Clinical trial NCT03918239
Conditions: Healthy Volunteers
Sponsor: Shire
Start date: 2019-05-14; Completion date: 2019-11-13
Enrollment: 190 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate bioavailability of lanadelumab (SHP643) following a single, 2 milliliter (mL) subcutaneous (SC) dose of 300 milligrams (mg) delivered by prefilled syringe (PFS) or auto injector (AI) in healthy adult participants.

Detailed description:

Arms: arm 1: Participants will receive 300 milligram (mg) of SHP643 PFS Subcutaneous (SC) injection into the abdomen on Day 1 during the in-house period (Day 1 to Day 5). arm 2: Participants will receive 300 mg of SHP643 AI SC injection into the abdomen on Day 1 during the in-house period (Day 1 to Day 5).
Interventions: intervention 1: SHP643
Intervention descriptions: intervention 1: Participants will receive injection of SHP643.

Protocol documents:
Prot_000.pdf: 
PROTOCOL:  SHP643-102
TITLE:
A Randomized, Open-label, Single-dose, Parallel-arm, Single-center, 
Phase 1 Study to Determine the Bioavailability of Lanadelumab 
Administered Subcutaneously with the Prefilled Syringe and the 
Autoinjector in Healthy Adult Volunteer Subjects
DRUG:
SHP643, lanadelumab (formerly DX-2930)
IND:
116647
EUDRACT NO.:
Non-EUDRACT
SPONSOR: 
Dyax Corp. (a wholly-owned, indirect subsidiary of Shire plc)
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
PROTOCOL 
HISTORY:
Original Protocol:  29 Jan 2019
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations.  This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.
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EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the "Shire Clinical Study Adverse 
Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as Required by the 
Protocol" within 24 hours to the Shire Global Drug Safety Department. The fax number and e-
mail address are provided on the form (sent under separate cover). A copy of this form must also 
be sent to the contract research organization (CRO) (as applicable)/Shire Medical Monitor using 
the details below.
E-mail: 
For protocol- or safety-related questions or concerns during normal business hours the 
investigator must contact the Shire Medical Monitor:
 (Business hours)
 (24-hour coverage)
For protocol- or safety-related questions or concerns outside of normal business hours, the 
investigator must contact the Shire Medical Monitor:
 (24-hour coverage)
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Shire within 24 hours.  If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
This includes any instances wherein the quality or performance of a Shire product (marketed or 
investigational) does not meet expectations (eg, inadequate or faulty closure, product 
contamination); or that the product did not meet the specifications defined in the application for 
the product (eg, wrong product such that the label and contents are different products); or a 
product deficiency that relates to identity, quality, durability, reliability, safety and performance 
of the product but did not result in an AE, which include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or design 
function, eg, reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (eg, potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product causing it 
to malfunction or to present a hazard or fail to meet label claims
For instructions on reporting AEs related to product complaints, see Appendix 4.4. 
Please use the information below as applicable to report the Product Quality Complaint or Non-
Medical Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone number (provided for reference if needed):
Shire, Lexington, MA (USA)
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
TABLE OF CONTENTS.................................................................................................................5
LIST OF TABLES...........................................................................................................................9
LIST OF FIGURES .........................................................................................................................9
ABBREVIATIONS .......................................................................................................................10
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULE(S) ...............................................................................................................17
1.
BACKGROUND INFORMATION.......................................................................................20
1.1
Indication and Current Treatment Options...............................................................20
1.2
Product Background.................................................................................................21
1.2.1
Preclinical Information ..........................................................................................21
1.2.2
Clinical Information...............................................................................................21
1.3
Risk/Benefit and Ethical Assessment.......................................................................21
1.4
Compliance Statement..............................................................................................21
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................22
2.1
Rationale for the Study.............................................................................................22
2.2
Study Objectives ......................................................................................................22
2.2.1
Primary Objective..................................................................................................22
2.2.2
Secondary Objective..............................................................................................22
2.2.3
Exploratory Objectives ..........................................................................................22
3.
STUDY DESIGN ...................................................................................................................23
3.1
Study Design and Flow Chart ..................................................................................23
3.2
Duration and Study Completion Definition .............................................................24
3.3
Sites and Regions .....................................................................................................24
4.
STUDY POPULATION.........................................................................................................25
4.1
Inclusion Criteria......................................................................................................25
4.2
Exclusion Criteria.....................................................................................................25
4.3
Restrictions...............................................................................................................27
4.4
Reproductive Potential .............................................................................................27
4.4.1
Female Contraception............................................................................................27
4.4.2
Male Contraception................................................................................................28
4.5
Discontinuation of Subjects .....................................................................................28
4.5.1
Reasons for Study Discontinuation........................................................................29
4.5.2
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit..................................29
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5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................30
5.1
Prior Treatment ........................................................................................................30
5.2
Concomitant Treatment............................................................................................30
5.2.1
Permitted Treatment...............................................................................................30
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....................................................................................................................31
6.2.3
Unblinding the Treatment Assignment..................................................................31
6.3
Labeling, Packaging, Storage, and Handling ...........................................................32
6.3.1
Labeling .................................................................................................................32
6.3.2
Packaging...............................................................................................................32
6.3.3
Storage ...................................................................................................................32
6.3.4
Special Handling....................................................................................................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 7-112).....................................................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 .....................................................................................................................36
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 Tests.......................................................................39
7.2.2.6
Pregnancy Test .......................................................................................41
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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
Blood Sample Collection and Handling Procedures..............................43
7.2.3.2
Shipment of Plasma, Pharmacokinetic Samples ....................................43
7.2.3.3
Plasma Drug Assay Methodology..........................................................44
7.2.3.4
Immunogenicity Testing for Anti-Drug Antibodies...............................44
7.2.4
Volume of Blood to be Drawn from Each Subject................................................44
8.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................46
8.1
Data Collection.........................................................................................................46
8.2
Clinical Data Management.......................................................................................46
8.3
Data Handling ..........................................................................................................46
8.4
Statistical Analysis Process......................................................................................46
8.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......47
8.6
Sample Size Calculation and Power Considerations................................................47
8.7
Study Population ......................................................................................................47
8.8
Analysis of Disposition ............................................................................................47
8.9
Demographics and Baseline Characteristics Analyses.............................................48
8.10
Treatment Compliance and Extent of Exposure ......................................................48
8.11
Pharmacokinetic Analyses .......................................................................................48
8.11.1 Pharmacokinetic Analysis......................................................................................48
8.11.1.1
Statistical Analysis of Pharmacokinetic Parameters ..............................48
8.12
Safety Analyses........................................................................................................49
8.13
Other Analyses .........................................................................................................50
9.
REFERENCES .......................................................................................................................51
10. APPENDICES ........................................................................................................................52
Appendix 1
Protocol History .....................................................................................53
Appendix 2
...................54
Appendix 3
Regulatory, Ethical, and Study Oversight  Considerations....................55
Appendix 3.1
Regulatory and Ethical Considerations..................................................56
Appendix 3.2
Sponsor’s Responsibilities .....................................................................57
Appendix 3.3
Investigator’s Responsibilities ...............................................................59
Appendix 3.4
Ethical Considerations............................................................................62
Appendix 4
Adverse Events: Definitions and Procedures for  Recording, 
Evaluating, Follow-Up, and Reporting ..................................................65
Appendix 4.1
Adverse Event Definitions .....................................................................66
Appendix 4.2
Collection of Adverse Events.................................................................69
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Appendix 4.3
Assessment of Adverse Events ..............................................................70
Appendix 4.4
Safety Reporting.....................................................................................72
Appendix 4.5
Serious Adverse Event Collection Time Frame.....................................73
Appendix 4.6
Serious Adverse Event Onset and Resolution Dates..............................74
Appendix 4.7
Fatal Outcome ........................................................................................75
Appendix 4.8
Pregnancy...............................................................................................76
Appendix 4.9
Abuse, Misuse, Overdose, and Medication Error ..................................77
Appendix 4.10
Urgent Safety Measures .........................................................................78
Appendix 4.11
Regulatory Agency, Institutional Review Board,  Ethics 
Committee, and Site Reporting..............................................................79
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LIST OF TABLES
Table 1:
Schedule of Assessments...............................................................................17
Table 2:
Detailed Schedule of In-Patient Assessments (Days 1-5) .............................18
Table 3:
Detailed Schedule of Out-Patient Assessments (Study Days 7-112) ............19
Table 4:
Volume of Blood to Be Drawn from Each Subject.......................................44
LIST OF FIGURES
Figure 1:
Study Design Flow Chart ..............................................................................24
Figure 2:
Procedures for Screening Vital Signs (Blood Pressure - Pulse) -
Healthy Subjects Only...................................................................................39
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ABBREVIATIONS
ADA
anti-drug antibody
AE
AI
aPTT
BA
BE
adverse event
autoinjector
activated partial thromboplastin time
bioavailability
bioequivalence
-hCG
BMI
BP
beta-human chorionic gonadotropin
body mass index
blood pressure
CM
concomitant medication
CRA
clinical research associate
CRC
clinical research center
CRF
case report form
CRO
contract research organization
DMC
data monitoring committee
EC
ethics committee
ECG
electrocardiogram
EU
European Union
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
HAE
Good Clinical Practice
hereditary angioedema
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HEOR
Health Economics and Outcome Research
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
INR
international normalized ratio
IP
investigational product
IRB
Institutional Review Board
IRT
PE
PFS
PK
interactive response technology
physical exam
prefilled syringe
pharmacokinetic
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PT
prothrombin time
SAE
serious adverse event
SAP
SC
TEAE
statistical analysis plan
subcutaneous
treatment emergent adverse event(s)
T3
T4
triiodothyronine
thyroxine
TSH
thyroid stimulating hormone
US
United States
UDS
urine drug screen
VS
vital signs
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in the abdomen in a single 2 mL dose using either the PFS or the AI per their randomized assignment. This 
study is open-label and does not require the use of a placebo.

Comparator products in this study are the PFS versus the AI.
Methodology:
This study is a Phase 1, randomized, open-label, single-dose, parallel-arm, single-center study to evaluate the 
PK, safety and tolerability of 300 mg of lanadelumab administered to healthy adult volunteer subjects either via 
a PFS or via an AI. A total of approximately 176 subjects between the ages of 18-55, inclusive, will be enrolled.
All randomized subjects will receive a single subcutaneous (SC) 300 mg dose of lanadelumab administered into 
the abdomen.  Fifty-percent of the subjects will receive the lanadelumab injection via a PFS, and the other 50% 
will receive the lanadelumab injection via an AI.  
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 [± 2 days], 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. Day -1 is considered part of the screening period. Subject eligibility will be determined prior 
to randomization.
In-House Confinement Treatment Period

On Day 1, all randomized subjects will receive lanadelumab as a single 2 mL 300 mg SC injection into 
the abdomen with either the PFS or the AI per their randomized assignment.

All subjects will remain in the CRC until collection of the 96 hour post-dose 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.

Safety and tolerability, including immunogenicity, will be determined through assessment of treatment-
emergent adverse events (TEAEs), vital signs, electrocardiogram (ECG), antidrug antibodies (ADAs) 
and clinical laboratory evaluations on 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 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 days; ie, Day 27, 28 or 29) 

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. 
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Inclusion and exclusion criteria:
Inclusion Criteria:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions.
2.
Ability to voluntarily provide written, signed, and dated informed consent to participate in the study.
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.
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.
5.
Must be considered “healthy”, per the investigator. Healthy status is defined by absence of evidence of any 
active or chronic disease following a detailed medical and surgical history, a complete physical examination 
including vital signs, 12-lead ECG, hematology, blood chemistry, and urinalysis.
6.
Body mass index between 18.5-33 kg/m², inclusive, with a body weight ≥45 kg (99 lbs). This inclusion 
criterion will only be assessed at the initial screening visit and on Day -1. 
7.
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 blood samples 
are collected.
Exclusion Criteria:
1.
Per the investigator, a 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.
Per the investigator, a 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) >139 mmHg or <89 mmHg, and diastolic BP >89 mmHg or 
<49 mmHg.
9.
Twelve-lead ECG values demonstrating QTcF >450 msec (males) or >470 msec (females) at the 
screening visit or Day -1. If QTcF exceeds 450 msec (males) or 470 msec (females), the ECG should 
be repeated 2 more times and the average of the 3 QTcF values should be used to determine the 
subject’s eligibility.
10. Positive screen for drugs of abuse and/or disallowed drugs (ie, amphetamines, benzodiazepines, 
barbiturates, cocaine, opiates, phencyclidine) at screening, or drugs of abuse or alcohol on Day -1. This 
screen will include marijuana.
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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 (5 oz/150 mL) or 1 liquor (1.5 oz/40 mL) or 0.75 oz 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 6 oz (180 mL) cup of 
coffee, two 12 oz (360 mL) cans of cola, one 12 oz cup of tea, and three 1 oz (85 g) 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. (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 parameters:

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 based 
on the predicted concentration at tlast

Cmax: Maximum observed plasma drug concentration

tmax: Minimum time to reach Cmax

t½: Terminal half-life

CL/F: Apparent total body clearance for extravascular administration divided by the fraction of 
dose absorbed

Vdz/F: Apparent volume of distribution associated with the terminal slope following extravascular 
administration divided by the fraction of dose absorbed

z: First order rate constant associated with the terminal (log-linear) portion of the curve
Safety endpoints:

Treatment-emergent adverse events (TEAEs)

Clinical laboratory results (hematology, clinical chemistry, coagulation and urinalysis)

Vital signs (including BP, pulse, body temperature), and 12-lead ECG

Antidrug antibodies (ADA) 
Analysis sets:

Safety analysis set, defined as all randomized subjects who received the dose of lanadelumab 
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(study drug). All safety analyses will be based on the safety analysis set.

Pharmacokinetic analysis set, defined as all randomized subjects who received the dose of 
lanadelumab and have at least 1 evaluable post-dose PK concentration value. All PK analyses will 
be based on the PK analysis set.
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STUDY SCHEDULE(S)
Table 1:
Schedule of Assessments
Visit
Screening
In-House 
Treatment 
Period a
Out-Patient
Visitsb, c
End of Study
(Day 112) or
Early 
Discontinuation  
Study Day
–28 to   -
02
-1h
1 to 5  
7 to 112
Informed consent
X
Refer to Table 2
Refer to Table 3
Inclusion/exclusion criteria
X
X
Demography 
X
X 
Medical/Medication History
X
X
X
Physical examination 
X
X
X
Vital signs (blood pressure, pulse) supine 
X
X
X
Body temperature (oral)
X
X
X
Height, Weight and BMId,e
X
X
X
Electrocardiogram (12-lead)
X f
X f
X
Biochemistry, hematology, and urinalysis 
X
X
X
TSH, T3, T4
X
PT, aPTT, INR
X
X
X
HIV, HBsAg, and HCV antibodies
X
Serum Pregnancy test (all females)
X
X
X
FSH (all females)
X
Urine drug and alcohol (breath test) 
screening
X
X
Pharmacokinetic blood sampling  (PK)
X
Anti-drug antibody blood sampling (ADA)
X
X
Check-in to the CRC
X
Out-patient visits
X
X
In-patient visit
X
Concomitant Medication
X
X
X
Adverse Event/Serious Adverse Event
X
X
X
aPTT= activated partial thromboplastin time; CRC=clinical research center; HBsAg=hepatitis B surface antigen; HCV=hepatitis 
C virus; INR=international normalized ratio; FSH=follicle-stimulating hormone; HIV=human immunodeficiency virus; 
PT=prothrombin time; T3=triiodothyronine; T4=thyroxine; TSH= thyroid-stimulating hormone
a Refer to Table 2 for the procedures and the timing of the procedures to be done during the in-house treatment period.
b Refer to Table 3 for the procedures and the timing of the procedures to be done during the out-patient visits.
c In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these 
assessments. End of study visit is Day 112. 
d Height will only be recorded at the first visit during the screening period.
e Body mass index criteria for eligibility will  be calculated at the first visit during the screening period and on Day -1.
f  Single ECG recordings  are  required; However, ECGs will be performed in triplicate if the QTcF interval (calculated on line on 
site) is increased by >45 msec from the baseline4, or an absolute QTcF value is >500 msec for any scheduled ECG, or if 
indicated per exclusion criteria #9 or in Section 7.2.2.9, then 2 additional ECGs will be collected, approximately 2-4 minutes 
apart, to confirm the original measurement. Thereafter, all subsequent ECGs will be single recordings. 
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Table 2:
Detailed Schedule of In-Patient Assessments (Days 1-5)
Study 
Day/Hour 
(relative 
to 
dosing time) 
PE
VS
Body 
Temperature
(oral)
Weight
ECG
Biochemistry, 
hematology, 
and urinalysis
PT, 
aPTT, 
INR
Serum 
Pregnancy 
(all women)
Randomizatione
IP 
administrationd
PK
ADA
AE/SAEb
CMb
Day 1Predosea
X
X
X
X
X
Xc
X
X
Day 1:0h
X
X
X
Day1: 1h post 
dose 
X
X
X
X
Day 1: 2h post 
dose 
X
X
X
Day 1:4h post 
dose 
X
X
X
X
Day 1:6h post 
dose 
X 
X
X
Day 1:8h post 
dose 
X
X
X
X
X
Day 1:12h post 
dose 
X
X
X
Day 2:24h post 
dose 
X
X
X
X
X
X
Day 3:48h post 
dose 
X
X
X
X
X
Day 4: 72h post 
dose 
X
X
X
X
X
Day 5:96h  post 
dose 
X
X
X
X
X
X
X
X
X
X
ADA=anti-drug antibody blood sampling; AE=adverse event; aPTT= activated partial thromboplastin time; CM=concomitant medication; CRC=clinical research center; ECG=12-
lead ECG; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; INR=international normalized ratio; FSH=follicle-stimulating hormone; HIV=human immunodeficiency 
virus; IP=investigational product; PE=physical exam; PT=prothrombin time; PK=pharmacokinetic blood sampling; SAE=serious adverse event; T3=
triiodothyronine;T4=thyroxine ; TSH= thyroid-stimulating hormone; UDS=urine drug screen; VS=vital signs
a Assessments to be done within 30 minutes prior the administration of IP.
b Adverse events/SAEs and CMs will be continuously monitored throughout the study.
c Pre-dose ADA can be collected within 60 minutes prior to the administration of IP.
d Investigational product administration start and stop times must be recorded in source and on the CRF.
 
e Randomization to be performed pre-dose on Day 1.
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Table 3:
Detailed Schedule of Out-Patient Assessments (Study Days 7-112)
Study Day
PE
VS
Body
Temperature
(oral)
Weight
ECG
Biochemistry, 
hematology, 
and urinalysis
PT, 
aPTT, 
INR
Serum 
Pregnancy 
(all women)
UDS & 
ETOH 
screen
PK
ADA
AE/SAEa
CMa
Day 7 (± 1)
X
X
X
X
X
X
X
X
X
X
X
X
Day 14 (± 1)
X
X
X
X
X
X
X
X
X
X
X
X
X
Day 21 (± 1) 
X
X
X
X
X
X
X
X
X
X
X
X
Day 28 (± 2)
X
X
X
X
X
X
X
X
X
X
X
X
X
Day 42 (± 2)
X
X
X
X
X
X
X
X
X
X
X
X
Day 56 (± 2)
X
X
X
X
X
X
X
X
X
X
X
X
X
Day 84 (± 3)
X
X
X
X
X
X
X
X
X
X
X
X
Day 112 (± 3)
(End of Study 
Visit/ or Early 
Discontinuation)
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA=anti-drug antibody blood sampling; AE=adverse event; aPTT= activated partial thromboplastin time; CM=concomitant medication; CRC=clinical research center; ECG=12-
lead ECG; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; INR=international normalized ratio; FSH=follicle-stimulating hormone; HIV=human immunodeficiency 
virus; IP=investigational product; PE=physical exam; PT=prothrombin time; PK=pharmacokinetic blood sampling; SAE=serious adverse event; T3=triiodothyronine;
T4=thyroxine; TSH=thyroid-stimulating hormone; UDS=urine drug screen; VS=vital signs
a Adverse events/SAEs and CMs will be continuously monitored throughout the study. 
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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 
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). Lanadelumab has 
been approved by the US Food and Drug Administration (FDA) for marketed use for the 
prevention of angioedema attacks in patients with hereditary angioedema (HAE).
For further details see the current lanadelumab Investigator’s Brochure.
1.1
Indication and Current Treatment Options 
Lanadelumab has been developed for the prevention of angioedema attacks in patients with 
Types I or II HAE, a rare and potentially life-threatening disease, and is indicated in the US for 
prophylaxis to prevent attacks of HAE in patients 12 years and older (reference to the FDA 
label).
Lanadelumab is a potent (Ki=125 pM) inhibitor of the proteolytic activity of plasma kallikrein 
(pKAL).
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 subcutaneous 
(SC) or submucosal edema of the face, larynx, gastrointestinal tract, limbs, and/or genitalia 
(Zuraw 2008). Swelling may last up to 5 days; most patients suffer multiple attacks per year. 
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 previously used for prophylaxis include purified plasma-derived C1-INH, attenuated 
androgens, and antifibrinolytic agents. 
These currently available therapies represent important therapeutic options for HAE patients; 
lanadelumab has been developed as a prophylactic therapy with improved efficacy, a longer half-
life and a more convenient administration frequency.
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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 doses 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®), a Japanese 
bridging Phase 1 study (SHP643-101) in healthy adult subjects and one ongoing open-label 
Phase 3 Study DX2930-04 (HELP Study Extension™) in adolescent and adult subjects with 
HAE.
1.3
Risk/Benefit and Ethical Assessment
There is no anticipated benefit from taking part in this study.
Always refer to the latest version of the lanadelumab investigator’s brochure (IB) for the overall 
benefit/risk assessment and the most accurate and current information regarding metabolism, 
pharmacokinetics, efficacy, and safety of lanadelumab.
1.4
Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, 1996; E6 R2, 2017), Title 21 
of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 2005/28/EC), 
and applicable national and local regulatory requirements.
The responsibilities of the study sponsor and investigator(s) are described fully in Appendix 3.
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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The currently approved presentation for lanadelumab is a vial configuration with the patients 
using ancillary components to withdraw and administer liquid drug product from the vial. 
Lanadelumab has been prepared and administered via vial and syringe throughout the clinical 
development of the drug for treatment of HAE. The FDA agreed that no dedicated PK study 
would be required for the transition from a vial to a prefilled syringe (PFS); (FDA 
correspondence on IND 116647 dated 13 January 2017). A clinical bioequivalence study, 
however, is necessary to bridge between the PFS and the autoinjector (AI), which is also 
currently under development at Shire. Shire considers that the AI will be more convenient for use 
by the patient (fewer preparation steps and easier administration) in comparison with other 
potential delivery methods (eg, vial / syringe or PFS). Extensive in vitro device design 
verifications will be performed to demonstrate the accuracy and consistency of dose delivery 
using the AI device, according to full ISO11608:2014 standards.
This study is being conducted to assess the bioavailability (BA) of lanadelumab administered as 
a single subcutaneous (SC) dose of 300 mg delivered by a 2 mL PFS or a 2 mL AI in healthy 
adult volunteer subjects and to evaluate the safety and tolerability of a single SC 300 mg dose of 
lanadelumab administered via PFS or AI. This study may be used to support the use of an AI-
based injection system in patients with HAE.
2.2
Study Objectives
2.2.1
Primary Objective
To evaluate bioavailability of lanadelumab following a single, 2 mL subcutaneous (SC) dose of 
300 mg delivered by prefilled syringe (PFS) or auto injector (AI) in healthy adult subjects.
2.2.2
Secondary Objective
To assess the safety and tolerability of a single 2 mL 300 mg SC injection of lanadelumab 
administered by a PFS or AI in healthy adult subjects.
2.2.3
Exploratory Objectives
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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 1, randomized, open-label, single dose, parallel-arm single-center study to 
evaluate the PK, safety and tolerability of lanadelumab administered via PFS or AI to healthy 
adult volunteer subjects. A total of approximately 176 subjects between the ages of 18-55, 
inclusive, will be enrolled. All subjects will be randomized 1:1 to receive a single 2 mL SC dose 
300 mg of lanadelumab by either PFS or AI in the abdomen on study day 1 administered by 
designated study site personnel. Fifty-percent of the randomized subjects will receive the 
lanadelumab injection via a PFS, and the other 50% will receive the lanadelumab injection via an 
AI. This study is a parallel group design rather than a crossover design, as a crossover design 
was not feasible due to the long half-life of lanadelumab (approximately 17-21 days). 
Randomization will be stratified by body weight (2 strata: 45 to <80 kg and ≥80 kg) to balance 
the two study arms more closely. 
The study duration will comprise of a 28-day screening period, one 5-day in-house treatment 
period, and 8 out-patient visits. The maximal total duration of study participation for a subject is 
approximately 140 days if the maximal screening, treatment, and out-patient visit durations are 
used.
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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 randomized before all inclusion criteria (including test results) are confirmed.
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.
2. Ability to voluntarily provide written, signed, and dated informed consent to participate in 
the study.
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. 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.
5. Must be considered “healthy”, per the investigator. Healthy status is defined by absence of 
evidence of any active or chronic disease following a detailed medical and surgical history, a 
complete physical examination including vital signs, 12-lead ECG, hematology, blood 
chemistry, and urinalysis.
6. Body mass index between 18.5-33 kg/m², inclusive, with a body weight ≥45 kg (99 lbs). This 
inclusion criterion will only be assessed at the screening visit and on Day -1.
7. 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 
blood samples are collected.
4.2
Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met. 
1. Per the investigator, a 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. Per the investigator, a 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.
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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) >139 mmHg or <89 mmHg, and diastolic BP 
>89 mmHg or <49 mmHg.
9. Twelve-lead ECG values demonstrating QTcF >450 msec (males) or >470 msec (females) at 
the screening visit or Day -1. If QTcF exceeds 450 msec (males) or 470 msec (females), the 
ECG should be repeated 2 more times and the average of the 3 QTcF values should be used 
to determine the subject’s eligibility.
10. Positive screen for drugs of abuse and/or disallowed drugs (ie, amphetamines, 
benzodiazepines, barbiturates, cocaine, opiates, phencyclidine) at screening, or drugs of 
abuse or alcohol on Day -1. This screen will include marijuana.
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 (5 oz/150 mL) or 1 liquor (1.5 oz/40 mL) or 0.75 oz 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 
6 oz (180 mL) cup of coffee, two 12 oz (360 mL) cans of cola, one 12 oz cup of tea, and 
three 1 oz (85 g) 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.
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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 
CRC and during the in-house stays at the CRC. In addition, subjects should refrain from 
strenuous physical exercise 30 minutes prior to all out-patient visits. 
2. Subjects should refrain from alcohol 48 hours prior to admission to the clinical research 
center (CRC) and during the in-house stay at the CRC (Days 1-5) and 48 hours prior to each 
outpatient visit during the study.
3. Subjects should refrain from the use of tobacco or any products containing nicotine within 
30 days of Day 1 of the 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) from the CRC on 
Day 5.
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. In addition, subject should 
also refrain from foods or beverages containing caffeine/xanthine 30 minutes prior to all out-
patient visits.
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 
menu will be provided to the sponsor for approval prior to the start of the study. 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, including the 112 days following the dose of investigational product. 
Female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and follicle stimulating 
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hormone (FSH) result in the laboratory post-menopausal range at screening)

Surgically sterile (having undergone one of the following surgical procedures: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and, at least, 
6 weeks post-sterilization, or

Females of childbearing potential with a negative 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).
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to his/her 
future medical care by the physician or at the institution, or may be withdrawn at any time at the 
discretion of the investigator or sponsor (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject with the medical monitor when possible.
If a subject discontinues from the study, regardless of the reason, the early withdrawal 
evaluations listed in Table 1 are to be performed as completely as possible. Whenever possible, 
all discontinued subjects should complete early termination procedures. Comments (spontaneous 
or elicited) or complaints made by the subject must be recorded in the source documents. The 
reason for discontinuation and date of discontinuation must be recorded in the source documents. 
Subjects who discontinue from the study will not be replaced.
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4.5.1
Reasons for Study Discontinuation
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s source document. If a subject discontinued for more than 1 reason, each reason should 
be documented in the source document.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol violation

Withdrawal by subject 

Lost to follow-up

Other
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. 
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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 received within 30 days [or PK 
equivalent of 5 half-lives, whichever is longer]) of the date of 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 wellbeing may be given at the discretion of the investigator. The administration of all 
concomitant medications must be listed on the appropriate CRF page.
Medications permitted during the study are listed below:

Hormonal contraceptives for females of child-bearing potential administered according to the 
package insert (see Section 4.4.1)

Hormone replacement therapy ≥3 months prior to dose of investigational product

Occasional use of nonsteroidal anti-inflammatory drug as prescribed by the principal 
investigator or delegate.
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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is lanadelumab (SHP643, formerly known as DX-2930), which will be provided 
for each subject as either a 300 mg/dose PFS or a 300 mg/dose AI for SC injection. Additional 
information about lanadelumab 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.
Subject screening numbers are assigned to all subjects as they consent to take part in the study. 
The subject screening number is assigned to subjects according to the sequence of presentation 
for study participation. This will be a 4-digit number starting with 0001.
The actual treatment given to individual subjects is determined by a randomization schedule.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, and will be allocated prior to dosing after eligibility has been 
determined.
A 4-digit randomization number, starting at 1001, will be allocated immediately prior to dosing 
after eligibility has been determined.  If a randomization number is allocated incorrectly the 
study monitor must be notified as soon as the error is discovered.  Once a randomization number 
has been assigned, that number must not be used again if, for example, a subject is withdrawn 
from the study.  For randomized subjects, the randomization number will be the identifying 
number used throughout CRF.
6.2.2
Dosing
After the subject completes the screening process and is found to be eligible for dosing, the 
subject will be randomized to receive either a single 300 mg lanadelumab SC injection in the 
abdomen administered via PFS or a single 300 mg lanadelumab SC injection in the abdomen 
administered via AI on Day 1 of the in-house confinement period. The start and stop times (to 
the nearest second) for IP injection (both PFS and AI) will be recorded in subject source 
documentation and the CRF. 
A full description of the details for the preparation and administration of the investigational 
product and of the devices for administration will be provided in a separate Pharmacy Manual.
6.2.3
Unblinding the Treatment Assignment
Not applicable.
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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, expiratory 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 
identifier 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
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) 
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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.
6.3.4
Special Handling
Refer to the SHP643-102 Pharmacy Manual for complete details regarding the lanadelumab 
(SHP643) investigational product and devices.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering 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.
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 administrations 
of IP will be documented in the subject's source 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 CRO). For unused 
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supplies where the original supplied tamper-evident feature is verified as intact, the 
tamper-evident feature must not be broken and the labeled amount is to be documented in lieu of 
counting. Shipment return forms, when used, must be signed prior to shipment from the site. 
Validated electronic return systems (ie, IRT) do not require a shipment form. Returned 
investigational 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 will be captured in the appropriate CRF.
6.6
Retention of Bioavailability and Bioequivalence Testing Samples
In compliance with 21 CFR 320.38 (1999), and as recommended in the Center for Drug 
Evaluation and Research Guidance for Industry dated May 2004 regarding retention of relevant 
reserve (BA and BE test samples), CROs, site management organizations, or clinical 
investigators must retain samples when relevant BA/BE testing has been performed under 
contract by the sponsor.  Retained samples must meet 21 CFR 320.38 (1999) and 320.63 (1999) 
requirements for reserve samples of test article and reference standards according to the 
following:

Reserve samples must be representative of the test batches provided and therefore must be 
randomly selected from identical test article and/or reference standards provided to the site

The quantity of retained samples should be sufficient optimally to permit the FDA to perform 
all release testing identified in the application 5 times

Samples are adequately identified so that the reserve sample can be positively identified as 
having come from the same batches as used in the BA/BE studies

Samples must be stored under conditions that maintain the identity, integrity, strength, 
quality, and purity of the samples.

Samples must be retained for at least 5 years following the date of New Drug Application or 
supplemental New Drug Application approval or, if the Investigational New Drug is 
discontinued, for at least 5 years following the date of completion of the BA/BE study

Samples must be annually inspected and documented to confirm integrity.
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7.
STUDY PROCEDURES
7.1
Study Schedule
See Table 1, Table 2, and Table 3 for study procedures.  
The following “priority order” will be in effect when more than 1 procedure or assessment are 
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

Physical examination.
NOTE: Blood sampling for PK 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 as appropriate 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 randomized 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.
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
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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 study 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 7-112) 
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). The first out-patient visit is on Day 7. 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 3).
These assessments include: blood and urine samples for clinical safety labs including pregnancy 
testing for all females, blood samples for PK 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, blood samples for ADA assessments 
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 3 for outlined study assessments and 
procedures.  All AEs and SAEs that are not resolved by the last study visit (Day 112) will be 
followed until closure (see Appendix 4.2).
7.1.3
Additional Care of Subjects After the Study
No after care is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics

Date of birth

Sex

Race and ethnicity
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.
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Actual safety assessment times will be monitored and recorded in the subject's source 
documentation. 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 on Days 1 through 5 will be considered a protocol deviation.
Adverse events, prior medication, and concomitant medication and therapy 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 performed at the screening visit/time points 
described in Table 1 by a qualified licensed physician, physician’s assistant, or a nurse 
practitioner.  The medical history will be reviewed and recorded, including:

Recent ingestion of medication (30 days prior to entering the screening period)

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, psychiatric, and other diseases

Smoking habits. 
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, 
Table 2, and Table 3 by a qualified licensed physician, physician’s assistant, or a 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)
Clinically significant (per investigator) abnormalities identified at the screening visit will be 
documented in the subject’s source documents and on the medical history CRF. Changes 
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(worsening in frequency or severity) 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. (Refer to Appendix 4 for 
AE definitions, assessment, collection time frame, and reporting procedures.)
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, Table 2, and Table 
3 of this protocol. Additional blood pressure 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 blood pressure 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).
At the screening visit, blood pressure should be compared between both arms.  When there is a 
consistent inter-arm difference confirmed over 3 consecutive measurements (>10 mmHg), the 
arm with the higher blood pressure should be used for inclusion at screening and the last 
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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 gel separator tube at 
the time points described in Table 1, Table 2, and Table 3.  The following parameters will be 
assessed:  
Sodium
Phosphorus
-hCGb
Potassium
Total protein
FSHb
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, Table 2, and Table 3 for collection time-points).
Hematology
Blood samples (4 mL) for hematology will be collected into a K2-EDTA tube at the time points 
described in Table 1, Table 2, and Table 3.  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)
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Coagulation
Blood samples (2.7 mL) for coagulation will be collected into a sodium citrate tube at the time 
points outlined in Table 1, Table 2, and Table 3. 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, Table 2, 
and Table 3.  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 -hCG pregnancy test will be performed on all females at the time points outlined in 
Table 1, Table 2, and Table 3 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, Table 2, and Table 3.  This screen will include marijuana. 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 screens will be reviewed and verified by the study monitor but 
will not be collected in the CRF database.
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 time point after the subject has been 
dosed, the principal investigator must contact the sponsor’s Medical Monitor to discuss and 
review the circumstances and to determine whether the subject may continue in the study. 
Details of the discussion taken must be properly recorded in the subject’s source documents.
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7.2.2.8
Serology Screen 
At the screening visit, a blood sample of approximately 8.5 mL 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, Table 2, and Table 3.  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 (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 outlined 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.  
One complete recording, including a 10 second rhythm strip, should be taken at each time point.  
It should be immediately assessed as a valid recording 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 pre-dose 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 on line on site) is increased by >45 msec from the baseline, or an 
absolute QTcF value is >500 msec 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 (>45 msec from the 
baseline; or is >500 msec), 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 500 msec (or >45 msec from the baseline) for >4 hours (or sooner 
at the discretion of the investigator); or QTcF intervals get progressively longer, the subject 
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should undergo continuous ECG monitoring.  A cardiologist should be consulted if QTcF 
intervals do not return to <500 msec (or to <45 msec above the baseline) after 8 hours of 
monitoring (or sooner at the discretion of the investigator).
If a machine-read QTcF value is prolonged, as defined above, repeat measurements may not be 
necessary if a qualified physician’s interpretation determines that the QTcF values are in the 
acceptable range.
7.2.3
Pharmacokinetic Procedures
The name and address of the bioanalytical laboratory(ies) for this study will be maintained in the 
investigator’s files at the/each site and in the Trial Master File at the CRO.
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 post-dose or by more than 15 
minutes for samples drawn beyond 4 hours post-dose on Day 1 through Day 5 only. Samples 
drawn outside these parameters will be considered a protocol deviation. 
7.2.3.1
Blood Sample Collection and Handling Procedures
Blood samples will be collected at the time specified in Table 2 and Table 3 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. 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. 
Pharmacokinetic samples will be stored nominally at -70°C (±10°C) prior to and after analysis at 
the CRO until further directions are authorized by Shire.
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7.2.3.3
Plasma Drug Assay Methodology
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 assessed or quantified as appropriate. Raw data will be stored in the archive 
of the designated bioanalytical contract laboratory.
7.2.3.4
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 CRO.
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 at 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 and 
Table 3 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. 
7.2.4
Volume of Blood to be Drawn from Each Subject
Table 4:
Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samplesa
5
14
70
HBsAg, HIV, HCV
5
1
5
Safety
Biochemistry, FSH 
and -hCGa,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
269.7
-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 1 mL is to be discarded. The 1 mL 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.
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During this study, it is expected that approximately 269.7 mL 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 269.7 mL. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the samples may be combined.
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8.
DATA MANAGEMENT AND STATISTICAL METHODS
8.1
Data Collection
The investigator’s authorized site personnel must enter the information required by the protocol 
into CRF according to the study CRF Completion Guidelines.  This study will be monitored 
according to ICH GCP Guidelines. 
A study monitor will visit the 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.  Once a subject is 
randomized, it is expected that site personnel will complete the CRF entry within approximately 
3 business days of the subject’s visit.
8.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan
and according to the study CRF Completion Guidelines.  Quality control and data validation 
procedures are applied to ensure the validity and accuracy of the clinical database.
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.
8.3
Data Handling
All analyses/summaries will be based on observed data, with no imputation for missing data, 
unless otherwise specified in the statistical analysis plan (SAP).
8.4
Statistical Analysis Process
The study data will be analyzed by the sponsor or its agent.
Unless otherwise specified, summary tabulations will be presented by treatment group. For 
categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented. The SAP will provide the statistical methods and definitions 
for the analysis of the pharmacokinetic, 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. 
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To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock.
Pharmacokinetic analyses will be performed using Phoenix® WinNonlin® (Certara, Princeton, 
NJ 08540). All other statistical analyses will be performed using SAS(SAS Institute, Cary, NC 
27513). 
8.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There are no planned interim analysis, adaptive design, or DMC in this study.
8.6
Sample Size Calculation and Power Considerations
The planned sample size for this study is approximately 176 subjects; 88 subjects in the PFS arm 
and 88 subjects in the AI arm. The sample size was calculated using SAS v9.3 based on the two 
one-sided tests procedure of Schuirmann on the log-transformed data.
Considering a parallel group design and assuming a total variability of 40% for Cmax (expected to 
be larger than the total variability for AUC) and a true ratio of test/reference of 100%, 
equivalence between test and reference in their bioavailability based on the acceptance interval 
of 80.00 to 125.00% can be demonstrated with a power of 90% and a type I error of 5% based on 
66 subjects per group (132 subjects in total). To account for up to 25% potential drop outs and/or 
non-reliable concentration time-profiles, approximately 88 subjects per group (176 in total) need 
to be randomized to ensure that at least 66 subjects complete the study in each administration 
type group .
8.7
Study Population  
Safety and PK analyses will be based on the following subject analysis sets, as defined:

The randomized set will consist of all subjects randomized to an administration type 
group.

Safety analysis set: All subjects who received the dose of lanadelumab (study drug). The 
safety analysis set will be used for the analysis of safety endpoints

Pharmacokinetic (PK) analysis set: All randomized subjects who received the dose of 
lanadelumab and have sufficient data to calculate at least 1 primary PK endpoint [AUC0-
last, AUC0-∞ or Cmax]. Subjects must not have protocol deviations that would impact data 
analysis. The PK analysis set will be used for the analysis of PK endpoints.
8.8
Analysis of Disposition
The numbers of subjects randomized, completing, or withdrawing, along with reasons for 
withdrawal, will be tabulated by treatment group and overall for the randomized set, safety 
analysis set, and pharmacokinetic analysis set.
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8.9
Demographics and Baseline Characteristics Analyses
Baseline and demographic variables will be descriptively summarized by treatment group and 
overall for the safety analysis set, and PK analysis set.
8.10 Treatment Compliance and Extent of Exposure
It is anticipated that all patients will be compliant with treatment because the study medication 
will be administered in the clinic.  The extent of exposure to study drug will be described by 
reporting the number and percentage of subjects with none or 1 injection for the safety analysis 
set and PK analysis set.
8.11
Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed for the subjects in the PK analysis set.
8.11.1
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. 
Baseline is defined as the Day 1 pre-dose concentration. Pharmacokinetic parameters will be 
estimated by non-compartmental 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 AUC0-last, Cmax, CL/F, and Vdz/F will be estimated as well.
8.11.1.1
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). 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). 
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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 below LLOQ prior to the first measurable concentration will be set to 
zero. The LLOQ values below LLOQ that are between measurable concentrations will be set to 
missing. The values below 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. 
8.12
Safety Analyses
Safety analyses will be performed for the subjects in the safety analysis set. Safety endpoints are 
defined in the Synopsis section.  Descriptive analysis, as described in Section 8.4 will be 
performed to evaluate all safety endpoints.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent AEs (TEAEs) are defined as AEs with onset at the time of or 
following the start of treatment with study medication, or medical conditions present prior to the 
start of treatment but increasing in severity or relationship at the time of or following the start of 
treatment. The number and percentage of subjects with TEAEs will be calculated overall, by 
system organ class (SOC), preferred term, and treatment group. Number and percentage of 
subjects with TEAEs will be further summarized by severity and relationship to investigational 
product. Subjects with TEAEs 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 listings.  All safety data, including derived data, will be presented in subject data listings, 
and all listings will include subject’s sex, age, race, weight and body mass index.
Actual values and change from baseline in clinical laboratory tests and vital signs will be 
summarized by treatment group and visit. Potentially clinically important findings will also be 
summarized or listed.
The number and percentage of subjects with normal, abnormal-not clinically significant, and 
abnormal-clinically significant ECG findings will be summarized by treatment group and visit. 
Abnormal ECG findings will be summarized or listed.
The number and percentage of subjects with neutralizing antibody, positive, negative, or not 
evaluable antibody results will be summarized for each treatment group by visit and overall. 
Positive immunogenicity results will be summarized or listed.
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD). Concomitant medications are medications that the subject started or continued 
using after the study medication administration.  Number of subjects with concomitant 
medications will be summarized by therapeutic class, preferred term, and treatment group.
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9.
REFERENCES
Bygum, A. 2009. Hereditary angio-oedema in Denmark: a nationwide survey. The British 
journal of dermatology, 161, 1153-8.
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.
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.
Zuraw, B. L. 2008. Clinical practice. Hereditary angioedema. N Engl J Med, 359, 1027-36.
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10.
APPENDICES
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APPENDIX 3
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS
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APPENDIX 3.1
REGULATORY AND ETHICAL CONSIDERATIONS
This study is conducted in accordance with current applicable regulations including ICH E6, EU 
Directive 2001/20/EC, and all updates, as well as local ethical and legal requirements. 
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki.
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.
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APPENDIX 3.2
SPONSOR’S RESPONSIBILITIES
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, current ICH GCP guideline E6 (1996), EU Directive 2001/20/EC 
Guidelines, 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 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.
Indemnity/Liability and Insurance
The sponsor will ensure that suitable clinical study insurance coverage is in place prior to the 
start of the study.  An insurance certificate will be supplied to the investigator as necessary.
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.
The timing for study registration and results summary posting(s) must be in accordance with 
applicable local and national requirements.
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 study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance.  
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 
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registered clinical study which has been posted to a designated public website will be updated 
accordingly.
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APPENDIX 3.3
INVESTIGATOR’S RESPONSIBILITIES
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and E6 R2 (2017), 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 will be 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). 
Protocol Adherence and Investigator Agreement
The investigator and any sub-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.
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.
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Documentation and Retention of Records
Case Report Forms
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 
relevant 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 CRA/study monitor will verify the CRF contents against the source data per the monitoring 
plan. If the data are unclear or contradictory, queries will be issued for corrections or verification 
of data.
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 source documents.
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 the 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.
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 
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Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
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).
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APPENDIX 3.4
ETHICAL CONSIDERATIONS
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 which was 
reviewed by the IRB/EC and which 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.
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 the 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.
Investigational product supplied will not be released until the sponsor and/or CRO have received 
written IRB/EC approval.
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. If required by local law, substantial amendments to the protocol must also 
be approved by the appropriate regulatory agency prior to implementation.
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For sites outside the EU, the investigator is responsible for keeping the IRB/EC appraised of the 
progress of the study and of any changes made to the protocol, at least annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC. This can be the responsibility of the sponsor or investigator for sites within the EU; or 
for multicenter studies, the coordinating principal investigator, according to national provisions.  
The investigator must also keep the local IRB/EC informed of any serious and significant AEs as 
required by IRB/EC procedures.
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the HIPAA of 1996.  A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the sponsor and/or CRO.
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(s) /EC(s) 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.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected, if permitted under local laws governing privacy.
The results of studies containing subjects’ unique identifying number, relevant medical records, 
and possibly initials and dates of birth, where allowed per local law, 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.
Study Results / Publication Policy
The term “Publication” shall mean any paper, article, manuscript, report, poster, internet posting, 
presentation slides, abstract, outline, video, instructional material, presentation (in the form of a 
written summary), or other public disclosure of the study results, in printed, electronic, oral, or 
other form. The parties understand and agree that participation in the study may involve a 
commitment to publish the data from all sites participating in the study in a cooperative 
publication with other investigators prior to publication or oral presentations of the study results 
on an individual basis. The site agrees not to publish or present the site’s study results until such 
time as either the aggregate multi-site study results are published in a cooperative publication or 
for a period of one (1) year after termination or completion of the study at all participating sites, 
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whichever shall first occur. After that time, the site may publish the site’s study results in 
scientific journals or present the study results at symposia or other professional meetings in 
accordance with the following provisions:
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.
At least sixty (60) days prior to submitting an abstract, manuscript, or other document for 
publication, a copy of the proposed publication will be provided to the sponsor by the site for 
review.  Upon the sponsor’s request, the site agrees to remove any and all confidential 
information (expressly excluding study results) identified in the publication and to delay such 
submission or presentation for an additional sixty (60) day period in order to allow the sponsor 
time to file any patent application(s).  All publications of the study results shall appropriately 
reference the multi-site study publication, if any, or the fact that the study results are a subset of 
data resulting from a larger multi-site study.
Shire is committed to transparent dissemination of all scientific, technical and medical 
manuscripts generated from Shire-supported research. Therefore, after January 1, 2018, Shire 
will require the submission of all Shire-supported research manuscripts to journals that offer 
public availability via Open Access (including publisher platforms/repositories and self-
archiving). Open Access refers to the free at point of entry, online availability of published 
research output with, where available, rights of re-use according to an End User License.
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) Recommendation for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical journals. Participation as an investigator does not confer any rights to 
authorship of publications.
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APPENDIX 4
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING
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APPENDIX 4.1
ADVERSE EVENT DEFINITIONS
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 
investigational product or medicinal product. 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).
Treatment-emergent Adverse Event
A treatment-emergent adverse event (TEAE) is defined as any event emerging or manifesting at 
or after the initiation of treatment with an investigational product or medicinal product or any 
existing event that worsens in either intensity or frequency following exposure to the 
investigational product or medicinal product. 
Serious Adverse Event 
A serious adverse event (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 investigations 
procedures or 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

Results in 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 bronchospasm associated with 
anaphylaxis 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.
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Unexpected Adverse Event
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the IB and/or prescribing 
information as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the product, but are not specifically mentioned as occurring with the particular 
product under investigation. 
The expectedness of AEs will be determined by the sponsor using the IB and/or prescribing 
information as the RSI. This determination will include considerations such as the number of 
AEs previously observed, but not on the basis of what might be anticipated form the 
pharmacological properties of a product.
Suspected Unexpected Serious Adverse Reaction 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (ie, including active comparators) that is both serious and 
unexpected. 
The event(s) must meet all of the following:
Suspected adverse reaction
Serious
Unexpected
Assessed as related to study treatment
Unanticipated Adverse Device Effect 
An unanticipated adverse device effect (UADE) is any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
study protocol or product labeling; or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects.
Clinical Laboratory and Other Safety Assessment
A change in the value of a clinical laboratory parameter, vital sign measure, or ECG assessment 
can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. When evaluating such changes, the extent of deviation 
from the reference range, the duration until return to the reference range, either while continuing 
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administration or after the end of administration with the investigational product, and the range
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), vital sign, or ECG values which were not present at the 
pretreatment evaluation 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 or expected disease evolution) is found for the abnormal 
values.
The investigator should assess, based on the above criteria and the clinical condition of the 
subject, whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
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APPENDIX 4.2
COLLECTION OF ADVERSE EVENTS
All AEs/SAEs 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. 
All AEs/SAEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to baseline), 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.
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APPENDIX 4.3
ASSESSMENT OF ADVERSE EVENTS
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 is captured as a new event. 
Worsening medical conditions, signs or symptoms present prior to initiation of investigational 
product, must be recorded as new AEs.
For example, if a subject reports mild intermittent dyspepsia prior to initiation of dosing with the 
investigational product, and the dyspepsia becomes severe and more frequent after first dose of a 
new AE of severe dyspepsia (with the appropriate date of onset) should be documented in the 
source.
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.
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.
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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.
Outcome Categorization
The outcome of AEs must be recorded in the source during the course of the study. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown
If applicable, action taken will also be recorded on the AE CRF. 
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APPENDIX 4.4
SAFETY REPORTING
Reference Safety Information
The reference for safety information for this study is the lanadelumab investigator’s brochure 
version 6.0 which the sponsor has provided under separate cover to all investigators.
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 becoming 
aware of the event.  Note:  The 24-hour reporting requirement for SAEs does not apply to reports 
of abuse, misuse, overdose, or medication errors (see Appendix 4.9) unless they result in an 
SAE.
The investigator must complete, sign, and date the Shire “Clinical Study Serious Adverse Event 
for Serious Adverse Events (SAEs) and Non-serious AEs as Required by 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 Form for Serious Adverse Events (SAEs) and Non-serious AEs as Required by 
Protocol (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.
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APPENDIX 4.5
SERIOUS ADVERSE EVENT COLLECTION TIME FRAME
All SAEs (regardless of relationship to investigational product) 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 becoming aware of the event.
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APPENDIX 4.6
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.
In addition, any signs or symptoms reported 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.
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APPENDIX 4.7
FATAL OUTCOME
Any SAE that results in the subject’s death (eg, 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 or it is a 
single dose study). The investigational product action of withdrawn should not be selected solely 
as a result of the subject’s death.
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APPENDIX 4.8
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 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 and 1 year 
post-partum.
Pregnancy complications such as spontaneous abortion/miscarriage, elective abortion 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.  
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.
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APPENDIX 4.9
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 Appendix 4.1. 
Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication error s 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

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 the unassigned treatment is/are always reportable as a 
medication error.
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 and a protocol deviation.
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. 
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APPENDIX 4.10
URGENT SAFETY MEASURES
An urgent safety measure is an immediate action taken, which is not defined by the protocol, in 
order to protect subjects participating in a clinical trial from immediate harm, these do not 
constitute de facto deviation from the protocol. Urgent safety measures may be taken by the 
sponsor or clinical investigator, and may include any of the following:

Immediate change in study design or study procedures

Temporary or permanent halt of a given clinical trial or trials

Any other immediate action taken in order to protect clinical trial participants from 
immediate hazard to their health and safety
The investigator may implement urgent safety measures to protect study subjects from 
immediate hazard to their health or safety. The measures should implement immediately and 
does not require prior authorization from the sponsor. In the event(s) of an apparent direct hazard 
to the subject, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing as soon as possible, and  within 1 calendar day after the 
change is implemented. The sponsor will also ensure the responsible EC(s) and relevant 
competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations. 
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APPENDIX 4.11
REGULATORY AGENCY, INSTITUTIONAL REVIEW BOARD, 
ETHICS COMMITTEE, AND SITE REPORTING
The sponsor and clinical CRO are responsible for notifying the relevant regulatory 
authorities/US local 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/EC of SAEs or significant safety 
findings, or the relevant local regulatory authority of all SAEs that occur at his or her site as 
required by IRB/EC procedures.
For non-commercial use only

SAP_001.pdf: 
Takeda       
  CONFIDENTIAL 
Page 1 of 37 
Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
STATISTICAL ANALYSIS PLAN 
SHP643, lanadelumab (formerly DX-2930) 
PHASE 1 
A Randomized, Open-label, Single-dose, Parallel-arm, Single-center, 
Phase 1 Study to Determine the Bioavailability of Lanadelumab 
Administered Subcutaneously with the Prefilled Syringe and the 
Autoinjector in Healthy Adult Volunteer Subjects 
PROTOCOL IDENTIFIER: SHP643-102 
Study Sponsor(s): 
Dyax Corp., a Takeda company 
300 Shire Way, Lexington, MA 02421 USA 
Author:
Protocol: 
Original Protocol: 2019 Jan 29 
SAP Version #: 
v1.0 
SAP Date: 
2019 November 19 
Status: 
Final 
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Takeda                                                             CONFIDENTIAL 
Page 2 of 37 
Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
REVISION HISTORY 
Version  
Issue Date 
Summary of Changes 
1.0 
19 November 
2019 
Initial final version 
 
 
 
 
 
 
 
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Takeda                                                             CONFIDENTIAL 
Page 3 of 37 
Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
TABLE OF CONTENTS 
REVISION HISTORY ......................................................................................................2 
TABLE OF CONTENTS ..................................................................................................3 
ABBREVIATIONS ............................................................................................................6 
1. 
INTRODUCTION..................................................................................................8 
2. 
OBJECTIVES AND ENDPOINTS ......................................................................8 
2.1 
Objectives ............................................................................................................8 
2.1.1  Primary Objective ........................................................................................8 
2.1.2  Secondary Objective(s) ................................................................................9 
2.1.3  Exploratory Objective(s) ..............................................................................9 
2.2 
Endpoints ............................................................................................................9 
2.2.1  Safety Endpoints ..........................................................................................9 
2.2.2  Pharmacokinetic Endpoint(s) .......................................................................9 
3. 
STUDY DESIGN ..................................................................................................10 
3.1 
General Description ..........................................................................................10 
3.2 
Randomization ..................................................................................................11 
3.3 
Blinding .............................................................................................................12 
3.4 
Sample Size and Power Considerations ............................................................12 
4. 
STATISTICAL ANALYSIS SETS .....................................................................12 
4.1 
Randomized Set ................................................................................................12 
4.2 
Safety Set ..........................................................................................................12 
4.3 
Pharmacokinetic Set ..........................................................................................13 
5. 
STUDY SUBJECTS .............................................................................................13 
5.1 
Disposition of Subjects .....................................................................................13 
5.2 
Demographic and Other Baseline Characteristics.............................................13 
5.3 
Medical History .................................................................................................14 
5.4 
Prior Therapies, Procedures, and Medication ...................................................14 
5.5 
Concomitant Therapies, Procedures, and Medications .....................................15 
5.6 
Exposure to Investigational Product .................................................................15 
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Takeda                                                             CONFIDENTIAL 
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
5.7 
Measurements of Treatment Compliance .........................................................16 
5.8 
Protocol Deviations ...........................................................................................16 
6. 
EFFICACY ANALYSES ....................................................................................16 
7. 
SAFETY ANALYSIS...........................................................................................16 
7.1 
Adverse Events .................................................................................................17 
7.2 
Clinical Laboratory Data ...................................................................................18 
7.3 
Vital Signs .........................................................................................................21 
7.4 
Electrocardiogram (ECG) .................................................................................22 
7.5 
Other Safety Data ..............................................................................................23 
7.5.1  Immunogenicity Testing for Anti-Drug Antibodies ..................................23 
7.5.2 
 ...........................................................25 
8. 
PHARMACOKINETIC ANALYSIS .................................................................25 
8.1 
Drug Concentration ...........................................................................................25 
8.2 
Handling Below Limit of Quantitation (BLQ) Values .....................................25 
8.3 
Pharmacokinetic Parameters .............................................................................26 
8.4 
Statistical Analysis of Pharmacokinetic Data ...................................................26 
9. 
PHARMACODYNAMIC ANALYSIS...............................................................27 
10. 
OTHER ANALYSES ...........................................................................................27 
11. 
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) 
COMMITTEE ......................................................................................................27 
12. 
DATA HANDLING CONVENTIONS ..............................................................28 
12.1 
General Data Reporting Conventions ...............................................................28 
12.2 
Derived Efficacy Endpoints ..............................................................................28 
12.3 
Repeated or Unscheduled Assessments of Safety Parameters ..........................28 
12.4 
Handling of Missing, Unused, and Spurious Data ............................................28 
12.4.1  Missing Date of Investigational Product ....................................................28 
12.4.2  Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) ..............................................................................29 
12.4.2.1  Incomplete Start Date ..................................................................29 
12.4.2.2  Incomplete Stop Date ..................................................................29 
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
12.4.3  Missing Date Information for Adverse Events ..........................................30 
12.4.3.1  Incomplete Start Date ..................................................................30 
12.4.3.2  Incomplete Stop Date ..................................................................31 
12.4.4  Missing Severity Assessment for Adverse Events.....................................31 
12.4.5  Missing Relationship to Investigational Product for Adverse Events .......31 
12.4.6  Character Values of Clinical Laboratory Variables ...................................31 
13. 
ANALYSIS SOFTWARE ...................................................................................31 
14. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ............................31 
15. 
REFERENCES .....................................................................................................32 
16. 
APPENDICES ......................................................................................................33 
16.1 
Schedule of Activities .......................................................................................33 
 
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Takeda                                                             CONFIDENTIAL 
Page 6 of 37 
Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
ABBREVIATIONS 
λz 
Terminal elimination rate constant 
ADA 
anti-drug antibody 
AE 
adverse event 
AI 
auto injector 
ANCOVA 
analysis of covariance 
AUC 
Area under the concentration-time curve 
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  
BMI 
body mass index 
BW 
body weight 
Cmax 
maximum observed plasma drug concentration 
CL/F 
Apparent body clearance 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
HAE 
hereditary angioedema 
IP 
investigational product 
LLOQ 
lower limit of quantification 
LS 
least-squares 
N 
number of subjects 
PCI 
potentially clinically important 
PFS 
prefilled syringe 
PK 
pharmacokinetic 
PT 
preferred term 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SC 
subcutaneous 
SD 
standard deviation 
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 
t½ 
Terminal half-life 
tmax 
Time to reach Cmax in plasma 
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Takeda                                                             CONFIDENTIAL 
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
Vdz/F 
Apparent volume of distribution associated with the terminal slope 
following extravascular administration 
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Takeda                                                             CONFIDENTIAL 
Page 8 of 37 
Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
1. 
INTRODUCTION  
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of pharmacokinetic (PK), safety and tolerability data as described in 
the original protocol dated 29 Jan 2019. Specifications for tables, figures, and listings are 
contained in a separate document.  
2. 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The currently approved presentation for lanadelumab is a vial configuration with the 
patients using ancillary components to withdraw and administer liquid drug product from 
the vial. Lanadelumab has been prepared and administered via vial and syringe 
throughout the clinical development of the drug for treatment of hereditary angioedema 
(HAE). The Food and Drug Administration (FDA) agreed that no dedicated PK study 
would be required for the transition from a vial to a prefilled syringe (PFS); (FDA 
correspondence on IND 116647 dated 13 January 2017). A clinical bioequivalence study, 
however, is necessary to bridge between the PFS and the auto injector (AI), which is also 
currently under development at Takeda. Takeda considers that the AI will be more 
convenient for use by the patient (fewer preparation steps and easier administration) in 
comparison with other potential delivery methods (eg, vial / syringe or PFS). Extensive in 
vitro device design verifications will be performed to demonstrate the accuracy and 
consistency of dose delivery using the AI device, according to full ISO11608:2014 
standards. 
This study is being conducted to assess the bioavailability of lanadelumab administered 
as a single subcutaneous (SC) dose of 300 mg delivered by a 2 mL PFS or a 2 mL AI in 
healthy adult volunteer subjects and to evaluate the safety and tolerability of a single SC 
300 mg dose of lanadelumab administered via PFS or AI. This study may be used to 
support the use of an AI based injection system in patients with HAE. 
2.1.1 Primary Objective 
To evaluate bioavailability of lanadelumab following a single, 2 mL SC dose of 300 mg 
delivered by PFS or AI in healthy adult subjects. 
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
2.1.2 Secondary Objective(s) 
To assess the safety and tolerability of a single 2 mL 300 mg SC injection of lanadelumab 
administered by a PFS or AI in healthy adult subjects. 
2.1.3 Exploratory Objective(s) 
2.2 
Endpoints 
2.2.1 Safety Endpoints 
 Treatment-emergent adverse events (TEAEs) 
 Clinical laboratory results (hematology, clinical chemistry, coagulation and 
urinalysis) 
 Vital signs (including blood pressure (BP), pulse rate, body temperature) 
 12-lead electrocardiogram (ECG) 
 Antidrug antibodies (ADA) 
2.2.2 Pharmacokinetic Endpoint(s) 
 AUC0-last: Area under the concentration-time curve from time zero to the last 
quantifiable concentration in plasma, calculated using the linear up/log down 
trapezoidal rule. 
 AUC0-∞: Area under the concentration-time curve from time zero extrapolated to 
infinity, calculated using the linear up/ log down trapezoidal rule 
 Cmax: Maximum observed plasma drug concentration 
 tmax: Time to reach Cmax in plasma 
 t1/2: Terminal half-life, calculated as ln(2)/λz 
 CL/F: Apparent clearance, calculated as: Dose/AUC0-∞ 
 Vdz/F: Apparent volume of distribution associated with the terminal slope 
following extravascular administration, calculated as: CL/F / λz 
 λz: Terminal elimination rate constant 
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Takeda                                                             CONFIDENTIAL 
Page 10 of 37 
Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
3. 
STUDY DESIGN 
3.1 
General Description 
This is a Phase 1, randomized, open-label, single dose, parallel-arm single-center study to 
evaluate the PK, safety and tolerability of lanadelumab administered via PFS or AI to 
healthy adult volunteer subjects. A total of approximately 176 subjects between the ages 
of 18-55, inclusive, will be enrolled. All subjects will be randomized 1:1 to receive a 
single 2 mL SC dose 300 mg of lanadelumab by either PFS or AI in the abdomen on 
study day 1 administered by designated study site personnel. Fifty-percent of the 
randomized subjects will receive the lanadelumab injection via a PFS, and the other 50% 
will receive the lanadelumab injection via an AI. This study is a parallel group design 
rather than a crossover design, as a crossover design was not feasible due to the long half-
life of lanadelumab (approximately 17-21 days). Randomization will be stratified by 
body weight (2 strata: 45 to <80 kg and ≥80 kg) to balance the two study arms more 
closely.  
The study duration will comprise of a 28-day screening period, one 5-day in-house 
treatment period, and 8 out-patient visits. The maximal total duration of study 
participation for a subject is approximately 140 days if the maximal screening, treatment, 
and out-patient visit durations are used.  
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
randomization number will be the identifying number used throughout the electronic case 
report form (eCRF). 
3.3 
Blinding  
This is an open-label study. However, the access to randomized treatment codes will be 
limited during the conduct of the study to avoid unnecessary bias. The PK scientist will 
not have access to the randomized treatment codes when reviewing the PK data before 
the database lock. The accessibility to treatment codes for each individual study team 
member is specified in the clinical trial integrity document. 
3.4 
Sample Size and Power Considerations 
The planned sample size for this study is approximately 176 subjects; 88 subjects in the 
PFS arm and 88 subjects in the AI arm. The sample size was calculated using SAS (SAS 
Institute, Cary, NC; version 9.3) based on the two one-sided tests procedure of 
Schuirmann on the log-transformed data. 
Considering a parallel group design and assuming a total variability of 40% for Cmax 
(expected to be larger than the total variability for AUC) and a true ratio of test/reference 
of 100%, equivalence between test and reference in their bioavailability based on the 
acceptance interval of 80.00 to 125.00% can be demonstrated with a power of 90% and a 
type I error of 5% based on 66 subjects per group (132 subjects in total). To account for 
up to 25% potential drop outs and/or non-reliable concentration time-profiles, 
approximately 88 subjects per group (176 in total) need to be randomized to ensure that 
at least 66 subjects complete the study in each administration type group. 
4. 
STATISTICAL ANALYSIS SETS 
4.1 
Randomized Set  
The Randomized Set consists of all subjects randomized to an administration type group.  
Background summaries (e.g., subject disposition) will be based on the Randomized Set, 
unless otherwise specified in this SAP. 
4.2 
Safety Set   
The Safety Set will consist of all randomized subjects who received the dose of 
lanadelumab.  Analysis will be performed according to the treatment actually received 
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
regardless of the randomized treatment. All safety analyses will be based on the Safety 
set. 
4.3 
Pharmacokinetic Set  
The PK Set is defined as all randomized subjects who received the complete dose of 
lanadelumab (as determined by the investigator or site staff) and have sufficient data to 
calculate at least 1 primary PK endpoint (AUC0-last, AUC0-∞ or Cmax). Subjects must not 
have protocol deviations that would impact data analysis. The PK Set will be used for the 
analysis of PK endpoints.  
The protocol deviation log will be reviewed on a case-by-case basis. Subjects’ 
inclusion/exclusion from the PK Set will be determined at the discretion of the Shire 
medical monitor/pharmacokineticist.  
5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
The number and percentage of subjects included in each analysis set (Randomized, 
Safety and PK) will be summarized as appropriate. The reasons for exclusion from the 
PK set will be included in the same summary. 
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 eCRF. All randomized 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 Randomized Set, and the 
summary will be presented by randomized treatment group and total. 
5.2 
Demographic and Other Baseline Characteristics 
The following demographic characteristics will be summarized in the following order in 
the tables: age (years), sex, ethnicity, race.  Other baseline characteristics include: weight 
(kg), weight category (45 to <80 kg and ≥80 kg), height (cm), and body mass index 
(BMI, kg/m2).  
Age will be calculated as the integer part of: (date of informed consent is signed – date of 
birth + 1)/365.25, and BMI will be calculated as: weight (kg) / (height [m])2. The last 
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Statistical Analysis Plan v1.0 
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height and weight measured prior to the administration of investigational product 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 (or the last value measured prior to the administration 
of investigational product). Summaries will be based on the Safety Set and PK Set, as 
appropriate. Demographics and other baseline characteristics data will be listed, and the 
listing will be based on the Safety Analysis Set.  
5.3 
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), 
history of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, psychiatric, other diseases, and smoking habits. 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 22.0.  
Medical history will be listed and summarized by system organ class (SOC) and 
preferred term (PT) for each randomized treatment group and total for the Safety Set. The 
summary will include number and percentage of subjects who experienced the event, and 
number of events experienced. System organ class will be sorted alphabetically, and PT 
will be sorted within each SOC in descending frequency in the table Total column.  
5.4 
Prior Therapies, Procedures, and Medication  
Prior medications will be coded using the World Health Organization (WHO) Drug 
Dictionary version Global B3 March 2019.  
Prior medication is defined as any medication with the start date prior to the date of the 
first dose of IP.  
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Statistical Analysis Plan v1.0 
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The prior medication usage will be summarized by the number and proportion of subjects 
in each randomized treatment group and in total subjects within each therapeutic class 
and PT for the Safety Set. Therapeutic class will be sorted alphabetically, and PT will be 
sorted within each therapeutic class in descending frequency in the table total column. 
Multiple medication usage by a subject in the same category will be counted only once. 
All prior therapies, procedures, and medication will be listed for the Safety Set. 
5.5 
Concomitant Therapies, Procedures, and Medications  
Concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary version Global B3 March 2019.  
Concomitant medication (therapy) is defined as any medication with start date on or after 
date of IP administration, or medications with start date prior to IP administration but 
continuing at or after IP 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. Therapeutic class will be sorted 
alphabetically, and PT will be sorted within each therapeutic class in descending 
frequency in the table total column. Multiple medication usage by a subject in the same 
category will be counted only once. 
All concomitant therapies, procedures, and medication will be listed for the Safety Set. 
5.6 
Exposure to Investigational Product 
The extent of exposure to study drug will be described by reporting the number and 
percentage of subjects with complete injection and subjects with incomplete injection for 
the Safety Set and the PK Set. 
 
 
  
Summary will include: n, mean, SD, median, minimum, and maximum, and based on the 
Safety Set and Pharmacokinetic set.  
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Statistical Analysis Plan v1.0 
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An exposure data listing, based on the Safety Set, will be provided and include start and 
end date and time of dose administration, 
, and other 
exposure data, e.g. planned dose/volume. 
5.7 
Measurements of Treatment Compliance  
This is a single-dose (single-administration) study in which the IP 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.  
5.8 
Protocol Deviations 
Protocol deviations will be recorded by the site separately from the clinical database. 
Protocol deviations will be classified as major or minor in accordance with applicable 
Takeda 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 / PK 
• 
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. 
Confirmed major and minor protocol deviations will be documented in the protocol 
deviation tracker for the study. Major/minor protocol deviations will be summarized by 
category for the Randomized Set. All protocol deviations will be presented in the 
protocol deviation listing and based on the Randomized Set. 
6. 
EFFICACY ANALYSES 
No efficacy analyses are planned for this study. 
7. 
SAFETY ANALYSIS  
The safety analysis will be performed using the Safety Set. Safety endpoints include 
TEAEs, clinical laboratory variables (hematology, clinical chemistry, coagulation and 
urinalysis), vital signs (systolic and diastolic BP, pulse rate, and body temperature), body 
weight, ECG variables, and immunogenicity response (development of ADAs). For each 
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safety variable, unless otherwise specified, the last non-missing value before the 
administration of IP will be used as baseline for all analyses of that safety endpoint.  
For categorical variables, the number and percentage of subjects within each category 
(with a category for missing data as needed) of the parameter will be presented. For 
continuous variables, the number of subjects (n), mean, median, standard deviation (SD), 
minimum, and maximum values will be presented. All safety data, including derived 
data, will be presented in subject data listings, and all listings will include subject’s sex, 
age, and race. 
7.1 
Adverse Events  
Adverse events will be coded MedDRA version 22.0. 
Treatment-emergent AEs are defined as AEs with onset at the time of or following the 
start of treatment with study medication, or medical conditions present prior to the start 
of treatment but increasing in severity, frequency, 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) or until closure (the subject’s health has returned to his/her 
baseline status or all variables have returned to baseline) if the AEs are not resolved at the 
Day 112/End of Study visit. 
An overall summary of the number of subjects with TEAEs, as well as the number of 
TEAEs, will be presented by treatment group and total, including: any TEAE, severe 
TEAEs, serious TEAEs, TEAEs related to investigational product, TEAEs related to 
device, TEAEs leading to discontinuation from the study, TEAEs resulting in 
hospitalization, and TEAEs leading to death. 
The number and percentage of subjects with TEAEs, as well as the number of TEAEs, 
will be calculated by SOC, PT and will be presented by treatment group and total. The 
TEAEs will be further summarized by severity, relationship to IP and relationship to 
device. If more than 1 AE occurs with 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 IP or device. For example, if a 
subject experienced a mild headache not related to IP, and a moderate headache related to 
IP, then the subject will be counted once for headache using the moderate headache 
related to IP. 
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Statistical Analysis Plan v1.0 
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Presentation by SOC and PT will present SOC sorted alphabetically and PT within SOC 
by descending frequency in the table total column. 
The TEAEs, TEAEs related to IP, and TEAEs related to device will be summarized by 
PT by descending frequency. 
Serious TEAEs, TEAEs related to investigational product, TEAEs related to device, 
TEAEs leading to discontinuation from the study, and TEAEs leading to death will be 
summarized by SOC and PT. 
All AEs (TEAEs and non-TEAEs) will be provided in the AE subject listings.  
7.2 
Clinical Laboratory Data 
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline 
at each assessment time point as well as shift tables from baseline to each visit for 
quantitative variables will be presented by treatment group for the following clinical 
laboratory variables: 
Biochemistry 
Sodium, potassium, glucose, blood urea nitrogen, creatinine, calcium, 
chloride, thyroid stimulating hormone (TSH), thyroxine (T4 total), 
triiodothyronine (T3), phosphorus, total protein, total CO2 
(bicarbonate), albumin, aspartate transaminase, alanine transaminase, 
gamma glutamyl transferase, alkaline phosphatase, total bilirubin, uric 
acid, β-hCG and FSH. 
Hematology 
Hemoglobin, hematocrit, red blood cells (RBC), platelet count, white 
blood cell count (WBC)- total and differential, total neutrophils 
(absolute), eosinophils (absolute), monocytes (absolute), lymphocytes 
(absolute) and basophils (absolute). 
Urinalysis 
pH, glucose, protein, blood, ketones, bilirubin, nitrites, leukocyte 
esterase, and specific gravity. 
Coagulation 
Prothrombin time (PT), activated partial thromboplastin time (aPTT), 
and international normalized ratio (INR). 
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Statistical Analysis Plan v1.0 
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Clinical laboratory test values are potentially clinically important (PCI) if they meet 
either the low or high PCI criteria listed in Table 1. The number and percentage of 
subjects with post-baseline PCI values will be tabulated by treatment group and total. 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 including the subject number, baseline, and 
post-baseline values.  
Table 1 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  
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Parameter 
Classification  
Criteria 
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 
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 
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Statistical Analysis Plan v1.0 
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Parameter 
Classification  
Criteria 
Glucose 
HIGH 
≥ 1+ 
Blood 
HIGH 
≥ 2+ 
Bilirubin  
 
Positive 
Protein 
HIGH 
≥ 2+ 
Nitrite  
 
Positive 
Ketones 
HIGH 
≥ 2+ 
Leukocyte 
Esterase 
 
Positive 
Coagulation  
INR 
HIGH 
>1.2 x ULN 
PT 
HIGH 
>1.2 x ULN 
aPTT 
HIGH 
>1.2 x ULN 
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, INR: international normalized ratio, PT: Prothrombin time, aPTT: 
activated partial thromboplastin time. 
 
All laboratory data will be listed for the Safety Set. Separate laboratory data listings will 
be generated presenting results in SI units and Western units respectively.  
7.3 
Vital Signs 
Descriptive statistics for vital signs (e.g., weight, systolic and diastolic BP, pulse rate, and 
body temperature) and their changes from baseline at each post-baseline visit will be 
presented by treatment group. 
Vital sign values will be considered PCI if they meet both the observed value criteria and 
the change from baseline criteria listed in Table 2. The number and percentage of 
subjects with PCI post-baseline values will be tabulated by treatment group and total. 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.  
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Table 2 Criteria for Potentially Clinically Important 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 
Weight 
HIGH 
Increase of  5% from baseline value 
LOW 
Decrease of  5% from baseline value 
All vital signs data (including height and weight) will be listed for the Safety Set. 
7.4 
Electrocardiogram (ECG) 
Descriptive statistics for ECG variables (eg, heart rate, PR, RR, QRS interval, QT 
interval, and QTc interval) and their changes from baseline at each assessment time point 
will be presented by treatment group. 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, it will be replaced with 60/heart rate in the correction formula. The ECG 
interpretation per the investigator will be summarized by visit. A shift table from baseline 
to each visit for qualitative ECG results will be presented.  
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 IP). 
Electrocardiogram variable values will be considered PCI if they meet or exceed the 
upper limit values listed in Table 3. The number and percentage of subjects with post-
baseline PCI values will be tabulated by treatment group. 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 ECG value. A listing of all subjects with post-baseline PCI value will be 
provided including the subject number, site, baseline, and post-baseline PCI values. 
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Statistical Analysis Plan v1.0 
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Table 3 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 
7.5 
Other Safety Data 
7.5.1 
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 treatment. 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).   
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Statistical Analysis Plan v1.0 
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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 
 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.  
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7.5.2 
 
 
. 
8. 
PHARMACOKINETIC ANALYSIS  
All summaries and analyses of the PK data will be based on the Pharmacokinetic Set 
defined in Section 4.3. 
8.1 
Drug Concentration 
Blood samples will be drawn from each subject during this study for the determination of 
plasma concentration of lanadelumab. Serial blood samples will be collected for PK 
analysis at predose and, 8, 24, 48, 72, 96 hours and days 7, 14, 21, 28, 42, 56, 84 and 112 
(end of study visit/or early discontinuation) post dose. Plasma concentrations of 
lanadelumab will be measured using a validated analytical method. 
8.2 
Handling Below Limit of Quantitation (BLQ) Values 
The following procedures will be used for plasma concentrations of lanadelumab data 
below the lower limit of quantification (LLOQ): 
 Samples that are below limit of quantification (BLQ) are reported as <LLOQ on 
the data listings, where LLOQ is replaced by the actual value for LLOQ for 
specific PK assay. 
 Samples that are BLQ are treated as zero in the calculation of summary statistics 
(eg, mean, SD, etc.) for the plasma concentrations at individual time points. 
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 conventions will be used to create the mean 
plasma concentration versus time plots. 
 For calculation of PK parameters, BLQ values prior to the first measurable 
concentration will be set to zero All BLQ values following the first measurable 
concentration will be set to “missing”. 
 Missing values will not be imputed. 
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Statistical Analysis Plan v1.0 
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8.3 
Pharmacokinetic Parameters 
Pharmacokinetic parameters will be determined for lanadelumab from the individual 
plasma concentration versus actual time data. Pharmacokinetic parameters will be 
estimated by non-compartmental analysis, as deemed appropriate, using Phoenix 
WinNonlin (Certara USA, Inc., Princeton, NJ) Version 8.0 or higher, and all calculations 
will be based on the actual time post dose.  
The PK parameters for lanadelumab will include, but may not be limited to: 
Parameter 
Description 
AUC0-last 
Area under the concentration-time curve from time zero to the last 
quantifiable concentration in plasma, calculated using the linear 
up/log down trapezoidal rule  
AUC0-∞ 
Area under the concentration-time curve from time zero extrapolated to 
infinity, calculated using the linear up/ log down trapezoidal rule  
Cmax 
Maximum observed plasma drug concentration  
tmax 
Time to reach Cmax in plasma 
λz 
Terminal elimination rate constant 
t½ 
Terminal half-life, calculated as ln(2)/λz 
CL/F 
Apparent clearance, calculated as: Dose/AUC0-∞  
Vdz/F 
Apparent volume of distribution associated with the terminal slope 
following extravascular administration, calculated as: 
CL/F / λz  
CL/F/BW 
Body weight adjusted CL/F 
Vdz/F/BW 
Body weight adjusted Vdz/F 
 
8.4 
Statistical Analysis of Pharmacokinetic Data 
Individual lanadelumab concentrations will be listed by subject, treatment group, day, 
and time and summarized by treatment group and time based on the Pharmacokinetic Set. 
The following descriptive statistics of plasma lanadelumab concentrations will be 
provided: n, arithmetic mean, geometric mean, SD, arithmetic CV%, geometric CV%, 
25th Percentile (Q1), 75th Percentile (Q3), median, minimum, and maximum.  
The mean and individual plasma lanadelumab concentrations versus time profiles by 
treatment group will be presented in figures on both linear and semi-logarithmic scales. 
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Statistical Analysis Plan v1.0 
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Mean (±SD) and individual plasma lanadelumab concentrations versus time profiles will 
be presented using nominal time based on the Pharmacokinetic Set. 
Individual lanadelumab PK parameters will be listed by subject and treatment group and 
summarized by treatment group based on the Pharmacokinetic Set with the following 
descriptive statistics: n, arithmetic mean, arithmetic SD, CV%, median, Q1, Q3, 
minimum, maximum, geometric mean, and geometric CV%. 
To assess the bioavailability of lanadelumab following a single, 2 mL SC dose of 300 mg 
delivered by PFS or AI, the plasma lanadelumab PK parameters AUC0-last, AUC0-∞ and 
Cmax will be natural log-transformed and analyzed using an analysis of variance 
(ANOVA) model to compare the PK of lanadelumab delivered by AI versus PFS. The 
ANOVA model will include treatment as a fixed effect. The treatment least-squares (LS) 
means, differences between LS means, and 90% CIs associated with these differences 
will be determined for each parameter. Those results will be then exponentiated to the 
original scale. Geometric LS means, geometric mean ratios and 90% CIs will be 
presented. If the 90% CIs lies between 0.8 and 1.25, the bioequivalence can be 
concluded. Ratios will be expressed as a percentage relative to the reference treatment 
(PFS). 
A similar analysis will be performed by excluding subjects enrolled before the Pharmacy 
Manual was revised (Cohorts 1 and 2) as a sensitivity analysis to assess the impact of 
revising the Pharmacy Manual. 
9. 
PHARMACODYNAMIC ANALYSIS 
Not applicable.   
10. 
OTHER ANALYSES 
Not applicable.   
11. 
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE  
No planned interim analysis, or data monitoring committee are planned for this study. 
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
12. 
DATA HANDLING CONVENTIONS  
12.1 
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. 
12.2 
Derived Efficacy Endpoints  
Not applicable.   
12.3 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated or unscheduled assessments before the start of IP, then the 
results from the most recent assessment made prior to the start of IP 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. 
12.4 
Handling of Missing, Unused, and Spurious Data  
12.4.1 Missing Date of Investigational Product 
Since this is a Phase 1 single-dose study in which the IP will be administered on Day 1, 
missing dates of IP are not expected. 
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
12.4.2 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) 
For prior or concomitant 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, impute the start date first. 
12.4.2.1 Incomplete Start Date  
The following rules will be applied to impute the missing start dates.  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. 
12.4.2.1.1 
Missing Day and Month 
 
If the year of the incomplete start date is the same as the year of the dose date of IP, 
then the day and month of the dose date of IP will be assigned to the missing fields 
 
If the year of the incomplete start date is before the year of the dose date of IP, then 
December 31 will be assigned to the missing fields 
 
If the year of the incomplete start date is after the year of the dose date of IP, then 
01 January will be assigned to the missing fields. 
12.4.2.1.2 
Missing Month Only 
 
The day will be treated as missing and both month and day will be replaced 
according to the above procedure. 
12.4.2.1.3 
Missing Day Only 
 
If the month and year of the incomplete start date are the same as the month and 
year of the dose date of IP, then the day of the dose date of IP will be assigned to 
the missing day 
 
If either the year is before the year of the dose date of IP or if both years are the 
same, but the month is before the month of the dose date of IP, then the last day of 
the month will be assigned to the missing day 
 
If either the year is after the year of the dose date of IP or if both years are the 
same, but the month is after the month of the dose date of IP, then the first day of 
the month will be assigned to the missing day. 
12.4.2.2 Incomplete Stop Date  
The following rules will be applied to impute the missing stop dates.  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. 
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
12.4.2.2.1 
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 IP, then the day and month of the date of the last dose of IP will be 
assigned to the missing fields 
 
If the year of the incomplete stop date is before the year of the dose date of IP, then 
31 December will be assigned to the missing fields 
 
If the year of the incomplete stop date is after the year of the dose date of IP, then 
01 January will be assigned to the missing fields. 
12.4.2.2.2 
Missing Month Only 
 
The day will be treated as missing and both month and day will be replaced 
according to the above procedure. 
12.4.2.2.3 
Missing Day Only 
 
If the month and year of the incomplete stop date are the same as the month and 
year of the dose date of IP, then the day of the dose date of IP will be assigned to 
the missing day 
 
If either the year is before the year of the dose date of IP or if both years are the 
same, but the month is before the month of the dose date of IP, then the last day of 
the month will be assigned to the missing day 
 
If either the year is after the year of the dose date of IP or if both years are the 
same, but the month is after the month of the dose date of IP, then the first day of 
the month will be assigned to the missing day. 
12.4.3 Missing Date Information for Adverse Events  
For AEs with partial start dates, non-missing date parts will be used to determine if the 
AE is treatment-emergent or not.  If a determination cannot be made using the 
non-missing date parts as to when the AE occurred relative to study drug administration, 
e.g. AE start year and month are the same as the year and month of the dose date of IP, 
then the AE will be classified as treatment-emergent. 
 
To facilitate categorization of AEs as treatment emergent, imputation of dates can be 
used.  For AEs, incomplete (i.e., partially missing) start dates start dates will be imputed 
and will follow the same rules as in Section 12.4.2.1. Incomplete stop dates will not be 
imputed.   
12.4.3.1 Incomplete Start Date  
Follow the same rules as in Section 12.4.2.1. 
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
12.4.3.2 Incomplete Stop Date  
Incomplete stop dates will not be imputed. 
12.4.4 Missing Severity Assessment for Adverse Events  
If severity is missing for an AE starting prior to the dose date of IP, then a severity of 
“Mild” will be assigned.  If the severity is missing for an AE starting on or after the dose 
date of IP, then a severity of “Severe” will be assigned.  The imputed values for severity 
assessment will be used for incidence summaries, while both the actual and the imputed 
values will be used in data listings. 
12.4.5 Missing Relationship to Investigational Product for Adverse Events  
If the relationship to IP is missing for an AE starting on or after the dose date of IP, 
a causality of “Related” will be assigned.  The imputed values for relationship to 
double-blind IP will be used for incidence summaries, while both the actual and the 
imputed values will be presented in data listings. 
12.4.6 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. 
13. 
ANALYSIS SOFTWARE  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS on a suitably 
qualified environment.   
PK analyses will be performed using Phoenix WinNonlin (Certara USA, Inc., Princeton, 
NJ) Version 8.0 or higher. 
14. 
 CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL 
Not applicable. 
For non-commercial use only


Takeda                                                             CONFIDENTIAL 
Page 32 of 37 
Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
15. 
REFERENCES 
Donald J. Schuirmann, A Comparison of the Two One-Sided Tests Procedure and the 
Power Approach for Assessing the Equivalence of Average Bioavailability, Journal of 
Pharmacokinetics and Biopharmaceutics, Vol. 15, No. 6, 1987 
For non-commercial use only


Takeda                                                             CONFIDENTIAL 
Page 33 of 37 
Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
16. 
APPENDICES  
16.1 
Schedule of Activities 
Table 4 Schedule of Assessments 
Visit 
Screening 
In-House 
Treatment 
Period a 
Out-Patient 
Visitsb, c 
End of Study 
(Day 112) or 
Early 
Discontinuation   
Study Day 
–28 to    
-02 
-1 
 1 to 5   
7 to 112 
  
Informed consent 
X 
 
Refer to Table 5 
Refer to Table 6 
  
Inclusion/exclusion criteria 
X  
X 
  
Demography  
X 
X  
  
Medical/Medication History 
X 
X 
X 
Physical examination  
X 
X 
X 
Vital signs (blood pressure, pulse) supine  
X  
X 
X  
Body temperature (oral) 
X 
 X 
X 
Height, Weight and BMId,e 
X 
X 
X 
Electrocardiogram (12-lead) 
X f 
X f 
X 
Biochemistry, hematology, and urinalysis  
X 
X 
X 
TSH, T3, T4 
X 
 
 
PT, aPTT, INR 
X 
X 
X 
HIV, HBsAg, and HCV antibodies 
X 
 
  
Serum Pregnancy test (all females) 
X 
X 
X 
FSH (all females)  
X 
 
  
Urine drug and alcohol (breath test) 
screening 
X 
X 
 
Pharmacokinetic blood sampling (PK) 
  
 
 
Anti-drug antibody blood sampling 
(ADA) 
  
  
X 
Check-in to the CRC 
 
X 
 
Out-patient visits 
X 
 
X 
In-patient visit 
 
X 
 
Concomitant Medication 
X 
X 
X 
Adverse Event/Serious Adverse Event 
X 
X 
X 
aPTT= activated partial thromboplastin time; CRC=clinical research center; HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; INR=international normalized ratio; FSH=follicle-stimulating hormone; HIV=human 
immunodeficiency virus; PT=prothrombin time; T3=triiodothyronine; T4=thyroxine; TSH= thyroid-stimulating 
hormone 
a Refer to Table 5 for the procedures and the timing of the procedures to be done during the in-house treatment period.  
b Refer to Table 6 for the procedures and the timing of the procedures to be done during the out-patient visits. 
c In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to 
complete these assessments. End of study visit is Day 112.  
d Height will only be recorded at the first visit during the screening period. 
e Body mass index criteria for eligibility will be calculated at the first visit during the screening period and on Day -1. 
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Page 34 of 37 
Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
19 November 2019 
f  Single ECG recordings  are  required; However, ECGs will be performed in triplicate if the QTcF interval (calculated 
on line on site) is increased by >45 msec from the baseline, or an absolute QTcF value is >500 msec for any scheduled 
ECG, or if indicated per exclusion criteria #9 or in protocol Section 7.2.2.9, then 2 additional ECGs will be collected, 
approximately 2-4 minutes apart, to confirm the original measurement. Thereafter, all subsequent ECGs will be single 
recordings.
For non-commercial use only


Takeda                                                                                                          CONFIDENTIAL 
 
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
 
 
 
 
 
 
 
 
 
 
 
  19 November 2019 
Table 5 Detailed Schedule of In-Patient Assessments (Days 1-5) 
Study 
Day/Hour 
(relative to 
dosing time)  
PE 
VS 
Body 
Temperature 
(oral) 
Weight 
ECG  
Biochemistry, 
hematology, 
and urinalysis  
PT, 
aPTT, 
INR 
Serum 
Pregnancy  
(all women)  
 
 
Randomizatione 
IP 
administrationd 
PK 
ADA 
AE/SAEb 
CMb 
Day 1Predosea 
  
X  
X 
  
X 
  
  
  
X 
  
Xc 
Xc 
X 
X 
Day 1:0h 
  
  
  
  
  
  
  
  
 
X 
  
  
X 
X 
Day1: 1h post 
dose  
  
X 
  
  
X  
  
  
  
 
  
  
  
X 
X 
Day 1: 2h post 
dose  
  
X 
  
  
  
  
  
  
 
  
  
  
X 
X 
Day 1:4h post 
dose  
  
X 
  
  
X  
  
  
  
 
  
  
  
X 
X 
Day 1:6h post 
dose  
  
X  
  
  
  
  
  
  
 
  
  
  
X 
X 
Day 1:8h post 
dose  
  
X 
  
  
X  
  
  
  
 
  
X  
  
X 
X 
Day 1:12h post 
dose  
  
 X 
  
  
  
  
  
  
 
  
  
  
X 
X 
 Day 2:24h post 
dose  
  
 X 
  
  
X  
X 
  
  
 
  
X  
  
X 
X 
Day 3:48h post 
dose  
  
 X 
  
  
X  
  
  
  
 
  
X  
  
X 
X 
Day 4: 72h post 
dose  
  
 X 
  
  
X  
  
  
  
 
  
X  
  
X 
X 
Day 5: 96h post 
dose  
X 
X 
  
X 
X  
X 
X 
X 
 
  
X  
  
X 
X 
ADA=anti-drug antibody blood sampling; AE=adverse event; aPTT= activated partial thromboplastin time; CM=concomitant medication; CRC=clinical research center; 
ECG=12-lead ECG; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; INR=international normalized ratio; FSH=follicle-stimulating hormone; HIV=human 
immunodeficiency virus; IP=investigational product; PE=physical exam; PT=prothrombin time; PK=pharmacokinetic blood sampling; SAE=serious adverse event; 
T3=triiodothyronine; T4=thyroxine; TSH= thyroid-stimulating hormone; UDS=urine drug screen; VS=vital signs 
a Assessments to be done within 30 minutes prior the administration of IP. 
b Adverse events/SAEs and CMs will be continuously monitored throughout the study. 
c Pre-dose ADA and PK samples can be collected within 60 minutes prior to the administration of IP. 
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
 
 
 
 
 
 
 
 
 
 
 
  19 November 2019 
d Investigational product administration start and stop times must be recorded in source and on the CRF. 
.   
e Randomization to be performed pre-dose on Day 1. 
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Statistical Analysis Plan v1.0 
Protocol Number: SHP643-102 
 
 
 
 
 
 
 
 
 
 
 
  19 November 2019 
Table 6 Detailed Schedule of Out-Patient Assessments (Study Days 7-112) 
Study Day 
PE 
VS 
Body 
Temperature 
(oral) 
Weight 
ECG 
Biochemistry, 
hematology, 
and urinalysis  
PT, aPTT, 
INR 
Serum 
Pregnancy  
(all women)  
UDS & 
ETOH screen 
PK 
ADA 
AE/SAEa 
CMa 
Day 7 (± 1) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Day 14 (± 1) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day 21 (± 1)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Day 28 (± 2) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day 42 (± 2) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Day 56 (± 2) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day 84 (± 3) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Day 112 (± 3) 
(End of Study Visit/ 
or Early 
Discontinuation) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADA=anti-drug antibody blood sampling; AE=adverse event; aPTT= activated partial thromboplastin time; CM=concomitant medication; CRC=clinical research center; 
ECG=12-lead ECG; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; INR=international normalized ratio; FSH=follicle-stimulating hormone; HIV=human 
immunodeficiency virus; IP=investigational product; PE=physical exam; PT=prothrombin time; PK=pharmacokinetic blood sampling; SAE=serious adverse event; 
T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; UDS=urine drug screen; VS=vital signs 
a Adverse events/SAEs and CMs will be continuously monitored throughout the study.  
 
 
 
 
For non-commercial use only