial 
302 are 
02 are 
o evalu
evalu
d will b
will b
dditiona
dition
eatmen
atmen
s across
acros
the e
the e
use
ld no
ld n
HAE
HAE
only 
ninterp
inter
remely
emely
ot o
t
and
small 
mall
prior t
rior 
subject 
fetety
the Japa
the Jap
rallel pla
allel pl
that th
that t
co
to
Given
Give
y pro
y pr
the
men 
pen
en-lab
lab
en t
en t
applicable 
oed
ns and 
s and 
opment 
pment
umab tre
mab t
ch. Ther
h. The
n obse
obse
Terms 
n 
vide
vide
dema
dema
of Use

Shire
Page 49
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
4.3
Justification for Dose
Lanadelumab was first approved overseas on 23 August 2018 for routine prophylaxis to prevent 
attacks of HAE in patients 12 years and older. In all the countries where lanadelumab is currently
approved, the recommended dose regimen is 300 mg q2wks. A dosing interval of 300 mg q4wks 
may be considered in patients who are stably attack free on treatment. 
Based on the totality of efficacy, PK and PD, and safety data from the pivotal overseas study in 
adolescent and adult subjects with HAE (Study DX-2930-03), the 300 mg q2wks 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-week 
treatment period. Lanadelumab treatment resulted in a high proportion of subjects being attack 
free on all dosing regimens evaluated (300 mg q2wks, 300 mg q4wks, and 150 mg q4wks), with 
the 300 mg q2wks dosing regimen having the highest percentage of subjects (44%) who were 
attack free for the entire 26 week treatment period, and ~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 q2wks 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. Sustained 
decreases in plasma levels of the pharmacodynamic biomarker, cHMWK, and significant 
improvements in health-related quality of life (as determined using the AE-QoL instrument; see 
below) in lanadelumab-treated subjects were observed in both DX-2930-03 and DX-2930-04, 
corroborating the efficacy outcomes.
Significant reductions of AE-QoL total and functioning scores (minimal clinically important 
difference [MCID] of 6 points) demonstrated significant improvement in HRQoL for subjects 
treated with lanadelumab in the pivotal study (DX-2930-03), and in the extension study
(DX-2930-04) this effect was sustained for the subjects who rolled over from the pivotal study
and a significant improvement was demonstrated for subjects who were previously treated with 
placebo.
Lanadelumab 300 mg q2wks 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 (46.8-150 kg), and the safety profile supports lanadelumab 300 mg 
q2wks 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 q2wks to q4wks 
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 recently completed Phase 1 clinical study (Study SHP643-101) evaluated the PK and safety of 
lanadelumab when administered as a single SC dose of 300 mg in healthy adult subjects of 
Property 
r
of
und
und
fle
fle
Takeda:
mab 3
mab 3
tration 
ration 
ge rang
ge ran
2wks a
2wks a
der
For 
0
non-commercial 
ts w
s.
QoL to
QoL to
ints) de
ts) d
b in the
in th
ffect wa
ect wa
mprove
mprove
use
yn
y
life (a
life (a
were
were
only 
or mo
or m
d relate
relat
namic
ami
and 
er tre
r tr
X-2930
-293
most
ost
subject 
Study
tudy DX
D
y
ntion of H
ion of H
rea
eatm
t
to 
ects
the
1
ects (4
ects (
ts att
s att
applicable 
regim
regim
reatmen
eatme
26-week
6-wee
ects bein
cts be
50 mg 
0 mg 
44
Terms 
dy in
y in
of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 51
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
5. STUDY POPULATION
The study will enroll Japanese subjects with a confirmed diagnosis of HAE (Type I or II), 
12 years of age and older. Only subjects who experience at least 1 investigator-confirmed attack 
per 4 weeks during the run-in period will enter the treatment period (Treatment Period A). 
Overall, 8 Japanese subjects with HAE are planned to enter the treatment period. All inclusion 
and exclusion criteria for enrolling subjects in this study are presented in Section 5.1 and 
Section 5.2, respectively.
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
5.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Be of Japanese descent, defined as born in Japan and having Japanese parents and Japanese
maternal and paternal grandparents.
2. The subject is male or female and ≥12 years of age at the time of informed consent.
3. Documented diagnosis of HAE (Type I or II) based upon all of the following:
•
Documented clinical history consistent with HAE (subcutaneous or mucosal, nonpruritic
swelling episodes without accompanying urticaria).
•
Diagnostic testing results obtained during screening that confirm HAE Type I or II: C1
inhibitor (C1-INH) functional level <40% of the normal level. Subjects with functional
C1-INH level 40-50% of the normal level may be enrolled if they also have a C4 level
below the normal range. With prior sponsor approval, subjects may be retested during the
run-in period if results are incongruent with clinical history or believed by the
investigator to be confounded by recent C1 inhibitor use.
•
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. Attack rate:
•
Subjects must experience at least 1 investigator-confirmed HAE attack per 4 weeks
during the run-in period to enter the lanadelumab treatment period.
5. The subject (or the subject’s parent/legal authorized representative, if applicable) has
provided written informed consent approved by the Institutional Review Board/Independent
Ethics Committee (IRB/IEC).
Property of Takeda:
ubject
ubject
during
during
The s
The 
pro
pr
For 
e:e:
non-commercial
ev
norm
norm
With pr
ith pr
are inc
re inc
nfound
found
he follo
foll
family
amily
use
durin
durin
el <4
el <4
only 
ith H
th H
ng urtica
g urtic
g
and
ed upo
d upo
HAE
HAE
subject 
Japan
apan
the time
he tim
to 
n
ne
the 
g all o
g all 
applicable 
nformed
forme
Terms of Use

Shire
Page 52
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
If the subject is an adult, be informed of the nature of the study and provide written 
informed consent before any study-specific procedures are performed.
OR
If the subject is a minor (ie, below the age of majority), have a parent/legally authorized 
representative who is informed of the nature of the study provide written informed 
consent (ie, permission) for the minor to participate in the study before any study-specific 
procedures are performed. Assent will be obtained from minor subjects.
6. Males, or nonpregnant, nonlactating females who are fertile and sexually active and who
agree to be abstinent or agree to comply with the applicable contraceptive requirements of
this protocol for the duration of the study, or females of nonchildbearing potential, defined as
surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal
ligation) or postmenopausal for at least 12 months.
7. Agree to adhere to the protocol-defined schedule of assessments and procedures.
5.2
Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met.
1. Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired
angioedema (AAE), HAE with normal C1-INH (also known as HAE Type 3), idiopathic
angioedema, or recurrent angioedema associated with urticaria.
2. Participation in a prior lanadelumab study.
3. Dosing with investigational drug or exposure to an investigational device within 4 weeks
prior to entering to screening.
4. Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing
medications with systematic absorption (such as oral contraceptives or hormonal replacement
therapy) within 4 weeks prior to screening.
5. Exposure to androgens (eg, danazol, methyltestosterone, testosterone) within 2 weeks prior to
entering the run-in period.
6. Use of long-term prophylactic therapy for HAE (C1-INH, attenuated androgens, or
anti-fibrinolytics) within 2 weeks prior to entering the run in period.
7. Use of short-term prophylaxis for HAE 7 days prior to entering the run-in period. Short-term
prophylaxis is defined as C1-INH, attenuated androgens, or anti-fibrinolytics used to avoid
angioedema complications from medically indicated procedures.
8. Any of the following liver function abnormalities: alanine aminotransferase (ALT) >3x upper
limit of normal, or aspartate aminotransferase (AST) >3x upper limit of normal or bilirubin
>2x upper limit of normal (unless the bilirubin is a result of Gilbert’s syndrome).
9. Pregnancy or breast feeding.
10. Subject has any condition that in the opinion of the investigator or sponsor, may compromise
their safety or compliance, preclude successful conduct of the study, or interfere with
Property of 
8.8.
Takeda: 
of shor
f shor
rophy
rophylala
angio
angio
A
For
term
term
oly
olytic
tic
y
non-commercial 
r e
nverting
erting
atic abs
c abs
ks prior
s prior
gens (e
ens (e
in per
n per
m p
m p
use 
dy.
xposu
xpos
only
H (a(
iated w
ated w
and
c, recur
recu
(also 
also
subject 
ollowing
llowing
to 
and
the 
d pro
d pro
applicable 
nd who
nd who
uirement
uiremen
tential, d
ential,
lateral t
ateral
Terms 
ecific
ecific
of Use

Shire
Page 53
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
interpretation of the results (eg, history of substance abuse, or dependence, significant pre-
existing illnesses or major comorbidity the investigator considers may confound the 
interpretation of the study results).
11. Subject has a known hypersensitivity to the investigational drug or its components.
5.3
Restrictions 
Medical Interventions
5.3.1
Medical interventions deemed necessary by the investigator for the health and well-being of the 
subjects will not be excluded during this study.
Fluid and Food Intake
5.3.2
There are no restrictions on fluid and food intake. Subjects may continue their usual dietary
regimens.
Activity
5.3.3
There are no activity restrictions. Subjects may continue their usual activity regimens.
5.4
Reproductive Potential
A study of lanadelumab in cynomolgus monkeys does not indicate effects on embryo-fetal 
development (see the latest version of lanadelumab IB). 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. Therefore, a decision should be 
made whether to initiate or discontinue treatment with lanadelumab, taking into account the 
risk/benefit of therapy.
No evidence of testicular toxicity or adverse effects on male fertility or teratogenicity
transferable to a fetus/embryo from animal studies were observed (see the latest version of 
lanadelumab IB). 
Female Contraception
5.4.1
Sexually active females of childbearing potential should use a medically acceptable form of 
contraception. Females of childbearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 70 days following the last dose of 
investigational product. 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 investigational product. 
Adult female subjects should be either:
•
Postmenopausal (12 consecutive months of spontaneous amenorrhea and age ≥51 years)
Property of
mu
mu
duri
dur
Takeda:
on
ptives 
tives 
igation
gation
packag
packag
ust ag
ust ag
For
e fema
e fem
. Fem
. Fem
non-commercial 
e tre
tr
city
ity or a
 or 
y
ryo from
o from
y
Contra
ontr
l
use
ro
annot 
annot
eatm
eatm
only 
does
doe
mab IB)
mab IB
om its 
m it
and 
es no
s no
subject 
ir usual a
r usual
to the
their 
heir
applicable 
eing of 
eing of
us
Terms of Use

Shire
Page 54
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
•
Surgically sterile (having undergone one of the following surgical acts: hysterectomy,
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least
6 weeks post-sterilization
•
Of childbearing potential with a negative urine beta-human chorionic gonadotropin
(β-hCG) pregnancy test at predose on Study Day 0 (Visit 1). Females of childbearing
potential must agree to abstain from sexual activity that could result in pregnancy or
agree to use acceptable methods of contraception.
•
Premenarchal with a negative urine β-hCG pregnancy test at predose on Study Day 0
(Visit 1).
Acceptable methods of contraception include the following: 
•
Intrauterine devices (IUD, all types) or intrauterine hormone releasing systems (IUS) plus
condoms
Male Contraception
5.4.2
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.
Property of Takeda: For non-commercial use only and
final
ina
subject 
tomy), w
omy),
se a med
e a med
al stu
l s
to the
asing 
ng
applicable 
y Day
Day
y
0
y
sy
Terms of Use

Shire
Page 55
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
6. STUDY INTERVENTION
6.1
Investigational Product
Identity of Investigational Product
6.1.1
The investigational product is lanadelumab, which will be provided as a sterile, 
preservative-free, ready-to-use solution at a concentration of 150 mg/mL in a single-use 5 mL 
glass vial (300 mg/2 mL). In addition, for Treatment Period B only, the proposed presentation 
may include a pre-filled syringe, if available and permitted per local regulations.
Additional information regarding the dosage forms is provided in the latest version of the 
lanadelumab IB or the medication guide. 
Blinding the Treatment Assignment
6.1.2
Not applicable. This is an open-label study. 
6.2
Administration of Investigational Product
Interactive Response Technology for Investigational Product Management
6.2.1
An Interactive Response Technology (IRT) vendor will be used for this study to manage 
packaged IMP supply, IMP shipments, receipt of IMP at clinical sites, randomization of IMP to 
subjects, expiry tracking, IMP returns, and IMP accountability.
Allocation of Subjects to Treatment 
6.2.2
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 randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. 
Individual subject treatment is automatically assigned by the IRT.
Dosing
6.2.3
Lanadelumab injection will be administered SC in the abdomen, thigh, or upper arm. The upper 
arm location is not recommended for self-administration but rather as an additional injection site 
when administered by a parent/caregiver or health care provider. 
The lanadelumab dose regimen for this study is 300 mg q2wks. All subjects will receive 
lanadelumab 300 mg q2wks throughout Treatment Period A (Visit 1 [Day 0] to Visit 14 
[Day 182]), for a total of 14 doses of lanadelumab in this treatment period. All dose of 
lanadelumab in Treatment Period A will be administered by site personnel.
Property
la
of
The
The
Takeda:
umab in
mab i
ocation
cation
en adm
en adm
For 
sing
sing
non-commercial
umb
umb
(numbe
numbe
o the se
the se
r repre
repre
 once e
nce 
treatm
reatm
use
ment
men
ers
ers
only 
MP
MP
P accoun
accou
and 
g
will be u
ill be u
P at
P at
subject 
ationa
ation
to the applicable 
tatio
ion of th
on of 
Terms 
mL
mL
ion
ion
of Use

Shire
Page 56
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Beginning in Treatment Period B:
•
Dose modification may be considered for individual subjects based on benefit-risk
assessment; refer to Section 6.2.5 for details.
•
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; refer to Section 8.2.6.7 for details.
Subjects who continue to receive lanadelumab at a dose of 300 mg q2wks throughout 
Treatment Period B will receive a further 14 doses of lanadelumab (for a total of 28 doses in the 
study). Subjects who receive a dose modification to 300 mg q4wks in Treatment Period B must 
receive their first dose on the q4wks regimen at an even-numbered visit (eg, Visit 16, 18, 20) and 
will receive between 6 and 11 doses of lanadelumab, depending on the exact timing of this dose 
modification. 
The presentation is a solution in vial (150 mg/mL) where 2 mL (300 mg) will be withdrawn from 
the vial and administered to the subject. In addition, for Treatment Period B only, the proposed 
presentation may include a PFS, if available and permitted per local regulations.
Unblinding the Treatment Assignment
6.2.4
Not applicable. This is an open-label study.
Dose Modification
6.2.5
An individual subject’s dose may also be modified based on a benefit-risk assessment and 
recommendation from the treating physician. Consultation with and approval by the sponsor's 
medical monitor is required. 
For example, subjects may administer lanadelumab 300 mg q4wks in Treatment Period B at the 
investigator’s discretion and sponsor’s medical monitor approval, if they are well controlled (eg., 
attack free) for 26 weeks with lanadelumab treatment in this study. Subjects who receive a dose 
modification to 300 mg q4wks in Treatment Period B must receive their first dose on the q4wks 
regimen at an even-numbered visit (eg, Visit 16, 18, 20). Note: The timing of PK, PD, and ADA 
assessments at Visit 27 will be adjusted for subjects receiving a dose modification, as shown in 
the Schedule of Activities (Table 2).
Other modifications may be considered at the discretion of the investigator in consultation with 
the sponsor’s medical monitor.
6.3
Labeling, Packaging, Storage, and Handling of Investigational Product
Labeling
6.3.1
Labels containing study information and pack identification are applied to the investigational 
product(s) container. 
Property 
6
of 
6.3
6.3
Takeda: 
e 
modific
modific
sponso
sponso
For
Visit 
Visit
of Ac
of Ac
non-commercial
ysici
ici
dminist
minist
nd spon
d spon
ks with 
with
mg q4w
mg q4
-numb
num
2
use 
modif
modif
ian
ian
only and subject
300 m
00 m
ment Per
ment Pe
per local
er loc
to 
mg
mg
the
act ti
ct t
applicable 
8 doses 
8 dose
nt Period
Perio
Visit 16
Visit 1
timin
timin
Terms 
eir
of Use

Shire
Page 57
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
All investigational product 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 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 site number, 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 investigational product 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.
Packaging
6.3.2
Investigational product is packaged in the following labeled containers:
•
Treatment Period A: 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 vial of
investigational product. Both the vial 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 including syringes, needles, and alcohol
wipes to subjects. The site has the option of using needles of a different gauge to aid
subject comfort with each SC injection.
•
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 vial of investigational product (or 1 PFS, if
available and permitted per local regulations). Both the vial (or 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 including, syringes (as
applicable), needles, and alcohol wipes to 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 investigational product will be 
provided to the clinical sites in a Pharmacy Manual.
Property of 
prov
pro
Takeda:
plicab
lica
needle
eedle
etailed 
etailed
ovid
vi
For 
priat
ri
er. The
er. The
ble
bl
non-c
dy
commercial
and b
and 
de anci
de anc
te has t
has t
each SC
ach SC
nadelu
adelu
. Each
. Eac
nd perm
d perm
atel
atel
use 
udy
udy
vial an
ial an
be
be
only 
nadelum
adelum
y. Ea
E
and 
labele
abele
subject 
or full ag
or full a
to the applicable 
y-case
cas
al
Terms of Use

Shire
Page 58
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Subjects (or parents/caregivers) who elect to self-administer investigational product, where 
permitted per protocol (see Section 8.2.6.7) will be provided the following supplies as 
applicable:
•
1 dose supply of investigational product
•
Ancillary supplies, and a container for sharps disposal
•
Subject accountability form to record investigational product administration details
All used and unused vials (or PFS) should be returned to the study kit cartons/boxes and 
transported to the site 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.
Storage and Handling
6.3.3
The investigator has overall responsibility for ensuring that investigational product 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. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier on the investigational product bottle/carton 
labels as they are distributed.
Lanadelumab should be stored in a refrigerator at 2-8°C. Vials should be removed from 
refrigeration and allowed to get to room temperature before administration. Do not freeze. The 
vial should be protected from light in the original carton. Refer to the latest version of the IB for 
current stability data.
Before use, each vial of study drug should be inspected for appearance. Any vial containing 
visible particles or discoloration should not be used (any such issues should be reported to the 
sponsor as per the instructions on the Product Quality Complaints page of this protocol). Avoid 
shaking or vigorous agitation of the vial. 
Any unused contents of a vial of study medication should be discarded in accordance with local 
requirements for investigational materials. Intact vials of study medication that are not used 
during the course of the clinical study should be returned according to direction from the 
sponsor.
Storage and handling of PFS will be similar to that described above for vials. Refer the latest 
version of the lanadelumab IB for details.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
Property 
S
of
du
du
spon
spo
Takeda: 
vig
nused c
used c
uiremen
uiremen
uring t
uring t
For
the in
the in
gorou
gorou
non-commercial 
a refrige
refrige
to room
o room
m light i
light 
l of stu
of st
disco
disco
use
dent
den
only 
ust be 
st be
mber of 
mber of 
tifie
tif
and
g that 
that 
ty ma
ma
y
d
subject 
cu
inv
i
to
ur wi
ur wi
the 
d
applicable 
ls
s and 
and 
ab handl
b hand
parent/ca
arent/
itional 
iona
Terms of Use

Shire
Page 59
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
product 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 investigational product 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 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering and dispensing investigational 
product (for dosing by site personnel and self-administration, respectively). Where permissible, 
tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately trained in the 
protocol and who works under the direct supervision of the investigator. This delegation must be 
documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study
delegation of authority form) will administer/dispense the investigational product only to 
subjects included in this study following the procedures set out in the study protocol. Each 
subject will be given only the investigational product carrying his/her treatment assignment. All 
administered/dispensed medication will be documented in the subject’s source and/or other 
investigational product record. The investigator is responsible for ensuring the retrieval of all 
study supplies from subjects. Due to the health/safety concerns with returning the investigational 
product container, the investigator must request that subjects keep the empty investigational 
product packaging after use and return it to the site for drug accountability purposes.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
Property 
N
of
prod
pro
Takeda:
red/di
red/d
gationa
ationa
y suppl
supp
y
oduct 
oduct 
du
For
ed in 
d in
e given
e given
isp
is
non-commercial
ility
lit
el and s
l and 
ified de
fied de
r the di
the d
ble stud
e stu
s/her d
/her d
orit
rity fo
y fo
thth
use 
y for
for
y
only 
ng sh
ng sh
d, used, 
used,
and 
of th
f th
investi
nvesti
hipm
hipm
subject 
he in
he i
to 
), eg
, e
the
the sto
the sto
eg, fu
g f
applicable
ll r
e impac
e impa
on as
n as
until the
ntil th
onsor.
nsor.
Terms 
ately
ately
requir
requir
of Use

Shire
Page 60
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
With the written agreement of the sponsor, at the end of the study all unused stock, 
subject-returned investigational product, and empty/used investigational product packaging may
be destroyed at the site or a local facility. In this case, destruction records identifying what was 
destroyed, when and how, must be obtained with copies provided to the sponsor. Destruction of 
investigational product must be in accordance with local, state, and national laws.
If the sponsor has not provided written agreement for destruction at the site or a local facility
then, at the end of the study or as instructed by the sponsor, all unused stock, subject-returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational product being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (or designated CRO). For unused supplies where the original supplied tamper-evident 
feature is verified as intact, the tamper-evident feature must not be broken and the labeled 
amount is to be documented in lieu of counting. Shipment return forms, when used, must be 
signed prior to shipment from the site. Validated electronic return systems (ie, IRT) do not 
require a shipment form. Returned investigational product must be packed in a tamper-evident 
manner to ensure product integrity. Contact the sponsor for authorization to return any 
investigational product prior to shipment. Shipment of all returned investigational product must 
comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Subjects must be instructed to bring unused investigational product and empty/used 
investigational product packaging to every visit. Drug accountability must be assessed at the 
container/packaging level for unused investigational product that is contained within the original 
tamper-evident sealed container (vials or PFS) or at the individual count level for opened 
containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.
6.6
Prior and Concomitant Therapy
All non-study treatment (including but not limited to all prescriptions, over-the-counter 
medications, herbal treatments, vitamins and supplements, behavioral treatment, non-
pharmacological treatments and procedures (such as psychotherapy, surgical, diagnostic, or 
dental), as appropriate, received within 28 days prior to the screening visit (or pharmacokinetic 
equivalent of 5 half-lives, whichever is longer) and through the final study contact (including 
protocol-defined follow-up period) must be recorded in the subject’s source document. 
Property 
p
of 
All
Al
me
me
Takeda: 
ility
ility f
y
Prio
Pri
l no
no
For
seale
eal
ckagin
ckagin
fo
fo
non-commercial 
anci
nci
ted to b
ed to 
ct pack
t pack
g level
g leve
ed
ed
use
ty
ose us
ose us
ies i
ies
only 
form
for
and
r for 
for 
of all r
f all r
subject
b
n forms
form
eturn s
eturn sy
must be
must be
aut
au
to
sup
roken
roke
the
ng
l site 
site
uppli
uppli
applicable 
al facilit
facil
ject
ect-retu
ret
e to be se
to be s
 return
return
pe
Terms 
n of 
n of 
of Use

Shire
Page 61
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Prior Treatment 
6.6.1
Prior treatment includes all non-study treatments received within 28 days (4 weeks) (or PK 
equivalent of 5 half-lives, whichever is longer) prior to screening visit. Prior treatment 
information must be recorded in the subject’s source document.
Concomitant Treatment
6.6.2
Concomitant treatment refers to all non-study treatments taken between the dates of the first dose 
of investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded in the subject’s source document.
Permitted Treatment 
6.6.3
The following concomitant therapies are allowed during the study:
•
Therapies for co-existing conditions, including those for acute attacks of HAE, are
permitted if not excluded during the study (see Section 6.6.4).
•
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 the day of
lanadelumab administration and/or receives treatment for an HAE attack. The
administration of lanadelumab can also be re-scheduled as long as the minimum and
maximum timeframe between doses are met based on subject preference or physician
discretion.
•
The use of periprocedural prophylactic treatment for HAE will be permitted if medically
indicated.
•
Therapies to treat any AEs the subject experiences during the study will be permitted.
Prohibited Treatment
6.6.4
Use of the following treatments will not be permitted during the study:
•
Long-term prophylaxis for HAE (eg, use of C1-INH for LTP, attenuated androgens, or
anti-fibrinolytics) within 2 weeks prior to entering the run-in period and during the study.
•
Angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to screening and
during the study.
•
Estrogen-containing medications with systemic absorption within 4 weeks prior to
screening and during the study.
•
Use of androgens (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone)
for non-HAE related medical conditions or for HAE within 2 weeks prior to entering the
run-in period and during the study.
•
Any other investigational drug or device.
Property of Takeda:
g
ntiti-fibr
fib
Ang
An
d
For 
in
term 
term 
non-commercial 
prophy
rophy
ny AEs
y AE
Treatm
Treat
ng trea
g tre
use
o
es are 
s are
only 
ct h
ives t
ves trer
o be re
be r
and 
ca
ca
ntinue w
tinue w
has s
as s
subject 
.4).)
un
un-in per
in p
ard of ca
d of ca
tions 
tion
to
e atta
e att
)
the 
tack
tack
applicable 
treatm
reatm
Terms 
st dos
st dos
of Use

Shire
Page 62
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT
DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Treatment
If investigational product is discontinued, regardless of the reason, the evaluations listed for the 
end of study (EOS) visit will be performed as completely as possible (see Section 8.1.3). 
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 
source documents. The reason for discontinuation of investigational product, date of 
discontinuation of the investigational product, and the total amount of investigational product 
administered must be recorded in the source documents.
Subjects who are discontinued from the study because they do not meet the minimum HAE 
attack rate during the run-in period, or who are otherwise determined to be ineligible based on 
screening assessments will be considered to be screen failures; they will be replaced with new 
HAE subjects until at least 8 subjects have entered Treatment Period A.
7.2
Reasons for Discontinuation 
The reason for discontinuation (from treatment and/or the study) must be determined by the 
investigator and recorded in the subject’s source document. If a subject is discontinued for more 
than 1 reason, each reason should be documented in the source and the primary reason should be 
indicated.
Reasons for discontinuation of study include, but are not limited to:
•
Withdrawal of consent (by a parent or both parents/legal authorized representative for
adolescent subjects)
•
Adverse event
•
Protocol deviation (eg, lack of compliance, use of experimental drug)
•
Pregnancy
•
Sponsor decision
•
Investigator decision
•
Death
•
Lost to follow-up
•
Lack of efficacy
•
Other (must specify on the electronic case report form [eCRF])
7.3
Withdrawal from the Study
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution, or may be withdrawn at any 
Property of Takeda: 
st
Death
eath
•
Lo
Lo
•
For 
dec
ec
igator
igator
non-commercial
paren
paren
n (eg, l
(eg, l
cisio
cisio
use
de, bu
de, b
only 
in t
n 
ut a
and
he s
e 
ument. 
ment.
the s
he s
subject 
od
study
study)
to 
will
d A.
A.
the
be ine
be ine
l be r
be r
applicable 
al produ
prod
minimu
minimu
lig
li
Terms 
n the
n the
of Use

Shire
Page 63
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
time at the discretion of the investigator or sponsor (eg, in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the medical monitor when 
possible.
7.4
Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject who is lost to 
follow-up at any time point prior to the last scheduled contact (office visit or site contact 
[preferably a phone call]). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that the subject return to the site for final safety 
evaluations and return any unused investigational product.
7.5
Stopping Rules 
Study Level Stopping Rules
7.5.1
Study data, including SAEs and AESI (as defined in Section 8.2.5.3), will be monitored regularly
throughout the duration of the study. If any potential safety signal is identified as a result of 
monitoring in this study, the sponsor may take actions as deemed appropriate, including 
suspending dosing in the study, while the potential risk is evaluated and a course of action has 
been determined.
Individual Stopping Rules
7.5.2
Dosing for any individual subject will be discontinued if the subject experiences a 
lanadelumab-related SAE (or a lanadelumab-related, clinically-significant, non-serious AE) that, 
in the assessment of the investigator, warrants discontinuation from further dosing for that 
subject’s well-being. The investigator has the ability to contact and consult with the medical 
monitor on such matters. Subjects who prematurely discontinue investigational product should 
undergo the evaluations listed for the end of study (EOS) visit as completely as possible (see 
Section 8.1.3).
Follow-Up for Subjects Meeting Stopping Criteria
7.5.3
Subjects that develop either an SAE or other toxicity considered clinically relevant 
(AE, laboratory, physical examination, or vital sign finding) will be carefully monitored until 
resolution, which may include the following:
•
Additional clinical laboratory tests and/or other clinical investigations
•
Additional visits or extended duration of follow-up
•
Obtaining a specialist consultation
Property of Takeda:
n, whi
n, whi
Add
Add
•
For
evelop
velo
ry
ry, ph
, ph
h
non-commercial
um
, warr
warr
gator ha
tor ha
ects wh
cts wh
ed for t
d for 
Up for S
p for 
p
use
iscon
iscon
mab
mab-
only 
tin
and
k is ev
is ev
subject 
2.5.3
5.3), w
),
signal is 
gnal i
deemed 
eeme
valu
to the applicable 
ten
en
final saf
final sa
Terms of Use

Shire
Page 64
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
8. STUDY ASSESSMENTS AND PROCEDURES
8.1
Study Periods
Refer to Table 1 and Table 2 for the schedule of study activities. Study assessments are detailed 
in Section 8.2.
Screening, Washout, and Run-in Period 
8.1.1
8.1.1.1
Screening Period (up to 4 weeks)
Informed consent must be obtained before any study specific procedures are performed.
As indicated in Table 1, following procedures and assessments are to be performed during 
Screening:
•
Informed consent
•
Demographics and medical history
•
Collection of historical HAE attack data
•
Prior/current medications, therapies and procedures
•
Vital signs including blood pressure (BP), heart rate (HR), body temperature, and
respiratory rate (RR)
•
Complete physical examination, including documentation of height and weight.
•
12-lead ECG
•
Pregnancy test (for female subjects)
•
Clinical laboratory testing including hematology, serum chemistry, coagulation, and
urinalysis
•
Functional C1-INH, C4, and C1q testing
•
Virology testing for Hepatitis B surface antigen (HbsAg), Hepatitis C Virus (HCV), and
Human Immunodeficiency Virus (HIV)
•
Adverse events collection
A subject should complete all screening procedures within 4 weeks. When all screening results 
are available, an eligibility review will be conducted by the site to determine if the subject meets 
all study eligibility criteria. (Note: As indicated in Section 8.1.1.2, a final eligibility review will 
be conducted prior to dosing on Day 0.)
Eligible subjects who are on LTP therapy for HAE are required to undergo a minimum 2-week 
washout period prior to the start of the run-in period. This LTP washout is permitted as long as 
the Investigator determines that doing so would not place the subject at any undue safety risk and 
the subject is at least 18 years of age. The Investigator must confirm that the subject has 
successfully completed the 2-week washout period before they can enter the run-in period.
CCI
E
of
be c
be 
Takeda: 
ct shou
shou
vailabl
vailabl
l study
l study
con
For 
mm
se 
se eve
eve
non-commercial
ubjects
bjects
ng inclu
g inclu
NH, C4
H, C4
ting for
ng fo
muno
muno
use only 
ding do
ng 
and 
res
re
art rat
art rat
sub
s
bject 
ubjec to the applicable 
rmed.
rmed.
formed d
ormed
Terms of Use

Shire
Page 65
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
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 
investigational product(s). 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.
8.1.1.2
Run-in Period (up to 8 weeks)
Eligible subjects who are not on LTP therapy for HAE, or who have completed the required 
washout period, will enroll and enter a run-in period to determine their baseline attack rate. The 
run-in period will be 4 weeks and may be extended up to 8 weeks, as described below. 
During the run-in period, the following information will be collected on an ongoing basis: 
•
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 HAE Attack Assessment and
Reporting Procedures (HAARP) 
]).
•
Prior/current medications, therapies, and procedures
•
Adverse events collection, including SAEs and AESIs
Subjects who report 3 or more than 3 investigator-confirmed HAE attacks before the end of the 
4-week run-in period may exit the run-in period early and proceed to the Treatment Period A. All
other subjects must stay in the run-in period for at least 4 weeks. A subject who does not
experience at least 1 investigator-confirmed attack after 4 weeks may have their run-in period
extended for another 4 weeks (a total of 8 weeks); these subjects must complete the entire
8-week run-in period and must experience at least 2 investigator-confirmed attacks during the
run-in period to be eligible for enrollment.
Subjects who experience at least 1 investigator-confirmed HAE attack per 4 weeks during the 
run-in period, and who remain eligible for the study based on an eligibility review conducted at 
Day 0, may begin treatment with lanadelumab in Treatment Period A.
Treatment Period 
8.1.2
8.1.2.1
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:
•
Confirmation of study eligibility
•
Vital signs, including body temperature, HR, BP and RR
•
Complete physical examination
•
12-lead ECG
•
Clinical laboratory testing including hematology, serum chemistry, coagulation, and
urinalysis
CCI
Property of Takeda: 
n Day
Day
perform
rform
•
For 
tudy V
tudy V
non-commercial
ience
ience
ollmen
llmen
east 1 i
ast 1 
main el
main el
ment w
ent w
ent Pe
nt Pe
use
atta
atta
8 week
 week
a
only 
early
arly a
y
or at lea
r at lea
ack
and 
AE
onfirm
nfirm
subject 
ESI
SIs
to
AE A
AE A
the 
attack 
attack 
Atta
tta
applicable 
ired
ired
k rate. T
rate. 
low. 
low. 
ngoing b
going
Terms 
d
of Use

Shire
Page 66
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
•
Pregnancy test (for female subjects)
•
Pharmacokinetic sample collection
•
Pharmacodynamic sample collection
•
Plasma ADA sample collection
•
Health-related quality of life assessment (AE-QoL)
•
Prior therapies, medications, and procedures
•
HAE attack data 
.
•
Adverse events collection, including SAEs and AESIs
As specified in Table 1 and Table 2, after lanadelumab administration (q2wks; Section 6.2.3), the 
following post treatment procedures and assessments will be performed:
•
Lanadelumab injection report
•
Vital signs including body temperature, HR, BP and RR at 1 hours and 2 hours post-dose
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
8.1.2.2
Study Visit 2 (Study Day 14) to Study Visit 14 (Study Day 182)
As indicated in Table 1, the following procedures and assessments are to be performed prior to 
the dose administration, as specified for a visit/study day during the treatment period:
•
Vital signs including body temperature, HR, BP and RR
•
Physical examination
•
12-lead ECG
•
Clinical laboratory testing, including hematology, serum chemistry, coagulation, and
urinalysis
•
Pregnancy test (for female subjects)
•
Pharmacokinetic predose sample collection
•
Pharmacodynamic predose sample collection
•
Plasma ADA predose sample collection
•
Health-related quality of life assessments (AE-QoL)
•
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
).
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
CCI
CCI
Property of Takeda:
harma
harma
Phar
Phar
•
For
ancy
ancy tete
y
non-commercial 
y tempe
tempe
ratory
atory t
y
use
edure
edur
a visit
a visi
only 
Study V
tudy V
es
and 
ure
ure
nd AE
d AE
subject 
RR at 1 
RR at 
es
to the
2wks
wks
:
applicable 
s; Se
; S
Terms of Use

Shire
Page 67
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
As specified in Table 1, after lanadelumab administration (q2wks; Section 6.2.3), the following 
post treatment procedures and assessments will be performed:
•
Lanadelumab injection report
•
Vital signs including body temperature, HR, BP and RR at 1 hours and 2 hours post-dose
(see Section 8.2.5.4 regarding elimination of the 2 hour post-dose measurement).
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
All scheduled study visits from Visit 2 through Visit 14 will be on-site visits. 
In addition, site personnel will contact the subject once between scheduled study visits (or 
approximately 7 days after last contact with subject) to solicit for any attacks not already 
reported by the subject and to collect information on AEs and concomitant medications. The 
preferred method of site contact is a telephone call; however, alternate methods of contact may
be considered as site policies permit.
8.1.2.3
Study Visit 15 (Study Day 196) to Study Visit 25 (Study Day 336)
As indicated in Table 2, the following procedures and assessments are to be performed prior to 
the dose administration, as specified for a visit/study day during the treatment period:
•
Vital signs including body temperature, HR, BP and RR
•
Physical examination
•
12-lead ECG
•
Clinical laboratory testing, including hematology, serum chemistry, coagulation, and
urinalysis
•
Pregnancy test (for female subjects)
•
Pharmacokinetic predose sample collection
•
Pharmacodynamic predose sample collection
•
Plasma ADA predose sample collection
•
Health-related quality of life assessments (AE-QoL)
•
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 
).
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
CCI
Property of Takeda: 
sma
Health
ealth
•
HA
H
For
odyn
y
a AD
a A
non-commercial 
ng, incl
g, incl
for fem
r fem
netic pr
etic p
na
na
use only 
udy
e, HR, 
HR
and 
d asses
asses
day
day
subject
rnate
nate
sit 25 (
it 25
to
mitan
mita
te m
te m
the 
d stu
stu
ttacks
tacks
ntnt
applicable 
udy
udy v
y
Terms of Use

Shire
Page 68
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
As specified in Table 2, after lanadelumab administration (q2wks or q4wks; Section 6.2.3), the 
following post treatment procedures and assessments will be performed:
•
Lanadelumab injection report
•
Vital signs including body temperature, HR, BP and RR at 1 hours and 2 hours post-dose
(see Section 8.2.5.4 regarding elimination of the 2 hour post-dose measurement).
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
On-site visits will be scheduled at Visits 17, 20, and 23 (non-shaded columns in Table 2). 
Other study visits may be scheduled as on-site visits or, if a subject is self-administering 
lanadelumab where permitted per protocol (see Section 8.2.6.7) or a subject is receiving 
lanadelumab q4wks and the visit is a non-dosing visit for the subject, then the study visit may be 
completed via a site check-in, which should occur within 3 days of the nominal study day. The 
preferred method of site check-in is a telephone call; however, alternate methods of contact may
be considered as site policies permit. During this site check-in, site personnel will ensure that 
self-administration of lanadelumab has occurred as scheduled (if applicable) and will solicit for 
any HAE attacks not already reported by the subject and collect information on AEs and 
concomitant medications. If a site check-in is performed within 3 days after a scheduled visit, it 
is not necessary to also have a site contact at 7 days after last contact with the subject as 
described below.
When scheduled visits are completed on site, site personnel will contact the subject once 
between scheduled study visits (or approximately 7 days after last contact with subject) to solicit 
for any attacks not already reported by the subject and to collect information on AEs and 
concomitant medications. The preferred method of site contact is a telephone call; however, 
alternate methods of contact may be considered as site policies permit.
8.1.2.4
Study Visit 26 (Study Day 350)
Note: The procedures and assessments at Visit 26 will differ depending on whether a subject is 
receiving lanadelumab q2wks or q4wks. Therefore, procedures and assessments are presented 
separately for each dosing regimen below.
Subjects on q2wk Dosing Regimen
Visit 26 will be an on-site visit for all subjects on the q2wk regimen. As indicated in Table 2, the 
following procedures and assessments are to be performed prior to the dose administration, as 
specified for a visit/study day during the treatment period:
•
Vital signs including body temperature, HR, BP and RR
•
Physical examination
•
12-lead ECG
Property of 
foll
fol
spe
spe
Takeda: 
ts on q
 on q
isit 26 w
isit 26 
low
ow
For
elum
um
each d
each d
non-commercial
pprox
pprox
ed b
d by th
y th
preferre
referr
may
may b
y
it 26 (S
26 (S
res and
es and
mab
mab
use 
site, s
site, 
i
only
orm
day
ays aft
s af
and
du
and col
nd co
med w
med w
subject
of the
f the
 alternat
altern
in, site 
n, site
uled (if
led (i
l
to
t, then
, the
he n
he n
the 
-adm
adm
bject is
ject is
n t
n
applicable 
Table 2
Table
minis
mini
Terms of Use

Shire
Page 69
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
•
Clinical laboratory testing, including hematology, serum chemistry, coagulation, and
urinalysis
•
Health-related quality of life assessments (AE-QoL)
•
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 
).
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
As specified in Table 2, after lanadelumab administration (q2wks; Section 6.2.3), the following 
post treatment procedures and assessments will be performed:
•
Lanadelumab injection report
•
Vital signs including body temperature, HR, BP and RR at 1 hours and 2 hours post-dose
(see Section 8.2.5.4 regarding elimination of the 2 hour post-dose measurement).
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
Site personnel will contact the subject once between Visit 26 and the next scheduled study visit 
at Visit 27 (or approximately 7 days after last contact with subject) to solicit for any attacks not 
already reported by the subject and to collect information on AEs and concomitant medications. 
The preferred method of site contact is a telephone call; however, alternate methods of contact 
may be considered as site policies permit.
Subjects on q4wk Dosing Regimen
Visit 26 will be an on-site visit for all subjects on the q4wk regimen. Completion of treatment or 
last dose administration will occur at Visit 26 (Day 350) for subjects on the q4wk regimen. 
As indicated in Table 2, the following procedures and assessments are to be performed prior to 
the dose administration, as specified for a visit/study day during the treatment period:
•
Vital signs including body temperature, HR, BP and RR
•
Physical examination
•
12-lead ECG
•
Clinical laboratory testing, including hematology, serum chemistry, coagulation, and
urinalysis
•
Pharmacokinetic predose sample collection
•
Pharmacodynamic predose sample collection
•
Plasma ADA predose sample collection
CCI
Property of Takeda: 
l s
Phy
Physic
sic
•
12
12
•
For 
tra
signs 
signs 
non-commercial 
men
en
sit for a
it for 
will occ
ll occ
e 2, the
th
ation, 
tion,
use
lepho
leph
only
en 
ontact w
ntact 
nforma
nform
one
and 
AE
AE
Visit
Visi
subject 
ostst-do
d
ESI
SIs
to
hour
hour
os
the applicable 
), the fol
the fo
Terms of Use

Shire
Page 70
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
•
Health-related quality of life assessments (AE-QoL)
•
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 
).
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
As specified in Table 2, after lanadelumab administration (q4wks; Section 6.2.3), the following 
post treatment procedures and assessments will be performed:
•
Lanadelumab injection report
•
Vital signs including body temperature, HR, BP and RR at 1 hours and 2 hours post-dose
(see Section 8.2.5.4 regarding elimination of the 2 hour post-dose measurement).
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
Site personnel will contact the subject once between Visit 26 and the next scheduled study visit 
at Visit 27 (or approximately 7 days after last contact with subject) to solicit for any attacks not 
already reported by the subject and to collect information on AEs and concomitant medications. 
The preferred method of site contact is a telephone call; however, alternate methods of contact 
may be considered as site policies permit.
8.1.2.5
Final Treatment Period Visit at Study Visit 27 (Study Day 364)
Note: The procedures and assessments at Visit 27 will differ depending on whether a subject is 
receiving lanadelumab q2wks or q4wks. Therefore, procedures and assessments are presented 
separately for each dosing regimen below.
Subjects on q2wk Dosing Regimen
Visit 27 will be an on-site visit for all subjects on the q2wk regimen. Completion of treatment or 
last dose administration will occur at Visit 27 (Day 364) for subjects on the q2wk regimen. 
As indicated in Table 2, the following procedures and assessments are to be performed prior to 
the dose administration, as specified for a visit/study day during the treatment period:
•
Vital signs including body temperature, HR, BP and RR
•
Physical examination
•
12-lead ECG
•
Clinical laboratory testing, including hematology, serum chemistry, coagulation, and
urinalysis
•
Pharmacokinetic predose sample collection
•
Pharmacodynamic predose sample collection
CCI
Property of Takeda:
admin
admin
•
Vit
Vit
•
For 
n Tab
Tab
non-commercial
ts at V
ts at V
q4wks. 
4wks. 
men be
men be
g Regim
Regi
n-site v
site
ation 
ation 
use 
it at S
it at S
Vi
Vi
only 
ne cal
e ca
and
with s
th s
ation o
tion o
all;
all;
subject 
26 and 
26 and 
subj
sub
to the
an
e mea
e mea
applicable
ollow
llow
nd 2 ho
d 2 h
Terms 
win
of Use

Shire
Page 71
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
•
Plasma ADA predose sample collection
•
Health-related quality of life assessments (AE-QoL)
•
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 
).
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
As specified in Table 2, after lanadelumab administration (q2wks; Section 6.2.3), the following 
post treatment procedures and assessments will be performed:
•
Lanadelumab injection report
•
Vital signs including body temperature, HR, BP and RR at 1 hours and 2 hours post-dose
(see Section 8.2.5.4 regarding elimination of the 2 hour post-dose measurement).
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
Subjects on q4wk Dosing Regimen
Visit 27 will be an on-site visit for all subjects on the q4wk regimen. This is a non-dosing visit 
for subjects on the q4wk regimen.
As indicated in Table 2, the following procedures and assessments will be performed at this visit: 
•
Vital signs including body temperature, HR, BP and RR
•
Physical examination
•
12-lead ECG
•
Clinical laboratory testing, including hematology, serum chemistry, coagulation, and
urinalysis
•
Health-related quality of life assessments (AE-QoL)
•
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 
).
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
Follow-up Period 
8.1.3
A site check-in will occur approximately every 7 days between the last visit in the treatment 
period at Day 364 and the on-site follow-up visit at Day 378/392. Subjects participating in Study 
TAK-743-5007 will receive a site check in at approximately Day 371; for all other subjects, the 
approximate study days for site check-in are Day 371, Day 378, and Day 385. The preferred 
CCI
CCI
Property 
8
of Takeda:
AE at
AE at
within
ithin
•
Co
C
•
For
relate
relate
t
non-commercial 
temper
emper
atory te
tory te
use 
ocedu
ocedu
only
n the q
the 
and subject 
SIs
to
dose
dose
the 
ur
urs an
s an
applicable 
he follow
e foll
Terms of Use

Shire
Page 72
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
method of site contact is a telephone call; however, alternate methods of contact may be 
considered as site policies permit.
At the end of the follow-up period at Day 378/ Day 392 there will be a scheduled on-site EOS 
visit, at which the following assessments and procedures will be performed: 
•
Vital signs including body temperature, HR, BP and RR
•
Physical examination
•
12-lead ECG
•
Clinical laboratory testing, including hematology, serum chemistry, coagulation, and
urinalysis
•
Pregnancy test (for female subjects)
•
Pharmacokinetic sample collection
•
Pharmacodynamic sample collection
•
Plasma ADA sample collection
•
Health-related quality of life assessments (AE-QoL)
•
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 
).
•
Concomitant therapies, 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 
.
Early Termination 
8.1.4
All procedures and assessments scheduled for the EOS visit will be followed for the early 
termination (ET) visit (see Table 2).
Additional Care of Subjects after the Study
8.1.5
No aftercare is planned for this study.
8.2
Study Assessments 
Please refer to the Study Schedule of Activities in Table 1 and Table 2.
Informed Consent 
8.2.1
Informed consent and assent forms must be approved for use by the reviewing IRB, research 
ethics board (REB) or IEC. Informed consent must be obtained for all subjects participating in 
the study (or their parent/caregiver, as applicable) prior to performing any study-related 
activities. Assent will also be obtained from each subject, where required in accordance with 
IRB/REB/IEC 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 
CCI
CCI
I
of
8.2.
8.2
Takeda:
tudy A
udy A
ase refe
e refe
1
For
s plann
s plann
non-commercial
ud
ud
is con
s con
ments s
ents s
see Tab
Tab
nal Ca
al Ca
use 
and
and
ing S
ng S
only
rt 
n accord
accor
d pro
d p
and
QoL)
oL)
detai
deta
subject 
)
to the applicable 
gulation
ulatio
Terms of Use

Shire
Page 73
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
be terminated at any time without the consent/assent of the subject (or their parent/caregiver, as 
applicable) as determined by the investigator.
Eligibility Review
8.2.2
The investigator or qualified site personnel will confirm that all inclusion criteria have been met 
(Sections 5.1) and none of the exclusion criteria have been met (Section 5.2).
Demographic and Other Baseline Characteristics
8.2.3
Subject demographic information including gender, age, and race will be collected prior to the 
subject receiving the first dose of investigational product. 
8.2.3.1
Medical and Medication History
Medical and medication history will be collected during screening and recorded in the subject’s 
source documents. 
Efficacy
8.2.4
8.2.4.1
Collection of Hereditary Angioedema Attacks 
Historical HAE attack information will be collected at screening. 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 Table 1 and Table 2. 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 HAARP 
. Site personnel will be trained on 
HAARP prior to screening subjects at their site.
8.2.4.2
Management of Acute Angioedema Attacks
As mentioned in Section 4.1, acute HAE attacks during the study are to be managed according to 
the local standard of care. In case of insufficient response to the first dose, additional rescue 
medications will be allowed.
Administration of the investigational product and study procedures will continue without 
alteration to the protocol-specified study schedule, even if the subject receives any treatment for 
an HAE attack.
Safety
8.2.5
8.2.5.1
Physical Examination
A complete physical examination will be performed by the investigator or his/her qualified 
designee according to the Study Schedule of Activities (Table 1 and Table 2). The date and time 
of each examination, and any findings, will be recorded on the source documents and eCRF. 
CCI
8
of
8.2.
8.2
Takeda:
tration
ration
ion to t
on to 
HAE at
HAE at
5
For
o
ill be 
ill be 
non-comme
bjects a
jects a
nt of A
t of A
tion
ion 4
of car
f car
cial
sment o
ment o
erci
use 
toto
only 
wn Ta
T
subject 
ubject
o the 
o the
and
scree
cree
on will
n will
abl
abl
subject 
ks 
enin
eni
to the
ecorde
ecorde
applicable 
prior to t
ior to
d
Terms of Use

Shire
Page 74
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
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.
8.2.5.2
Adverse Events 
Each subject will be monitored for the occurrence of AEs, including SAEs and AESIs, from 
signing of the informed consent form through the final follow-up visit:
•
Subjects will be questioned and/or examined by the investigator or a qualified designee
for evidence of AEs. The questioning of subjects with regard to the possible occurrence
of AEs will be generalized such as, "How have you been feeling since your last visit?”
The presence or absence of specific AEs should not be elicited from subjects.
•
The efficacy endpoint, HAE attacks, will also be captured as AEs in this study (see
details below).
•
Subjects having treatment-emergent AEs (TEAEs) will be monitored until resolution with
relevant clinical assessments and laboratory tests, as determined by the investigator.
Adverse events, actions taken as a result of AEs, and follow-up results must be recorded
in the eCRF as well as in the subject's source documentation. Follow-up laboratory
results should be filed with the subject's source documentation.
•
For any SAEs or AEs that require the subject to be discontinued from dosing, relevant
clinical assessments and laboratory tests will be repeated as clinically appropriate, until
final resolution or stabilization of the event(s). Subjects who discontinue treatment will
complete EOS visit procedures as described in Section 7.1.
Property of Takeda:
Subject
ubject
relev
relev
Ad
A
For
cacy
acy
s below
s below
non-commercial
e occ
e occ
orm thro
m thr
tioned 
oned
Es. The
s. The
general
neral
e or abs
or ab
en
en
use 
cur
only 
d at the 
at the
and subject to the applicable Terms of Use

Shire
Page 75
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
All AEs, regardless of seriousness, severity, or causal relationship to study drug, will be recorded 
on the AE page of the eCRF (see exception below for HAE attack AEs). Any AE meeting 
criteria for an SAE, 
, must also be reported to the sponsor using the 
SAE Reporting Form within 24 hours of the site becoming aware of the event. All AESIs, as 
defined in Section 8.2.5.3, must also be reported to the sponsor using the same timelines as 
described for SAE reporting.
Further information on AE definitions, collection time frame, assessment of causality and 
severity, and safety reporting is provided in 
. Information on SAE collection time frame, onset/resolution dates, 
and SAEs with a fatal outcome is presented in 
. 
The efficacy endpoint, HAE attacks, will also be captured as AEs in this study. To avoid 
complicating the interpretation of safety, 2 mutually exclusive subgroups of AEs will be defined 
based on whether the AE is (or is not) identified in the eCRF as a subject-reported HAE attack: 
•
Non-HAE attack AEs will include the subset of AEs that are not identified in the eCRF as
a subject-reported HAE attack. Essentially, this will be AEs excluding the subject-
reported HAE attack events. These 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 
.
•
HAE attack AEs will include the subset of AEs identified in the eCRF as a
subject-reported HAE attack. This will include, but will not be limited to,
investigator-confirmed HAE attacks. 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 SAEs that are reported as HAE attacks, the investigator will review the event within 
24 hours of initial notification and, in accordance with HAARP, evaluate if it represented a 
confirmed HAE attack. For all non-serious AEs that are reported as HAE attacks, the investigator 
will review the event within 3 days of initial notification and, in accordance with HAARP, 
evaluate if it represented a confirmed HAE attack. If necessary for the evaluation, the 
investigator or designee may contact the subject for additional information. Any subject-reported 
attack not confirmed by the investigator must have an alternate AE diagnosis recorded. All 
subject-reported and investigator-confirmed HAE attacks will be recorded in the eCRF. Note: 
Hereditary angioedema is the indication for treatment and should be considered expected as the 
events are considered disease related (progression of underlying disease) and not subject to 
expedited reporting.
Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
will be captured in the eCRF and reported to the Shire Global Drug Safety Department.
CCI
CCI
CCI
CCI
CCI
CCI
Property
e
of 
Her
He
eve
eve
Takeda: 
it rer
ator or 
or or 
k not co
k not co
bject
bject-rere
ered
ed
For
atta
tt
e even
e even
epre
ep
non-commercial
attack
attack
attack 
tack 
erc
rdance
dance
ia and 
a and
eported
ported
notificat
tifica
tack. 
ack. 
use 
bset 
bset
s will
s wil
on
of
ly 
(DM
DM
only and
attac
tac
d 
s will b
will b
MID
ID
subject 
sub
ub
hat are n
hat ar
ll be AE
l be AE
ck A
ck
to
oup
bject
bject
the
 study
study
ps of 
s of 
appl
T
cabl
ution dat
ion da
ble 
ble 
plica
Terms of Use

Shire
Page 76
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
8.2.5.3
Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) will be captured and monitored during this study. 
Investigators will report all AESI to the sponsor, regardless of causality, using the same 
timelines as described for SAE reporting. 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, PT, international normalized ratio [INR]) 
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.
8.2.5.4
Vital Signs
Vital signs will be assessed by the investigator or his/her qualified designee according to the 
Study Schedule of Activities in Table 1 and Table 2. Routine vital sign assessments will be taken 
with the subject in the sitting or supine position after 5 minutes at rest and will include body
temperature, HR, BP, and RR. 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.
Vital signs performed on dosing days should be obtained prior to dosing and at 1 hour and 
2 hours after completion of the injection of lanadelumab. After a subject has received 4 doses of 
lanadelumab in the study, the vital sign measurement at 2 hours post-dose may be eliminated at 
subsequent visits based on the discretion of the investigator and the absence of safety signals. 
There will be a ±15 minute time window for all vital sign measurements
of
Dur
Dur
Takeda:
du
subjec
ubjec
erature,
erature,
me equi
me equ
For
l be as
l be a
le of
le of
non-commercial
ssibly
sibl
l diagno
diagn
nsistent 
stent
Signs
igns
use 
ting
ing
when 
when 
y inin
y
only 
AES
AES
oses can
oses ca
g (aP
g (a
and
prolo
rol
measur
measur
SI f
subject 
ong
on
to the 
rs,s, o
applicable 
s, these
, thes
or signs a
or signs
sensitiv
ensiti
g admin
admi
only
only
Terms of Use

Shire
Page 77
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Every effort should be made to measure and record vital signs prior to any blood sample 
collection.
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.
8.2.5.5
Clinical Laboratory Tests for Safety Assessments
A complete list of clinical laboratory tests to be performed to assess general safety parameters is 
provided in 
. All safety laboratory assessments will be performed at a central 
laboratory.
All clinical laboratory tests will be performed according to the laboratory’s standard procedures, 
using established and validated methods. 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.
8.2.5.6
Pregnancy Test 
For all females, pregnancy testing (β-hCG) will be performed at the time points specified in 
Schedule of Activities in Table 1 and Table 2; 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.
8.2.5.7
Electrocardiogram
A standard 12-lead ECG (single recording) will be performed at the time points specified in 
Schedule of Activities in Table 1 and Table 2. The date and time of each ECG and its results will 
be documented in the source documents and eCRF.
Other Study Assessments
8.2.6
8.2.6.1
Clinical Pharmacology 
Blood samples for the measurement of plasma lanadelumab concentration will be obtained at the 
study days specified in Table 1 and Table 2. Samples should be obtained prior to dosing (ie, 
within 2 hours prior to dosing), with the exception of the EOS/ET visit.
8.2.6.2
Pharmacodynamics 
Blood samples for the measurement of cHMWK will be obtained at the study days specified in 
Table 1 and Table 2. Samples should be obtained prior to dosing (ie, within 2 hours prior to 
dosing), with the exception of the EOS/ET visit.
CCI
Property of 
8.2
8 2
Takeda: 
Cl
C
sample
ample
y day
 day
y
s
ithin 2
ithin 2
For
r Stu
Stu
lini
lin
non-commercial 
he e
tudy
udy m
 m
y
am
single r
ingle r
n Table
Tabl
e sourc
our
d
use
e 2
e 2; if
; i
stud
stud
only 
ll be p
l be
and
ed, ex
d, ex
subject 
ess o
ss 
ue(s) is/a
ue(s) is
atory val
ory va
he discr
e dis
pla
to
hang
hang
out
out
the
s st
lied by
lied by
ges
es
applicable 
rameter
ramete
central
central
tanda
anda
Terms of Use

Shire
Page 78
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
8.2.6.3
Immunogenicity (Anti-drug Antibody Testing)
Immunogenicity will be measured based on the presence or absence of neutralizing or 
non-neutralizing ADA in plasma. Blood samples will be collected at the study days specified in 
Table 1 and Table 2. Samples should be obtained prior to dosing (ie, within 2 hours prior to 
dosing), with the exception of the EOS/ET visit.
8.2.6.4
Biomarkers
C1-INH, C1q, and C4
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 
40-50%, 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.
8.2.6.5
Health-related Quality of Life 
Health-related quality of life will be assessed using the AE-QoL questionnaire, at the study visits 
specified in Table 1 and Table 2.
The AE-QoL questionnaire is a self-administered validated instrument to assess HRQoL among 
patients with recurrent angioedema (including HAE) (Weller et al., 2012). The AE-QoL consists 
of 17 disease-specific quality-of-life items, each of the 17 items has a five-point response scale 
ranging from 1 (Never) to 5 (Very Often). Per the developers’ guidelines (Weller et al., 2012), 
the questionnaire is scored to produce a total score and four domain scores (functioning, 
fatigue/mood, fear/shame, and nutrition). Raw domain scores (mean of the item scores within 
each scale) and the raw total score (mean of all item scores) are rescaled using linear 
transformations into final percentage scores ranging 0 to 100, based on the maximum possible 
score, where the lower the score the lower the impairment. The MCID for the total score is 6 
(Weller et al., 2012).
The AE-QoL has good psychometric properties, including reliability (test-retest and internal 
consistency), construct validity (convergent/divergent and known groups), ability to detect 
change and responder definition (Weller et al., 2012). The AE-QoL has been shown to be a 
content valid, reliable, construct valid, sensitive and interpretable measure of HR-QoL for 
patients with HAE.
8.2.6.6
Healthcare Resource Utilization 
Not applicable.
Property 
p
of
ch
ch
con
con
Takeda: 
l., ,
E-QoL
QoL
nsistenc
nsistenc
hange 
hange
For
nt
he low
he low
2012
2012
non-commercial
dmin
min
a (inclu
(inclu
f-life ite
ife ite
(Very
Very O
y
d to pro
to pro
me, and
, and
raw tota
w to
o fina
o fina
use 
nis
nis
only 
using th
sing th
and 
on of
n of
subject
or 
al histo
histo
use C1
use C
gator's di
ator's di
f elig
f el
to
ts 
appr
appr
the
g
s with
s with
with
with
applicable 
H, C4, an
H, C4, a
nsor
sor-app
ap
gibility
ibility
h a
h
Terms of Use

Shire
Page 79
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
8.2.6.7
Self-administration of Lanadelumab
Self-administration of lanadelumab is allowed in Treatment Period B only, and is defined as 
administration by the subject or their parent/caregiver at the investigational site or in an offsite 
location.
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. The subject is required to return to the site for visits as outlined in the 
schedule of events. At these on-site visits, the subject (or parent/caregiver) may continue to 
self-administer lanadelumab or may opt to have lanadelumab administered by study personnel or 
healthcare provider.
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 investigational product using a
sponsor-provided cooler, and the recommended storage conditions of investigational
product when stored at an offsite location.
•
Maintenance of accurate records regarding each administration of investigational product
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 vials (or PFS) of investigational product for drug
accountability purposes.
•
Additional information, as provided in the Pharmacy Manual.
If a subject (or parent/caregiver) is self-administering lanadelumab at home or another offsite 
location, site personnel will perform a site check-in (within 3 days after the study day) to ensure 
that self-administration of lanadelumab has occurred as scheduled. During this site check-in, the 
site will also solicit for any HAE attacks not already reported by the subject and collect 
information on AEs and concomitant medications. The preferred method of site contact is a 
telephone call; however, alternate methods of contact may be considered as site policies permit.
8.2.6.8
Injection Report
An Injection Report will be completed by the subject (or parent/caregiver) following each dose 
of lanadelumab, according to the assessment schedule in Table 1 and Table 2. The Injection 
Report will collect information on the subject’s experience with SC injection of lanadelumab. 
Study personnel will document the subject’s responses in the subjects’ medical record and eCRF.
Volume of Blood to Be Drawn from Each Subject
8.2.7
Laboratory testing will be performed according to the Study Activities Schedule (Table 1 and 
Table 2).
Property of
Re
Re
Stud
Stu
Takeda:
Inj
In
jection 
jection
lanadel
lanadel
eport 
eport 
For
howe
ow
jeje
non-commercial 
provide
rovide
er) is se
r) is s
l perfor
perfo
of lana
f lana
or any
any H
y
s and c
and 
eve
ev
use
als (o
als (
only 
ble, a
ble, 
or P
and 
adm
adm
mber), d
ber), d
an
any
n
subject 
estig
stig
e conditi
cond
minis
min
to 
gati
gati
the 
) wh
wh
applicable 
he
he
nue to
nue to
dy person
perso
y
ho el
ho el
Terms 
ed 
ng of 
ng of 
of Use

Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 81
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
9. STATISTICAL CONSIDERATIONS
9.1
Statistical Analysis Process
General Considerations
9.1.1
The study will be analyzed by the sponsor or its agent. 
The statistical analysis plan (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, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock.
All statistical analyses will be performed using SAS® Version 9.4 or higher (SAS Institute, Cary, 
NC 27513). 
9.2
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
Interim analyses of study data will be undertaken as described below. No adaptive design or data 
monitoring committee (DMC) is planned for this study. Two formal interim data analyses to 
support the Japanese New Drug Application (JNDA) submission will be completed. Both will 
summarize efficacy, safety, PK, HRQoL, PD, and immunogenicity of treatment with 
lanadelumab in Japanese subjects with HAE. The first interim analysis will be conducted when 
the first 6 subjects enrolled in the study have reached Day 182 or discontinued in Treatment 
Period A (26 weeks of treatment); enabling comparison to the DX-2930-03 pivotal overseas 
study data. The second interim analysis will be done when the first 4 subjects enrolled in the 
study have reached Day 364 or discontinued. An interim clinical study report summarizing data 
will be prepared for both analyses.
9.3
Sample Size and Power Considerations
The planned total sample size for this study is 8 subjects and is based on feasibility
considerations. No formal sample size calculation was performed for this study. 
9.4
Statistical Analysis Set(s)
Full analysis set (FAS) is defined as all subjects who received at least 1 dose of lanadelumab 
(investigational product). All safety, efficacy, and HRQoL analyses will be based on the FAS.
Pharmacokinetic set (PK Set) is defined as all subjects in the FAS who have at least 1 evaluable 
post dose PK concentration value. All PK analyses will be based on the PK set. 
Pharmacodynamic set (PD Set) is defined as all subjects in the FAS who have at least 1 
evaluable post dose PD value. All PD analyses will be based on the PD set.
Property of 
Ful
Fu
(inv
(inv
Takeda:
tions.
ons.
Stat
Sta
ll an
a
For 
otal sa
otal sa
N
non-commercial 
h HA
HA
tudy
udy ha
ha
); enab
enab
m anal
anal
4 or di
or d
h anal
analy
ze and
e and
use
(JN
(
PD, an
PD, a
AE.
AE
only 
as d
as d
his study
s stud
JNDA
NDA
and
and D
nd 
desc
desc
subject
.4 or 
4 or hih
Dat
Da
to the
s, t
s, the S
he 
applicable
r th
o be tak
be tak
s and bas
and b
dications
icatio
a will b
will be
A
Terms 
he
he
of Use

Shire
Page 82
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
9.5
Disposition, Demographics and Baseline Characteristics, and Exposure 
Subject Disposition
9.5.1
The numbers of subjects treated with study drug, completed Treatment Period A, completed the 
study, and discontinued prematurely by reason will be summarized for each analysis population.
Demographics and Other Baseline Characteristics
9.5.2
Baseline HAE characteristics and demographic variables will be summarized for each analysis 
population.
Medical History
9.5.3
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by system organ class (SOC) and preferred term (PT) for each analysis 
population.
Treatment Exposure and Compliance
9.5.4
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.
Prior and Concomitant Medications
9.5.5
Concomitant medications will be coded using the World Health Organization-Drug Dictionary. 
The number and percentage of subjects with prior or concomitant medications will be 
summarized by therapeutic class and PT for each analysis population. A separate, similar table 
will be provided for the subset of concomitant medications classified as rescue medications.
9.6
Efficacy Analyses
No statistical hypothesis testing will be performed. The totality of results across all efficacy
endpoints will be the measure of overall treatment benefit, with the primary goal of 
demonstrating consistency across the endpoints, especially the primary efficacy endpoint, with 
the pivotal overseas study (DX-2930-03).
•
Continuous efficacy endpoints will be summarized using number of subjects (n), mean,
SD, median, minimum, and maximum. Whenever appropriate, raw (actual) values and
changes from baseline will be summarized at each scheduled time point. Additionally, the
attack rates will be calculated using the number of attacks divided by the duration of time
for each subject for each efficacy evaluation period.
•
Categorical efficacy endpoints (eg, attack severity) will be summarized in terms of the
number and percentage of subjects in each category of the efficacy endpoint.
•
Time-to-event endpoint (eg, time to the first HAE attack) will be summarized using
Kaplan-Meier (KM) estimates. Summaries will include 25th, 50th (median), and 75%
Property of Takeda: 
Contin
ontin
SD, 
SD,
c
For 
onsi
ns
erseas
erseas
non-commercial
s w
d PT fo
d PT f
f conco
conco
sis test
is test
he mea
e mea
iste
iste
use
sing th
ing th
with p
with p
only 
ns
ns
and
al n
l 
at rece
t rece
subject 
drug will
ug wi
numbe
numb
i
to the
y A
y
for ea
or eac
applicable 
anal
nalys
y
Activit
ctivi
h
Terms 
is
of Use

Shire
Page 83
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
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 summaries will be based on the FAS. Efficacy data, including derived data, will be 
presented in subject data listings.
If applicable, efficacy endpoints will be evaluated for the following 4 efficacy evaluation 
periods: 
•
Day 0 (after study drug administration) through Day 182 (the end of Treatment Period A)
•
Day 0 (after study drug administration) through Day 364 (the end of Treatment Period B)
•
Presumed steady-state period from Day 70 through Day 182
•
Presumed steady-state period from Day 70 through Day 364
Primary Efficacy Endpoint
9.6.1
The primary efficacy endpoint is the achievement of attack-free status for the efficacy evaluation 
period of Day 0 through Day 182. A subject is considered as attack free during an efficacy 
evaluation period if the subject has no investigator-confirmed HAE attacks during that efficacy
evaluation period. For subjects who discontinue treatment during an efficacy evaluation period, 
the evaluation period will end at the time of treatment discontinuation 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 for the efficacy evaluable period of 
Day 0 through Day 182 will be summarized for the FAS. A 95% confidence interval for the 
proportion of subjects achieving attack-free will be derived using the exact method. 
Other Efficacy Endpoints
9.6.2
Other efficacy endpoints are as follows:
•
Number of investigator-confirmed HAE attacks during each of the efficacy evaluation
periods.
•
Number of investigator-confirmed HAE attacks requiring acute treatment during each of
the efficacy evaluation periods.
•
Number of investigator-confirmed moderate or severe HAE attacks during the each of
efficacy evaluation periods.
•
Maximum attack severity during each of the efficacy evaluation periods.
•
Number of investigator-confirmed high-morbidity attacks during each of the efficacy
evaluation periods; a high morbidity HAE attack is defined as any attack that has at least
1 of the following characteristics: severe, 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.
of Takeda: 
effi
eff
Numb
Numb
eff
eff
•
For
er of in
er of i
icac
ica
non-commercial
riri
ack
ck-fre
fre
dpoints
points
re as fo
e as fo
vestiga
vestiga
use
hievin
ievin
ed fo
ed fo
only 
mentn
ject was
ct wa
and 
irm
rm
ment d
ment d
nt dis
t dis
subject 
ee status
ee statu
as attack
s attack
med H
med H
to the applicable 
ent Perio
nt Per
atment P
tment
Terms of Use

Shire
Page 84
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
•
Time to first HAE attack after Day 0 for the efficacy evaluation period of Day 0 through
Day 182.
•
Time to first HAE attack after Day 0 for the efficacy evaluation period of Day 70 through
Day 182.
•
Achievement of at least a 50%, 70% and 90% reduction in the investigator-confirmed
normalized number of attacks (NNA) per 4 weeks relative to the run-in period NNA for
each of the efficacy evaluation periods.
•
Achievement of an efficacy evaluation period NNA <1.0 per 4 weeks, <0.75 per 4 weeks,
<0.50 per 4 weeks, and <0.25 per 4 weeks for each of the efficacy evaluations periods.
•
Achievement of attack-free status for each of the efficacy evaluation periods of Day 0
through Day 364, Day 70 through Day 182, and Day 70 through Day 364.
•
Achievement of attack-free status for monthly increments through Day 364.
•
Achievement of attack-free intervals.
•
Percentage of attack free days during each of the efficacy evaluation period.
9.6.2.1
Statistical Methods Analyzing Other Efficacy Endpoints
Normalized Number of Investigator-confirmed Hereditary Angioedema Attacks 
The normalized number of investigator-confirmed HAE attacks (NNA) during each efficacy
evaluation period will be expressed as a monthly (28 days) HAE attack rate and will be analyzed 
using the FAS.
The investigator-confirmed HAE attack rate during each efficacy evaluation period will be 
calculated for each subject as the number of investigator-confirmed HAE attacks occurring 
during the efficacy evaluation period divided by the number of days the subject contributed to 
the efficacy evaluation period multiplied by 28 days.
The baseline investigator-confirmed HAE attack rate will be calculated for each subject as the 
number of investigator-confirmed HAE attacks occurring during the run-in period divided by the 
number of days the subject contributed to the run-in 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.
The baseline investigator-confirmed attack rate, as well as the investigator-confirmed attack rate, 
change from baseline, and percent change from baseline for each efficacy evaluation period will 
be summarized for the FAS. In addition to the descriptive statistics for attack rates, the summary
will include the total number of investigator-confirmed HAE attacks reported during each period 
and subject-time in months that each subject contributed to each period. Figures will be created 
for the FAS by plotting the on-study investigator-confirmed HAE attacks reported during each 
efficacy evaluation period for each subject.
Property 
c
of
The
The
h
Takeda:
ment p
ment p
ubject 
ubject 
ack rate
ack rate
For
iga
g
ys the s
s the 
non-commercial 
attack r
ttack r
he num
e num
on perio
n perio
eriod m
od m
gator
ator-c
ator
ator
use
onthl
onthl
only 
He
med HA
med H
y (
y
and 
icac
ca
ered
ered
subject 
cacy
acy eval
ev
y
acy En
cy E
to 
ug
the 
ay
gh Da
gh D
applicable 
per 4 w
per 4 w
ions per
ions pe
periods o
eriod
364.
364.
Terms 
A for
A for
of Use

Shire
Page 85
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
The number of investigator-confirmed HAE attacks per month will be summarized by month 
(per 28-day interval) for the FAS. The summary will include descriptive statistics for run-in 
period investigator-confirmed attack rate, as well as monthly investigator-confirmed attack rates, 
monthly change from baseline, and monthly percent change from baseline for each efficacy
evaluation period. Investigator-confirmed HAE attacks will be grouped into 28-day intervals 
using the start date of the HAE attack. The date of the first exposure to study drug in this study
will be used as the start of the first interval and end of the interval will be the date of first 
exposure to study drug in this study plus 28 days. Each successive interval will start the last day
of the prior interval plus 1 day and end 28 days later.
Similar summary tables will be presented for the following clinical outcome measures for the 
FAS:
•
Normalized number of investigator-confirmed HAE attacks requiring acute treatment
•
Normalized number of moderate or severe investigator-confirmed HAE attacks
•
Normalized number of high-morbidity investigator-confirmed HAE attacks
Time to First Attack
The time to the first investigator-confirmed HAE attack (days) after Day 0 for the efficacy
evaluation period of Day 0 through Day 182 and Day 70 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 open-label dose for 
that efficacy evaluation period. 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. 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 and time of study
discontinuation. Time to the first investigator-confirmed HAE attack will be summarized using 
Kaplan-Meier methods.
Characteristics of Investigator-confirmed Hereditary Angioedema Attacks
Characteristics of investigator-confirmed HAE attacks will be summarized the run-in period and 
each efficacy evaluation period at both the subject level and event-level. The calculations 
described below will be conducted for clinical outcomes data partitioned within each efficacy
evaluation period.
Subject level HAE attack characteristics:
•
HAE Attack Duration: For each subject, the mean duration of all investigator-confirmed
HAE attacks will be calculated in hours and summarized. For efficacy evaluation period
summaries, mean attack duration will be summarized for all subjects or only subjects
with attacks. The subject-level average attack duration will be categorized into 12-hour
intervals and tabulated by category (<12 hours, 12-24 hours, >24-48 hours, and >48
hours).
Property of Takeda:
below
elow
ion per
on per
ubject l
ubject l
For 
of inin
evalua
evalua
w
non-commercial
he d
he 
ficacy
cacy e
y
AE attac
E atta
first inv
rst inv
nvestig
vestig
nves
nve
use
me
who do
who do
dat
date
only 
Day
Day
delumab
eluma
ed HA
d H
and 
ack (da
ck (da
70
70
subject
firmed H
rmed 
to
rmed
rmed
the
uiring a
iring 
d H
applicable 
las
asures fo
sures f
Terms 
y
st day
st day
of Use

Shire
Page 86
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
•
HAE Attack Severity: For each subject, the mean severity of all investigator-confirmed
HAE attacks will be calculated using a numerical rating and summarized. For efficacy
evaluation period summaries, mean attack severity will be summarized for all subjects or
only subjects with attacks. The number and percentage of subjects will be tabulated by
maximum attack severity (no attacks, mild, moderate, and severe).
Event level HAE attack characteristics:
•
HAE Attack Location: The number and percentage of subjects with attacks, as well as the
total number of attacks, will be tabulated by the primary attack location (peripheral,
abdominal, and laryngeal) as determined by the investigator. Additionally, the attack
location will be reclassified and summarized with an emphasis on the laryngeal attack. In
this summary, an attack with either the primary or secondary location(s) identified as
laryngeal will be considered as a laryngeal attack; otherwise attacks will be classified by
their reported primary attack location.
•
Rescue Medication Use: The number and percentage of subjects with rescue medication
use for an HAE attack, as well as the number of rescue medications, will be tabulated by
rescue medication by type (ecallantide, icatibant, nano-filtered C1-INH, plasma-derived
C1-INH, recombinant C1-INH, fresh frozen plasma, and other) as reported on the
angioedema attack page of the eCRF.
•
Supportive Treatment Use: The number and percentage of subjects with supportive
treatment use for an HAE attack, as well as the number of supportive treatment, will be
tabulated by supportive treatment type (IV fluids, pain medication, oxygen, anti-emetic,
and other) as reported on the angioedema attack page of the eCRF.
Achievement of At Least 50%, 70%, and 90% Reduction in the Investigator-confirmed 
Normalized Number of Attacks per 4 Weeks Relative to the Run-in Period
For each subject, a treatment period HAE attack rate and run-in period HAE attack rate will be 
calculated. The percentage reduction will be calculated as the run-in period HAE attack rate 
minus the treatment period HAE attack rate divided by the run-in period HAE attack rate. 
Number and percentage of subjects achieving for each of the three predefined threshold will be 
summarized for each of the efficacy evaluation period. The three classes of responders are nested 
within each other and not mutually exclusive.
Achievement of an Efficacy Evaluation Period Normalized Number of Attacks <1.0, <0.75, 
<0.50, and <0.25 per 4 Weeks 
For each subject, a treatment period NNA will be calculated. The number and percentage of 
subjects achieving each of the four predefined threshold will be summarized for each of the 
efficacy evaluation period. The four classes of responders are nested within each other and not 
mutually exclusive.
Property 
e
of
For 
For
sub
su
Takeda: 
vement
ement
50, and
0, and
e
For
r each
r eac
ther a
ther a
non-commercial 
0%, an
%, an
ks per 4
per 4
ent peri
nt peri
age red
e red
period 
eriod 
ntage o
ntage o
h
use 
pe (
e (
oedem
oedem
only 
and pe
nd p
ell as the
l as th
(IV
IV f
and 
ma
ma
erc
subject 
ubject
bjec
e medica
medic
ano
no-filte
filte
a, and
a, an
to 
ctst
the
on
acks wi
cks w
applicable
well a
well 
ripheral,
phera
y, the att
, the a
lary
aryngea
nge
y
n(s) ide
(s) id
ll
Terms of Use

Shire
Page 87
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Achievement of Attack-free Status
The number and percentage of subjects that are attack-free will be summarized for each of the 
efficacy evaluation periods of Day 70 through Day 182, Day 0 through Day 364, and Day 70 
through Day 364. For subjects who discontinue treatment during an efficacy evaluation period, 
the evaluation period will end at the time of treatment discontinuation and attack-free status will 
be evaluated for the period of time that the subject was in the evaluation period.
Achievement of Attack-free Status for Monthly Increments through Day 364 (i.e., Month 1,
Month 2, Month 3, etc)
The number and percentage of subjects achieving attack-free status for monthly increments 
(Month 1, Month 2, Month 3, etc) through Day 364 (Month 13) will be summarized. A two-sided 
95% CI for the proportion of subjects achieving attack-free will be derived using the exact 
method.
For subjects who discontinue the study during a monthly increment, 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.
Achievement of investigator-confirmed HAE attack-free intervals 
A subject is considered as attack free during a time period if the subject has no investigator-
confirmed HAE attacks during that time period. Subjects who discontinued during a time period 
are considered as non-responders for that time period. 
The number and percentage of subjects who achieve investigator-confirmed HAE attack free 
intervals which will include but may not be limited to 1 month (4 weeks; ‘Day 0 to one day
before Day 28 visit’), 3 months (12 weeks; ‘Day 0 to one day before Day 84 visit’), or until the 
Day 182 visit (approximately 6 months or 24 weeks; ‘Day 0 to Day 182 visit’) during the 
treatment period will be tabulated by treatment group.
Percentage of Attack-free Days
The percentage of HAE attack free days will be calculated by counting the number of days in the 
efficacy evaluation period without an HAE attack and dividing by the number of days the subject 
contributed to the efficacy evaluation period. An attack-free day is defined as a calendar day with 
no investigator-confirmed HAE attack. Descriptive statistics for the percentage of HAE attack 
free days will be summarized.
Exploratory Endpoints 
9.6.3
Not applicable.
9.7
Safety Analyses
No statistical hypothesis testing will be performed. All safety summaries will be based on the 
FAS. 
Property 
N
of
9.6.
9.6
Takeda:
alu
ed to t
ed to t
vestigat
vestigat
e day
e days
For
e of H
e of H
uation
uation
non-commercial
cts wh
cts wh
may not 
ay not 
s (12 w
(12 w
y 6 mo
6 mo
y
abulate
bulat
ck-
k-free
fre
use
me p
me p
h
only
me per
me pe
d. Sub
. Subj
er
and
k-free
free
subject 
ent, th
nt, th
ttack
ack-fre
f
n period.
period
to 
h
the
ed usi
ed us
applicable 
Mont
Mon
ly increm
incre
y
marized
marized
ng
Terms 
ll
t
of Use

Shire
Page 88
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
•
Continuous safety endpoints (eg, change in laboratory parameter) will be summarized
using number of subjects (n), mean, standard deviation (SD), median, minimum value,
and maximum value. As appropriate, raw (actual) values and changes from baseline will
be summarized overall and at each scheduled time point.
•
Categorical endpoints (eg, presence or absence of an outcome measure) will be
summarized using counts and percentages. Summaries will include but are not limited to:
number and percentage of subjects with an outcome measure, and laboratory shift tables
(categorical change from baseline).
•
Only treatment-emergent AEs (TEAEs) will be analyzed. The number and percentage of
subjects reporting any TEAEs, SAEs, TEAEs related to the investigational product,
TEAEs leading to withdrawal, severe TEAEs and absolute count of events will be
summarized by PT and SOC.
•
All AEs (TEAEs and non-TEAEs) will be provided in the AE subject listing. All safety
data, including derived data, will be presented in subject data listings.
•
Clinical laboratory tests and vital signs will be summarized by visit. Potentially clinically
important findings will also be summarized or listed.
Adverse Events
9.7.1
Adverse events will be coded using the MedDRA coding dictionary.
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. 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.
The analyses described in this section will be based on treatment-emergent AEs; plainly referred 
to as AEs in this section for brevity.
Related AEs are AEs classified as related to study drug by the investigator. Severe AEs are AEs 
classified as severe (grade 3) or life threatening (grade 4) by the investigator.
For this analysis, AEs will be classified to one of two analysis periods:
•
Treatment Period AEs will include all AEs starting at or after the first exposure to
lanadelumab in this study to those starting before or at the subject’s last visit date during
the treatment period in this study (AEs starting at or after treatment on Day 0 through
Day 364 visit). Treatment Period AEs will be further summarized for Treatment Period A
(Day 0 through Day 182), Treatment Period B (Day 183 through Day 364), and overall
for the entire Treatment Period (Day 0 through Day 364).
Property of Takeda: 
s se
s
is anal
s anal
•
For
re AE
re AE
ever
eve
non-commercial
re
t time
time
not. If a
ot. If 
ed relat
d relat
rgent.
gent.
d in thi
n thi
ction fo
on fo
use
medic
medic
ation
ation
only 
cod
o
with on
ith o
al
and 
ding
ding
subject 
ized by
ized by
to
su
a listin
listi
the 
ubject
ubjec
applicable 
percenta
ercen
nal produ
al prod
vents wi
ents w
Terms 
d to:
to:
ables
ables
of Use

Shire
Page 89
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
•
Follow-up Period AEs will include all AEs starting at or after the subject’s last visit date
of the treatment period in this study (AEs starting after the Day 364 visit).
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 for each analysis period. The number of 
deaths due to an AE, hospitalization due to an AE and study discontinuation due to an AE will be 
summarized for each analysis period.
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by SOC, and PT for each analysis period. This tabulation will be repeated for 
related AEs, SAEs, related SAEs, severe AEs, related severe AEs, and investigator-reported 
AESI for treatment period and follow-up period AEs.
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by PT for treatment period AEs only. This tabulation will be repeated for related 
AEs and serious AEs for treatment period AEs.
All AEs will be provided in subject listings. Listings will be presented separately for each 
analysis period. 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 interest for this study are hypersensitivity reactions and disordered 
coagulation (hypercoagulability events and bleeding events). Standardized MedDRA Queries 
(SMQ) for each AESI will be performed using the study data. The number an percentage of 
subjects with SMQ-defined AESI, as well as the total number of SMQ-defined AESIs, will be 
summarized by SOC and PT for each analysis period. 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. A listing detailing the PT within the SMQ 
will be provided.
Laboratory Test Results
9.7.2
Baseline is defined as the last non-missing value prior to the first exposure to lanadelumab. 
Actual values and change from baseline 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.
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 
Property 
s
of
Lab
Lab
sigi
Takeda:
alues a
lues a
f more 
more 
missin
missin
For
ned a
ned 
non-commercial
ed d 
as well 
well
each an
ch an
or those
those
vere, an
re, an
ory Te
ry T
use
y
d blee
blee
usin
usin
only 
y are h
are
y
di
and 
sing
ng
s, and i
 and i
subject 
wi
be presen
e presen
g disc
g di
to
al n
ill be
ll be
the 
numb
numb
applicable 
AEs, will
Es, wi
peated fo
eated 
gator
ator-re
Terms 
of 
ill be
ill be
of Use

Shire
Page 90
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
laboratory result is reported per study visit per parameter, the result yielding the most severe 
classification 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. 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.
All laboratory test results will be presented in subject listings.
Vital Signs
9.7.3
Baseline is defined as the last non-missing value prior to the first exposure to lanadelumab. 
Actual values and changes from baseline in vital signs will be summarized by study visit and 
study time point. All vital sign data will be presented in subject listings.
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.
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.
9.8
Other Analyses
Health-related Quality of Life Analyses
9.8.1
The AE-QoL total score and domain scores will be summarized using descriptive statistics by
scheduled visit. A change in scores from baseline (Day 0) to Day 182 and Day 364 will be 
reported
Pharmacokinetic/Pharmacodynamic Analyses
9.8.2
No formal statistical hypothesis will be tested. Individual PK concentrations and cHMWK levels 
will be provided in subject data listing(s) and summarized using descriptive statistics (number of 
subjects, arithmetic mean, SD, coefficient of variation [CV%], median, minimum, maximum, 
geometric mean, and %CV of geometric mean). Figures of individual and mean (± SD) 
concentration-time profiles plasma lanadelumab will be generated. Tabular and graphical 
summaries will be analyzed based on the PK set and PD set, as appropriate
Property 
g
of 
will
wil
sub
su
Takeda: 
Ph
Ph
o forma
o form
ll b
For
al 
t. A ch
t. A c
non-commercial 
al si
l s
hat was
at was
tudy
udy tim
tim
y
ated Q
ted Q
score
score
use 
ign
ign
only 
If mor
f mo
 the resu
the res
and
ng res
res
d clini
d clini
orere
subject 
mma
m
t listings
t listing
gnifican
nifica
sult
ul
to 
arize
arize
the
ure to l
ure to 
applicable Terms of Use

Shire
Page 91
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Immunogenicity Analyses
9.8.3
Immunogenicity data will be summarized using descriptive statistics, and the effect on 
lanadelumab plasma concentrations, cHMWK, and the number of investigator confirmed HAE 
attacks during the efficacy evaluation periods will be evaluated.
9.9
Statistical/Analytic Considerations 
Multiplicity Adjustment
9.9.1
Not applicable; no hypothesis testing is planned 
Control of Type I Error
9.9.2
Not applicable; no hypothesis testing is planned 
Handling of Missing Data
9.9.3
All available data will be included in the analysis. No imputation of missing data will be 
performed.
Multicenter Studies 
9.9.4
Data from all study sites that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analyses.
Subgroup Analyses 
9.9.5
Subgroup analyses may be performed; details will be described in the SAP, as applicable.  
9.10
Sensitivity Analyses 
The primary analysis and some of the other efficacy analyses will be repeated using all 
subject-reported HAE attacks instead of limiting the analysis to those attacks that were 
investigator-confirmed. See Table 6 for details of sensitivity analyses on other efficacy endpoints 
using all subject-reported HAE attacks.
Property of Takeda: For non-commercial 
me of th
 of th
cks inst
ks ins
See
ee Ta
Ta
orted H
rted H
use 
tails w
tails w
only and 
col wil
ol wil
subject 
of m
of m
to 
mis
mis
the applicable Terms of Use

Shire
Page 92
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Table 6:
Sensitivity Analysis for Other Efficacy Endpoints
Other Efficacy Endpoints
Sensitivity Analysis Using All Attacks
Number of HAE attacks
x
Number of HAE attacks requiring acute treatment
x
Number of moderate or severe HAE attacks 
x
Characteristics of HAE attacks 
x
Number of high-morbidity HAE attacks
x
Time to first HAE attack after Day 0 or Day 70
x
Achievement of attack reduction from run-in period
x
Achievement of predefined attack rate
x
Achievement of attack-free
x
Percentage of attack-free days
x
HAE=hereditary angioedema
Property of Takeda: For non-commercial use only 
nly and 
d
n
subject 
ect
x
u
to 
o the 
t
applicable 
ble
lic
a
Terms s
ms
Te
of Use

Shire
Page 93
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Shire
Page 94
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Propert
perty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
Page 95
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Prope
perty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

Shire
Page 96
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Prope
perty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use
U

Shire
Page 97
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Property
erty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

Shire
Page 98
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Prope
perty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

Shire
Page 99
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
U

Shire
Page 100
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use
U

Shire
Page 101
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Property of Takeda: For non-commercial use only and subject to the
he applicable Terms of 
of Use

Shire
Page 102
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
Page 103
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Property of Takeda: For non-commercial use only an
and subject to the applicable Terms of 
of Use

Shire
Page 104
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

Shire
Page 105
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Prope
perty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
Page 106
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Prope
perty of Takeda: For non-commercial use only and subject to the applicable Terms of Use
U

Shire
Page 107
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Proper
erty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
Page 108
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Proper
erty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
Page 109
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

Shire
Page 110
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Prope
perty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

Shire
Page 111
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
Page 112
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Prope
perty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

Shire
Page 113
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Property of Takeda: For non-commercial use only and subject to the ap
applicable Terms of 
of Use

Shire
Page 114
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Property of Takeda: For non-commercial use only and subject to the app
pplicable Terms f 
of Use
U

Shire
Page 115
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of f Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 116
CCI
Property of Takeda: For no
non-commercial use only and subject to the applicable Terms of Use
U





Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 117
CCI
Property of Takeda: For non-commercial use
se only and subject to the applicable Terms of Use
Us

6KLUH




/DQDGHOXPDE6+3

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 118
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

6KLUH




/DQDGHOXPDE6+3

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 119
CCI
Property of Takeda: For non-commercicial use only and subject to the applicable Terms of 
of Use

6KLUH




/DQDGHOXPDE6+3

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 120
CCI
Proper
perty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

6KLUH




/DQDGHOXPDE6+3

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 121
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

6KLUH




/DQDGHOXPDE6+3

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 122
CCI
Prope
perty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

6KLUH




/DQDGHOXPDE6+3

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 123
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

6KLUH




/DQDGHOXPDE6+3

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 124
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms s
f 
of Use
U

6KLUH




/DQDGHOXPDE6+3

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 125
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 126
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Term
rms of 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 127
CCI
Property of Takeda: For non-commercial use
se only and subject to the applicable Terms of 
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 128
CCI
Prope
perty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 129
CCI
Property of Takeda: For non-comm
mmercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 130
CCI
Property
rty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 131
CCI
Property of Takeda: : For non-commercial use only and subject to the applicable Terms of 
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 132
CCI
Property of Takeda: For non-
n-commercial use only and subject to the applicable Terms of 
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 133
CCI
Property of Takeda: For
or non-commercial use only and subject to the applicable Terms of 
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 134
CCI
Property of Takeda: For non-commercial use on y
nly and subject to the applicable Terms of 
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 135
CCI
Property of Tak
akeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 136
CCI
Property of Tak
akeda: For non-commercial use only and subject to the applicable Terms of 
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 137
CCI
Property of Takeda: For non-comm
mmercial use only and subject to the applicable Terms of 
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 138
CCI
Property 
ty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 139
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Term
rms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 140
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 141
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 142
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 143
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 144
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 145
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 146
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 147
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 148
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 149
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 150
CCI
Pro
roperty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 151
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 152
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 153
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 154
CCI
Prop
operty of Takeda: For non-commercial use only and subject to the applicable Terms of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 155
CCI
Prope
perty of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 156
CCI
Property of Takeda: For non-comm
mmercial use only and subject to the applicable Terms of 
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Page 157
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms f 
of Use
U

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
11. REFERENCES
Baldrick, P. 2010. Juvenile animal testing in drug development - Is it useful? Regulatory 
Toxicology and Pharmacology, 57, 291-299.
Banerji, A. 2013. The burden of illness in patients with hereditary angioedema. Ann Allergy 
Asthma Immunol, 111, 329-36.
Banerji, A., Busse, P., Shennak, M., Lumry, W., Davis-Lorton, M., Wedner, H. J., Jacobs, J., 
Baker, J., Bernstein, J. A., Lockey, R., Li, H. H., Craig, T., Cicardi, M., Riedl, M., Al-
Ghazawi, A., Soo, C., Iarrobino, R., Sexton, D. J., TenHoor, C., Kenniston, J. A., 
Faucette, R., Still, J. G., Kushner, H., Mensah, R., Stevens, C., Biedenkapp, J. C., 
Chyung, Y.and Adelman, B. 2017. Inhibiting Plasma Kallikrein for Hereditary
Angioedema Prophylaxis. N Engl J Med, 376, 717-728.
Bork, K. 2014a. Current drugs in early development for hereditary angioedema: potential for 
effective treatment. Expert Opin Investig Drugs, 23, 887-91.
Bork, K. 2014b. An evidence based therapeutic approach to hereditary and acquired angioedema. 
Current Opinion in Allergy and Clinical Immunology, 14, 354-362.
Bork, K., Hardt, J.and Witzke, G. 2012. Fatal laryngeal attacks and mortality in hereditary
angioedema due to C1-INH deficiency. J Allergy Clin Immunol, 130, 692-7.
Bygum, A. 2009. Hereditary angio-oedema in Denmark: a nationwide survey. The British 
journal of dermatology, 161, 1153-8.
Caballero, T., Aygoren-Pursun, E., Bygum, A., Beusterien, K., Hautamaki, E., Sisic, Z., Wait, 
S.and Boysen, H. B. 2014. The humanistic burden of hereditary angioedema: results from
the Burden of Illness Study in Europe. Allergy Asthma Proc, 35, 47-53.
Cicardi, M., Bork, K., Caballero, T., Craig, T., Li, H. H., Longhurst, H., Reshef, A.and Zuraw, 
B. 2012. Evidence-based recommendations for the therapeutic management of
angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an
International Working Group. Allergy, 67, 147-57.
Cornpropst, M., Dobo, S., Collier, J., Rose, A., Wilson, R., Babu, Y. S., Collis, P., Zong, J.and 
Sheridan, W. P. 2016. BCX7353, a Potent Inhibitor of Plasma Kallikrein, Shows 
Sustained Maximal Enzyme Inhibition When Dosed Orally Once Daily: Results from a 
Phase I Trial in Healthy Subjects. Journal of Allergy and Clinical Immunology, The, 137, 
AB401.
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.
Craig, T. J., Levy, R. J., Wasserman, R. L., Bewtra, A. K., Hurewitz, D., Obtulowicz, K., Reshef, 
A., Ritchie, B., Moldovan, D., Shirov, T., Grivcheva-Panovska, V., Kiessling, P. C., 
Keinecke, H. O.and Bernst 2009. Efficacy of human C1 esterase inhibitor concentrate 
compared with placebo in acute hereditary angioedema attacks. Journal of Allergy and 
Clinical Immunology, The, 124, 801-808.
Davis, A. E. 2005. The pathophysiology of hereditary angioedema. Clinical Immunology, 114, 3-
9.
El-Hachem, C., Amiour, M., Guillot, M.and Laurent, J. 2005. Hereditary angioneurotic edema: a 
case report in a 3-year-old child. Archives de pédiatrie, 12, 1232-6.
Page 158
Property of Takeda:
t, A
Manage
anage
, T. J., 
, T. J., 
A
For
, E
ckey
ckey, R
,
A., P
A., P
non-commercial 
ary C
y
up.p. Alle
Alle
er, J., R
r, J., R
. BCX
BCX
al Enzy
Enzy
Health
ealth
E. A.,
E. A.
use
T., L
T., 
endati
endati
1
only 
ic burd
c bu
Allergy
Allergy
Li, H
Li
and 
sterien
terien
rd
subject
354
5
and mo
and m
n Immun
 Immu
a nationw
natio
to 
ry an
an
y
4-36
4-36
the 
dem
and a
nd
applicable 
, 
A.,.,
J. C.,
. C.,
ditary
ditary
ma: po
ma: p
Terms 
., 
Al
Al-
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Fouche, A. S., Saunders, E. F. H.and Craig, T. 2014a. Depression and anxiety in patients with 
hereditary angioedema. Annals of Allergy, Asthma & Immunology, 112, 371-375.
Fouche, C., Kenealy, T., Mace, J.and Shaw, J. 2014b. Practitioner perspectives from seven health 
professional groups on core competencies in the context of chronic care. J Interprof 
Care, 28, 534-40.
Gordon, E. M., Donaldson, V. H., Saito, H., Su, E.and Ratnoff, O. D. 1981. Reduced titers of 
Hageman factor (factor XII) in Orientals. Annals of internal medicine, 95, 697-700.
Goring, H. D., Bork, K., Spath, P. J., Bauer, R., Ziemer, A., Hintner, H.and Wuthrich, B. 1998. 
Hereditary angioedema in the German-speaking region. Hautarzt, 49, 114-22.
Horiuchi, T., Ohi, H., Ohsawa, I., Fujita, T., Matsushita, M., Okada, N., Seya, T., Yamamoto, T., 
Endo, Y., Hatanaka, M., Wakamiya, N., Mizuno, M., Nakao, M., Okada, H., Tsukamoto, 
H., Matsumoto, M., Inoue, N., Nonaka, M.and Kinoshita, T. 2012. Guideline for 
hereditary angioedema (HAE) 2010 by the Japanese Association for Complement 
Research - secondary publication. Allergology international : official journal of the 
Japanese Society of Allergology, 61, 559-62.
Iwamoto, K., Tanaka, A., Hiragun, M., Kawai, M., Mihara, S., Takenaka, M., Shibuya, M., 
Inomata, N., Hatano, Y., Shimizu, F., Kousaka, T.and Hide, M. 2012. Novel and 
recurrent C1 inhibitor gene mutations in nine Japanese patients with hereditary
angioedema. Journal of dermatological science, 68, 68-70.
Kenniston, J. A., Faucette, R. R., Martik, D., Comeau, S. R., Lindberg, A. P., Kopacz, K. J., 
Conley, G. P., Chen, J., Viswanathan, M., Kastrapeli, N., Cosic, J., Mason, S., DiLeo, M., 
Abendroth, J., Kuzmic, P., Ladner, R. C., Edwards, T. E., TenHoor, C., Adelman, B. A., 
Nixon, A. E.and Sexton, D. J. 2014. Inhibition of plasma kallikrein by a highly specific 
active site blocking antibody. J Biol Chem, 289, 23596-608.
Leeb-Lundberg, L. M. F., Marceau, F., Müller-Esterl, W., Pettibone, D. J.and Zuraw, B. L. 2005. 
International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: 
from Molecular Mechanisms to Pathophysiological Consequences. Pharmacological 
Reviews, 57, 27-77.
Lei, W. T., Shyur, S. D., Huang, L. H., Kao, Y. H.and Lo, C. Y. 2011. Type I hereditary
angioedema in Taiwan -- clinical, biological features and genetic study. Asian Pac J 
Allergy Immunol, 29, 327-31.
Lumry, W. R. 2013. Overview of epidemiology, pathophysiology, and disease progression in 
hereditary angioedema. American journal of managed care, The, 19, s103-10.
Lumry, W. R., Miller, D. P., Newcomer, S., Fitts, D.and Dayno, J. 2014. Quality of life in 
patients with hereditary angioedema receiving therapy for routine prevention of attacks. 
Allergy and asthma proceedings, 35, 371-6.
Martin, P. L.and Weinbauer, G. F. 2010. Developmental Toxicity Testing of Biopharmaceuticals 
in Nonhuman Primates. International Journal of Toxicology, 29, 552-568.
Maurer, M., Magerl, M., Ansotegui, I., Aygoren Pursun, E., Betschel, S., Bork, K., Bowen, T., 
Balle Boysen, H., Farkas, H., Grumach, A., Hide, M., Katelaris, C., Lockey, R., 
Longhurst, H., 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.
Page 159
Property of 
Ma
Ma
Takeda: 
ients
n
Allergy 
lergy
n, P. L
n, P. L
inin
aure
ur
For
y a
y
, Mille
, Mille
s w
s w
non-commercial
acolo
acolo
ms to P
ms to P
ang, L.
ng, L
iwan
wan -
ol, 29, 
29, 
. Overv
Over
angio
ngio
use
Che
Che
Müller
Müller
g
only 
, Edwa
Edw
hibition
hibition
em
and
 S. R.
S. R
astrape
strap
subject 
aken
ken
Hide, M
Hide, M
se patien
e pati
8, 68
, 68-70
L
to 
naka
naka
the
or C
fficial j
ficial j
applicable 
 1
Yam
amamo
am
 H., Tsu
H., T
uideline 
deline
Comp
Comp
Terms 
998. 
998. 
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Morford, L. L., Bowman, C. J., Blanset, D. L., Bogh, I. B., Chellman, G. J., Halpern, W. G., 
Weinbauer, G. F.and Coogan, T. P. 2011. Preclinical safety evaluations supporting 
pediatric drug development with biopharmaceuticals: strategy, challenges, current 
practices. Birth Defects Res B Dev Reprod Toxicol, 92, 359-80.
Nanda, M. K., Elenburg, S., Bernstein, J. A.and Assa'ad, A. H. 2015. Clinical Features of 
Pediatric Hereditary Angioedema. Journal of Allergy and Clinical Immunology: In 
Practice, The, 3, 392-395.
Nielsen, E., Johansen, H., Holt, J.and Mollnes, T. 1994. C1 inhibitor and diagnosis of hereditary 
angioedema in newborns. Pediatric Research, 35, 184-187.
Nordenfelt, P., Dawson, S., Wahlgren, C. F., Lindfors, A., Mallbris, L.and Bjorkander, J. 2014. 
Quantifying the burden of disease and perceived health state in patients with hereditary
angioedema in Sweden. Allergy Asthma Proc, 35, 185-90.
Nzeako, U. C., Frigas, E.and Tremaine, W. J. 2001. Hereditary angioedema, a broad review for 
clinicians. Archives of Internal Medicine, 161, 2417-2429.
Ohi, H., Itabashi, T.and Shinohara, N. 2017. Educational Activities Significantly Improved 
Diagnosis of the Rare Disease Hereditary Angioedema. The Journal of Angioedema, 2, 
18-20.
Ohsawa, I., Honda, D., Nagamachi, S., Hisada, A., Shimamoto, M., Inoshita, H., Mano, S.and 
Tomino, Y. 2015. Clinical manifestations, diagnosis, and treatment of hereditary
angioedema: survey data from 94 physicians in Japan. Ann Allergy Asthma Immunol,
114, 492-8.
Pappalardo, E., Cicardi, M., Duponchel, C., Carugati, A., Choquet, S., Agostoni, A.and Tosi, M. 
2000. Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients 
with angioedema. Journal of Allergy and Clinical Immunology, The, 106, 1147-1154.
Read, N., Lim, E., Tarzi, M. D., Hildick-Smith, P., Burns, S.and Fidler, K. J. 2014. Paediatric 
hereditary angioedema: a survey of UK service provision and patient experience. Clin 
Exp Immunol, 178, 483-8.
Renne, T.and Gruber, A. 2012. Plasma kallikrein: novel functions for an old protease. Thromb 
Haemost, 107, 1012-3.
Roach, B., Kim, Y., Jerome, E.and Michael, A. F. 1981. Influence of age and sex on serum 
complement components in children. American journal of diseases of children (1960),
135, 918-20.
Roche, O., Blanch, A., Caballero, T., Sastre, N., Callejo, D.and Lopez-Trascasa, M. 2005. 
Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to 
the prevalence in Spain. Ann Allergy Asthma Immunol, 94, 498-503.
Sabharwal, G.and Craig, T. 2017. Pediatric hereditary angioedema: an update. F1000Research,
6.
Stray-Pedersen, Sorte, Samarakoon, Gambin, Chinn, Coban Akdemir, Erichsen, Forbes, Gu, 
Yuan, Jhangiani, Muzny, Rødningen, Sheng, Nicholas, Noroski, Seeborg, Davis, Canter, 
Mace, Vece, Allen, Abhyankar, Boone, Beck, Wiszniewski, Fevang, Aukrust, 
Tjønnfjord, Gedde-Dahl, Hjorth-Hansen, Dybedal, Nordøy, Jørgensen, Abrahamsen, 
Øverland, Bechensteen, Skogen, Osnes, Kulseth, Prescott, Rustad, Heimdal, Belmont, 
Rider, Chinen, Cao, Smith, Caldirola, Bezrodnik, Lugo Reyes, Espinosa Rosales, 
Guerrero-Cursaru, Pedroza, Poli, Franco, Trujillo Vargasand Aldave Becerr 2017. 
Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous 
Mendelian disorders. Journal of Allergy and Clinical Immunology, The, 139, 232-245.
Page 160
Property of Takeda: 
prev
re
wal, G.a
al, G.a
6.6.
ray
ray-Ped
Ped
For
ch, 
h,
itary
itary an
 a
y
vale
va
non-commercial
vey
vey o
y
Plasma
Plasm
3.
me, E.a
e, E.a
ompone
mpone
A., C
A., C
use
y and
y an
Smith
Smith
f U
f U
only 
ugati, A
gati,
exon d
exon d
d C
d
and
n Japa
Japa
A
subject 
he Jo
e J
oto, M., 
to, M
is, and 
s, and
n
to
Signi
Sign
Jour
Jour
the 
ma, a
,
nific
nific
applicable 
red
der, J. 2
der, J. 
with her
with he
a broa
a bro
Terms 
ditary
ditary
of Use

Shire
SHP643-302 Protocol Amendment 2
Lanadelumab (SHP643)
05 Oct 2020
Tosi, M. 1998. Molecular genetics of C1 inhibitor. Immunobiology, 199, 358-65.
Weller, K., Groffik, A., Magerl, M., Tohme, N., Martus, P., Krause, K., Metz, M., Staubach, 
P.and Maurer, M. 2012. Development and construct validation of the angioedema quality
of life questionnaire. Allergy, 67, 1289-98.
Yamamoto, T., Horiuchi, T., Miyahara, H., Yoshizawa, S., Maehara, J., Shono, E., Takamura, 
K., Machida, H., Tsujioka, K., Kaneko, T., Uemura, N., Suzawa, K., Inagaki, N., 
Umegaki, N., Kasamatsu, Y., Hara, A., Arinobu, Y., Inoue, Y., Niiro, H., Kashiwagai, Y., 
Harashima, S., Tahira, T., Tsukamoto, H.and Akashi, K. 2012. Hereditary angioedema in 
Japan: genetic analysis of 13 unrelated cases. The American journal of the medical 
sciences, 343, 210-4.
Zuraw, B.and Christiansen, S. 2016. HAE Pathophysiology and Underlying Mechanisms. 
Clinical Reviews in Allergy & Immunology, 51, 216-229.
Zuraw, B. L. 2008. Clinical practice. Hereditary angioedema. N Engl J Med, 359, 1027-36.
Zuraw, B. L., Bernstein, J. A., Lang, D. M., Craig, T., Dreyfus, D., Hsieh, F., Khan, D., Sheikh, 
J., Weldon, D., Bernstein, D. I., Blessing-Moore, J., Cox, L., Nicklas, R. A., 
Oppenheimer, J., Portnoy, J. M., Randolph, C. R., Schuller, D. E., Spector, S. L., Tilles, 
S. A., Wallace, D., American Academy of Allergy, A., Immunology, American College
of Allergy, A.and Immunology 2013. A focused parameter update: hereditary
angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme
inhibitor-associated angioedema. J Allergy Clin Immunol, 131, 1491-3.
Page 161
Property of Takeda: For non-commercial use only and
n Imm
Imm
subject 
r, D
Immuno
mmun
ameter u
meter 
angiot
angio
mun
to 
Nick
Nic
D. E
D E
the
ed,
eh, F., 
h, F., 
kla
kla
applicable 
de
dical 
dical 
chanism
hanis
359, 
359,
Terms 
ai, Y., 
ai, Y., 
ema i
ema i
of Use