Clinical trial NCT03401671
Conditions: Healthy Volunteers
Keywords: Lanadelumab
Sponsor: Shire
Start date: 2018-01-15; Completion date: 2018-05-30
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the pharmacokinetics (PK), safety and tolerability and pharmacodynamics (PD) of lanadelumab in healthy adult Japanese subjects and matched non-Hispanic healthy adult Caucasian subjects.

Detailed description:

Arms: arm 1: Healthy subjects of Japanese descent will receive a single dose of 300 milligrams (mg) lanadelumab subcutaneous (SC) injection in the abdomen. arm 2: Healthy Non-Hispanic Caucasian subjects will receive a single dose of 300 mg lanadelumab SC injection in the abdomen
Interventions: intervention 1: Lanadelumab
Intervention descriptions: intervention 1: SC injection of 300mg in 2mL (150 mg/mL) solution of lanadelumab will be administered as a single dose injection in the abdomen.

Protocol documents:
Prot_000.pdf: 
35272&2/6+3
7,7/(
$3KDVH2SHQODEHO6WXG\WR(YDOXDWHWKH3KDUPDFRNLQHWLFV6DIHW\
DQG7ROHUDELOLW\DQG3KDUPDFRG\QDPLFVRID6LQJOH'RVHRI
/DQDGHOXPDE$GPLQLVWHUHG6XEFXWDQHRXVO\LQ+HDOWK\$GXOW-DSDQHVH
6XEMHFWVDQG0DWFKHG+HDOWK\$GXOW&DXFDVLDQ6XEMHFWV
'58*
6+3ODQDGHOXPDEIRUPHUO\';
,1'

(8'5$&712
1RQ(8'5$&7
6321625
'\D[&RUSDQLQGLUHFWDQGZKROO\RZQHGVXEVLGLDU\RI6KLUHSOF
6KLUH:D\/H[LQJWRQ0$ 86$
35,1&,3$/
&225',1$7,1*
,19(67,*$725
0'
:HVW&RDVW&OLQLFDO7ULDOV
:HVW&HUULWRV$YHQXH
&\SUHVV&$  86$
35272&2/
+,6725<
2ULJLQDO3URWRFRO 1RY
7KLVGRFXPHQWFRQWDLQVFRQILGHQWLDODQGSURSULHWDU\LQIRUPDWLRQRI6KLUHDQGLVGLVFORVHGSXUVXDQWWR
FRQILGHQWLDOLW\DQGQRQGLVFORVXUHREOLJDWLRQV7KLVLQIRUPDWLRQVKRXOGEHXVHGVROHO\IRUWKHSXUSRVHVIRUZKLFK
LWZDVSURYLGHGDQGVKRXOGQRWEHFRSLHGVKDUHGZLWKRUGLVFORVHGWRDQ\WKLUGSDUW\ZLWKRXWWKHH[SUHVVZULWWHQ
FRQVHQWRI6KLUH
PPD








6KLUH
&21),'(17,$/
3DJH
3URWRFRO6+3
/DQDGHOXPDE
1RY
352'8&748$/,7<&203/$,176
,QYHVWLJDWRUVDUHUHTXLUHGWRUHSRUWLQYHVWLJDWLRQDOSURGXFWTXDOLW\FRPSODLQWVWR6KLUHZLWKLQ
 KRXUV7KLVLQFOXGHVDQ\LQVWDQFHVZKHUHLQWKHTXDOLW\RUSHUIRUPDQFHRID6KLUHSURGXFW
PDUNHWHGRULQYHVWLJDWLRQDOGRHVQRWPHHWH[SHFWDWLRQVHJLQDGHTXDWHRUIDXOW\FORVXUH
SURGXFWFRQWDPLQDWLRQRUWKDWWKHSURGXFWGLGQRWPHHWWKHVSHFLILFDWLRQVGHILQHGLQWKH
DSSOLFDWLRQIRUWKHSURGXFWHJZURQJSURGXFWVXFKWKDWWKHODEHODQGFRQWHQWVDUHGLIIHUHQW
SURGXFWV)RULQVWUXFWLRQVRQUHSRUWLQJ$(VUHODWHGWRSURGXFWFRPSODLQWVVHH6HFWLRQ
3OHDVHXVHWKHLQIRUPDWLRQEHORZDVDSSOLFDEOHWRUHSRUWWKH3URGXFW4XDOLW\&RPSODLQW
2ULJLQ RI3URGXFW4XDOLW\&RPSODLQW
(PDLO$GGUHVV
1RUWKDQG6RXWK$PHULFD
(XURSHDQ8QLRQDQG5HVWRI:RUOG
7HOHSKRQHQXPEHUVSURYLGHGIRUUHIHUHQFHLIQHHGHG
6KLUH/H[LQJWRQ0$86$
PPD
PPD
PPD


Shire
CONFIDENTIAL
Page 6
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
ADDITIONAL CONTACT INFORMATION................................................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
ABBREVIATIONS .......................................................................................................................11
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULE(S) ...............................................................................................................19
1
BACKGROUND INFORMATION.......................................................................................22
1.1
Indication and Current Treatment Options...............................................................22
1.2
Product Background.................................................................................................23
1.2.1
Preclinical Information ..........................................................................................23
1.2.2
Clinical Information...............................................................................................23
1.3
Risk/Benefit and Ethical Assessment.......................................................................23
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................23
2.1
Rationale for the Study.............................................................................................23
2.2
Study Objectives ......................................................................................................24
2.2.1
Primary Objectives.................................................................................................24
2.2.2
Secondary Objectives.............................................................................................24
2.2.3
Exploratory Objectives ..........................................................................................24
3
STUDY DESIGN ...................................................................................................................25
3.1
Study Design and Flow Chart ..................................................................................25
3.2
Duration and Study Completion Definition .............................................................26
3.3
Sites and Regions .....................................................................................................26
4
STUDY POPULATION.........................................................................................................26
4.1
Inclusion Criteria......................................................................................................26
4.2
Exclusion Criteria.....................................................................................................27
4.3
Restrictions...............................................................................................................28
4.4
Reproductive Potential .............................................................................................29
4.4.1
Female Contraception............................................................................................29
4.4.2
Male Contraception................................................................................................29
4.5
Discontinuation of Subjects .....................................................................................30
4.5.1
Reasons for Discontinuation..................................................................................30
4.5.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................30


Shire
CONFIDENTIAL
Page 7
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................31
5.1
Prior Treatment ........................................................................................................31
5.2
Concomitant Treatment............................................................................................31
5.2.1
Permitted Treatment...............................................................................................31
6
INVESTIGATIONAL PRODUCT ........................................................................................31
6.1
Identity of Investigational Product...........................................................................31
6.1.1
Blinding the Treatment Assignment......................................................................31
6.2
Administration of Investigational Product ...............................................................31
6.2.1
Allocation of Subjects to Treatment ......................................................................31
6.2.2
Dosing....................................................................................................................32
6.2.3
Unblinding the Treatment Assignment..................................................................32
6.3
Labeling, Packaging, Storage, and Handling ...........................................................32
6.3.1
Labeling .................................................................................................................32
6.3.2
Packaging...............................................................................................................33
6.3.3
Storage ...................................................................................................................33
6.4
Drug Accountability.................................................................................................33
6.5
Subject Compliance..................................................................................................34
6.6
Retention of Bioavailability and Bioequivalence Testing Samples.........................34
7
STUDY PROCEDURES........................................................................................................35
7.1
Study Schedule.........................................................................................................35
7.1.1
Screening Period....................................................................................................35
7.1.1.1
Screening Failure....................................................................................35
7.1.1.2
Rescreening of Subjects .........................................................................35
7.1.2
Treatment Period....................................................................................................36
7.1.2.1
In-house Confinement Period (Day 1 to Day 5) ....................................36
7.1.2.2
Out-Patient Visit Period (Day 6 to Day 112) .........................................36
7.1.2.3
Final Visit (Day 112)..............................................................................36
7.1.3
Additional Care of Subjects after the Study ..........................................................36
7.2
Study Evaluations and Procedures ...........................................................................36
7.2.1
Demographic and Other Baseline Characteristics .................................................36
7.2.2
Safety .....................................................................................................................37
7.2.2.1
Medical and Medication History............................................................37
7.2.2.2
Physical Examination (Including Height and Weight) ..........................37
7.2.2.3
Adverse Event Collection.......................................................................38
7.2.2.4
Vital Signs..............................................................................................38
7.2.2.5
Clinical Laboratory Evaluations.............................................................40
7.2.2.6
Pregnancy Test .......................................................................................41


Shire
CONFIDENTIAL
Page 8
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
7.2.2.7
Drug and Alcohol Screen .......................................................................41
7.2.2.8
Serology Screen......................................................................................42
7.2.2.9
Electrocardiogram ..................................................................................42
7.2.3
Pharmacokinetic Procedures..................................................................................43
7.2.3.1
Pharmacokinetic Sample Collection and Handling Procedures.............43
7.2.3.2
Shipment of Plasma Pharmacokinetic Samples .....................................44
7.2.3.3
Plasma Drug Assay Methodology..........................................................44
7.2.4
Pharmacodynamic Assessments ............................................................................44
7.2.4.1
Pharmacodynamic Sample Collection and Handling Procedures..........45
7.2.4.2
Shipment of Plasma Pharmacodynamic Samples ..................................45
7.2.4.3
Plasma Pharmacodynamic Assay Methodology ....................................45
7.2.5
Immunogenicity Testing for Anti-Drug Antibodies ..............................................45
7.2.6
Volume of Blood to Be Drawn from Each Subject ...............................................46
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................46
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................46
8.1.1
Severity Categorization..........................................................................................47
8.1.2
Relationship Categorization...................................................................................47
8.1.3
Outcome Categorization ........................................................................................48
8.1.4
Clinical Laboratory and Other Safety Evaluations................................................48
8.1.5
Pregnancy...............................................................................................................49
8.1.6
Abuse, Misuse, Overdose, and Medication Error..................................................49
8.2
Serious Adverse Event Procedures ..........................................................................50
8.2.1
Reference Safety Information................................................................................50
8.2.2
Reporting Procedures.............................................................................................50
8.2.3
Serious Adverse Event Definition .........................................................................51
8.2.4
Serious Adverse Event Collection Time Frame.....................................................51
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................51
8.2.6
Fatal Outcome........................................................................................................52
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................52
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................52
9.1
Data Collection.........................................................................................................52
9.2
Clinical Data Management.......................................................................................52
9.3
Data Handling Considerations..................................................................................53
9.4
Statistical Analysis Process......................................................................................53
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......54
9.6
Sample Size Calculation and Power Considerations................................................54


Shire
CONFIDENTIAL
Page 9
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
9.7
Analysis Populations/ Analysis Sets ........................................................................54
9.8
Pharmacokinetic and Pharmacodynamic Analyses..................................................54
9.8.1
Pharmacokinetic Analysis......................................................................................54
9.8.1.1
Statistical Analysis of Pharmacokinetic Parameters ..............................55
9.8.2
Pharmacodynamic Analysis...................................................................................55
9.8.3
Pharmacokinetic and Pharmacodynamic Analysis ................................................56
9.9
Safety Analyses........................................................................................................56
9.10
Other Analyses .........................................................................................................56
9.10.1 Exploratory Analysis .............................................................................................56
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................57
10.1
Sponsor’s Responsibilities .......................................................................................57
10.1.1 Good Clinical Practice Compliance.......................................................................57
10.1.2 Indemnity/Liability and Insurance.........................................................................57
10.1.3 Public Posting of Study Information......................................................................57
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................57
10.1.5 Study Suspension, Termination, and Completion..................................................58
10.2
Investigator’s Responsibilities .................................................................................58
10.2.1 Good Clinical Practice Compliance.......................................................................58
10.2.2 Protocol Adherence and Investigator Agreement..................................................58
10.2.3 Documentation and Retention of Records.............................................................59
10.2.3.1
Case Report Forms.................................................................................59
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................59
10.2.3.3
Audit/Inspection.....................................................................................60
10.2.3.4
Financial Disclosure...............................................................................60
10.3
Ethical Considerations..............................................................................................60
10.3.1 Informed Consent...................................................................................................60
10.3.2 Institutional Review Board or Ethics Committee..................................................61
10.4
Privacy and Confidentiality......................................................................................61
10.5
Study Results/Publication Policy .............................................................................62
11 REFERENCES .......................................................................................................................64
12 APPENDICES ........................................................................................................................65
Appendix 1
Protocol History .....................................................................................66


Shire
CONFIDENTIAL
Page 10
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
LIST OF TABLES
Table 1: 
Schedule of Assessments...............................................................................19
Table 2: 
Detailed Schedule of Assessments ................................................................20
Table 3: 
Volume of Blood to Be Drawn from Each Subject.......................................46
LIST OF FIGURES
Figure 1:
Study Design Flow Chart ..............................................................................25
Figure 2:
Procedures for Screening Vital Signs (Blood Pressure – Pulse) –
Healthy Subjects Only...................................................................................39


Shire
CONFIDENTIAL
Page 11
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
ABBREVIATIONS
z
%CV
AE
Terminal elimination rate constant
Percent coefficient of variation
Adverse Event
ADA
Anti-drug antibody
aPTT
AUC0-last
AUC0-∞
Activated partial thromboplastin time
Area under the concentration-time curve from time zero to the last 
quantifiable concentration in plasma
Area under the concentration-time curve from time zero extrapolated to 
infinity
-hCG
Beta-Human Chorionic Gonadotropin
BMI
BP
CRA
Body Mass Index
Blood Pressure
Clinical Research Associate
CRC
Clinical Research Center
CRF
cHMWK
Cmax
C1-INH
Case Report Form
Cleaved High Molecular Weight Kininogen
Maximum Observed Plasma Drug Concentration
C1 Inhibitor
CHO
CL/F
Chinese Hamster Ovary
Apparent Clearance
CRO
CV%
Contract Research Organization
Coefficient of Variation
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
EMA
Electrocardiogram
European Medicines Agency
EU
European Union
FDA
FSH
Food and Drug Administration
Follicle Stimulating Hormone
GCP
Good Clinical Practice
HAE
HBsAg
HCV
Hereditary Angioedema
Hepatitis B Surface Antigen
Hepatitis C Virus


Shire
CONFIDENTIAL
Page 12
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
HIPAA
HIV
Health Insurance Portability and Accountability Act
Human Immunodeficiency Virus
ICH
INR
IgG1
International Conference on Harmonisation
International Normalized Ratio
Immunoglobulin G Subclass 1
IRB
Institutional Review Board
IRT
Ki
Interactive Response Technology
Inhibition Constant
MHLW
LLOQ
Mg
mL
mmHG
PD
PK
PMDA
PR
PT
QRS
QT
QTcB
QTcF
RR
Ministry of Health, Labor and Welfare
Lower limit of Quantification
Milligram
Milliliter 
Millimeters Mercury
Pharmacodynamic
Pharmacokinetic
Pharmaceuticals and Medical Devices Agency
Time elapsed from P wave to R wave in an electrocardiogram
Prothrombin Time
Measure of time for the 3 main deflections in an electrocardiogram
Measure of time between the start of the Q wave and the end of the T 
wave in an electrocardiogram
Measure of time between the start of the Q wave and the end of the T 
wave using Bazett’s formula in an electrocardiogram
Measure of time between the start of the Q wave and the end of the T 
wave using Fridericia’s formula in an electrocardiogram
The time between heart beats in an electrocardiogram
SAE
Serious Adverse Event
SAP
SC
SD
TEAE
t½
Statistical Analysis Plan
Subcutaneous
Standard Deviation
Treatment-Emergent Adverse Event
Terminal half-life
US
Vdz/F
United States
Apparent Volume of Distribution


6KLUH
&21),'(17,$/
3DJH
3URWRFRO6+3
/DQDGHOXPDE
1RY
678'<6<1236,6
3URWRFROQXPEHU6+3
'UXJ /DQDGHOXPDE
7LWOHRIWKHVWXG\$3KDVH2SHQODEHO6WXG\WR(YDOXDWHWKH3KDUPDFRNLQHWLFV6DIHW\DQG7ROHUDELOLW\DQG
3KDUPDFRG\QDPLFVRID6LQJOH'RVHRI/DQDGHOXPDE$GPLQLVWHUHG6XEFXWDQHRXVO\LQ+HDOWK\$GXOW-DSDQHVH
6XEMHFWVDQG0DWFKHG+HDOWK\$GXOW&DXFDVLDQ6XEMHFWV
1XPEHURIVXEMHFWVWRWDODQGIRUHDFKWUHDWPHQWDUP
$WRWDORIKHDOWK\DGXOWPDOHDQGRUIHPDOHVXEMHFWVZLOOEHHQUROOHGLQWRWKHVWXG\FRPSULVLQJVXEMHFWVRI
-DSDQHVHGHVFHQWDQGPDWFKHGQRQ+LVSDQLF&DXFDVLDQVXEMHFWV$VVXPLQJDGURSRXWUDWH DSSUR[LPDWHO\
VXEMHFWVIURPHDFKUDFHHWKQLFLW\DUHH[SHFWHGWRFRPSOHWHWKHVWXG\ 6WXG\VXEMHFWVZKRZLWKGUDZRU
GLVFRQWLQXHHDUO\PD\EHUHSODFHGDWWKHGLVFUHWLRQRIWKHVSRQVRU 1RQ+LVSDQLF&DXFDVLDQVXEMHFWVZLOOEH
PDWFKHGWRVXEMHFWVRI-DSDQHVHGHVFHQWEDVHGRQVH[ PDOHPDOHIHPDOHIHPDOHDJH\HDUV DQGERG\
PDVVLQGH[
•
7KHVXEMHFWVRI-DSDQHVHGHVFHQWZLOOUHFHLYHRQHVLQJOHPJVXEFXWDQHRXV6&GRVHRIODQDGHOXPDE
•
0DWFKHGQRQ+LVSDQLF&DXFDVLDQVXEMHFWVZLOOUHFHLYHRQHVLQJOHPJ6&GRVHRIODQDGHOXPDE
,QYHVWLJDWRUV
0'
6LWHVDQG5HJLRQV
:HVW&RDVW&OLQLFDO7ULDOV
&HUULWRV$YH
&\SUHVV&$ 
6WXG\SHULRGSODQQHG

&OLQLFDOSKDVH

2EMHFWLYHV
3ULPDU\7RHYDOXDWHWKHSKDUPDFRNLQHWLF3.SURSHUWLHVRIODQDGHOXPDEDGPLQLVWHUHGDVDVLQJOH6&GRVHRI
PJLQKHDOWK\DGXOWYROXQWHHUVXEMHFWVRI-DSDQHVHGHVFHQWDQGPDWFKHGQRQ+LVSDQLF &DXFDVLDQKHDOWK\
YROXQWHHUVXEMHFWV
6HFRQGDU\7RDVVHVVWKHVDIHW\DQGWROHUDELOLW\RIODQDGHOXPDEDGPLQLVWHUHGDVDVLQJOH6&GRVHRIPJWR
KHDOWK\DGXOWYROXQWHHUVXEMHFWVRI-DSDQHVHGHVFHQWDQGPDWFKHGQRQ+LVSDQLF&DXFDVLDQKHDOWK\YROXQWHHU
VXEMHFWV
(QGSRLQWVFRUUHVSRQGLQJWRWKHSULPDU\DQGVHFRQGDU\REMHFWLYHVDUHGHILQHGLQWKHHQGSRLQWVDQGVWDWLVWLFDODQDO\VLV
VHFWLRQRIWKLV6\QRSVLV
5DWLRQDOH
7KLVVWXG\LVEHLQJFRQGXFWHGWRFKDUDFWHUL]HWKH3.DQGSKDUPDFRG\QDPLF3' SURSHUWLHVRIODQDGHOXPDEDQGWR
HYDOXDWHWKHVDIHW\DQGWROHUDELOLW\RIODQDGHOXPDEDGPLQLVWHUHGDVDVLQJOH6&GRVHRIPJLQKHDOWK\VXEMHFWVRI
-DSDQHVHGHVFHQWDQGLQPDWFKHGKHDOWK\QRQ+LVSDQLF &DXFDVLDQVXEMHFWV 7KHUHVXOWVRIWKLVVWXG\ZLOOEHXVHGWR
VXSSRUWWKHVHOHFWLRQRIWKHGRVLQJUHJLPHQIRUD3KDVHVWXG\FRQGXFWHGLQ -DSDQHVHSDWLHQWVZLWKKHUHGLWDU\
DQJLRHGHPD+$(
7KH-DSDQHVHUHJXODWRU\DJHQFLHV3KDUPDFHXWLFDOVDQG0HGLFDO'HYLFHV$JHQF\30'$DQGWKH0LQLVWU\RI
+HDOWK/DERUDQG:HOIDUH0+/:UHTXLUHHYLGHQFHWKDWFXUUHQWGDWDLQQRQ-DSDQHVHVXEMHFWVFDQEHH[WUDSRODWHG
WRWKH-DSDQHVHSRSXODWLRQ )RUWKLVUHDVRQWKH6+3VWXG\LVGHVLJQHGWRFKDUDFWHUL]H3.DQG3'SURILOHVDV
ZHOODVWRHYDOXDWHWKHVDIHW\DQGWROHUDELOLW\RIODQDGHOXPDELQ-DSDQHVHDQGPDWFKHGQRQ+LVSDQLF&DXFDVLDQ
KHDOWK\YROXQWHHUVXEMHFWV
PPD


Shire
CONFIDENTIAL
Page 14
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Investigational product, dose, and mode of administration:

Lanadelumab, 300mg SC injection into the abdomen.

Lanadelumab is a recombinant, fully human immunoglobulin G subclass 1 (IgG1), a kappa light chain 
monoclonal antibody expressed in Chinese Hamster Ovary (CHO) cells. Lanadelumab is a potent 
(Ki = 125 pM) inhibitor of the proteolytic activity of plasma kallikrein. Lanadelumab drug product is a colorless 
to yellow, sterile, preservative-free solution, appearing either clear or with slight opalescence. The active 
ingredient, lanadelumab, is formulated using the following compendial components: 30mM sodium phosphate 
dibasic dihydrate, 19.6mM citric acid, 50 mM histidine, 90 mM sodium chloride, 0.01% Polysorbate 80. Each 
vial contains a nominal concentration of 300 mg in 2 mL (150 mg/mL) solution. A 300 mg, single SC dose was 
selected for this study. For each 300 mg dose of lanadelumab, each subject will receive a total of 2 mL, which 
will be administered in a single 2 mL SC injection. This study is open-label and does not require the use of a 
placebo.
Methodology:
This study is a Phase 1, open-label, matched-control, single-dose, single-center study to evaluate the PK, safety and 
tolerability and PD of lanadelumab administered to healthy adult volunteer subjects of Japanese descent and 
matched non-Hispanic, Caucasian healthy adult volunteer subjects. A total of 32 subjects between the ages of 18-55, 
inclusive will be enrolled: 16 non-Hispanic Caucasian subjects and 16 subjects of Japanese descent. Assuming a 
25% dropout rate, approximately 24 subjects (12 subjects from each race/ethnicity) are expected to complete the 
study. Non-Hispanic Caucasian subjects will be matched to Japanese subjects based on sex (1:1 male: male, female: 
female), age (±5 years), and body mass index (BMI) (±15%). For example, a Japanese male, age 40 years, and BMI 
of 22 kg/m2 will be matched with a Caucasian male, age 40 ± 5 years (35-45 years [inclusive]), and BMI of 
22 ±15% (18.7-25.3 kg/m2). 
All subjects will receive a single dose of 300 mg of lanadelumab administered by SC injection into the abdomen.
The study duration will be comprised of a 28-day screening period, one 5-day in-house treatment period, and 
multiple out-patient visits (Day 7 [± 1 day], Day 14 [± 1 day], Day 21 [± 1 day], Day 28 [± 1 day], Day 42 
[± 2 days], Day 56 [± 2 days], Day 84 [± 3 days] and Day 112 [± 3 days]) after the single dose of investigational 
product is administered. The maximal total duration of study participation for a subject is approximately 140 days if 
the maximal screening, treatment, and out-patient durations are used.
Screening Period
Screening will occur within 28 days of the first dose. Subjects will be admitted to the Clinical Research Center 
(CRC) on Day -1.
In-House Confinement Treatment Period

On Day 1, all subjects will receive lanadelumab as a single 300 mg SC injection into the abdomen.

All subjects will remain in the CRC until completion of the 96 hour postdose PK sample on Day 5.
Assessments

Serial blood samples for PK analysis will be collected for the determination of plasma lanadelumab 
concentrations from Day 1 predose and up to 96 hours post dose during the in-house confinement period 
and up to Day 112 during the out-patient visit period. These blood samples will be collected according to 
the Schedule of Assessments.


Shire
CONFIDENTIAL
Page 15
Protocol SHP643-101  
Lanadelumab
27 Nov 2017

Safety and tolerability including anti-drug antibodies (ADAs) will be determined through assessment of 
treatment-emergent adverse events (TEAEs) and vital signs, electrocardiogram (ECG) findings, and clinical 
laboratory evaluations on Day 1 predose and up to 96 hours postdose during the in-house confinement 
period and up to Day 112 during the out-patient visit period according to the Schedule of Assessments.

Serial blood samples for PD analysis will be collected for kallikrein activity and for cleaved high molecular 
weight kininogen (cHMWK) from Day 1 predose and up to 96 hours postdose during the in-house 
confinement period and up to Day 112 during the out-patient visit period. These blood samples will be 
collected according to the Schedule of Assessments.
Out-Patient Visit Period
Out-patient visits will be completed on the following Study Days:

Day 7 (± 1 day; ie, Day 6, 7, or 8) 

Day 14 (± 1 day; ie, Day 13, 14 or 15) 

Day 21 (± 1 day; ie, Day 20, 21 or 22)

Day 28 (± 2 day; ie, Day 26, 27 28, 29, or 30) 

Day 42 (± 2 days; ie, Day 40, 41, 42, 43 or 44) 

Day 56 (± 2 days; ie, Day 54, 55, 56, 57 or 58) 

Day 84 (± 3 days; ie, Day 81, 82, 83, 84, 85, 86 or 87)

Day 112 (± 3 days; ie, Day 109, 110, 111, 112, 113, 114 or 115) 
after the single dose of investigational product is administered. Refer to Table 2 for complete details.
Inclusion Criteria:
1.
Ability to voluntarily provide written, signed, and dated informed consent as applicable to 
participate in the study.
2.
An understanding, ability, and willingness to fully comply with study procedures and restrictions.
3.
Age 18-55, inclusive, at the time of consent. The date of signature of the informed consent is 
defined as the beginning of the Screening Period. This inclusion criterion will only be assessed at 
the first screening visit.
4.
Subjects must be either:
a.
A subject of Japanese descent born in Japan, who has resided outside of Japan for no 
longer than 5 years and is of Japanese parentage, defined as having 2 Japanese parents 
and 4 Japanese grandparents, all born in Japan
b.
A non-Hispanic, Caucasian subject who has 2 non-Hispanic, Caucasian parents and 
4 non-Hispanic, Caucasian grandparents
5.
Male or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of nonchildbearing potential.
6.
Considered “healthy” by the investigator. Healthy status is defined by absence of evidence of any 
active or chronic disease following a detailed medical and surgical history, as well as a complete 
physical examination including vital signs, 12-lead ECG, hematology, blood chemistry, and 
urinalysis.


Shire
CONFIDENTIAL
Page 16
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
7.
Body mass index between 18.5-33 kg/m², inclusive, with a body weight ≥45 kg (99lbs). This 
inclusion criterion will only be assessed at the screening visit.
8.
Willing and able to consume standardized meals during the confinement period of the study. All 
participants will be required to consume the identical meals on study days when serial PK and PD 
blood samples are collected.
Exclusion Criteria:
1.
History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or 
psychiatric disease, gall bladder removal, or current or recurrent disease that could affect the 
action, absorption, or disposition of the investigational product, or clinical or laboratory 
assessments.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may require 
treatment or make the subject unlikely to complete the study, or any condition that presents undue 
risk from the investigational product or procedures.
3.
Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
4.
Significant illness, as judged by the investigator, within 2 weeks of the dose of investigational 
product.
5.
Known history of alcohol or other substance abuse within the last year, per the investigator.
6.
Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to receiving the 
dose of investigational product.
7.
Within 30 days prior to the dose of investigational product:
a.
Have used an investigational product (if elimination half-life is <6 days, otherwise 
5 half-lives).
b.
Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study.
8.
Confirmed systolic blood pressure (BP) >139mmHg or <89mmHg, and diastolic BP >89mmHg or 
<49mmHg.
9.
Twelve-lead ECG values (average of triplicate readings) demonstrating QTc >450msec (males) or 
>470msec (females) at the Screening Visit or Day -1.
10.
Positive screen for drugs of abuse (i.e. amphetamines, benzodiazepines, barbiturates, cocaine,
marijuana, opiates, phencyclidine) at Screening, or drugs of abuse or alcohol on Day -1.
11.
Male subjects who consume more than 21 units of alcohol per week or 3 units per day. Female 
subjects who consume more than 14 units of alcohol per week or 2 units per day. One alcohol 
unit=1 beer or 1 wine (5oz/150mL) or 1 liquor (1.5oz/40mL) or 0.75oz alcohol.
12.
Positive HIV, HBsAg, or HCV antibody screen.
13.
Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing products in any 
form (eg, gum, patch, electronic). Ex-users must report that they have stopped using tobacco for at 
least 30 days prior to receiving the dose of investigational product.


Shire
CONFIDENTIAL
Page 17
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
14.
Routine consumption of more than 2 units of caffeine per day or subjects who experience caffeine 
withdrawal headaches. One caffeine unit is contained in the following items: one 6oz (180mL) cup 
of coffee, two 12oz (360mL) cans of cola, one 12 oz cup of tea, and three 1oz (85g) chocolate 
bars. Decaffeinated coffee, tea, or cola are not considered to contain caffeine).
15.
Current use of any medication (including over-the-counter, herbal, or homeopathic preparations; 
with the exception of stable hormonal replacement therapy or hormonal contraceptives). Current 
use is defined as use within 14 days of the dose of investigational product. See Section 5 (Prior 
and Concomitant Treatment) for a list of permitted medications.
16.
Abnormal laboratory values considered clinically significant, as determined by the investigator at 
Screening or Day -1.
17.
History of any clinically significant surgery or procedure within 8 weeks of receiving the dose of 
investigational product, as determined by the investigator.
Maximum duration of subject involvement in the study:

Planned duration of screening period: 28 days maximum

Planned duration of in-house confinement period: 5 days 

Planned duration of out-patient visit period: 107 days 
Endpoints and statistical analysis:
Pharmacokinetic endpoint(s)/parameters:

Cmax: Maximum observed plasma drug concentration

tmax: Time to reach Cmax in plasma

AUC0-last: Area under the concentration-time curve from time zero to the last quantifiable concentration in 
plasma

AUC0-∞ : Area under the concentration-time curve from time zero extrapolated to infinity

z: Terminal elimination rate constant

t½: Terminal half-life

CL/F: Apparent clearance

Vdz/F: Apparent volume of distribution
Safety is the secondary objective of this study. Safety endpoint(s):

Treatment-emergent adverse events: Number and percentage of subjects with TEAEs; severity; seriousness; 
causality; number of TEAEs. 

Clinical laboratory results (hematology, clinical chemistry, coagulation and urinalysis): Changes from 
baseline to post-baseline time points; clinically significant abnormal laboratory assessments.

Other: Vital signs (including BP, pulse, body temperature), 12-lead ECG, and physical examination: 
Changes from baseline to post-baseline time points.

Anti-drug antibodies


Shire
CONFIDENTIAL
Page 18
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Analysis populations/analysis sets:

Safety population (Safety Analysis Set), defined as all subjects who received at least 1 dose of lanadelumab 
(study drug). All safety analyses will be based on the Safety population/Safety Analysis Set.

Pharmacokinetic population (PK Analysis Set), defined as all subjects who received at least 1 dose of 
lanadelumab and have at least 1 evaluable postdose PK concentration value. All PK analyses will be based 
on the PK population/PK Analysis Set).
Statistical analysis:
No statistical hypothesis testing is planned. Analysis details will be provided in the study Statistical Analysis Plan 
(SAP), which will be finalized prior to study database lock. Only descriptive analysis will be performed to evaluate 
all primary and secondary endpoints. Summaries will be presented by racial/ethnic group (Japanese vs. 
non-Hispanic Caucasians), and, if appropriate, by time point. All data, including derived data, will be presented in 
subject data listings, and all listings will include subject’s sex, age, race/ethnicity, and BMI.

No interim analysis or Data Monitoring Committee (DMC) is planned.


Shire
CONFIDENTIAL
Page 19
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
STUDY SCHEDULE(S)
Table 1: Schedule of Assessments
Visit
Screening
In-House Treatment Period
Out-Patient 
Visitsa/ Early 
Discontinuationb
Study Day
–28 to -02
-1
1
2
3
4
5
Informed consent
X
Inclusion/exclusion criteria
X
X
Demography and medical/medication 
history
X
X c
Physical examination 
X
X
X
X
Vital signs (blood pressure, pulse) 
supine d
X
X
X
X
X
X
X
X
Body temperature (oral)
X
X
X
Height, Weight and BMI e,f
X
X
X
X
Electrocardiogram (12-lead) d
X g
X g
X
X
X
X
X
X
Biochemistryh, 
hematology, 
and 
urinalysis 
X
X
X
X
X
PT, aPTT, INR
X
X
X
X
HIV, HBsAg, and HCV antibodies
X
Serum Pregnancy test (all females) d
X
X
X
X
FSH (females only)
X
Urine drug and alcohol (breath test) 
screening i
X
X
X j
Investigational Product administration
X
Pharmacokinetic blood sampling d
X
X
X
X
X
X j
Anti-drug antibody testing d
X
X
Pharmacodynamic blood sampling d
X
X
X
X
X
X j
Check-in to the CRC
X
Discharge from the CRC
X
In-house confinement
X
X
X
X
X
Out-patient visits
X
X
Adverse events/serious adverse events 
X
X
X
X
X
X
X
X
Concomitant medication 
X
X
X
X
X
X
X
X
HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus
a There will be multiple out-patient visits on: Day 7 (± 1 day), Day 14 (± 1 day), Day 21 (± 1 day), Day 28 (± 1 day), Day 42 (± 
2 days), Day 56 (± 2 days), Day 84 (± 3 days) and End of Study Day 112 (± 3 days), after the dose of investigational product
is administered on Day 1. Refer to Table 2 for complete details.
b In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete
these assessments.
c Medical history and medication history review only
d See Table 2 for detailed collection time points
e Height will be recorded at the Screening Visit only
f BMI criteria for eligibility will be calculated at the Screening Visit.
g ECGs will be performed in triplicate at Screening and Day -1 only. Thereafter, all subsequent ECGs will be single recordings
h Thyroid function tests (TSH, T3, T4) will be collected as part of the biochemistry panel at Screening only.
i Drugs of abuse at screening, and drugs of abuse and alcohol (breath test) on Day -1 and at all out-patient visits. 
j No PK or PD sample, or urine drug or alcohol screen should be collected for early discontinuation.


Shire
CONFIDENTIAL
Page 20
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Table 2: Detailed Schedule of Assessments
In-House Treatment Period
Out-Patient Visits
Study Day
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
7±1
Day
14±1
Day
21±1
Day
28±2
Day
42±2
Day
56±2
Day
84± 3
Day
112±3
End of 
Study 
(or Early 
Term.a)
Hour (relative to 
dosing time)
Pre
dose
0
1h
2h
4h
6h
8h
12h
24h
48h
72h
96h
Physical 
examination 
X
X
X
X
X
X
X
X
X
Vital signs 
(blood pressure, 
pulse) supine
Xb
X
X
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body temperature 
(oral)
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
Electrocardiogram 
(12-lead) c
Xb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biochemistry, 
hematology, and 
urinalysis
X
X
X
X
X
X
X
X
X
X
PT, aPTT, INR
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
(all women)
X
X
X
X
X
X
X
X
X
Urine drug and 
alcohol (breath test) 
screen
X
X
X
X
X
X
X
X d
Investigational 
Product
administration
X
Pharmacokinetic 
blood sampling
Xb
X
X
X
X
X
X
X
X
X
X
X
X
X d
Pharmacodynamic 
blood sampling
Xb
X
X
X
X
X
X
X
X
X
X
X
X
X d
Anti-drug antibody 
sampling
Xb
X
X
X
X
Adverse 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Shire
CONFIDENTIAL
Page 21
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Table 2: Detailed Schedule of Assessments
In-House Treatment Period
Out-Patient Visits
Study Day
Day 1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
7±1
Day
14±1
Day
21±1
Day
28±2
Day
42±2
Day
56±2
Day
84± 3
Day
112±3
End of 
Study 
(or Early 
Term.a)
Hour (relative to 
dosing time)
Pre
dose
0
1h
2h
4h
6h
8h
12h
24h
48h
72h
96h
events/serious 
adverse events 
Concomitant 
medication 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
b These assessments should be performed within 60 minutes prior to dose administration.
c ECG’s will be performed as single records at each timepoint.
d No PK or PD sample, or urine drug or alcohol screen should be collected for early discontinuation.


Shire
CONFIDENTIAL
Page 22
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
1
BACKGROUND INFORMATION
Lanadelumab (SHP643, formerly DX-2930) is a recombinant, fully human immunoglobulin G 
subclass 1 (IgG1), a kappa light chain monoclonal antibody expressed in Chinese Hamster Ovary 
(CHO) cells that has been studied in a double-blind, pivotal Phase 3 study (Study DX-2930-03), 
and is being studied in an on-going open-label Phase 3 study (Study DX-2930-04) to determine 
if it is safe and effective for the prevention of angioedema attacks in patients with hereditary 
angioedema (HAE).
This study is being conducted to evaluate the PK, safety and tolerability, and pharmacodynamic 
(PD) of lanadelumab administered as a single subcutaneous (SC) dose of 300 mg in a Japanese 
population in comparison with a single SC dose of 300 mg in a matched non-Hispanic,
Caucasian population.
For further details see the current lanadelumab Investigator’s Brochure.
1.1
Indication and Current Treatment Options 
Lanadelumab is in development for prevention of angioedema attacks in patients with Types I or 
II HAE, a rare and potentially life-threatening disease.
Lanadelumab is a recombinant, fully human IgG1, kappa light chain, monoclonal antibody 
expressed in CHO cells. Lanadelumab is a potent (Ki = 125 pM) inhibitor of the proteolytic 
activity of plasma kallikrein.
The activity, potency and, specificity of lanadelumab have been demonstrated in vitro and ex 
vivo and have been confirmed in clinical studies.
Hereditary angioedema is a long-term, debilitating, and potentially life-threatening disease 
caused by mutations in the C1-inhibitor (C1-INH) gene, resulting in deficiency or dysfunction of 
C1-INH protein. HAE manifests clinically as unpredictable, intermittent attacks of SC or 
submucosal edema of the face, larynx, gastrointestinal tract, limbs, and/or genitalia (Zuraw, 
2008). Swelling may last up to 5 days; most patients suffer multiple attacks per year. HAE is an 
orphan disease. Its exact prevalence is unknown; however, current estimates range from 1 per 
10,000 to 1 per 150,000 persons, with many authors agreeing that 1 per 50,000 is likely the 
closest estimate (Bygum, 2009; Goring et al., 1998; Lei et al., 2011; Nordenfelt et al., 2014; 
Roche et al., 2005).
Currently, HAE drugs are indicated either for prophylaxis against attacks or for treatment of 
acute attacks. Acute treatments include purified, plasma-derived C1-INH, recombinant C1-INH, 
a plasma kallikrein inhibitor, and a bradykinin type 2 (B2) receptor antagonist. While acute 
treatments are effective at resolving the symptoms of acute attacks, they do not prevent attacks 
and thus leave patients at risk of developing debilitating and potentially life-threatening attacks.
Agents used for prophylaxis include purified plasma-derived C1-INH, attenuated androgens, and 
antifibrinolytic agents.


Shire
CONFIDENTIAL
Page 23
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
These currently available therapies represent an important addition to the therapeutic options for 
HAE patients; however, there remains a need for more optimal prophylactic therapy with 
improved efficacy, longer half-lives and more convenient administration frequencies.
1.2
Product Background
1.2.1
Preclinical Information
Nonclinical studies to evaluate the pharmacokinetic (PK) and toxicology of systemically 
administered lanadelumab have been completed in rats and cynomolgus monkeys.
Single-dose, 28-day and 6-month multidose studies of systemically administered lanadelumab in 
cynomolgus monkeys did not identify toxicologically significant effects at doses up to 
50 mg/kg administered weekly by SC injections. Studies to evaluate male and female fertility in 
the cynomolgus monkey, at similar dose levels, revealed no adverse treatment-related findings.
There were no adverse treatment-related findings after 28 days of IV dosing up to 50 mg/kg
In addition, results from a separate lanadelumab single-dose SC injection study to evaluate 
potential toxicity and toxicokinetic profiles in Sprague-Dawley rats, showed lanadelumab to be 
well-tolerated at up to 50 mg/kg.
Refer to the lanadelumab Investigator’s Brochure for further information.
1.2.2
Clinical Information
The clinical development program for lanadelumab consists of two completed Phase 1 studies: a 
single-ascending dose Phase 1a Study, DX2930 01 in healthy adult subjects and a multiple-
ascending dose and Phase 1b Study DX2930 02 in adult subjects with HAE; a completed pivotal, 
double-blind, placebo-controlled Phase 3 Study DX2930 03 (HELP Study®), and one ongoing 
open-label Phase 3 Study DX2930 04 (HELP Study Extension™) in adolescents and adult 
subjects with HAE.
Always refer to the latest version of the lanadelumab Investigator’s Brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the metabolism, 
pharmacokinetics, efficacy, and safety of lanadelumab.
1.3
Risk/Benefit and Ethical Assessment
There is no anticipated benefit from taking part in this study.
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
This study is being conducted to characterize the PK and PD properties of lanadelumab and to 
evaluate the safety and tolerability of lanadelumab administered as a single SC dose of 300 mg in 
healthy subjects of Japanese descent and in matched healthy non-Hispanic, Caucasian subjects.


Shire
CONFIDENTIAL
Page 24
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
The results of this study will be used to support the selection of the dosing regimen for a Phase 3 
study conducted in Japanese patients with HAE.
The Japanese regulatory agencies, Pharmaceuticals and Medical Devices Agency (PMDA), and 
the Ministry of Health, Labor and Welfare (MHLW), require evidence that current data in 
non-Japanese subjects can be extrapolated to the Japanese population. For this reason, the 
SHP643-101 study is designed to characterize PK and PD profiles, as well as to evaluate the 
safety and tolerability of lanadelumab in Japanese and matched non-Hispanic, Caucasian healthy 
volunteer subjects.
A number of scientific publications have suggested the similarity of the PK profiles of 
monoclonal antibody products between ethnic healthy subjects groups (Chiba et al., 2014; 
Morrison et al., 2015), thereby supporting the extrapolation of safety and efficacy data from 
other ethnic groups to Japanese patients with HAE. This study is aimed to specifically confirm 
this observation for lanadelumab administered as a single SC 300 mg dose. The study can be 
conducted in a clinical research facility that is located outside of Japan as long as steps are taken 
to ensure the Japanese subjects are verified as Japanese, as noted in Inclusion Criterion 4.
2.2
Study Objectives
2.2.1
Primary Objectives
To evaluate the PK properties of lanadelumab administered as a single SC dose of 300 mg in 
healthy adult volunteer subjects of Japanese descent and matched non-Hispanic, Caucasian 
healthy volunteer subjects.
2.2.2
Secondary Objectives
To assess the safety and tolerability of lanadelumab administered as a single SC dose of 300 mg 
to healthy adult volunteer subjects of Japanese descent and matched, non-Hispanic Caucasian 
healthy volunteer subjects.
2.2.3
Exploratory Objectives
To explore the PD properties of lanadelumab including plasma kallikrein activity and cleaved 
high molecular weight kininogen (cHMWK) plasma levels after a single SC dose of 300 mg of 
lanadelumab administered to healthy adult volunteer subjects of Japanese descent and matched 
non-Hispanic, Caucasian healthy volunteer subjects.
Endpoints corresponding to the primary and secondary objectives are defined in the 
Study Synopsis, and endpoints corresponding to the exploratory objective are defined in 
Section 9.8.2.




Shire
CONFIDENTIAL
Page 26
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 140 days. The 
study is expected to be completed in approximately 20 weeks. 
The Study Completion Date is defined as the date the final subject completes their final 
protocol-defined assessment. Please note that this includes the follow-up visit or contact, 
whichever is later. The Study Completion Date is used to ascertain timing for study results 
posting and reporting.
3.3
Sites and Regions
This study will be performed at one study site within the United States.
4
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
Subjects cannot be enrolled before all inclusion criteria (including test results) are confirmed.
1. Ability to voluntarily provide written, signed, and dated informed consent as applicable to 
participate in the study.
2. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.
3. Age 18-55, inclusive, at the time of consent. The date of signature of the informed consent is 
defined as the beginning of the Screening Period. This inclusion criterion will only be 
assessed at the first screening visit.
4. Subjects must be either:
a.
A subject of Japanese descent born in Japan, who has resided outside of Japan 
for no longer than 5 years and is of Japanese parentage, defined as having 
2 Japanese parents and 4 Japanese grandparents, all born in Japan.
b. A non-Hispanic, Caucasian subject who has 2 non-Hispanic, Caucasian 
parents and 4 non-Hispanic, Caucasian grandparents.
5. Male or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential.


Shire
CONFIDENTIAL
Page 27
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
6. Considered “healthy” by the investigator. Healthy status is defined by absence of evidence of 
any active or chronic disease following a detailed medical and surgical history, as well as a 
complete physical examination including vital signs, 12-lead ECG, hematology, blood 
chemistry, and urinalysis.
7. Body mass index between 18.5-33 kg/m², inclusive, with a body weight ≥45 kg (99lbs). This 
inclusion criterion will only be assessed at the screening visit.
8. Willing and able to consume standardized meals during the confinement period of the study. 
All participants will be required to consume the identical meals on study days when serial PK 
and PD blood samples are collected.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or 
psychiatric disease, gall bladder removal, or current or recurrent disease that could affect the 
action, absorption, or disposition of the investigational product, or clinical or laboratory 
assessments.
2. Current or relevant history of physical or psychiatric illness, any medical disorder that may 
require treatment or make the subject unlikely to complete the study, or any condition that 
presents undue risk from the investigational product or procedures.
3. Known or suspected intolerance or hypersensitivity to the investigational product, closely-
related compounds, or any of the stated ingredients.
4. Significant illness, as judged by the investigator, within 2 weeks of the dose of 
investigational product.
5. Known history of alcohol or other substance abuse within the last year, per the investigator.
6. Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to 
receiving the dose of investigational product.
7. Within 30 days prior to the dose of investigational product:
a.
Have used an investigational product (if elimination half-life is <6 days, 
otherwise 5 half-lives).
b.
Have been enrolled in a clinical study (including vaccine studies) that, in 
the investigator’s opinion, may impact this Shire-sponsored study.
8. Confirmed systolic blood pressure (BP) >139mmHg or <89mmHg, and diastolic BP
>89mmHg or <49mmHg.
9. Twelve-lead ECG values (average of triplicate readings) demonstrating QTc >450msec 
(males) or >470msec (females) at the Screening Visit or Day -1.
10. Positive screen for drugs of abuse (ie, amphetamines, benzodiazepines, barbiturates, cocaine, 
marijuana, opiates, phencyclidine) at Screening, or drugs of abuse or alcohol on Day -1.


Shire
CONFIDENTIAL
Page 28
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
11. Male subjects who consume more than 21 units of alcohol per week or 3 units per day.
Female subjects who consume more than 14 units of alcohol per week or 2 units per day. One
alcohol unit=1 beer or 1 wine (5oz/150mL) or 1 liquor (1.5oz/40mL) or 0.75oz alcohol.
12. Positive HIV, HBsAg, or HCV antibody screen.
13. Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing products 
in any form (eg, gum, patch, electronic). Ex-users must report that they have stopped using 
tobacco for at least 30 days prior to receiving the dose of investigational product.
14. Routine consumption of more than 2 units of caffeine per day or subjects who experience 
caffeine withdrawal headaches. One caffeine unit is contained in the following items: one 
6oz (180mL) cup of coffee, two 12oz (360mL) cans of cola, one 12oz cup of tea, and three 
1oz (85g) chocolate bars. Decaffeinated coffee, tea, or cola are not considered to contain 
caffeine.
15. Current use of any medication (including over-the-counter, herbal, or homeopathic 
preparations; with the exception of hormonal replacement therapy or hormonal 
contraceptives). Current use is defined as use within 14 days of the dose of investigational 
product. See Section 5 (Prior and Concomitant Treatment) for a list of permitted medications.
16. Abnormal laboratory values considered clinically significant, as determined by the 
investigator at Screening or Day -1.
17. History of any clinically significant surgery or procedure within 8 weeks of receiving the 
dose of investigational product, as determined by the investigator.
4.3
Restrictions 
1. Subjects should refrain from strenuous physical exercise 48 hours prior to admission to the 
clinical research center (CRC) and during the in-house stays at the CRC.
2. Subjects should refrain from alcohol 48 hours prior to admission to the CRC and during the 
in-house stay at the CRC (Day 1-5) and 48 hours prior to each outpatient visit during the 
study.
3. Subjects must refrain from use of tobacco or any products containing nicotine within 30 days
of Day 1 of the treatment period through the completion of the last treatment period.
4. Subjects should refrain from taking or regularly using any medication (including over-the 
counter multivitamin, herbal, or homeopathic preparations) with the exception of those listed 
in Section 5.2.1 from 14 days prior to receiving the dose of the investigational product 
through the completion of the discharge assessments and procedures.
5. Subjects should refrain from foods or beverages containing caffeine/xanthine 48 hours prior 
to admission to the CRC and during the in-house stay at the CRC.
6. Subjects will be required to follow standardized meal schedules and eat the meals provided 
by the site while housed in the CRC. No outside food or beverages (including gum, mints, 
etc.) will be permitted. Menus will be identical for all subjects at the CRC. Copies of the 
menus will be provided to the sponsor for approval prior to the start of the study. 


Shire
CONFIDENTIAL
Page 29
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
While confined, the total daily nutritional composition should be approximately 50% 
carbohydrate, 35% fat, and 15% protein. The daily caloric intake per subject should not 
exceed approximately 3200 kcal.
4.4
Reproductive Potential
4.4.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception. Females of childbearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 112 days following the dose of investigational 
product. If hormonal contraceptives are used, they should be administered according to the 
package insert. Females of childbearing potential who are not currently sexually active must 
agree to use acceptable contraception, as defined below, if they become sexually active during 
the period of the study and 112 days following the dose of investigational product. 
Female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and follicle stimulating 
hormone (FSH) result in the laboratory post-menopausal range at Screening)

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, or

Females of childbearing potential with a negative urine and/or serum beta-Human chorionic 
gonadotropin (-hCG) pregnancy test at the Screening Visit and Day -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.
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the first dose of investigational product, plus condoms. Note: If subject 
becomes sexually active during the study, they should use one of the other acceptable 
methods noted above in addition to the hormonal contraceptive until it has been stabilized for 
30 days.
4.4.2
Male Contraception
Male subjects must be advised to use acceptable contraceptives throughout the study period and 
for 160 days following the dose of investigational product. Male subjects must be advised not to 
donate sperm during the course of the study and within 160 days of the dose of investigational 
product. Acceptable methods of contraception for male subjects include:

Double-barrier methods (eg, Condoms and diaphragms with spermicidal gel or foam).


Shire
CONFIDENTIAL
Page 30
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the early withdrawal 
evaluations listed in Table 2 are to be performed as completely as possible. Whenever possible, 
all discontinued subjects should also undergo the protocol-specified follow-up (ie Day 112/ End 
of Study Visit). Comments (spontaneous or elicited) or complaints made by the subject must be 
recorded in the source documents. The reason for termination and date of stopping 
investigational product must be recorded in the case report form (CRF) and source documents.
Subjects who withdraw or discontinue early may be replaced (if needed) at the discretion of the 
sponsor, to ensure that approximately 24 subjects (12 from each race/ethnicity) complete the 
study.
4.5.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF.
Reasons for discontinuation include but are not limited to:

Adverse event (AE)

Protocol deviation

Withdrawal by subject

Lost to follow-up

Other Bygum, 2009
4.5.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). 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 they 
return to the site for final safety evaluations.


Shire
CONFIDENTIAL
Page 31
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
5
PRIOR AND CONCOMITANT TREATMENT
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins,
and nonpharmacological treatments such as psychotherapy as appropriate) received within 
30 days (or PK equivalent of 5 half-lives, whichever is longer) of the date of the dose of 
investigational product. Prior treatment information must be recorded on the appropriate CRF 
page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the date of the administration of 
investigational product and the end of the follow-up period (ie Day 112/ End of Study Visit), 
inclusive. Concomitant treatment information must be recorded on the appropriate CRF page.
5.2.1
Permitted Treatment
Subjects should refrain from taking any medications (excluding those medications listed below) 
during the course of the study. Any medication which is considered necessary for the subject’s 
safety and well-being may be given at the discretion of the investigator. The administration of all 
medications (including investigational products) must be listed on the appropriate CRF page.
Medications permitted during the study are listed below:

Hormonal contraceptives for females of childbearing potential administered according to the 
package insert (see Section 4.4.1)

Stable hormone replacement therapy ≥3 months prior to dose of investigational product

Occasional use of a nonsteroidal anti-inflammatory drug as prescribed by the principal 
investigator or delegate.
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is lanadelumab (SHP643, formerly known as DX-2930), which will be provided 
in 300mg vials for SC injection. Additional information is provided in the current lanadelumab 
Investigator’s Brochure.
6.1.1
Blinding the Treatment Assignment
Not Applicable.
6.2
Administration of Investigational Product
6.2.1
Allocation of Subjects to Treatment
This is an open-label single-center study.


Shire
CONFIDENTIAL
Page 32
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Subject (screening) numbers are assigned to all subjects as they consent to take part in the study. 
The subject number is assigned to subjects according to the sequence of presentation for study 
participation. This will be a 4-digit number starting at 0001.
A 4-digit subject number, starting at 1001, will be allocated immediately prior to dosing after 
eligibility has been determined. If a subject number is allocated incorrectly, the study monitor 
must be notified as soon as the error is discovered. Once a subject number has been assigned, 
that number must not be used again if, for example, a subject is withdrawn from the study. For 
enrolled subjects, the subject number will be the identifying number used throughout the CRF.
6.2.2
Dosing
After the subject completes the screening process and is found to be eligible for dosing, the 
subject will receive a single 300mg lanadelumab SC injection in the abdomen on Day 1 of the 
in-house confinement period.
A full description of the details and preparation and administration of investigational product 
will be provided in a Pharmacy and Investigational Product Administration Manual, provided 
separately.
6.2.3
Unblinding the Treatment Assignment
Not Applicable.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product container.
All investigational product is labeled with a minimum of the protocol number, dosage form
(including product name), directions for use, storage conditions, expiry date (if applicable), Lot 
number and/or packaging reference, the statements “For clinical trial use only” and/or 
“CAUTION: New Drug – Limited by Federal (or US) Law to Investigational Use,” and “Keep 
out of reach of children,” and the sponsor's name and address.
Space is allocated on the label so that the site representative can record a unique subject 
identified and initials.
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


Shire
CONFIDENTIAL
Page 33
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
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 and initials on the investigational product 
bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
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-upon 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 investigational product. 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.


Shire
CONFIDENTIAL
Page 34
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer 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 
investigational product will be documented on the CRFs and/or other investigational product 
record.
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.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, and empty/used 
investigational product packaging are to be sent to a nominated contractor on behalf of the 
sponsor. Investigational products being returned to the sponsor’s designated contractors must be 
counted and verified by clinical site personnel and the sponsor (or designated contract research 
organization [CRO]). For unused supplies where the originally 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, interactive response technology 
[IRT]) do not require a shipment form. Returned investigational products 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
Compliance must be assessed by observation of dosing by the investigator or designee. The 
investigator/nominated person will record details on the drug accountability log(s) and/or source 
documents. In addition, details of the dosing time (time, date, dose level) will be captured in the 
appropriate CRF.
6.6
Retention of Bioavailability and Bioequivalence Testing Samples
Not applicable.


Shire
CONFIDENTIAL
Page 35
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
7
STUDY PROCEDURES
7.1
Study Schedule
See Table 1 and Table 2 for study procedures. The following “priority order” will be in effect 
when more than 1 procedure or assessment is required at a particular time point.

Spontaneous or solicited AE reporting

Electrocardiogram (ECG)

Vital signs

Clinical laboratory tests 

Pharmacokinetic blood sampling

Anti-drug antibody (ADA) sampling

Pharmacodynamic blood sampling

Physical examination
NOTE: Blood sampling for PK and PD evaluation must be performed at the precise 
protocol-scheduled time. Actual sampling time(s) must be accurately recorded in the source 
document and appropriate CRF.
7.1.1
Screening Period 
Screening procedures must be completed within 28 days prior to receiving the dose of 
investigational product. All screening assessments and procedures are to be performed by the 
principal investigator or a qualified designee. See Table 1 for a complete list of screening 
procedures to be performed.
Written, signed, and dated informed consent from the subject prior to the performance of any 
study-related procedures must be obtained by the principal investigator or a designee. A copy of 
the signed informed consent form must be given to the subject for their records.
7.1.1.1
Screening Failure
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been enrolled or administered 
investigational product.
7.1.1.2
Rescreening of Subjects
Subjects who fail to meet all inclusion/exclusion criteria will not be permitted to be rescreened 
for the study at any point.


Shire
CONFIDENTIAL
Page 36
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Eligible subjects who meet all inclusion/exclusion criteria but are unable to participate in the 
study due to scheduling conflicts/timing may be rescreened based on investigator discretion and 
sponsor approval should their availability to participate fall outside the screening window. In 
these cases, a new screening number must be assigned for each subject who is rescreened and a 
new informed consent form must be signed.
7.1.2
Treatment Period 
7.1.2.1
In-house Confinement Period (Day 1 to Day 5)
Study assessments for Day 1 to Day 5 of the in-house confinement treatment period are outlined 
in Table 1 and Table 2. Administration of investigational product will occur on Day 1 (for all 
study subjects) of the in-house confinement treatment period.
Subjects will be discharged from the CRC following completion of the last study assessment on 
Day 5 of the in-house confinement period.
7.1.2.2
Out-Patient Visit Period (Day 6 to Day 112)
The out-patient visit period for this protocol begins following discharge on Day 5, and continues
until the last out-patient visit (Day 112 ± 3 days). During this out-patient period, subjects will 
return to the CRC for 8 visits in order to complete scheduled assessments and procedures (as 
detailed in Table 1 and Table 2).
These assessments include: blood and urine samples for clinical safety labs including pregnancy 
for all females, blood samples for PK and PD assessments, urine for drug and alcohol testing, 
physical examination (including weight), vital signs (including BP, pulse, and oral body 
temperature), ECG, serious adverse events (SAEs), AEs, and concomitant medications.
7.1.2.3
Final Visit (Day 112)
The final visit will be the Day 112 (±3 days) out-patient visit. This visit also serves as the 
follow-up visit for this study. Refer to Table 1 and Table 2 for outlined study assessments and 
procedures. All AEs and SAEs that are not resolved by the last study visit (Day 112) will be 
followed to closure (see Section 8.1).
7.1.3
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Demographic information will be collected at the initial screening visit. Information to be 
collected will include:

Date of birth

Sex

Race and ethnicity


Shire
CONFIDENTIAL
Page 37
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
7.2.2
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
Actual safety assessment times will be monitored and recorded. The sponsor’s expectation is that 
the investigator will ensure that every effort is made to perform all assessments at the precise 
protocol-scheduled time. Any safety assessment that deviates from the scheduled assessment 
time set forth in the protocol by more than 15 minutes will be considered a protocol deviation.
Adverse events, prior medication, and concomitant medication use will be assessed and 
monitored from the time the subject signs the informed consent form to completion of the study 
(including to time of screen failure or drop out/discontinuation). During the study, subject safety 
will be closely monitored by vital sign measurements, ECG measurements, clinical safety labs,
and physician oversight. 
7.2.2.1
Medical and Medication History
A complete medical and medication history will be collected at the screening visit and time 
points described in Table 1 and Table 2 by a qualified licensed physician, physician’s assistant, 
or a nurse practitioner. The medical history will be reviewed and recorded in the source records 
(and entered in the CRF), which will include:

Recent use of medication (30 days prior to entering the screening period)

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, psychiatric, and other diseases
7.2.2.2
Physical Examination (Including Height and Weight)
A complete physical examination will be performed at the time points described in Table 1 and 
Table 2 by a qualified licensed physician, physician’s assistant, or nurse practitioner.
The physical examination will include a review of the following body systems:

General appearance

Skin

Head, eyes, ears, nose, and throat

Spine/neck/thyroid

Musculoskeletal

Respiratory

Cardiovascular

Neurological

Abdomen (including liver and kidneys)


Shire
CONFIDENTIAL
Page 38
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Clinically significant abnormalities identified at the screening visit will be documented in the 
subject’s source documents and on the medical history CRF. Changes after the screening visit 
will be captured as AEs on the AE CRF page, as deemed by the investigator.
7.2.2.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.)
7.2.2.4
Vital Signs
Blood Pressure and Pulse Rate
Blood pressure and pulse rate will be measured at times specified in Table 1 and Table 2 of this 
protocol. Additional BP and pulse rate measurements may be performed, as determined by the 
investigator, in order to ensure appropriate monitoring of subject safety and accurate recording of 
vital sign measurements. Any changes from baseline which are deemed clinically significant by 
the investigator are to be recorded as an AE.
The same method for obtaining BP measurement (auscultatory or oscillometric) should be used 
throughout the study for all subjects (and documented). In addition, the conditions of vital sign 
measurements should be controlled and as consistent as possible during the study, in order to 
minimize external variability of the readings. It is advised that measurements be collected at a 
comfortable room temperature with little to no background noise, using the same (appropriately 
sized) cuff placed at the same location of the same arm during the study. The bladder deflation 
rate should be deflated (calibrated for oscillometric method or manually by auscultatory method) 
at a rate of 2-3 mmHg/s (and the first and last audible sounds recorded as systolic and diastolic 
pressure) after at least 5 minutes of rest in the assumed position.
The cuff should have a bladder length that is 80% and a width that is at least 40% of arm 
circumference (a length-to-width ratio of 2:1). 
The subject should be asked to remove all clothing that covers the location of cuff placement. 
The subject should not have exercised or consumed caffeine, alcohol, or nicotine within the time 
frame(s) outlined in the Restrictions Section 4.3. The subject should be instructed to relax as 
much as possible for at least 5 minutes prior to collection. The subject should remain quiet 
during this time and through the measurement.
The subject should be lying comfortably, with the legs uncrossed. The arm should be supported 
with a pillow, such that the middle of the cuff on the upper arm is at the level of the right atrium 
(approximately halfway between the bed and the level of the sternum).




Shire
CONFIDENTIAL
Page 40
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
7.2.2.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. 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.
The following clinical laboratory assessments will be performed: 
Biochemistry
Blood samples (8.5 mL) for serum biochemistry will be collected into a red top gel separator 
tube at the time points described in Table 1 and Table 2. The following parameters will be 
assessed: 
Sodium
Phosphorus
-hCG b
Potassium
Total protein
FSH b
Glucose 
Total CO2 (Bicarbonate)
Blood urea nitrogen
Albumin
Creatinine
Aspartate transaminase 
Calcium
Alanine transaminase 
Chloride
Gamma glutamyl transferase 
Thyroid stimulating hormone (TSH) a
Alkaline phosphatase 
Thyroxine (T4 total) a
Total bilirubin 
Triiodothyronine (T3) a
Uric acid
a Collected at Screening only.
b Females only (Please refer to Table 1 and Table 2 for collection timepoints). 
Hematology
Blood samples (4mL) for hematology will be collected into a K2-EDTA tube at the time points 
described in Table 1 and Table 2. 


Shire
CONFIDENTIAL
Page 41
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
The following parameters will be assessed:
Hemoglobin
Total neutrophils (absolute)
Hematocrit
Eosinophils (absolute)
Red blood cells
Monocytes (absolute)
Platelet count
Basophils (absolute)
White blood cell count; total and differential
Lymphocytes (absolute)
Coagulation
Blood samples (2.7mL) for coagulation will be collected into a sodium citrate tube at the time 
points outlined in Table 1 and Table 2. The following parameters will be assessed:
PT
PTT
INR
Urinalysis
A urine sample for urinalysis will be collected at the time points described in Table 1 and Table 
2. The following parameters will be assessed:
pH
Blood
Nitrites
Glucose
Ketones
Leukocyte esterase
Protein
Bilirubin
Specific gravity
Microscopic examination will be conducted if protein and/or blood is/are detected during 
urinalysis. At a minimum the microscopic examination will consist of red blood cells, white 
blood cells, casts, and bacteria. 
7.2.2.6
Pregnancy Test 
A serum β-HCG pregnancy test is to be performed on all females at the timepoints outlined in 
Table 1 and Table 2; if pregnancy is suspected; or on withdrawal of the subject from the study.
7.2.2.7
Drug and Alcohol Screen 
A urine screen for drugs of abuse and alcohol (breath test) will be performed at the time points 
described in Table 1 and Table 2. Additional drug and alcohol screens may be performed at the 
investigator’s discretion.
Urine samples are to be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiate metabolite, and phencyclidine.
Results of urine drug and alcohol (breath test) screens will be reviewed and verified by the study 
monitor, but will not be collected in the CRF database.


Shire
CONFIDENTIAL
Page 42
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Any positive result for drugs of abuse or alcohol at screening or on Day -1 will exclude the 
subject from further participation in the study.
If any drugs of abuse or alcohol results are positive at any timepoint after the subject has been 
dosed, the principal investigator must contact the Sponsor’s Medical Monitor to discuss and 
review the circumstances, and determine whether the subject may continue in the study. Details 
of the discussion and decision taken must be properly recorded in the subject’s source 
documents.
7.2.2.8
Serology Screen 
At the screening visit, a blood sample of approximately 8.5mL will be drawn into a serum 
separator tube to test for the presence of HIV, HBsAg, and HCV antibody.
The test results must be confirmed negative prior to enrollment in the study. If a test result is 
positive, the subject will be excluded from entering the study. Results of the virology screen will 
be reviewed and verified by the study monitor, but will not be collected in the CRF database.
7.2.2.9
Electrocardiogram 
Twelve-lead ECGs will be performed at the times specified in Table 1 and Table 2. Triplicate 
ECGs will be performed at Screening and Day -1 only. Thereafter, single ECG recordings will 
be performed at all subsequent timepoints. All ECGs will be performed using the equipment 
supplied by the CRC. 
The following parameters will be recorded on the appropriate CRF page: heart rate, PR, RR, 
QRS, and QT intervals. The QTcB and QTcF will be derived from the data in the database. The 
investigator’s assessment of the ECG tracing as normal or abnormal must be documented, and if 
abnormal, his/her determination of whether the abnormality is clinically significant or not will be 
documented on the tracing and recorded in the CRF.
The subject should be asked to remove all clothing that covers the location of lead placement. 
The subject should not have exercised or consumed caffeine, alcohol, or nicotine within the 
timeframe as described in the Restrictions Section 4.3. The subject must be resting in the supine 
position for at least 5 minutes prior to collecting the ECG.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings. 
Triplicate ECG Recordings – (Screening and Day -1)
Triplicate recording, including a 10-second rhythm strip, will be obtained approximately 
2-4 minutes apart at the initial Screening Visit and at check in to the CRC on Day -1. Each ECG 
parameter obtained with the 3 assessments will be recorded in the CRF. The average of the 
triplicate ECG measurements collected at each nominal time point will be used for analysis. The 
3 recordings should be immediately assessed as valid recordings and if not valid, they should be 
repeated in order to obtain a total of 3 valid recordings. Invalid recordings will not be entered in 
the CRF.


Shire
CONFIDENTIAL
Page 43
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Single ECG Recordings – (Day 1 through Day 112)
One complete recording, including a 10-second rhythm strip, should be taken at all time points 
except at the initial Screening Visit and at check in to the CRC on Day -1. It should be 
immediately assessed as a valid recoding and if not valid, it should be repeated. Invalid 
recordings will not be entered in the CRF.
When a single ECG recording is performed at each time point, the ECG collected predose on 
Day 1 will serve as the subject’s baseline ECG.
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.
If the QTcF interval (calculated online on site) is increased by >45msec from the baseline or an 
absolute QTcF value is >500msec for any scheduled ECG, then 2 additional ECGs will be 
collected, approximately 2-4 minutes apart, to confirm the original measurement. If either of the 
QTcF values from these repeated ECGs remains above the threshold value (>4 msec from the 
baseline; or is >500msec), then a single ECG must be repeated at least hourly until QTcF values 
from 2 successive ECGs fall below the threshold value that triggered the repeat measurement.
If QTcF values remain above 500msec (or >45msec from the baseline) for >4 hours (or sooner at 
the discretion of the investigator) or QTcF intervals get progressively longer, the subject should 
undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF intervals do 
not return to <500msec (or to <45msec above the baseline) after 8 hours of monitoring (or 
sooner at the discretion of the investigator).
If a machine-read QTcF/QTcB value is prolonged, as defined above, repeat measurements may 
not be necessary if a qualified physician’s interpretation determines that the QTcF/QTcB values 
are in the acceptable range.
7.2.3
Pharmacokinetic Procedures
The name and address of the bioanalytical laboratory for this study will be maintained in the 
investigator’s files at the study site and in the Trial Master File at the sponsor.
Actual pharmacokinetic blood sample collection times versus time of dosing will be monitored. 
The sponsor’s expectation is that the investigator will ensure that every effort is made to collect 
all pharmacokinetic blood samples at the precise protocol scheduled time. Pharmacokinetic 
blood collection must not deviate from the nominal collection time set forth in the protocol by 
more than 5 minutes from samples drawn within 4 hours postdose or by more than 15 minutes 
for samples drawn beyond 4 hours postdose. Samples drawn outside these parameters will be 
considered a protocol deviation. 
7.2.3.1
Pharmacokinetic Sample Collection and Handling Procedures
Pharmacokinetic blood samples will be collected at the time specified in Table 1 and Table 2 to 
measure plasma concentrations of lanadelumab. A full description of the PK blood collection, 
handling, storage, and shipping can be found in the provided laboratory manual.


Shire
CONFIDENTIAL
Page 44
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Plasma sample tubes for bioanalysis must be freezer-safe and identified with freezer-safe labels 
provided by the CRC. The labels will contain the following information:

Study number

Subject identifier

Nominal day

Nominal time

Matrix identifier (plasma)

Split (primary or backup)
7.2.3.2
Shipment of Plasma Pharmacokinetic Samples
Instructions for shipment of all PK samples (along with the corresponding documentation) can 
be found in the laboratory manual provided under a separate cover.
Pharmacokinetic samples will be stored nominally at -70(±10)°C prior to and after analysis at the 
CRO until further directions are authorized by Shire.
7.2.3.3
Plasma Drug Assay Methodology
Plasma sample analysis will be performed according to Shire Standard Operating Procedure 
BC-104 (current version). Under circumstances where this Shire Standard Operating Procedure 
does not apply, relevant TGA Sciences (the bioanalytical lab) Operating Procedures will be 
followed.
Plasma concentrations will be measured using the most current validated bioanalytical method. 
In addition, selected plasma samples may be used to investigate incurred sample reproducibility 
(full details will be described in the bioanalytical study plan). The presence of other metabolites 
or artifacts may be monitored or quantified as appropriate. Raw data will be stored in the archive 
of the designated bioanalytical contract laboratory. 
7.2.4
Pharmacodynamic Assessments
The names and addresses of the bioanalytical laboratories for this study will be maintained in the 
investigator’s files at the site and in the Trial Master File at the sponsor.
Actual PD blood sample collection times versus time of dosing will be monitored. The sponsor’s 
expectation is that the investigator will ensure that every effort is made to collect all PD blood 
samples at the precise protocol scheduled time. Pharmacodynamic blood collection must not 
deviate from the nominal collection time set forth in the protocol by more than ±5 minutes from 
samples drawn within 4 hours postdose or by more than ±15 minutes for samples drawn at 
4 hours post dose and beyond while in the CRC. For PD samples drawn during the out-patient 
visits refer to Table 2 for time point parameters. Samples drawn outside the parameters set forth 
in the protocol will be considered a protocol deviation.


Shire
CONFIDENTIAL
Page 45
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
7.2.4.1
Pharmacodynamic Sample Collection and Handling Procedures
Pharmacodynamic blood samples will be collected at the time specified in Table 1 and Table 2 to 
measure plasma concentrations of kallikrein activity and cHMWK. A full description of the PD 
blood collection, handling, storage and shipping can be found in the provided laboratory manual.
Plasma sample tubes for bioanalysis must be freezer-safe and identified with freezer-safe labels 
provided by the CRC. The labels will contain the following information:

Study number

Subject identifier

Nominal day

Nominal time

Matrix identifier (plasma)

Analyte (kallikrein activity or cHMWK)

Split (primary or backup)
7.2.4.2
Shipment of Plasma Pharmacodynamic Samples
Instructions for shipment of all PD samples (along with the corresponding documentation) can 
be found in the laboratory manual provided under a separate cover.
Pharmacodynamic samples will be stored nominally at -70(±10)°C prior to and after analysis at 
the CRO until further direction is authorized by Shire.
7.2.4.3
Plasma Pharmacodynamic Assay Methodology
Plasma levels of kallikrein activity and cHMWK will be measured using the most current 
validated bioanalytical methods. The presence of other metabolites or artifacts may be monitored 
or quantified as appropriate. Raw data will be stored in the archive of the designated 
bioanalytical contract laboratory.
7.2.5
Immunogenicity Testing for Anti-Drug Antibodies
The name and address of the bioanalytical laboratory conducting ADA immunogenicity testing 
for this study will be maintained in the investigator’s files at the study site and in the Trial 
Master File at the sponsor.
Actual ADA blood sample collection times versus time of dosing will be monitored. The 
sponsor’s expectation is that the investigator will ensure that every effort is made to collect all 
anti-drug blood samples as the precise protocol scheduled time. Anti-drug antibody blood 
collection will be collected on Day 1 prior to dose (within 60 minutes of dose). See Table 2 for a 
detailed schedule of time points. A full description of the ADA blood collection, handling, 
storage and shipping can be found in the provided laboratory manual.
In the event anti-drug antibodies are detected following analysis for a subject, the investigator 
will be notified by the sponsor. It will be the investigator’s responsibility to notify the subject.


Shire
CONFIDENTIAL
Page 46
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
7.2.6
Volume of Blood to Be Drawn from Each Subject
Table 3: Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samples a
5
14
70
Pharmacodynamic (cHMWK and 
plasma kallikrein activity) samples 
5
14
70
HBsAg, HIV, HCV
8.5
1
8.5
Safety
Biochemistry, FSH 
and -hCG a,b,c
8.5
12
102
Hematology
4
12
48
Coagulation
(PT, aPTT, INR)
2.7
11
29.7
Anti-Drug Antibody samples
3
5
15
Total mL
343.2
-hCG=beta-human chorionic gonadotropin; FSH = follicle stimulating hormone; HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; TSH=thyroid stimulating hormone; T3=triiodothyronine; 
T4= thyroxine
a If a catheter is used for any blood draw or series of blood draws then the first 1mL is to be discarded. The 1mL discard has 
been taken into account in the table above and the total blood volume required for this study.
b -hCG and FSH testing for females only.
c TSH, T3 and T4 will be included in the biochemistry panel, and collected at Screening only.
During this study, it is expected that approximately 343.2mL of blood will be drawn from all 
subjects, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 343.2mL. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments may be combined.
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995).


Shire
CONFIDENTIAL
Page 47
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.2.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.


Shire
CONFIDENTIAL
Page 48
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown
8.1.4
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.


Shire
CONFIDENTIAL
Page 49
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
8.1.5
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.2.3.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Global Drug Safety Department using 
the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days post partum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine -hCG 
test or ultrasound result will determine the pregnancy onset date.
8.1.6
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose –Intentional or unintentional intake of a dose of investigational product higher 
than the protocol-prescribed dose


Shire
CONFIDENTIAL
Page 50
Protocol SHP643-101  
Lanadelumab
27 Nov 2017

Medication Error –An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
The administration of investigational product to an eligible volunteer following a temperature 
excursion as outlined in the pharmacy manual, without assessment of the excursion and 
permission of the sponsor to proceed is deemed a medication error.
It is not expected that overdose would occur in this study. The investigational product used in 
this study is supplied in 1strength (300 mg) and is administered once per volunteer by a trained 
and responsible staff member at the study site with sponsor oversight. 
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the lanadelumab Investigator’s Brochure 
which the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global
Drug Safety Department and the CRO/Shire medical monitor within 24 hours of the first 
awareness of the event. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors (see Section 8.1.6) unless they result in 
an SAE.
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Drug Safety 
Department. A copy of the Shire Clinical Study Serious Adverse Event and Non-serious AEs 
Required by the Protocol Form (and any applicable follow-up reports) must also be sent to the 
CRO/Shire medical monitor using the details specified in the emergency contact information 
section of the protocol.


Shire
CONFIDENTIAL
Page 51
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations that are the result of elective or previously scheduled surgery for 
pre-existing conditions and have not worsened after initiation of treatment should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.2.3 and must be 
reported to the Shire Global Drug Safety Department and the CRO/Shire medical monitor within 
24 hours of the first awareness of the event.
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.


Shire
CONFIDENTIAL
Page 52
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of withdrawn should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor is responsible for notifying the relevant regulatory authorities/US Central 
Institutional Review Board (IRB) of related, unexpected SAEs.
In addition the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the SHP643 program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is enrolled, it is expected that site personnel 
will complete the CRF entry within approximately 3 business days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.


Shire
CONFIDENTIAL
Page 53
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are to be documented in an auditable manner.
9.3
Data Handling Considerations 
All analyses/summaries will be based on observed data, with no imputation for missing data, 
unless otherwise specified in the study Statistical Analysis Plan (SAP).
9.4
Statistical Analysis Process
No statistical hypothesis testing is planned. Analysis details will be provided in the SAP.
Study data will be analyzed by the sponsor or its agent (CRO). To preserve the integrity of the 
statistical analysis and study conclusions, the SAP will be finalized prior to study database lock. 
The SAP will provide the statistical methods and definitions for the analysis of the 
pharmacokinetic, pharmacodynamic, 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.
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513). 
Descriptive analysis will be performed to evaluate all primary, secondary and exploratory 
endpoints, and the following, including the definition below, will apply:

Continuous endpoints (eg, change in parameter) will be summarized, displaying: number of 
subjects (n), mean, standard deviation (SD), median, minimum and maximum value. As 
appropriate, raw (actual) values, changes from baseline, and percent changes from baseline 
will be summarized overall and at each scheduled timepoint. Baseline is defined as the last 
non-missing value prior to dosing with investigational product (lanadelumab). Additional 
summary statistics will be provided for pharmacokinetic and pharmacodynamics endpoints 
and are indicated in Sections 9.8.1 and 9.8.2. 

Categorical endpoints (eg, presence or absence of an outcome measure) will be summarized, 
displaying counts and percentages. Summaries will include, where applicable: number and 
percentage of subjects with an outcome measure and shift tables (categorical change from 
baseline).Summaries will be presented by racial/ethnic group (Japanese vs. non-Hispanic 
Caucasians), and, if appropriate, by timepoint. Matching of non-Hispanic Caucasian subjects 
to Japanese subjects, according to the study design, is intended to ensure that the ethnic/racial 
groups are comparable at baseline with respect to the matching factors (sex, age, and body 
mass index). All subject volunteers will receive a single SC dose 300mg of lanadelumab in 
the abdomen on 
Day 1.


Shire
CONFIDENTIAL
Page 54
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
All data, including derived data, will be presented in subject data listings and all listings will 
include subject’s sex, age, race/ethnicity, and body mass index.
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
No interim analysis, adaptive design, or Data Monitoring Committee (DMC) is planned.
9.6
Sample Size Calculation and Power Considerations
The planned sample size for this study is 32 subjects: 16 subjects of Japanese descent and 
16 matched non-Hispanic Caucasian subjects. 
Assuming a 25% dropout rate, the sample size ensures approximately 24 subjects (12 Japanese 
and 12 matched Caucasians) complete the study, and 24 subjects are evaluable for 
pharmacokinetic analysis purposes. The sample size is considered adequate for the primary and 
secondary objectives of the study and therefore adequate for providing reliable estimates of 
pharmacokinetic parameters. 
The sample size was based on clinical judgment and precedent pharmacokinetic studies of 
similar design and similar subject population and not on statistical considerations such as study 
power. Subjects who prematurely discontinued the study, whether subjects are part of matched 
pairs or are not yet matched, may be replaced at the discretion of the study sponsor to ensure 
there are approximately 12 evaluable subjects in each racial/ethnic group for pharmacokinetic 
analysis purposes.
9.7
Analysis Populations/ Analysis Sets
Safety, PK and PD analyses will be based on the following subject populations (analysis sets), as 
defined:

Safety population (Safety Analysis Set): All subjects who received at least 1 dose of 
lanadelumab (study drug).

Pharmacokinetic population (PK Set): All subjects who received at least 1 dose of 
lanadelumab and have at least 1 evaluable postdose PK concentration value.

Pharmacodynamic population (PD Analysis Set): All subjects who received at least 1 dose of 
lanadelumab and have at least 1 evaluable postdose PD concentration value. 

Enrolled Set: All subjects for whom an enrollment number has been assigned.
9.8
Pharmacokinetic and Pharmacodynamic Analyses
9.8.1
Pharmacokinetic Analysis
Pharmacokinetic parameters will be calculated using plasma concentration-time data by 
non-compartmental methods and all calculations will be based on actual sampling times. 


Shire
CONFIDENTIAL
Page 55
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Baseline is defined as the Day 1 predose concentration. Pharmacokinetic parameters will be 
estimated by noncompartmental analysis and will include, but not be limited to, the following:

Cmax: Maximum observed plasma drug concentration

tmax: Time to reach Cmax in plasma

AUC0-last: Area under the concentration-time curve from time zero to the last quantifiable 
concentration in plasma

AUC0-∞: Area under the concentration-time curve from time zero extrapolated to infinity

z: Terminal elimination rate constant

t½: Terminal half-life

CL/F: Apparent clearance

Vdz/F: Apparent volume of distribution
Body weight-adjusted AUClast, Cmax, CL/F, and Vdz/F will be estimated as well.
9.8.1.1
Statistical Analysis of Pharmacokinetic Parameters
Pharmacokinetic parameters of lanadelumab and plasma concentrations at each nominal 
sampling time 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), presented by racial/ethnic 
group (Japanese vs non-Hispanic, Caucasian). In addition, 95% confidence intervals for key PK
parameters will be provided as appropriate, as well as graphs of individual and mean (± SD) 
concentration-time profiles plasma lanadelumab and graph(s) of observed and weight-adjusted 
PK parameters (y-axis) versus body weight (x-axis). 
All plasma concentration values below the lower limit of quantification (LLOQ) will be set to 
zero when calculating summary statistics. For the calculation of PK parameters, all plasma 
concentrations that are LLOQ prior to the first measurable concentration will be set to zero. The 
LLOQ values that are between measurable concentrations will be set to missing. The LLOQ 
values following the last quantifiable timepoints will be set to missing. No concentration 
estimates will be imputed for missing sample values. Any sample with a missing value will be 
treated as if the sample had not been scheduled for collection and will be ignored when 
calculating mean concentrations or PK parameters.
Pharmacokinetic analysis will be based on the Pharmacokinetic population.
9.8.2
Pharmacodynamic Analysis
Pharmacodynamic assessment is an exploratory objective of the study. Individual subject plasma 
kallikrein activity and plasma cHMWK with and without baseline correction will be provided in 
subject data listings and summarized using descriptive statistics (number of subjects, arithmetic 
mean, SD, CV%, median, minimum, maximum, geometric mean, and %CV of geometric mean),
presented by racial/ethnic group (Japanese vs. non-Hispanic, Caucasian). 


Shire
CONFIDENTIAL
Page 56
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
In addition, 95% confidence intervals will be provided as appropriate. Graphs of individual and 
mean (±SD) activity-time profiles will be generated.
Pharmacodynamic analysis will be based on the Pharmacodynamic population.
9.8.3
Pharmacokinetic and Pharmacodynamic Analysis
Not applicable.
9.9
Safety Analyses
Safety endpoints are defined in the Synopsis section. Descriptive analysis, as described in 
Section 9.4 will be performed to evaluate all safety endpoints.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The 
number of events, incidence, and percentage of treatment-emergent adverse events (TEAEs) will 
be calculated overall, by system organ class, by preferred term, and by treatment group.
Treatment-emergent adverse events will be further summarized by severity and relationship to 
investigational product. Adverse events related to investigational product, AEs leading to 
withdrawal, SAEs, and deaths will be similarly summarized/ listed.
Only TEAEs will be analyzed. 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, 
and all listings will include subject’s sex, age, race/ethnicity, and body mass index.
Clinical laboratory tests, vital signs, and ECG findings will be summarized, as appropriate, by 
racial/ethnic group (Japanese vs. non-Hispanic, Caucasian) and visit. Potentially clinically 
important findings will also be summarized or listed in subject data listing.
Safety analysis will be based on the Safety population.
Definition
Treatment-emergent adverse events (TEAEs): TEAEs are AEs with onset at the time of or 
following the first exposure to study drug, or medical conditions present prior to the start of 
study drug but increasing in severity or relationship at the time of or following the start of 
treatment, up to the last follow-up visit.
9.10
Other Analyses
No other analyses are planned.
9.10.1
Exploratory Analysis
Pharmacodynamic analysis is the exploratory analysis. Refer to Section 9.8.2 for analysis.


Shire
CONFIDENTIAL
Page 57
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current good clinical practice (GCP) and the 
respective local and inter/national government regulations and guidelines. Records and data may 
additionally be reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the investigator as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. 


Shire
CONFIDENTIAL
Page 58
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
Agreement with the final clinical study report is documented by the signed and dated signature 
of the principal investigator, in compliance with Directive 2001/83/EC as amended by Directive 
2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.


Shire
CONFIDENTIAL
Page 59
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or, for 
multicenter studies, the coordinating principal investigator, according to national provisions, and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
CRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.


Shire
CONFIDENTIAL
Page 60
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s legally authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.


Shire
CONFIDENTIAL
Page 61
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the clinical trial agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor or investigator, or, for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by HIPAA 
must provide documentation of this fact to the sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives’ 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market lanadelumab; national or local regulatory authorities; and the IRB/EC which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.


Shire
CONFIDENTIAL
Page 62
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee. The purpose of 
the publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.


Shire
CONFIDENTIAL
Page 63
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.


Shire
CONFIDENTIAL
Page 64
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
11
REFERENCES
Bygum, A. 2009. Hereditary angio-oedema in Denmark: a nationwide survey. The British 
journal of dermatology, 161, 1153-8.
Chiba, K., Yoshitsugu, H., Kyosaka, Y., Iida, S., Yoneyama, K., Tanigawa, T., Fukushima, T. & 
Hiraoka, M. 2014. A comprehensive review of the pharmacokinetics of approved 
therapeutic monoclonal antibodies in Japan: Are Japanese phase I studies still needed? 
Journal Of Clinical Pharmacology, 54, 483-494.
Goring, H. D., Bork, K., Spath, P. J., Bauer, R., Ziemer, A., Hintner, H. & Wuthrich, B. 1998. 
Hereditary angioedema in the German-speaking region. Hautarzt, 49, 114-22.
Lei, W. T., Shyur, S. D., Huang, L. H., Kao, Y. H. & Lo, C. Y. 2011. Type I hereditary 
angioedema in Taiwan -- clinical, biological features and genetic study. Asian Pac J 
Allergy Immunol, 29, 327-31.
Morrison, M., Palermo, G. & Schmitt, C. 2015. Lack of ethnic differences in the 
pharmacokinetics and pharmacodynamics of inclacumab in healthy Japanese and 
Caucasian subjects. European Journal of Clinical Pharmacology, 71, 1365-1374.
Nordenfelt, P., Dawson, S., Wahlgren, C. F., Lindfors, A., Mallbris, L. & 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.
Roche, O., Blanch, A., Caballero, T., Sastre, N., Callejo, D. & 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.
Rosario, M., Dirks, N. L., Milch, C., Parikh, A., Bargfrede, M., Wyant, T., Fedyk, E. & Fox, I. 
2017. A Review of the Clinical Pharmacokinetics, Pharmacodynamics, and 
Immunogenicity of Vedolizumab. Clin Pharmacokinet, 56, 1287-1301.
Zuraw, B. L. 2008. Clinical practice. Hereditary angioedema. N Engl J Med, 359, 1027-36.


Shire
CONFIDENTIAL
Page 65
Protocol SHP643-101  
Lanadelumab
27 Nov 2017
12
APPENDICES



SAP_001.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN Sec 12.1.3 
Protocol No.: 
SHP643-101 
Protocol Title: 
A Phase 1, Open-label Study to Evaluate the 
Pharmacokinetics, Safety and Tolerability, and 
Pharmacodynamics of a Single Dose of Lanadelumab 
Administered Subcutaneously in Healthy Adult Japanese 
Subjects and Matched Healthy Adult Caucasian Subjects 
Drug: 
SHP643, lanadelumab (formerly DX-2930) 
Sponsor:  
Dyax Corp. (an indirect and wholly-owned subsidiary of 
Shire plc) 
300 Shire Way, Lexington, 
MA 02421 USA  
Version No. and Date 
Version 1.0, Date 21 Jun 2018 
 
Version 
No: 
Document History 
Description of Update 
Author(s) 
Effective 
Date 
0.1 
Draft 
, MS 
 
 
PPD 
 BSc (Hons) 
, PPD 
12Feb2018 
0.2 
Draft 
, MS 
 
 
PPD 
, BSc (Hons) 
, PPD 
05Mar2018 
0.3 
Stable Draft 
, MS 
 
 
PPD 
, BSc (Hons) 
, PPD 
30Mar2018 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
 
1.0 
Final 
 MS 
 
PPD 
, BSc (Hons) 
, PPD 
21Jun2018 
 
PPD
PPD
PPD
PPD


Shire                                                              CONFIDENTIAL                                                  21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101 
   Version 1.0 
              Page 3 of 53 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................ 3 
LIST OF TABLES ...................................................................................................................... 6 
ABBREVIATIONS .................................................................................................................... 7 
1. 
INTRODUCTION .......................................................................................................... 9 
2. 
STUDY DESIGN ......................................................................................................... 10 
2.1 
General Study Design ................................................................................................... 10 
2.2 
Randomizatioprior ton .................................................................................................. 11 
2.3 
Blinding ........................................................................................................................ 11 
2.4 
Schedule of Assessments .............................................................................................. 12 
2.5 
Determination of Sample Size ...................................................................................... 16 
3. 
OBJECTIVES ............................................................................................................... 17 
3.1 
Primary Objective ......................................................................................................... 17 
3.2 
Secondary Objective ..................................................................................................... 17 
3.3 
Exploratory Objectives ................................................................................................. 17 
4. 
ANALYSIS POPULATIONS/ANALYSIS SETS ....................................................... 18 
4.1 
Enrolled Set .................................................................................................................. 18 
4.2 
Safety Analysis Set ....................................................................................................... 18 
4.3 
Pharmacokinetic Set ..................................................................................................... 18 
4.4 
Pharmacodynamic Set .................................................................................................. 18 
5. 
SUBJECT DISPOSITION ............................................................................................ 19 
6. 
PROTOCOL DEVIATIONS ........................................................................................ 20 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 21 
7.1 
Demographic and other Baseline Characteristics ......................................................... 21 
7.2 
Medical History ............................................................................................................ 21 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ............................. 22 
8.1 
Exposure to Investigational product ............................................................................. 22 
8.2 
Measurement of Treatment Compliance ...................................................................... 22 
9. 
PRIOR AND CONCOMITANT MEDICATIONS/TREATMENTS .......................... 23 


Shire                                                              CONFIDENTIAL                                                  21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101 
   Version 1.0 
              Page 4 of 53 
 
10. 
EFFICACY ANALYSES ............................................................................................. 24 
11. 
SAFETY ANALYSES ................................................................................................. 25 
11.1 
Adverse Events ............................................................................................................. 25 
11.2 
Clinical Laboratory Variables ...................................................................................... 26 
11.3 
Vital Signs (Including Height and Weight) .................................................................. 30 
11.4 
Electrocardiogram (ECG) ............................................................................................. 31 
11.5 
Other Safety Variables .................................................................................................. 32 
11.5.1 Immunogenicity Testing for Anti-Drug Antibodies .............................................. 32 
12. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES.. 34 
12.1 
Pharmacokinetic Methods ............................................................................................ 34 
12.1.1 Concentration Data ................................................................................................ 34 
12.1.2 Handling BLQ Values ............................................................................................ 34 
12.1.3 Pharmacokinetic Parameters .................................................................................. 35 
12.2 
Statistical Analysis of Pharmacokinetic Parameters .................................................... 36 
12.3 
Pharmacodynamic Methods ......................................................................................... 36 
12.3.1 Pharmacodynamic Data ......................................................................................... 36 
12.3.2 Baseline-adjusted Pharmacodynamic Data ............................................................ 37 
12.3.3 Pharmacodynamic Parameters ............................................................................... 37 
12.4 
Statistical Analysis of Pharmacodynamic Parameters .................................................. 37 
13. 
OTHER ANALYSES ................................................................................................... 38 
14. 
INTERIM ANALYSIS ................................................................................................. 39 
15. 
DATA MONITORING/REVIEW COMMITTEE ....................................................... 40 
16. 
COMPUTER METHODS ............................................................................................ 41 
17. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ....................................... 42 
18. 
DATA HANDLING CONVENTIONS ........................................................................ 43 
18.1 
General Data Reporting Conventions ........................................................................... 43 
18.2 
Derived Efficacy Endpoints .......................................................................................... 43 
18.3 
Repeated or Unscheduled Assessments of Safety Parameters ..................................... 43 
18.4 
Missing Date of Investigational Product ...................................................................... 43 
18.5 
Missing Date Information for Prior or Concomitant Medications ............................... 43 
18.5.1 Incomplete Start Date............................................................................................. 44 
18.5.2 Incomplete Stop Date ............................................................................................. 44 
18.6 
Missing Date Information for Adverse Events ............................................................. 45 


Shire                                                              CONFIDENTIAL                                                  21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101 
   Version 1.0 
              Page 5 of 53 
 
18.7 
Missing Severity Assessment for Adverse Events ....................................................... 45 
18.8 
Missing Relationship to Investigation Product for Adverse Events ............................. 45 
18.9 
Character Values of Clinical Laboratory Variables ..................................................... 45 
19. 
REFERENCES ............................................................................................................. 46 
20. 
TABLE OF CONTENTS FOR TABLES, FIGURES, AND LISTINGS .................... 47 


Shire                                                              CONFIDENTIAL                                                  21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101 
   Version 1.0 
              Page 6 of 53 
 
LIST OF TABLES 
Table 1: Schedule of Assessments ............................................................................................ 12 
Table 2: Detailed Schedule of Assessments ............................................................................. 14 
Table 3: Primary Criteria for Potentially Clinically Important Laboratory Tests .................... 27 
Table 4: Secondary Criteria for Potentially Clinically Important Laboratory Tests ................ 29 
Table 5: Criteria for Potentially Clinically Significant Vital Signs .......................................... 30 
Table 6: Criteria for Potentially Clinically Important ECG Values ......................................... 31 


Shire                                                              CONFIDENTIAL                                                  21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101 
   Version 1.0 
              Page 7 of 53 
 
ABBREVIATIONS 
λZ 
first order rate constant associated with the terminal (log-linear) phase of 
elimination 
%CV 
percent coefficient of variation 
ADA 
anti-drug antibody 
AE 
adverse event 
ANOVA 
analysis of variance 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
AUC0-last 
area under the concentration-time curve from time zero to the last 
quantifiable concentration in plasma 
AUC0-∞ 
area under the concentration-time curve from time zero extrapolated to 
infinity  
BLQ 
below the limit of quantification 
BMI 
body mass index 
BUN 
blood urea nitrogen 
HMWK 
intact high molecular weight Kininogen 
cHMWK 
cleaved high molecular weight Kininogen 
CI 
confidence interval 
Cmax 
maximum observed plasma drug concentration 
CL/F 
apparent clearance following extravascular administration divided by the 
fraction of dose absorbed 
CSR 
Clinical Study Report 
DMC 
data monitoring committee 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
FXII(a) 
factor XII (activated) 
GGT 
gamma glutamyl transferase 
ISR 
injection site reactions 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
number of subjects 
PCI 
potentially clinically important 
PD 
pharmacodynamic 
PK 
pharmacokinetic 


Shire                                                              CONFIDENTIAL                                                  21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101 
   Version 1.0 
              Page 8 of 53 
 
pKal 
plasma kallikrein 
PT 
preferred term 
RBC 
red blood cells 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
standard deviation 
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 
TFL 
table, figure, and listing  
t½ 
terminal half-life 
T3 
tri-iodothyronine 
T4 
Thyroxine 
tmax 
time of maximum observed concentration sampled during a dosing 
interval 
TSH 
thyroid-stimulating hormone 
Vz/F 
apparent volume of distribution associated with the terminal slope 
following extravascular administration divided by the fraction of dose 
absorbed 
WBC 
white blood cell 
WHO 
World Health Organization 


Shire                                                              CONFIDENTIAL                                                  21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101 
   Version 1.0 
              Page 9 of 53 
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of pharmacokinetic (PK), safety and tolerability, and pharmacodynamic (PD) data 
described in the approved study protocol dated 27 Nov 2017, the Protocol Administrative 
Change Memo #1 dated 05 Dec 2017, and the Protocol Administrative Change Memo #2 dated 
26 Jan 2018. Specifications for tables, figures, and listings (TFLs) are contained in a separate 
document (SHP643-101 TFL Shells). 
No formal statistical hypothesis will be tested. The following summaries will be provided for all 
PK, safety and tolerability, and PD analysis endpoints, unless otherwise specified in this SAP: 
For continuous variables (e.g., age): number of subjects (n), mean, standard deviation (SD), 
median, minimum and maximum value; for categorical variables (e.g., sex): number and 
percentage of subjects. Summaries will be presented by ethnic group (Japanese, Caucasian) and 
for all groups combined (overall), as appropriate. For the PK parameters/endpoints, appropriate 
point estimates and confidence intervals (CIs) will be provided, but no formal between-ethnic 
group comparisons will be performed.   
   


Shire                                                              CONFIDENTIAL                                                  21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101 
   Version 1.0 
              Page 10 of 53 
 
2. 
STUDY DESIGN  
2.1 
General Study Design 
This study is a Phase 1, open-label, matched-control, single-dose, single-center study to evaluate 
the PK, safety and tolerability, and PD of lanadelumab administered to healthy adult volunteer 
subjects of Japanese descent and matched non-Hispanic, Caucasian healthy adult volunteer 
subjects.  
A total of 32 subjects between the ages of 18-55, inclusive, will be enrolled:  
 16 subjects of Japanese descent born in Japan, who have resided outside of Japan for no 
longer than 5 years and are of Japanese parentage, defined as having 2 Japanese parents 
and 4 Japanese grandparents, all born in Japan, and  
 16 non-Hispanic Caucasian subjects, each of whom has 2 non-Hispanic, Caucasian 
parents and 4 non-Hispanic, Caucasian grandparents.  
Assuming a 25% dropout rate (based on previous clinical experience), approximately 24 subjects 
(12 subjects from each ethnic group) are expected to complete the study. Study subjects who 
withdraw or discontinue early may be replaced at the discretion of the sponsor.  
Non-Hispanic Caucasian subjects will be matched in a 1:1 ratio to Japanese subjects based on 
sex (1:1 male: male, female: female), age (±5 years), and body mass index (BMI) (±15%). For 
example, a Japanese male, age 40 years, and BMI of 22 kg/m2 will be matched with a Caucasian 
male, age 40 ± 5 years (35-45 years [inclusive]), and BMI of 22 ±15% (18.7-25.3 kg/m2, 
inclusive). Matching is intended to ensure that the ethnic groups are comparable at baseline with 
respect to sex, age, and BMI. All subjects will receive a single dose of 300 mg of lanadelumab 
administered by subcutaneous (SC) injection into the abdomen on Day 1.  
The study duration will be comprised of a 28-day screening period, one 5-day in-house treatment 
period, and multiple out-patient visits (Day 7 [± 1 day], Day 14 [± 1 day], Day 21 [± 1 day], Day 
28 [± 1 day], Day 42 [± 2 days], Day 56 [± 2 days], Day 84 [± 3 days] and Day 112 [± 3 days]) 
after the single dose of investigational product is administered. The maximal total duration of 
study participation for a subject is approximately 140 days if the maximal screening, treatment, 
and out-patient durations are used. 


Shire                                                              CONFIDENTIAL                                                  21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101 
   Version 1.0 
              Page 11 of 53 
 
Figure 1: Study Design Flow Chart 
 
2.2 
Randomization 
Not applicable. 
2.3 
Blinding 
Not applicable. This study is open-label.


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                          Version 1.0                                                   Page 12 of 53 
 
2.4 
Schedule of Assessments  
Table 1: Schedule of Assessments  
 
HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus 
a. 
There will be multiple out-patient visits on: Day 7 (± 1 day), Day 14 (± 1 day), Day 21 (± 1 day), Day 28 (± 1 day), Day 42 
(± 2 days), Day 56 (± 2 days), Day 84 (± 3 days) and End of Study Day 112 (± 3 days), after the dose of investigational 
product is administered on Day 1. Refer to Table 2 for complete details. 
b. 
In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete 
these assessments. 
c. 
Medical history and medication history review only 
d. 
See Table 2 for detailed collection time points 
e. 
Height will be recorded at the Screening Visit only 
f. 
BMI criteria for eligibility will be calculated at the Screening Visit. 
g. 
ECGs will be performed in triplicate at Screening and Day -1 only. Thereafter, all subsequent ECGs will be single 
recordings 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                          Version 1.0                                                   Page 13 of 53 
 
h. 
Thyroid function tests (TSH, T3, T4) will be collected as part of the biochemistry panel at Screening only. 
i. 
Drugs of abuse at screening, and drugs of abuse and alcohol (breath test) on Day -1 and at all out-patient visits. 
j. 
No PK or PD sample, or urine drug or alcohol screen should be collected for early discontinuation. 


Shire                                                                                                   CONFIDENTIAL                                                                              21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                                                             Version 1.0                                                                                  Page 14 of 53 
 
Table 2: Detailed Schedule of Assessments 
 


Shire                                                                                                   CONFIDENTIAL                                                                              21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                                                             Version 1.0                                                                                  Page 15 of 53 
 
 
a. 
In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments. 
b. 
These assessments should be performed within 60 minutes prior to dose administration. 
c. 
ECG’s will be performed as single records at each timepoint. 
d. 
No PK or PD sample, or urine drug or alcohol screen should be collected for early discontinuation. 
 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 16 of 53 
 
2.5 
Determination of Sample Size 
The planned sample size for this study is 32 subjects: 16 subjects of Japanese descent and 
16 matched non-Hispanic Caucasian subjects. 
Assuming a 25% dropout rate (based on previous clinical experience), the sample size ensures 
approximately 24 subjects (12 Japanese and 12 matched non-Hispanic Caucasians) complete the 
study, and 24 subjects are evaluable for PK analysis purposes. The sample size is considered 
adequate for the primary objective of the study (defined in Section 3) and therefore adequate for 
providing reliable estimates of PK parameters, and similarly for the secondary objective. 
No formal statistical hypothesis will be tested. The sample size was based on clinical judgment, 
precedent PK studies of similar design, and similar subject population, not on statistical 
considerations such as study power. Any subject who prematurely discontinues the study, 
whether part of a matched pair or is not yet matched, may be replaced at the discretion of the 
study sponsor to ensure there are approximately 12 evaluable subjects in each ethnic group for 
PK analysis purposes. 
 
 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 17 of 53 
 
3. 
OBJECTIVES 
3.1 
Primary Objective 
To evaluate the PK properties of lanadelumab administered as a single SC dose of 300 mg in 
healthy adult volunteer subjects of Japanese descent and matched non-Hispanic, Caucasian 
healthy volunteer subjects. 
3.2 
Secondary Objective 
To assess the safety and tolerability of lanadelumab administered as a single SC dose of 300 mg 
to healthy adult volunteer subjects of Japanese descent and matched, non-Hispanic Caucasian 
healthy volunteer subjects. 
3.3 
Exploratory Objectives 
To explore the PD properties of lanadelumab including plasma kallikrein (pKal) activity and 
cleaved high molecular weight kininogen (cHMWK) plasma levels after a single SC dose of 300 
mg of lanadelumab administered to healthy adult volunteer subjects of Japanese descent and 
matched non-Hispanic, Caucasian healthy volunteer subjects. 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 18 of 53 
 
4. 
ANALYSIS POPULATIONS/ANALYSIS SETS 
4.1 
Enrolled Set 
The Enrolled Set will consist of all subjects for whom an enrollment number has been assigned. 
Background summaries (e.g., subject disposition) will be based on the Enrolled Set, unless 
otherwise specified in this SAP. 
4.2 
Safety Analysis Set  
The Safety Analysis Set will consist of all subjects who received at least 1 dose of lanadelumab 
(investigational product). All safety analyses will be based on the Safety Analysis Set. 
4.3 
Pharmacokinetic Set  
The PK Set will consist of all subjects in the Safety Analysis Set who have at least 1 evaluable 
postdose PK concentration value. All PK analyses will be based on the PK Set. 
4.4 
Pharmacodynamic Set  
The PD Set will consist of all subjects in the Safety Analysis Set who have at least 1 evaluable 
postdose PD value. All PD analyses will be based on the PD Set. 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 19 of 53 
 
5. 
SUBJECT DISPOSITION 
The number and percentage of subjects included in each analysis set (Enrolled, Safety, PK and 
PD) will be summarized as appropriate.  
The number and percentage of subjects who completed the study or prematurely discontinued 
will be presented, along with primary reasons for discontinuation, as recorded on the study 
completion page of the electronic case report form (eCRF). All enrolled subjects who 
prematurely discontinued the study will be listed in the subject disposition listing along with 
reasons for discontinuation.  
Subject disposition summary and listing will be based on the Enrolled Set, and the summary will 
be presented by ethnic group and for all groups combined. 
 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 20 of 53 
 
6. 
PROTOCOL DEVIATIONS 
Protocol deviations will be classified as major or minor in accordance with applicable Shire 
standard operating procedures and based on the following definitions:  
 Major protocol deviation is a subset of protocol deviations that may significantly 
impact subject's rights, safety or well-being, the statistical analysis, and/or the 
interpretation of product safety / efficacy 
 
 Minor protocol deviation is a subset of protocol deviations, which include changes or 
alterations in the conduct of the study that do not have a significant impact on the 
subject's rights, safety or well-being, or the completeness, accuracy and reliability of the 
study data. 
All protocol deviations will be presented in the protocol deviation listing and based on the 
Enrolled Set. No summaries are planned. 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 21 of 53 
 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
7.1 
Demographic and other Baseline Characteristics 
The following demographic and other baseline characteristics will be summarized by ethnic 
group and overall. Demographics include: age (years), sex (male, female), ethnicity (not 
Hispanic or Latino), and race (White, Asian). Other baseline characteristics include: weight (kg), 
height (cm), and BMI (kg/m2). Note: sex, age and BMI are the matching factors. 
Age will be calculated as the integer part of: (date of screening – date of birth + 1)/365.25, and 
BMI will be calculated as: weight (kg) / (height [m])2. Height and weight at screening 
assessment will be used to calculate BMI.  
Continuous variables, such as age, weight, height, and BMI will be summarized using 
descriptive statistics including n, mean, SD, median, minimum, and maximum. Categorical 
variables such as sex, ethnicity, and race will be summarized by reporting the number and 
percentage of subjects in each category.  
 
All demographic and other baseline characteristics variables that will be summarized will be 
taken from the Screening Visit. Summaries will be based on the Safety Analysis Set, PK Set and 
PD Set, as appropriate. Demographics and other baseline characteristics data will be listed, and 
the listing will be based on the Safety Analysis Set. Subject matching will be listed only, and the 
listing will be based on the Enrolled Set. 
7.2 
Medical History 
A complete medical and medication history will be collected at the Screening Visit including 
recent use of medication (30 days prior to entering the screening period) and history of 
respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, hematological, 
neurological, psychiatric, and other diseases.  
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, 
version 20.1 or higher). 
Medical history will be listed and summarized by system organ class (SOC) and preferred term 
(PT), and based on the Safety Analysis Set. The summary will include number and percentage of 
subjects who experienced the event, and number of events experienced. SOC will be sorted 
alphabetically, and PT will be sorted within each SOC in descending frequency in the table Total 
column (i.e., the Total column will be sorted in descending order after sorting by SOC and PT). 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 22 of 53 
 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1 
Exposure to Investigational product  
Exposure in this single-dose (300 mg, single-administration) study will be summarized in terms 
of the total dose (mg) administered and summarized by ethnic group and overall.  
Total dose administered (mg) will be calculated as follows: 
Total dose administered (mg) = Planned dose (mg) × Total volume administered (mL)
Planned volume (mL)
 
where the planned dose is 300 mg; the planned volume is 2 mL; and the total volume 
administered will be collected in the eCRF. 
Summary will include: n, mean, SD, median, minimum, and maximum, and based on the Safety 
Analysis Set. An exposure data listing, based on the Safety Analysis Set, will be provided and 
include date and time of dose administration and other exposure data, e.g. planned dose/volume, 
total dose/volume and location of dose.  
8.2 
Measurement of Treatment Compliance 
This is a single-dose (single-administration) study in which the investigational product will be 
administered on Day 1 to all subjects and at the study site only (in-house confinement treatment 
period). All compliance-related data will be included in the exposure data listing. No separate 
treatment compliance summary or data listing will be provided. 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 23 of 53 
 
9. 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications will be coded using the World Health Organization-Drug 
Dictionary (WHO-DD) Version September 2017 or higher.  
For statistical analysis purposes, prior and concomitant medications are defined as follow 
(“time” implies date and time): 
 Prior medication: Any medication with start time prior to time of investigational 
product administration.   
 
 Concomitant medication: Any medication with start time at or after time of 
investigational product administration, OR medications with start time prior to 
investigational product administration but continuing at or after investigational product 
administration. Any medication with a start date after the end of the follow-up period 
(Day 112/ End of Study Visit) will be considered post-treatment medication and not 
concomitant medication. 
For medications with partial onset times, non-missing date parts will be used to determine if the 
medication is concomitant or prior medication. If a determination cannot be made using the non-
missing date parts as to when the medication occurred relative to investigational product 
administration then the medication will be classified as concomitant medication. Additional 
information is provided in Section 18.5. 
Both prior and concomitant medication usage will be summarized by therapeutic class and 
preferred term, and based on the Safety Analysis Set. The summary will include number and 
percentage of subjects who took the medication. Therapeutic class will be sorted alphabetically, 
and PT will be sorted within each therapeutic class in descending frequency in the table Total 
column (i.e., the Total column will be sorted in descending order after sorting by therapeutic 
class and PT). Medications can be counted both as prior and concomitant medications. Multiple 
medication usage by a subject in the same PT will be counted only once for that PT. All prior 
and concomitant medications will be listed, and the listings will be based on the Safety Analysis 
Set. 
 
 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 24 of 53 
 
10. 
EFFICACY ANALYSES 
Not applicable. 
 
 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 25 of 53 
 
11. 
SAFETY ANALYSES 
Safety endpoints include the occurrence and number of treatment-emergent adverse events 
(TEAEs), vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature), 
electrocardiogram (ECG) results, body weight, clinical laboratory test results (hematology, 
clinical chemistry, coagulation and urinalysis), and immunogenicity response (development of 
anti-drug antibodies [ADAs]). For each safety endpoint, unless otherwise specified, the last non-
missing value before the administration of investigational product will be used as baseline for all 
analyses of that safety endpoint.  
All safety analyses will be descriptive and based on the Safety Analysis Set. Continuous variable 
summaries will include: number of subjects (n), mean, SD, median, minimum and maximum 
values, and categorical variable summaries will include: number and percentage of subjects.    
 
11.1 
Adverse Events  
Adverse events (AEs) will be coded using the MedDRA (Version 20.1 or higher).  
Treatment-emergent AEs are AEs with onset at the time of or following the first exposure to 
investigational product, or medical conditions present prior to the start of investigational product 
but increased in severity or relationship at the time of or following the start of treatment, up to 
the last follow-up visit. Note: In this study, all AEs will be collected from the time the informed 
consent is signed through the last follow-up visit (Day 112/End of Study). 
An overall summary of the number of subjects with TEAEs will be presented, including, but not 
limited to: the number and percentage of subjects with any TEAEs, severe TEAEs, serious 
TEAEs, TEAEs related to investigational product, TEAEs leading to discontinuation from the 
study, TEAEs resulting in hospitalization, and TEAEs leading to death. An overall summary of 
the number of TEAEs will be summarized also. 
 
In addition, the number of TEAEs and number and percentage of subjects reporting TEAEs will 
be tabulated by SOC and PT. The number and percentage of subjects reporting TEAEs will be 
summarized by SOC, PT, and maximum severity, as appropriate, based on applicable Shire TFL 
standards.  (Note: all severity levels will be presented in the summary). SOC will be sorted 
alphabetically, and PT will be sorted within each SOC in descending frequency in the table Total 
column (i.e., the Total column will be sorted in descending order after the sorting by SOC and 
PT). Also, all TEAEs and related TEAEs will each be summarized by PT only and in decreasing 
frequency in the table Total column, and separately non-SAEs will be summarized by SOC and 
PT and sorted as planned for the other summaries. TEAEs considered related to investigational 
product will also be summarized by SOC and PT. If more than 1 TEAE occurs within the same 
PT for the same subject, then the subject will be counted only once for that PT using the most 
severe and most related occurrence for the summarization by severity and by relationship to 
investigational product. For example, if a subject experienced a mild headache not related to 
investigational product, and a moderate headache related to investigational product, then the 
subject will be counted once for headache using the moderate headache related to investigational 
product. 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 26 of 53 
 
Serious TEAEs, TEAEs related to investigational product, TEAEs leading to discontinuation 
from the study, and TEAEs leading to death will be summarized by SOC and PT. Injection site 
reactions (ISRs) are not predefined in the study protocol. Any ISRs, if reported as AEs, will be 
summarized along with all other TEAEs as appropriate. 
All AE data will be listed. Listings will be presented for all AEs (TEAEs and non-TEAEs), 
serious AEs, severity of AEs, AEs related to investigational product, AEs leading to 
discontinuation from the study, and AEs leading to death. 
All TEAE summaries will be based on the Safety Analysis Set. Listings will be based on all 
enrolled subjects. 
11.2 
Clinical Laboratory Variables 
Raw (actual) clinical laboratory values (in SI units) and changes in raw values from baseline at 
each post-baseline assessment time point will be summarized as continuous variables. Shift 
tables from baseline to each assessment time point will be provided for categorical variables. The 
following laboratory variables/parameters will be summarized: 
Hematology 
Hemoglobin, hematocrit, red blood cells (RBC), platelet count, white blood cell 
(WBC) count – total and differential, total neutrophils (absolute), eosinophils 
(absolute), monocytes (absolute), basophils (absolute), and lymphocytes 
(absolute). 
Coagulation       Prothrombin Time, activated partial thromboplastin time, and international 
normalized ratio 
Biochemistry 
Sodium, potassium, glucose, blood urea nitrogen (BUN), creatinine, calcium, 
chloride, phosphorus, total protein, total CO2 (bicarbonate), albumin, aspartate 
transaminase (AST), alanine transaminase (ALT), gamma glutamyl transferase 
(GGT), alkaline phosphatase (ALP), total bilirubin, and uric acid. 
Urinalysis 
pH, glucose, protein, blood, ketones, bilirubin, nitrites, leukocyte esterase, and 
specific gravity. 
Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 3 and Table 4. The number and percentage of subjects 
with post-baseline PCI values at each scheduled time point will be tabulated for each set of PCI 
criteria. The percentages will be calculated relative to the number of subjects with available 
baseline values and at least 1 post-baseline assessment. The numerator is the total number of 
subjects with at least 1 post-baseline PCI value. A supportive listing of subjects with post-
baseline PCI values will be provided for each set of PCI criteria including the subject number, 
baseline, and post-baseline values. 
All clinical laboratory data will be listed, and listings will be based on the Safety Analysis Set.  


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 27 of 53 
 
 
Table 3: Primary Criteria for Potentially Clinically Important Laboratory Tests 
Parameter 
Classification  
Criteria 
Biochemistry 
Sodium 
HIGH 
 5 mmol/L (5 mEq/L) above ULN  
LOW 
 5 mmol/L (5 mEq/L) below LLN 
Potassium 
HIGH + INCREASE 
Above ULN and increase of  0.5 mmol/L (0.5 mEq/L) from 
baseline value  
LOW + DECREASE 
Below LLN and decrease of  0.5 mmol/L (0.5 mEq/L) from 
baseline value  
Creatinine 
HIGH + INCREASE 
 150µmol/L and increase > 30% from baseline value 
BUN 
HIGH 
 1.5 x ULN 
Glucose 
(fasting) 
HIGH 
≥ 6.7 mmol/L 
LOW 
≤ 4.2 mmol/L 
Calcium 
HIGH and INCREASE 
Above ULN and Increase of  0.25 mmol/L (1.0 mg/dL) from 
baseline value  
LOW and DECREASE 
Below LLN and Decrease of  0.25 mmol/L (1.0 mg/dL) from 
baseline value  
Phosphorus 
HIGH 
 0.162 mmol/L (0.5 mg/dL) above ULN 
LOW 
 0.162 mmol/L (0.5 mg/dL) below LLN 
Total protein 
HIGH and INCREASE 
Above ULN and Increase of  20 g/L (2.0 g/dL) from baseline 
value  
LOW and DECREASE 
Below LLN and Decrease of  20 g/L (2.0 g/dL) from baseline 
value  
Albumin 
HIGH and INCREASE 
Above ULN and Increase of  10 g/L (1.0 g/dL) from baseline 
value  
LOW and DECREASE 
Below LLN and Decrease of  10 g/L (1.0 g/dL) from baseline 
value  
Uric acid (with 
normal diet) 
HIGH and INCREASE 
Above ULN and Increase of  0.119 mmol/L (2.0 mg/dL) from 
baseline value  
LOW and DECREASE 
Below LLN and Decrease of  0.119 mmol/L (2.0 mg/dL) from 
baseline value  
ALT 
HIGH 
 2 x ULN   
AST 
HIGH 
 2 x ULN   
ALP 
HIGH 
 1.5 x ULN   
GGT 
HIGH 
 1.5 x ULN    
Total bilirubin 
HIGH 
 1.5 x ULN  
 T4 
HIGH 
> 140.28 nmol/L  
LOW 
< 57.92 nmol/L  
 T3 
HIGH 
> 2.765 nmol/L 
LOW 
< 0.922 nmol/L 
 TSH 
HIGH 
>5.0 µU/mL 
LOW 
<0.5 µU/mL 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 28 of 53 
 
Parameter 
Classification  
Criteria 
Hematology 
RBC count 
HIGH 
>7.5 x1012/L 
LOW 
<3 x1012/L 
Hematocrit 
HIGH 
>1.3 x ULN 
LOW and DECREASE 
≤0.6 x LLN and Decrease of  0.06 L/L (6.0%) from baseline 
value   
Hemoglobin 
HIGH 
>200 g/L (20g/dL) 
LOW and DECREASE 
< 100g/L (10g/dL) and Decrease of  20g/L (2.0 g/dL) from 
baseline value  
WBC count 
HIGH 
>2 x ULN OR >16.0 x 109/L (16 x 103/L) 
LOW 
< 0.5 x LLN OR  3.0 x 109/L (3 x 103/L) 
Neutrophils 
HIGH 
> 6.2 x 109/L (6.2 x 103/L) OR > 70 % 
LOW 
 1.5 x 109/L (1.5 x 103/L) OR < 40% 
Lymphocytes 
HIGH 
> 4.0 x 109/L (1.5 x 103/L) OR > 44 % 
LOW 
 0.8 x 109/L (0.8 x 103/L) OR < 22 % 
Monocytes 
HIGH 
> 1.1 x 109/L (1.1 x 103/µL) or > 11% 
Eosinophils 
HIGH 
 0.5 x 109/L (> 500/L) and  10.0% 
LOW 
NA 
Basophils 
HIGH 
> 0.2 x 109/L (0.2 x 103/µL) or > 2% 
LOW 
NA 
Platelet count 
(thrombocytes) 
HIGH 
1.5 x ULN OR > 500 x 109/L (100 x 103/L) 
LOW 
<0.6 x LLN OR  100 x 109/L (100 x 103/L) 
Urinalysis 
Glucose 
HIGH 
≥ 1+ 
Blood 
HIGH 
≥ 2+ 
Bilirubin  
 
Positive 
Protein 
HIGH 
≥ 2+ 
Nitrite  
 
Positive 
Ketones 
HIGH 
≥ 2+ 
Leukocyte 
Esterase 
 
Positive 
BUN: blood urea nitrogen, AST: aspartate transaminase, ALT: alanine transaminase, ALP: alkaline phosphatase, GGT: 
gamma glutamyl transferase, T3: triiodothyronine, T4: thyroxine, TSH: thyroid-stimulating hormone, RBC: red blood cell, 
WBC: white blood cell, NA: not available. 
 
 
 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 29 of 53 
 
Table 4: Secondary Criteria for Potentially Clinically Important Laboratory Tests 
Parameter 
Classification  
Criteria 
Biochemistry 
Sodium 
HIGH 
≥ 148 mEq/L 
LOW 
≤ 129 mEq/L 
Potassium 
HIGH  
≥ 5.5 mEq/L 
LOW  
≤ 3.2 mEq/L 
Creatinine 
HIGH  
≥ 2.1 mg/dL 
BUN 
HIGH 
> 31 mg/dL 
Glucose 
(fasting) 
HIGH 
> 125 mg/dL 
LOW 
≤ 54 mg/dL 
Calcium 
HIGH  
≥ 11.6 mg/dL 
LOW 
≤ 7.4 mg/dL 
Phosphorus 
HIGH 
NA 
LOW 
≤ 1.9 mg/dL 
Total protein 
HIGH 
NA 
LOW  
< 5.0 g/dL 
Albumin 
HIGH 
NA 
LOW 
< 2.5 g/dL 
ALT 
HIGH 
≥ 5.1 x ULN 
AST 
HIGH 
≥ 5.1 x ULN 
ALP 
HIGH 
≥ 3.1 x ULN 
Total bilirubin 
HIGH 
≥ 1.51 x ULN 
Hematology 
Hemoglobin 
(Female) 
HIGH 
NA 
LOW and DECREASE  
≤ 9.4 gm/dL and Decrease of  2.1 gm/dL from baseline value   
Hemoglobin 
(Male) 
HIGH 
NA 
LOW and DECREASE 
≤ 10.4 gm/dL and Decrease of  2.1 gm/dL from baseline value   
WBC count 
INCREASE 
 ≥ 20,001 cell/mm
3
 
DECREASE 
≤ 1,499 cell/mm
3
 
Neutrophils 
HIGH 
NA 
DECREASE 
≤ 999 cell/mm
3
 
Lymphocytes 
HIGH 
NA 
DECREASE 
≤ 499 cell/mm
3
 
Eosinophils 
HIGH 
> 5000 cell/mm
3
 
LOW 
NA 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 30 of 53 
 
Parameter 
Classification  
Criteria 
Platelet count 
(thrombocytes) 
HIGH 
NA 
LOW 
≤ 99,000 cell/mm
3
 
Urinalysis 
Glucose 
HIGH 
≥ 2+ 
Protein 
HIGH 
≥ 2+ 
BUN: blood urea nitrogen, AST: aspartate transaminase, ALT: alanine transaminase, ALP: alkaline phosphatase, WBC: 
white blood cell, NA: not available. 
Based on Grade 3 or Grade 4 criteria from Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials (FDA Guidance for Industry, September 2007). 
11.3 
Vital Signs (Including Height and Weight) 
Raw (actual) values for vital signs (e.g., systolic and diastolic blood pressure, pulse rate, and 
body temperature) and their changes from baseline at each post-baseline assessment time point 
will be summarized.  
Vital sign values will be considered PCI if they meet both the observed value criteria and the 
change from baseline criteria listed in Table 5. The number and percentage of subjects with PCI 
post-baseline values at each scheduled time point will be tabulated. The percentages will be 
calculated relative to the number of subjects with baseline and at least 1 post-baseline 
assessment. The numerator is the total number of subjects with at least 1 PCI post-baseline vital 
sign value. A supportive listing of subjects with post-baseline PCI values will be provided 
including the subject number, baseline, and post-baseline PCI values.  
All vital signs data (including height and weight) will be listed, and listing(s) will be based on 
the Safety Analysis Set. 
Table 5: Criteria for Potentially Clinically Significant Vital Signs 
Parameter 
Classification 
Criteria 
Systolic blood pressure 
(mm Hg) 
HIGH and INCREASE 
 140 and increase of  20 from baseline value 
LOW and DECREASE 
 90 and decrease of  20 from baseline value 
Diastolic blood 
pressure (mm Hg) 
HIGH and INCREASE 
 90 and increase of  15 from baseline value 
LOW and DECREASE 
 50 and decrease of  15 from baseline value 
Pulse rate (bpm) 
HIGH and INCREASE 
 100 and increase of  15 from baseline value 
LOW and DECREASE 
 45 and decrease of  15 from baseline value 
Temperature 
HIGH 
 38.3C or  100.9F 
LOW 
 35C or  95F 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 31 of 53 
 
11.4 
Electrocardiogram (ECG) 
Raw (actual) values for ECG variables (e.g., heart rate, RR interval, PR interval, QRS interval, 
QT interval, and QTc interval) and their changes from baseline at each post-baseline assessment 
time point will be presented. QTc interval will be calculated using both Bazett 
(QTcB=QT/(RR)1/2) and Fridericia (QTcF=QT/(RR)1/3) corrections; and if RR is not available, 
then 60/heart rate will be used in the correction formula. Electrocardiogram interpretation, per 
the investigator, will be summarized by assessment time point for all scheduled assessments. In 
addition, a shift table from baseline to each post-baseline assessment time point for categorical 
ECG results will be provided.  
Subject’s baseline ECG is defined as the single ECG collected predose on Day 1 (or unscheduled 
ECG collected after the scheduled predose timepoint but prior to the administration of 
investigational product).  
Electrocardiogram variable values will be considered PCI if they meet or exceed the upper limit 
values listed in Table 6. The number and percentage of subjects with post-baseline PCI values at 
each scheduled time point will be tabulated. The percentages will be calculated relative to the 
number of subjects with available non-PCI baseline and at least 1 post-baseline assessment. The 
numerator is the total number of subjects with at least 1 PCI post-baseline ECG value. A listing 
of all subjects with post-baseline PCI values will be provided including the subject number, 
baseline, and post-baseline PCI values. 
All ECG data will be listed, and listing will be based on the Safety Analysis Set. Listings of ECG 
data, including interpretation by individual subject, will also be produced. 
Table 6: Criteria for Potentially Clinically Important ECG Values 
Parameter 
Classification  
Criteria 
Overall Evaluation 
ABNORMAL 
Overall Evaluation is ABNORMAL 
Heart rate (bpm) 
HIGH and INCREASE 
 100 and increase of  15 from baseline value 
LOW and DECREASE 
 45 and decrease of  15 from baseline value 
PR interval (msec) 
HIGH and INCREASE 
 200 and increase of  20 from baseline value 
QRS interval (msec) 
HIGH 
 120 
QTc interval (men) 
(msec) 
HIGH 
 430 and increase from baseline value > 30 
QTc interval (women) 
(msec) 
HIGH 
 450 and increase from baseline value > 30 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 32 of 53 
 
11.5 
Other Safety Variables 
11.5.1 
Immunogenicity Testing for Anti-Drug Antibodies 
For immunogenicity, the number and percentage of subjects with ADA prevalence, ADA 
incidence, pre-existing ADA, treatment-induced ADA, treatment-boosted ADA, transient ADA, 
persistent ADA, non-neutralizing ADA, and neutralizing ADA will be summarized by ethnic 
group. The ADA titer and reactivity, as well as the neutralizing antibody responses will be listed.  
Pre-existing ADA: a laboratory reported confirmatory positive ADA prior to treatment. 
Treatment-induced ADA: ADA developed de novo (seroconversion) following biologic drug 
administration (i.e., formation of ADA any time after the initial drug administration in a subject 
without pre-existing ADA). 
Treatment-boosted ADA: Pre-existing ADA that were boosted to a higher level following 
biologic drug administration (i.e., any time after the initial drug administration the ADA titer is 
greater than the baseline titer by 4-fold increase or more), where the fold increase will be 
calculated as: log2(post-dose ADA titer/pre-existing ADA titer).   
ADA prevalence: The proportion of all individuals having drug-reactive antibodies (including 
pre-existing antibodies) at any point in time. This term is distinct from ADA incidence (see 
below). 
ADA incidence: The proportion of the study population found to have seroconverted or boosted 
their pre-existing ADA during the study period. Synonymous with “treatment-emergent ADA”, 
ADA incidence is the sum of both treatment-induced and treatment-boosted ADA-positive 
subjects as a proportion of the evaluable subject population. 
Transient ADA response:  
 Treatment-induced ADA detected only at one sampling time point during the treatment or 
follow-up observation period (excluding the last sampling time point, which ought to be 
considered persistent unless shown to be undetectable at a later time) or 
 Treatment-induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period less 
than 16 weeks, and the subject’s last sampling time point is ADA-negative. 
Persistent ADA response:  
 Treatment-induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period of 
16 weeks or longer or 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 33 of 53 
 
 Treatment-induced ADA incidence only in the last sampling time point of the treatment 
study period or at a sampling time point with less than 16 weeks before an ADA-negative 
last sample. 
All immunogenicity summaries and data listing(s) will be based on the Safety Analysis Set. The 
overall ADA status (positive or negative) of each subject will be presented in the listing. Subjects 
meeting the criteria for ADA incidence will be considered positive for overall ADA status, and 
all other subjects will be considered negative for overall ADA status.  


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 34 of 53 
 
12. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES 
12.1 
Pharmacokinetic Methods 
Individual PK data will be listed, and listing(s) will be based on the Safety Analysis Set; all 
summaries and analyses of the PK data will be based on the PK Set. 
12.1.1 
Concentration Data 
Blood samples will be drawn from each subject during this study for the determination of plasma 
concentrations of lanadelumab. Serial blood samples will be collected during the in-house 
treatment period on Days 1 to 5 for PK analysis at predose, and at 8, 24, 48, 72, and 96 hours 
after administration of the investigational product. One postdose blood sample will be also drawn 
from each subject on Days 7, 14, 21, 28, 42, 56, 84 and 112 for the determination of lanadelumab 
concentrations. Actual sampling times post-dose will be considered protocol deviations where 
the sample deviated from nominal collection time by more than ±5 minutes within the first 4 
hours, ±15 minutes between 4 and 96 hours, ±1 day between Days 7 and 21, ±2 days between 
Days 28 and 56, and ±3 days on Days 84 and 112. Samples collected outside these windows will 
be flagged in data listings. Plasma concentrations of lanadelumab will be measured using a 
validated analytical method. 
Individual lanadelumab plasma concentrations will be listed by ethnic group, subject, overall 
ADA status, day, and time based on the Safety Analysis Set and summarized by ethnic group and 
time, and separately by ethnic group, overall ADA status and nominal time, all based on the PK 
Set. Summaries will include: number of subjects (n), arithmetic mean, SD, percent coefficient of 
variation (%CV), median, minimum, maximum, geometric mean, and %CV of geometric mean. 
In addition, the mean and individual lanadelumab plasma concentration versus time profiles by 
ethnic group and overall ADA status will be presented in figures on both linear and semi-
logarithmic scales. Mean (±SD) lanadelumab plasma concentration versus nominal time profiles 
will be presented for the PK Set using nominal time. All sampling times considered to be 
protocol deviations will be excluded from summaries and mean plots. Individual lanadelumab 
plasma concentration versus time profiles will be presented using nominal time based on the 
Safety Analysis Set. 
12.1.2 
Handling BLQ Values 
The following procedures will be used for lanadelumab plasma PK concentrations below the 
lower limit of quantification (LLOQ): 
 Samples that are below limit of quantification (BLQ) will be reported as <LLOQ in the 
data listings, where LLOQ is replaced by the actual value for LLOQ for specific PK 
assay. 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 35 of 53 
 
 Samples that are BLQ are treated as zero in the calculation of summary statistics (e.g. 
mean, SD, etc.) for the plasma PK concentrations at individual time points. Geometric 
mean and %CV of geometric mean will be set to missing where zero values exist. 
 Mean concentrations are reported as zero if all values are BLQ or zero, and no other 
descriptive statistics are reported. If the calculated mean (±SD) concentration is less than 
the LLOQ, the value will be reported as calculated. The mean values derived using these 
concentrations will be used to create the mean plasma concentration versus time plots. 
 For calculation of area under the plasma concentration curve (AUC), BLQ values are set 
equal to zero in the dataset loaded into Phoenix® WinNonlin® (Certara USA, Inc, 
Princeton, NJ) for PK analysis. WinNonlin® uses the zero values that occur before the 
first time point with a concentration greater than LLOQ. Values that are BLQ after the 
first measurable concentration will be set to “missing” in the dataset loaded into 
WinNonlin®. 
 Missing values will not be imputed.   
12.1.3 
Pharmacokinetic Parameters 
The PK analysis will be conducted using Phoenix® WinNonlin® (Certara USA, Inc, Princeton, 
NJ) Version 6.4 or higher. Pharmacokinetic parameters will be determined from the lanadelumab 
plasma concentration-time data using non-compartmental analysis based on actual sampling 
times. All samples will be used in the PK analysis regardless of whether they are considered 
protocol deviations or not. 
The PK parameters for lanadelumab will include, but may not be limited to: 
 Cmax 
Maximum observed lanadelumab plasma concentration 
 tmax 
Time of maximum observed lanadelumab plasma concentration 
 AUC0-last 
Area under the lanadelumab plasma concentration-time curve from time zero 
to the last quantifiable plasma concentration, calculated using the linear-
up/log-down trapezoidal rule 
In this method, the linear trapezoidal method of calculation is used for each 
incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid 
 AUC0-∞ 
Area under the lanadelumab plasma concentration-time curve from time zero 
extrapolated to infinity 
 λz 
First order rate constant associated with the terminal (log-linear) portion of 
the lanadelumab plasma concentration curve 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 36 of 53 
 
 t½ 
Terminal half-life 
 CL/F 
Apparent clearance 
 Vz/F 
Apparent volume of distribution 
Body weight-adjusted AUC0-last, AUC0-∞, Cmax, CL/F, and Vz/F PK parameters will also be 
determined. 
12.2 
Statistical Analysis of Pharmacokinetic Parameters 
Descriptive statistical analysis of PK parameters will be based on the PK Set. The plasma PK 
parameters of lanadelumab will be summarized by ethnic group, and separately by ethnic group 
and overall ADA status. Summaries will include: n, arithmetic mean, SD, %CV, median, 
minimum, maximum, geometric mean, and %CV of geometric mean. In addition, 95% 
confidence intervals (CIs) for PK parameters will be provided. Listing of individual plasma PK 
parameters of lanadelumab will be provided based on the Safety Analysis Set. Individual 
(observed) and body weight-adjusted PK parameters (y-axis) versus body weight (x-axis) by 
ethnic group and overall ADA status will be presented in figures on both linear and semi-
logarithmic scales for AUC0-last, AUC0-∞, Cmax, CL/F, and Vz/F. 
Following ln-transformation, the PK parameters Cmax, AUC0-last, and AUC0-∞, will be analyzed 
using an analysis of variance (ANOVA) model, for estimation purposes. No formal hypothesis 
testing will be performed. The model will include ethnic group as a fixed effect. Point estimates 
and their associated 90% CIs will be constructed for the differences in the ln-transformed 
parameters. The point estimates and their associated 90% CIs will be then back-transformed to 
provide point estimates for the ratio (Japanese Subjects/Caucasian Subjects) of geometric least 
squares means and associated 90% CIs on the original scale. 
To assess the impact of overall ADA status on the ethnic group comparison, if data permits, a 
sensitivity analysis will be performed by repeating the above ANOVA analyses by overall ADA 
status. 
12.3 
Pharmacodynamic Methods 
Individual PD data will be listed, and listing(s) will be based on the Safety Analysis Set; all 
summaries and analyses of the PD data will be based on the PD Set. 
12.3.1 
Pharmacodynamic Data 
Blood samples will be drawn from each subject during this study for the determination of 
inhibition of pKal activity and plasma cHMWK levels. Serial blood samples will be collected 
during the in-house treatment period on Days 1 to 5 for PD analysis at predose, and at 8, 24, 48, 
72, and 96 hours after administration of the investigational product. Post-dose blood samples will 
be also drawn from each subject on Days 7, 14, 21, 28, 42, 56, 84 and 112 for the determination 
of inhibition of pKal activity and plasma cHMWK levels. Actual sampling times post-dose will 
be considered protocol deviations where the sample deviated from nominal collection time by 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 37 of 53 
 
more than ±5 minutes within the first 4 hours, ±15 minutes between 4 and 96 hours, ±1 day 
between Days 7 and 21, ±2 days between Days 28 and 56, and ±3 days on Days 84 and 112. 
Samples collected outside these windows will be flagged in data listings. The pKal activity and 
plasma cHMWK levels will be measured using validated analytical methods.  
Individual pKal activity, inhibition of pKal, and plasma cHMWK levels (from both untreated 
and treated samples (including intact 110 kDa, 56 kDa, 46 kDa and %cHMWK) will be listed by 
subject, ethnic group, day, and time based on the Safety Analysis Set and summarized by ethnic 
group and nominal time based on the PD set. Summaries will include: n, arithmetic mean, SD, 
%CV, median, minimum, maximum, geometric mean, and %CV of geometric mean. In addition, 
the mean and individual inhibition of pKal activity and plasma cHMWK levels (%cHMWK from 
treated samples only) versus nominal time by ethnic group will be presented in figures on a 
linear scale. Mean (±SD) inhibition of pKal activity and mean (+SD) plasma cHMWK levels 
(treated samples only) versus nominal time will be presented for the PD Set using nominal time. 
All sampling times considered to be major protocol deviations will be excluded from summaries 
and mean plots. Individual inhibition of pKal activity and plasma cHMWK levels versus time 
will be presented using nominal time based on the Safety Analysis Set.  
12.3.2 
Baseline-adjusted Pharmacodynamic Data 
Individual plasma cHMWK levels (treated samples only) will be baseline-adjusted at each time 
point. Baseline is defined as the predose cHMWK level on Day 1. Baseline-adjusted levels of 
cHMWK will be calculated by subtracting the appropriate baseline values from the reported 
laboratory levels for that particular subject. If the baseline-adjusted cHMWK level gives a 
negative value then the negative level will be used as is for analysis.  
Individual baseline-adjusted cHMWK levels (from both untreated and treated samples including 
intact 110 kDa, 56 kDa, 46 kDa and %cHMWK) will be listed by subject, ethnic group, day, and 
time based on the Safety Analysis Set and summarized by ethnic group and time based on the PD 
Set separately for original and baseline-adjusted cHMWK. Summaries will include: n, arithmetic 
mean, SD, %CV, median, minimum, and maximum. In addition, the mean and individual 
baseline-adjusted plasma cHMWK levels (treated samples only) versus time by ethnic group will 
be presented in figures on a linear scale. Mean (SD) baseline-adjusted plasma cHMWK levels 
(treated samples only) versus time will be presented for the PD Set using nominal time. All 
sampling times considered to be protocol deviations will be excluded from summaries and mean 
plots. Individual baseline-adjusted plasma cHMWK levels versus time will be presented using 
nominal time based on the Safety Analysis Set. 
12.3.3 
Pharmacodynamic Parameters 
Not applicable. 
12.4 
Statistical Analysis of Pharmacodynamic Parameters 
Not applicable. 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 38 of 53 
 
13. 
OTHER ANALYSES 
No other analyses are planned for this study. 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 39 of 53 
 
14. 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 40 of 53 
 
15. 
DATA MONITORING/REVIEW COMMITTEE 
No Data Monitoring Committee (DMC) is planned for this study. 
 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 41 of 53 
 
16. 
COMPUTER METHODS  
Statistical analyses will be performed using Version 9.3 of SAS or higher on a suitably qualified 
environment. Phoenix® WinNonlin® (Certara USA, Inc, Princeton, NJ) Version 6.4 or higher 
will be used for calculating PK parameters. 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 42 of 53 
 
17. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
The following changes have been made to the PK analyses specified in the protocol (dated 27 
Nov 2017): 
 
 Inclusion of overall ADA status in PK concentration and parameter listings. Additionally, 
PK concentrations and parameters will be summarized by overall ADA status. 
 Addition of the body weight-adjusted PK parameter AUC0-∞. 
 Addition of ANOVA statistical analysis model to evaluate the PK of lanadelumab 
between ethnic groups. 
 Removal of the word ‘concentration’ from the PD population definition, which is not 
applicable for the PD markers in this study. 
 
No other changes to the analyses specified in the protocol (dated 27 Nov 2017) have been made. 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 43 of 53 
 
18. 
DATA HANDLING CONVENTIONS 
18.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics:  number of 
subjects (n), mean, median, SD, minimum, maximum.  Unless specified otherwise, summary 
statistics will be presented to 1 more significant digit than the raw data. The minimum and 
maximum values will be presented to the same number of decimal places as the raw data; the 
mean and median will be presented to 1 more decimal place than the raw data; and the SD and 
standard error will be presented to 2 more decimal places than the raw data. BMI, averaged 
laboratory results e.g. diastolic/systolic blood pressure and pulse (when taken in triplicate), and 
derived questionnaire scores will be rounded to 1 decimal place for reporting. 
Categorical and count variables will be summarized by the number of subjects and the percent of 
subjects in each category, as appropriate.  Percentages will be presented as whole numbers.  
18.2 
Derived Efficacy Endpoints  
Not applicable. 
18.3 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated or unscheduled assessments before the start of investigational product, 
then the results from the most recent assessment made prior to the start of investigational product 
will be used as baseline.  
If post-baseline assessments are repeated, these will be captured as unscheduled visits, and the 
value recorded at the scheduled visit will be used for generating descriptive statistics. 
All assessments, including unscheduled and repeated assessments, will be presented in the data 
listings.  
18.4 
Missing Date of Investigational Product  
Since this is a Phase 1 single-dose study in which the investigational product will be 
administered on Day 1, missing dates of investigational product are not expected.  
18.5 
Missing Date Information for Prior or Concomitant Medications  
For prior or concomitant medications, including rescue medications, incomplete (i.e., partially 
missing) start date and/or stop date will be imputed.  When the start date and the stop date are 
both incomplete for a subject, the start date will be imputed first.     


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 44 of 53 
 
18.5.1 
Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields.  If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Note: This is a single-dose study, and thus the use of “first dose” below equates to “dose.”  
Missing day and month 
 
If the year of the incomplete start date is the same as the year of the date of the first dose of 
investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields. 
 
If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields. 
 
If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
 
If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of investigational product, then the day of the date of the first dose of 
investigational product will be assigned to the missing day 
 
If either the year is before the year of the date of the first dose of investigational product or 
if both years are the same but the month is before the month of the date of the first dose of 
investigational product, then the last day of the month will be assigned to the missing day 
 
If either the year is after the year of the date of the first dose of investigational product or if 
both years are the same but the month is after the month of the date of the first dose of 
investigational product, then the first day of the month will be assigned to the missing day.  
18.5.2 
Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields.  If the date of the last 
dose of investigational product is missing, then it will be replaced with the last visit date.  If the 
imputed stop date is before the start date (imputed or non-imputed start date), then the imputed 
stop date will be equal to the start date. 
Missing day and month 
 
If the year of the incomplete stop date is the same as the year as of the date of the last dose 
of investigational product, then the day and month of the date of the last dose of 
investigational product will be assigned to the missing fields 
 
If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 45 of 53 
 
 
If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
 
If the month and year of the incomplete stop date are the same as the month and year of the 
date of the last dose of investigational product, then the day of the date of the last dose of 
investigational product will be assigned to the missing day 
 
If either the year is before the year of the date of the last dose of investigational product or 
if both years are the same but the month is before the month of the date of the last dose of 
investigational product, then the last day of the month will be assigned to the missing day 
 
If either the year is after the year of the last dose of investigational product or if both years 
are the same but the month is after the month of the date of the last dose of investigational 
product, then the first day of the month will be assigned to the missing day. 
18.6 
Missing Date Information for Adverse Events  
For AEs, incomplete (i.e., partially missing) start dates will be imputed and will follow the same 
rules as in Section 18.5.1.  Incomplete stop dates will not be imputed.   
18.7 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned.  If the severity is missing for an AE starting 
on or after the date of the first dose of investigational product, then a severity of “Severe” will be 
assigned.  The imputed values for severity assessment will be used for incidence summaries, 
while the actual values will be used in data listings. 
18.8 
Missing Relationship to Investigation Product for Adverse Events 
If the relationship to investigational product is missing for an AE starting on or after the date of 
the first dose of investigational product, a causality of “Related” will be assigned.  The imputed 
values for relationship to the investigational product will be used for incidence summaries, while 
the actual values will be presented in data listings. 
18.9 
Character Values of Clinical Laboratory Variables  
The actual values of clinical laboratory variables as reported in the database will be presented in 
data listings. No coded values (e.g., when a character string is reported for a numerical variable) 
are necessary. 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 46 of 53 
 
19. 
REFERENCES 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials (FDA Guidance for Industry, September 2007) 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 47 of 53 
 
20. 
TABLE OF CONTENTS FOR TABLES, FIGURES, AND LISTINGS 
This summary lists the planned TFLs. The list may differ from TFLs actually produced for the 
Clinical Study Report (CSR). If changes to the list are made after the SAP sign-off, the SAP will 
not be modified to reflect the changes. Refer to the CSR for TFLs actually produced. 
Table 
Title 
14.1.1.1 
Disposition by Ethnic Group (Enrolled Set) 
14.1.4.1.1 
Demographic Characteristics by Ethnic Group (Safety Analysis Set) 
14.1.4.1.2 
Demographic Characteristics by Ethnic Group (Pharmacokinetic Set) 
14.1.4.1.3 
Demographic Characteristics by Ethnic Group (Pharmacodynamic Set) 
14.1.4.2.1 
Baseline Characteristics by Ethnic Group (Safety Analysis Set) 
14.1.4.2.2 
Baseline Characteristics by Ethnic Group (Pharmacokinetic Set) 
14.1.4.2.3 
Baseline Characteristics by Ethnic Group (Pharmacodynamic Set) 
14.1.4.3.1 
Medical History by System Organ Class, Preferred Term and Ethnic Group (Safety 
Analysis Set) 
14.1.4.4.1 
Prior Medications by Ethnic Group (Safety Analysis Set) 
14.1.4.5.1 
Concomitant Medications by Ethnic Group (Safety Analysis Set) 
14.2.5.1 
Summary of Lanadelumab Plasma Concentrations (units) versus Time by Ethnic 
Group (Pharmacokinetic Set) 
14.2.5.2 
Summary of Lanadelumab Plasma Concentrations (units) versus Time by Ethnic 
Group and Overall ADA Status (Pharmacokinetic Set) 
14.2.5.3 
Summary of Lanadelumab Plasma Pharmacokinetic Parameters by Ethnic Group 
(Pharmacokinetic Set) 
14.2.5.4 
Summary of Lanadelumab Plasma Pharmacokinetic Parameters by Ethnic Group 
and Overall ADA Status (Pharmacokinetic Set) 
14.2.5.5 
Statistical Analysis of Lanadelumab Plasma Pharmacokinetic Parameters 
(Pharmacokinetic Set) 
14.2.5.6 
Statistical Analysis of Lanadelumab Plasma Pharmacokinetic Parameters by 
Overall ADA Status (Pharmacokinetic Set) 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 48 of 53 
 
Table 
Title 
14.2.5.7 
Summary of Inhibition of pKal Activity (%) versus Time by Ethnic Group 
(Pharmacodynamic Set) 
14.2.5.8 
Summary of Plasma cHMWK Levels (%) versus Time by Ethnic Group 
(Pharmacodynamic Set) 
14.2.5.9 
Summary of Baseline Adjusted Plasma cHMWK Levels (%) versus Time by 
Ethnic Group (Pharmacodynamic Set) 
14.3.1.1 
Overall Treatment-Emergent Adverse Events by Ethnic Group (Safety Analysis 
Set) 
14.3.1.2.1 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and 
Ethnic Group (Safety Analysis Set) 
14.3.1.2.2 
Treatment-Emergent Adverse Events by Preferred Term and Ethnic Group (Safety 
Analysis Set) 
14.3.2.1 
Treatment-Emergent Adverse Events by Maximum Severity, System Organ Class, 
Preferred Term and Ethnic Group (Safety Analysis Set) 
14.3.2.2.1 
Treatment-Emergent Adverse Events Considered Related to Investigational 
Product by System Organ Class, Preferred Term and Ethnic Group (Safety 
Analysis Set) 
14.3.2.2.2 
Treatment-Emergent Adverse Events Considered Related to Investigational 
Product by Preferred Term and Ethnic Group (Safety Analysis Set) 
14.3.3.1 
Treatment-Emergent Adverse Events Leading to Death by System Organ Class, 
Preferred Term and Ethnic Group (Safety Analysis Set) 
14.3.3.2 
Treatment-Emergent Adverse Events Leading to Discontinuation by System Organ 
Class, Preferred Term and Ethnic Group (Safety Analysis Set) 
14.3.3.3 
Serious Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term and Ethnic Group (Safety Analysis Set) 
14.3.3.4 
Non-Serious Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Ethnic Group (Safety Analysis Set) 
14.3.4.1 
Quantitative Clinical Laboratory Results by Ethnic Group: Hematology (Safety 
Analysis Set) 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 49 of 53 
 
Table 
Title 
14.3.4.2 
Shift from Baseline in Clinical Laboratory Results by Ethnic Group: Hematology 
(Safety Analysis Set) 
14.3.4.3 
Primary Potentially Clinically Important (PCI) Laboratory Results by Ethnic 
Group: Hematology (Safety Analysis Set) 
14.3.4.4 
Secondary Potentially Clinically Important (PCI) Laboratory Results by Ethnic 
Group: Hematology (Safety Analysis Set) 
14.3.4.5 
Quantitative Clinical Laboratory Results by Ethnic Group: Biochemistry (Safety 
Analysis Set) 
14.3.4.6 
Shift from Baseline in Clinical Laboratory Results by Ethnic Group: Biochemistry 
(Safety Analysis Set) 
14.3.4.7 
Primary Potentially Clinically Important (PCI) Laboratory Results by Ethnic 
Group: Biochemistry (Safety Analysis Set) 
14.3.4.8 
Secondary Potentially Clinically Important (PCI) Laboratory Results by Ethnic 
Group: Biochemistry (Safety Analysis Set) 
14.3.4.9 
Quantitative Clinical Laboratory Results by Ethnic Group: Urinalysis (Safety 
Analysis Set) 
14.3.4.10 
Qualitative Clinical Laboratory Results by Ethnic Group: Urinalysis (Safety 
Analysis Set) 
14.3.4.11 
Shift from Baseline in Clinical Laboratory Results by Ethnic Group: Urinalysis 
(Safety Analysis Set) 
14.3.4.12 
Primary Potentially Clinically Important (PCI) Laboratory Results by Ethnic 
Group: Urinalysis (Safety Analysis Set) 
14.3.4.13 
Secondary Potentially Clinically Important (PCI) Laboratory Results by Ethnic 
Group: Urinalysis (Safety Analysis Set) 
14.3.5.1 
Actual Values and Change from Baseline in Vital Signs by Ethnic Group (Safety 
Analysis Set) 
14.3.5.2 
Potentially Clinically Important (PCI) Vital Sign Results by Timepoint and Ethnic 
Group (Safety Analysis Set) 
14.3.6.1 
Actual Values and Change from Baseline in ECG by Timepoint and Ethnic Group 
(Safety Analysis Set) 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 50 of 53 
 
Table 
Title 
14.3.6.2 
ECG Interpretation by Timepoint and Ethnic Group (Safety Analysis Set) 
14.3.6.3 
Shift from Baseline to Post-baseline Timepoint in Qualitative ECG Results by 
Ethnic Group (Safety Analysis Set) 
14.3.6.4 
Potentially Clinically Important (PCI) ECG Results by Timepoint and Ethnic 
Group (Safety Analysis Set) 
14.3.6.5 
Summary of Immunogenicity Response by Ethnic Group (Safety Analysis Set) 
14.3.6.6 
Number (Percent) of Subjects with Positive Anti-Drug Antibodies Responses by 
Timepoint and Ethnic Group (Safety Analysis Set) 
14.3.6.7 
Number (Percent) of Subjects with Positive Neutralizing Antibodies Responses by 
Timepoint and Ethnic Group (Safety Analysis Set) 
14.3.7.1 
Investigational Product Exposure by Ethnic Group (Safety Analysis Set) 
 
Figure 
Title 
14.2.5.1 
Mean (±SD) Lanadelumab Plasma Concentrations (units) versus Time by Ethnic 
Group (Pharmacokinetic Set) 
14.2.5.2 
Mean (±SD) Lanadelumab Plasma Concentrations (units) versus Time by Ethnic 
Group and Overall ADA Status (Pharmacokinetic Set) 
14.2.5.3 
Individual Lanadelumab Plasma Concentrations (units) versus Time (Safety 
Analysis Set) 
14.2.5.4 
Mean (±SD) Inhibition of pKal Activity (%) versus Time by Ethnic Group 
(Pharmacodynamic Set) 
14.2.5.5 
Individual Inhibition of pKal Activity (%) versus Time (Safety Analysis Set) 
14.2.5.6 
Mean (+SD) Plasma cHMWK Levels (%) versus Time by Ethnic Group 
(Pharmacodynamic Set) 
14.2.5.7 
Mean (SD) Baseline-Adjusted Plasma cHMWK Levels (%) versus Time by Ethnic 
Group (Pharmacodynamic Set) 
14.2.5.8 
Individual Plasma cHMWK Levels (%) versus Time (Safety Analysis Set) 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 51 of 53 
 
Figure 
Title 
14.2.5.9 
Individual Baseline-Adjusted Plasma cHMWK Levels (%) versus Time (Safety 
Analysis Set) 
14.2.5.10 
Individual and Mean (±SD) Lanadelumab Plasma Cmax Values versus Body 
Weight (Pharmacokinetic Set) 
14.2.5.11 
Individual and Mean (±SD) Lanadelumab Plasma Weight-adjusted Cmax Values 
versus Body Weight (Pharmacokinetic Set) 
14.2.5.12 
Individual and Mean (±SD) Lanadelumab Plasma AUC0-last Values versus Body 
Weight (Pharmacokinetic Set) 
14.2.5.13 
Individual and Mean (±SD) Lanadelumab Plasma Weight-adjusted AUC0-last 
Values versus Body Weight (Pharmacokinetic Set) 
14.2.5.14 
Individual and Mean (±SD) Lanadelumab Plasma AUC0-inf Values versus Body 
Weight (Pharmacokinetic Set) 
14.2.5.15 
Individual and Mean (±SD) Lanadelumab Plasma Weight-adjusted AUC0-inf 
Values versus Body Weight (Pharmacokinetic Set) 
14.2.5.16 
Individual and Mean (±SD) Lanadelumab Plasma CL/F Values versus Body 
Weight (Pharmacokinetic Set) 
14.2.5.17 
Individual and Mean (±SD) Lanadelumab Plasma Weight-adjusted CL/F Values 
versus Body Weight (Pharmacokinetic Set) 
14.2.5.18 
Individual and Mean (±SD) Lanadelumab Plasma Vz/F Values versus Body 
Weight (Pharmacokinetic Set) 
14.2.5.19 
Individual and Mean (±SD) Lanadelumab Plasma Weight-adjusted Vz/F Values 
versus Body Weight (Pharmacokinetic Set) 
 
Listing 
Title 
16.2.1.1 
Subject Disposition (Enrolled Set) 
16.2.1.2 
Subjects Who Discontinued from the Study (Enrolled Set) 
16.2.1.3 
Study Analysis Set Classification (Enrolled Set) 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 52 of 53 
 
Listing 
Title 
16.2.1.4 
Subject Matching (Enrolled Set) 
16.2.2.1 
Deviations from Inclusion/Exclusion Criteria (Enrolled Set) 
16.2.2.2 
Listing of Protocol Deviations (Enrolled Set) 
16.2.4.1 
Subject Demographics (Safety Analysis Set) 
16.2.4.2 
Subject Baseline Characteristics (Safety Analysis Set) 
16.2.4.3 
Medical History (Safety Analysis Set) 
16.2.4.4 
Prior and Concomitant Medications (Safety Analysis Set) 
16.2.4.5 
Prior and Concomitant Procedures/ Therapies (Safety Analysis Set) 
16.2.5.1 
Investigational Product Exposure (Safety Analysis Set) 
16.2.5.2 
Pharmacokinetic Blood Plasma Draw Times and Lanadelumab Concentration Data 
(Pharmacokinetic Set) 
16.2.5.3 
Lanadelumab Pharmacokinetic Parameters (Pharmacokinetic Set) 
16.2.5.4 
Pharmacodynamic Blood Plasma Draw Times and Inhibition of pKal Activity Data 
(Pharmacodynamic Set) 
16.2.5.5 
Pharmacodynamic Blood Plasma Draw Times and Kinnogen Data 
(Pharmacodynamic Set) 
16.2.7.1 
Adverse Events (Enrolled Set) 
16.2.7.2 
Serious Adverse Events (Enrolled Set) 
16.2.7.3 
Adverse Events Leading to Discontinuation from the Study (Enrolled Set) 
16.2.7.4 
Adverse Events Considered Related to Investigational Product (Enrolled Set) 
16.2.7.5 
Adverse Events Leading to Death (Enrolled Set) 
16.2.8.1.1 
Clinical Laboratory Test Results (Safety Analysis Set) 
16.2.8.1.2 
Subjects with Primary Potentially Clinically Important Laboratory Test Results 
(Safety Analysis Set) 


Shire                                                                CONFIDENTIAL                                                21 Jun 2018 
Final Statistical Analysis Plan 
Protocol SHP643-101                                         Version 1.0                                                     Page 53 of 53 
 
Listing 
Title 
16.2.8.1.3 
Subjects with Secondary Potentially Clinically Important Laboratory Test Results 
(Safety Analysis Set) 
16.2.8.2.1 
Vital Signs (Safety Analysis Set) 
16.2.8.2.2 
Subjects with Potentially Clinically Important Vital Signs (Safety Analysis Set) 
16.2.8.3.1 
12-lead ECG Results and Interpretation (Safety Analysis Set) 
16.2.8.3.2 
Subjects with Potentially Clinically Important ECG Results (Safety Analysis Set) 
16.2.8.4 
Anti-drug Antibody Results (Safety Analysis Set)