SPRING STUDY: An Open-Label, Multicenter, Phase 3 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Lanadelumab for Prevention Against Acute Attacks of Hereditary Angioedema (HAE) in Pediatric Subjects 2 to <12 Years of Age
Phase: PHASE3
Conditions: Hereditary Angioedema
Sponsor: Shire

CLINICAL STUDY PROTOCOL 
 
 
NCT Number:  
NCT04070326 
 
Study Title: 
SPRING STUDY: An Open-Label, Multicenter, Phase 3 Study to Evaluate 
the Safety, Pharmacokinetics, and Pharmacodynamics of Lanadelumab 
for Prevention Against Acute Attacks of Hereditary Angioedema (HAE) 
in Pediatric Subjects 2 to <12 Years of Age 
 
 
 
Study Number: 
SHP643-301 
 
Protocol Version and Date: 
Amendment 1: 
12 Aug 2019 
 

PROTOCOL: SHP643-301
TITLE:
SPRING STUDY: An Open-Label, Multicenter, Phase 3 Study to Evaluate 
the Safety, Pharmacokinetics, and Pharmacodynamics of Lanadelumab for 
Prevention Against Acute Attacks of Hereditary Angioedema (HAE) in 
Pediatric Subjects 2 to <12 Years of Age
SHORT TITLE:
Safety, Pharmacokinetics, and Pharmacodynamics Study of Lanadelumab 
to Prevent Hereditary Angioedema (HAE) Attacks in Pediatric Subjects 2 
to <12 Years of Age
STUDY PHASE:
Phase 3
DRUG:
Lanadelumab; TAK-743 (formerly SHP643, DX-2930)
IND NUMBER:
116647
EUDRACT 
NUMBER:
2018-002093-42
SPONSOR:
Dyax Corp. (a wholly-owned, indirect subsidiary of Shire plc) (Shire plc, a 
wholly-owned subsidiary of Takeda)
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
Multicenter study
PROTOCOL 
HISTORY:
Original Protocol: 06 May 2019
Amendment 1.0: 12 Aug 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.
For non-commercial use only

For non-commercial use only

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this study.
Corrected the name of the pregnancy reporting form for consistency as the 
Shire Investigational and Marketed Products Pregnancy Report Form was 
retired. The current form is the Clinical Study Pregnancy Report Form.
Appendix 3.8
See Appendix 8 for protocol history, including all amendments.
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the “Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol” within 24 hours to the Shire Global Drug Safety Department. The fax 
number and e-mail address are provided on the form (sent under separate cover). A copy of this 
form must also be sent to the contract research organization (CRO) using the details below.
PPD Pharmacovigilance Group Fax: 
For protocol- or safety-related questions or concerns during normal business hours (09:00 
to 17:00 EST), the investigator must contact the Shire medical monitor:
, MD, PhD
Phone: 
Mobile: 
For protocol- or safety-related questions or concerns outside of normal business hours, the 
investigator must contact the Shire medical monitor:
, MD, PhD
Mobile: 
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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.
A product quality complaint includes any instances where there is an allegation or report relating 
to Shire licensed or investigational products, received in writing, electronically, or orally, which 
indicates an impact to a product’s strength, identity, safety, purity, or quality, or which suggests 
that a product did not meet the criteria defined in the regulatory applications, licenses, or 
marketing authorizations for the product. Examples of investigational product quality complaints 
include, but are not limited to, the following:
Unit issues

Capsule fill empty or overage

Bottle/vial fill shortage or overage

Capsule/tablet damaged/broken

Syringe/vial cracked/broken

Syringe leakage

Missing components

Product discoloration

Device malfunction
Labeling

Label missing

Leaflet or Instructions For Use 
(IFU) missing 

Label illegible

Incomplete, inaccurate, or 
misleading labeling

Lot number or serial number missing
Packaging

Damaged packaging (e.g., 
secondary, primary, bag/pouch)

Tampered seals

Inadequate or faulty closure

Missing components within package
Foreign 
material

Contaminated product

Particulate in bottle/vial

Particulate in packaging
Please report the product quality complaint using the “Product Complaint Data Collection Form” 
via the email address:
Telephone number (provided for reference if needed):
Shire, Lexington, MA (USA)
For instructions on reporting AEs related to product complaints, see Appendix 3.4.
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TABLE OF CONTENTS
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION..................................3
LIST OF TABLES.........................................................................................................................12
LIST OF FIGURES .......................................................................................................................12
1.
PROTOCOL SUMMARY......................................................................................................13
1.1
Synopsis ...................................................................................................................13
1.2
Schema .....................................................................................................................20
1.3
Schedule of Activities ..............................................................................................21
2.
INTRODUCTION..................................................................................................................30
2.1
Disease Etiology and Pathophysiology....................................................................30
2.2
Disease Diagnosis in the Pediatric Population.........................................................31
2.3
Epidemiology in the Pediatric Population................................................................32
2.4
Indication and Current Treatment Options...............................................................33
2.5
Product Background and Clinical Information ........................................................34
2.5.1
Drug Information..........................................................................................34
2.5.2
Nonclinical Studies with Lanadelumab........................................................36
2.5.3
Clinical Studies with Lanadelumab..............................................................36
2.5.4
Adolescent Clinical Trial Experience ..........................................................39
2.6
Study Rationale ........................................................................................................40
2.7
Benefit/Risk Assessment..........................................................................................41
2.8
Compliance Statement..............................................................................................44
3.
OBJECTIVES AND ENDPOINTS........................................................................................45
3.1
Study Objectives ......................................................................................................45
3.1.1
Primary Objective ........................................................................................45
3.1.2
Secondary Objectives...................................................................................45
45
3.2
Study Endpoints .......................................................................................................45
4.
STUDY DESIGN ...................................................................................................................48
4.1
Overall Design..........................................................................................................48
4.2
Scientific Rationale for Study Design......................................................................49
4.3
Justification for Dose ...............................................................................................51
4.4
Duration of Subject Participation and Study Completion Definition ......................54
4.5
Sites and Regions .....................................................................................................55
5.
STUDY POPULATION.........................................................................................................56
5.1
Inclusion Criteria......................................................................................................56
5.2
Exclusion Criteria.....................................................................................................57
5.3
Restrictions...............................................................................................................57
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5.3.1
Medical Interventions...................................................................................57
5.3.2
Fluid and Food Intake ..................................................................................57
5.3.3
Activity.........................................................................................................58
5.4
Reproductive Potential .............................................................................................58
5.4.1
Female Contraception ..................................................................................58
5.4.2
Male Contraception......................................................................................59
6.
STUDY INTERVENTION ....................................................................................................60
6.1
Investigational Product.............................................................................................60
6.1.1
Identity of Investigational Product...............................................................60
6.1.2
Blinding the Treatment Assignment ............................................................60
6.2
Administration of Investigational Product ...............................................................60
6.2.1
Interactive Response Technology for Investigational Product 
Management.................................................................................................60
6.2.2
Allocation of Subjects to Treatment.............................................................60
6.2.3
Dosing ..........................................................................................................60
6.2.4
Unblinding the Treatment Assignment ........................................................63
6.2.5
Dose Modification........................................................................................63
6.3
Labeling, Packaging, Storage, and Handling of Investigational Product.................63
6.3.1
Packaging and Labeling ...............................................................................63
6.3.2
Storage and Handling...................................................................................64
6.4
Drug Accountability.................................................................................................65
6.5
Subject Compliance..................................................................................................66
6.6
Prior and Concomitant Therapy...............................................................................66
6.6.1
Prior Treatment ............................................................................................67
6.6.2
Concomitant Treatment................................................................................67
6.6.3
Permitted Treatment.....................................................................................67
6.6.4
Prohibited Treatment....................................................................................67
7.
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL..........................................................................69
7.1
Discontinuation of Study Treatment ........................................................................69
7.2
Reasons for Discontinuation ....................................................................................69
7.3
Withdrawal from the Study......................................................................................69
7.4
Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit..............................70
7.5
Stopping Rules .........................................................................................................70
7.5.1
Study Level Stopping Rules.........................................................................70
7.5.2
Individual Stopping Rules............................................................................70
7.5.3
Follow-Up for Subjects Meeting Stopping Criteria .....................................70
8.
STUDY ASSESSMENTS AND PROCEDURES..................................................................71
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8.1
Study Periods............................................................................................................71
8.1.1
Screening Period (up to 4 weeks).................................................................71
8.1.2
Baseline Observation Period (up to 12 weeks) ............................................72
8.1.3
Treatment Period..........................................................................................72
8.1.3.1
Study Visit 1; Study Day 0................................................................72
8.1.3.2
Study Visit 2-Visit 52; Study Day 4- Study Day 364 .......................73
8.1.3.3
Final Treatment Visit (Study Visit 52; Study Day 364)....................74
8.1.4
Follow-up Period..........................................................................................75
8.1.5
Early Termination ........................................................................................76
8.1.6
Additional Care of Subjects after the Study.................................................76
8.2
Study Assessments ...................................................................................................76
8.2.1
Informed Consent.........................................................................................76
8.2.2
Eligibility Review ........................................................................................76
8.2.3
Demographic and Other Baseline Characteristics........................................76
8.2.3.1
Medical and Medication History.......................................................76
8.2.4
Clinical Outcomes........................................................................................76
8.2.4.1
Collection of Hereditary Angioedema Attacks .................................76
8.2.4.2
Management of Acute Hereditary Angioedema Attacks...................77
8.2.5
Safety............................................................................................................77
8.2.5.1
Physical Examination........................................................................77
8.2.5.2
Vital Signs .........................................................................................78
8.2.5.3
Pregnancy Test ..................................................................................78
8.2.5.4
Clinical Laboratory Tests for Safety Assessments............................78
8.2.5.5
Adverse Events..................................................................................79
8.2.5.6
Adverse Events of Special Interest (AESI) .......................................81
8.2.6
Other.............................................................................................................81
8.2.6.1
Clinical Pharmacology ......................................................................81
8.2.6.2
Pharmacodynamics............................................................................81
8.2.6.3
Immunogenicity (Anti-drug Antibody Testing) ................................82
8.2.6.4
Biomarkers ........................................................................................82
83
8.2.6.6
Healthcare Resource Utilization........................................................84
8.2.6.7
Self-administration of Lanadelumab .................................................85
8.2.6.8
Injection Report and Subcutaneous Administration Survey .............86
8.2.7
Volume of Blood to Be Drawn from Each Subject......................................86
8.2.8
Blood Sample Collection, Storage, and Shipping........................................87
9.
STATISTICAL CONSIDERATIONS ...................................................................................88
9.1
Statistical Analysis Process......................................................................................88
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9.2
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......88
9.3
Sample Size and Power Considerations...................................................................88
9.4
Statistical Analysis Set(s).........................................................................................89
9.5
Analysis Set Description and Exposure ...................................................................89
9.5.1
Subject Disposition ......................................................................................89
9.5.2
Demographics and Other Baseline Characteristics ......................................89
9.5.3
Medical History............................................................................................89
9.5.4
Treatment Exposure and Compliance ..........................................................89
9.5.5
Prior and Concomitant Medications.............................................................89
9.6
Clinical Outcome Analyses......................................................................................89
9.6.1
Primary Clinical Outcome Endpoint............................................................90
9.6.2
Secondary Clinical Outcome Endpoints ......................................................90
9.6.2.1
Normalized Number of Investigator-confirmed Hereditary 
Angioedema Attacks .........................................................................91
9.6.2.2
Time to First Attack...........................................................................92
9.6.2.3
Characteristics of Investigator-confirmed Hereditary Angioedema 
Attacks...............................................................................................92
9.6.2.4
Achievement of Attack-free Status ...................................................93
93
9.7
Safety Analyses........................................................................................................93
9.7.1
Adverse Events.............................................................................................93
9.7.2
Laboratory Test Results ...............................................................................94
9.7.3
Vital Signs....................................................................................................95
9.8
Other Analyses .........................................................................................................95
95
9.8.2
Pharmacokinetic/Pharmacodynamic Analyses.............................................96
9.8.3
Immunogenicity Analyses............................................................................96
9.9
Statistical/Analytic Considerations ..........................................................................96
9.9.1
Multiplicity Adjustment ...............................................................................96
9.9.2
Handling of Missing Data ............................................................................96
9.9.3
Multicenter Studies ......................................................................................96
9.9.4
Subgroup Analyses.......................................................................................96
9.10
Sensitivity Analyses .................................................................................................97
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .........98
Appendix 1 Regulatory, Ethical, and Study Oversight Considerations...........................99
Appendix 1.1
Regulatory and Ethical Considerations .............................................99
Appendix 1.2
Sponsor’s Responsibilities.................................................................99
Appendix 1.3
Investigator’s Responsibilities.........................................................100
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Appendix 1.4
Data Management Considerations...................................................103
Appendix 1.5
Ethical Considerations.....................................................................103
Appendix 2 Clinical Laboratory Tests...........................................................................107
Appendix 3 Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ......................................................108
Appendix 3.1
Adverse Event Definitions ..............................................................108
Appendix 3.2
Collection of Adverse Events..........................................................111
Appendix 3.3
Assessment of Adverse Events........................................................111
Appendix 3.4
Safety Reporting..............................................................................113
Appendix 3.5
Serious Adverse Event Collection Time Frame ..............................113
Appendix 3.6
Serious Adverse Event Onset and Resolution Dates.......................113
Appendix 3.7
Fatal Outcome .................................................................................114
Appendix 3.8
Pregnancy ........................................................................................114
Appendix 3.9
Abuse, Misuse, Overdose and Medication Error.............................115
Appendix 3.10 Urgent Safety Measures ..................................................................116
Appendix 3.11 Regulatory Agency, Institutional Review Board, Ethics 
Committee and Site Reporting ........................................................116
.117
Appendix 5 Hereditary Angioedema Attack Assessment and Reporting Procedures 
(HAARP)....................................................................................................118
Appendix 6 National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity 
Tables (US National Institutes of Health; National Institute of Allergy 
and Infection Diseases) ..............................................................................128
Appendix 7 Abbreviations .............................................................................................141
Appendix 8 Protocol History .........................................................................................144
11. REFERENCES .....................................................................................................................145
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LIST OF TABLES
Table 1:
Schedule of Activities- Screening and Baseline Observation Period............21
Table 2:
Schedule of Activities- Treatment Period A (Day 0 [Week 1] to Day 
182 [Week 26])..............................................................................................23
Table 3:
Schedule of Activities- Treatment Period B (Day 183 [Week 27] 
through Day 364 [Week 52]) and Follow-up Period.....................................26
Table 4:
Objectives and Endpoints..............................................................................46
Table 5:
Lanadelumab Exposure in Virtual Pediatric Patients (6 to <12 years, 
150 mg q2wks) Relative to Patients with HAE ≥12 years (300 mg 
q2wks) ...........................................................................................................53
Table 6:
Lanadelumab Exposure in Virtual Pediatric Patients (2 to <6 years, 
150 mg q4wks) Relative to Patients with HAE ≥12 years(300 mg 
q2wks) ...........................................................................................................54
Table 7:
Treatment Period Dosing Schedule...............................................................62
Table 8:
Volume of Blood to Be Drawn from Each Subject.......................................87
LIST OF FIGURES
Figure 1:
Study Design .................................................................................................20
Figure 2:
Lanadelumab Specifically Inhibits Plasma Kallikrein (pKal).......................35
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1.
PROTOCOL SUMMARY
1.1
Synopsis
Protocol number: SHP643-301
Drug: Lanadelumab
Title of the study: SPRING STUDY: An Open-Label, Multicenter, Phase 3 Study to Evaluate the Safety, 
Pharmacokinetics, and Pharmacodynamics of Lanadelumab for Prevention Against Acute Attacks of Hereditary 
Angioedema (HAE) in Pediatric Subjects 2 to <12 Years of Age
Short title: Safety, Pharmacokinetics, and Pharmacodynamics Study of Lanadelumab to Prevent Hereditary 
Angioedema (HAE) Attacks in Pediatric Subjects 2 to <12 Years of Age
Number of subjects (total and per treatment arm):
At least 20 male or female subjects with HAE Type I or II, 2 to <12 years of age, will be enrolled (signed informed 
consent form and met eligibility criteria), including at least 5 subjects in each age cohort of 2 to <9 years and 9 to 
<12 years. A minimum of 15 subjects must complete 1 year (52 weeks) of treatment on the study. 
Investigator(s): This is a multicenter study.
Site(s) and Region(s): 
Approximately 18 sites in North America (United States, Canada) and Europe (Germany, Spain, Hungary) will 
participate.
Study period (planned):
June 2019 to October 2021
Clinical phase:
3
Objectives:
Primary: 
The primary objective of the study is to evaluate the safety and pharmacokinetics (PK) of lanadelumab in children (2 
to <12 years of age) with HAE.
Secondary: 
The secondary objectives of the study are:

To evaluate the clinical activity/outcomes (hereafter referred to as clinical outcomes) of lanadelumab in 
preventing HAE attacks in children (2 to <12 years of age) with HAE.

To characterize the pharmacodynamics (PD) of lanadelumab in children (2 to <12 years of age) with HAE.

To assess the immunogenicity of chronically administered lanadelumab and its effect on PK, PD, clinical 
outcomes, and safety in children (2 to <12 years of age) with HAE.
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Rationale:
An unmet medical need for effective, safe, and convenient treatment options exist among children (2 to <12 years of 
age) with HAE. The unpredictable nature of HAE attacks in children results in significant decrements in vocational 
and school achievement, which impact the overall quality of life. Prophylactic treatment with lanadelumab may be 
beneficial for children based on demonstrated efficacy, safety, and tolerability in adults and adolescents with the 
reduced treatment burden of a low volume, infrequent, subcutaneous (SC) administration. The similarity of 
pathophysiology and clinical symptoms for HAE attacks between adults and children suggest the involvement of 
plasma kallikrein and bradykinin in both groups of patients. Lanadelumab is expected to provide significant benefit 
to young children suffering from HAE.
Investigational product, dose, and mode of administration:
The proposed dose regimens are shown below, and are based on population PK modeling and simulation, the 
similarity of etiology of HAE between adult, adolescent, and pediatric subjects with HAE, and body weight 
distribution information on the related age groups. Dosing regimen will be determined based on a subject’s age on 
the date of informed consent, and subjects will remain in the same age category throughout the study.

6 to <12 years: 150 mg q2wks

2 to <6 years: 150 mg q4wks
Subjects in the 6 to <12 years age group who have been well controlled (eg., attack free) for 26 weeks with 
lanadelumab treatment in this study may switch to a dose of 150 mg q4wks during Treatment Period B at the 
investigator's discretion and following approval by the sponsor's medical monitor. Subjects 2 to <6 years will 
receive lanadelumab 150 mg q4wks in both Treatment Period A and Treatment Period B.
The drug product is a sterile, preservative-free, ready-to-use solution with a lanadelumab concentration of 
150 mg/mL provided in a single-use 2 mL glass vial (150 mg/1 mL). For use in children less than 12 years, the full 1 
mL (150 mg) dose will be withdrawn from the vial and administered to the subject.
Lanadelumab is formulated as liquid for injection and is intended for SC administration in the abdomen, thigh, or 
upper arm. Administration of lanadelumab by a subject (aged 6 years or older) or parent/caregiver (hereafter referred 
to as self-administration) is allowed after the subject (aged 6 years or older) or parent/caregiver has received 
appropriate training by the investigator or designee and their understanding is confirmed. Subjects (aged 6 years or 
older) or parents/caregivers may initiate self-administration after the subject has received the first 2 doses of 
lanadelumab at the study site and may continue to self-administer all subsequent doses. Note: Subjects less than 6 
years of age must have a parent/caregiver self-administer lanadelumab. Self-administration of lanadelumab by the 
subject is only permitted for those aged 6 years or older and who have demonstrated the necessary skills for self-
treatment, as assessed the investigator.
Methodology:
This study targets to enroll at least 20 pediatric subjects (2 to <12 years of age; at least 5 subjects in each age group 
of 2 to <9 years of age and 9 to <12 years of age) to ensure that a minimum of 15 subjects complete 1 year (52 
weeks) of treatment on the study. All subjects must have a diagnosis of HAE (Type I or II) with a history of ≥1.0 
angioedema attacks per 3 months (12 weeks). Subjects meeting all eligibility criteria will be enrolled and enter the 
observation period for up to 12 weeks; all subjects must discontinue long-term prophylaxis (LTP) before entering 
the observation period. The attack rate in the observation period will serve as the baseline for the study. Subjects 
who experience ≥1.0 angioedema attacks per 3 months during the 12-week baseline observation period and who 
remain eligible per study criteria will enter the lanadelumab treatment period for 52 weeks. Subjects must stay in the 
observation period for a minimum of 4 weeks except for those subjects who report more than 2 HAE attacks 
(confirmed by the investigator and agreed with the sponsor’s medical monitor) within the first 2 weeks of the 
observation period. Subjects may exit the observation period after reporting 1 investigator-confirmed attack after 
4 weeks in the observation period; subjects will then enter the treatment period.
The 52-week treatment period will comprise a 26-week Treatment Period A and a 26-week Treatment Period B. 
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Subjects who complete Treatment Period A will immediately continue into Treatment Period B. Subjects 6 to <12 
years will receive lanadelumab 150 mg q2wks in Treatment Period A and may remain on the same dose regimen in 
Treatment B or, if the subject has been well controlled (eg, attack free) for 26 weeks with lanadelumab treatment in 
this study, the subject may switch to a dose of 150 mg q4wks at the discretion of the investigator and following 
approval by the sponsor’s medical monitor. Subjects 2 to <6 years will receive lanadelumab 150 mg q4wks in both 
Treatment Period A and Treatment Period B.
Acute HAE attacks during the treatment period will be managed in accordance with the investigator’s usual care of 
their patients, including use of individualized acute therapy that the investigator deems medically appropriate. 
C1-INH will be permitted as an acute attack therapy but not as a long-term prophylactic therapy during the study. 
After 5 subjects receive at least 5 doses of lanadelumab, an interim PK analysis will be conducted to evaluate the 
proposed dose regimens using available data for this study.
Individual subject participation from screening through the completion of safety follow-up visit will be 
approximately 72 weeks (see below for duration of each study period).
Inclusion and Exclusion Criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the criteria below.
1.
Be a child (male or female) 2 to <12 years of age at the time of signing the informed consent form (screening).
2.
Documented diagnosis of HAE (Type I or II) based upon both of the following:

Documented clinical history consistent with HAE (SC or mucosal, nonpruritic swelling episodes without 
accompanying urticaria);

Diagnostic testing results obtained during screening from a sponsor-approved central laboratory that 
confirm C1 esterase inhibitor (C1-INH) functional level <40% of the normal level. Subjects with functional 
C1-INH level 40-50% of the normal level may be enrolled if they also have a C4 level below the normal 
range. With prior sponsor approval, subjects may be retested during the baseline observation period if 
results are incongruent with clinical history or believed by the investigator to be confounded by recent C1 
inhibitor use.
3.
A historical baseline HAE attack rate of at least 1 attack per 3 months. Note: In addition, subjects who 
experience ≥1.0 angioedema attacks per three months during the 12-week baseline observation period and who 
remain eligible per the inclusion criteria will enter the lanadelumab treatment period.
4.
Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
5.
Have a parent(s)/legal guardian who is informed of the nature of the study and can provide written informed 
consent for the child to participate in the study before any study-specific procedures are performed (with assent 
from the child when appropriate).
6.
Females of childbearing potential must agree to be abstinent or agree to comply with the applicable 
contraceptive requirements of this protocol through the duration of the study from screening through 70 days 
after the final study visit.
Exclusion Criteria:
The subject will be excluded from the study if any of the following exclusion criteria are met. 
1.
Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE), 
HAE with normal C1-INH, idiopathic angioedema, or recurrent angioedema associated with urticaria.
2.
Dosing with an investigational drug or exposure to an investigational device within 4 weeks prior to screening.
3.
Be pregnant or breastfeeding. 
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4.
Have initiated androgen treatment (eg, stanozolol, danazol, oxandrolone, methyltestosterone, and testosterone) 
within 2 weeks prior to entering the observation period.
5.
Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with 
systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to 
screening.
6.
Have any active infectious illness or fever defined as an oral temperature >38°C (100.4°F), tympanic >38.5°C 
(101.3°F), axillary >38°C (100.4°F), or rectal/core >38.5°C (101.3°F) within 24 hours prior to the first dose of 
study drug in Treatment Period A.
7.
Have any HAE attack that is not resolved prior to the first dose of study drug in Treatment Period A.
8.
Have any of the following liver function test abnormalities: alanine aminotransferase (ALT) >3x upper limit of 
normal, or aspartate aminotransferase (AST) >3x upper limit of normal, or total bilirubin >2x upper limit of 
normal (unless the bilirubin elevation is a result of Gilbert’s syndrome).
9.
Have any condition (any surgical or medical condition) that, in the opinion of the investigator or sponsor, may 
compromise their safety or compliance, preclude the successful conduct of the study, or interfere with 
interpretation of the results (eg, significant pre-existing illness or other major comorbidity that the investigator 
considers may confound the interpretation of study results).
10. Subject has a known hypersensitivity to the investigational product or its components.
Maximum duration of subject participation in the study:

Planned duration of screening period: up to 4 weeks.
o
Planned duration of enrollment period: up to 4 weeks, including the screening period and baseline 
observation period. An enrolled subject will have met the inclusion/exclusion criteria to participate in 
the trial and will have signed an informed consent form.

Planned duration of baseline observation period: up to 12 weeks. The baseline observation period will be at 
least 4 weeks except for those subjects who report more than 2 HAE attacks (confirmed by the investigator and 
agreed with the sponsor’s medical monitor) within the first 2 weeks of the observation period.

Planned duration of treatment period: 52 weeks

Planned duration of follow-up period: 4 weeks
Statistical analysis:
Primary Analyses
Safety
Assessment of safety is a primary endpoint for the study. The safety measures will include:

Adverse events (AEs) including serious adverse events (SAEs) and adverse events of special interest (AESI).

Clinical laboratory testing (hematology, clinical chemistry, coagulation)

Vital signs including blood pressure, heart rate, body temperature, and respiratory rate.
Pharmacokinetics
Assessment of PK is a primary endpoint for the study. The PK endpoints include:

Plasma concentrations of lanadelumab over the treatment period.

PK parameters in plasma, by age group, will be estimated by a population modelling and simulation approach 
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and reported separately:
o
Cmax,ss: Maximum observed concentration at steady state
o
Cavg,ss: Average concentration over dosing interval at steady state
o
Ctrough,ss: Predose concentration at steady state
o
tmax: Time to reach Cmax in plasma
o
AUCtau,ss: Area under the concentration-time curve over the dosing interval at steady state
o
t½: Terminal half-life
o
CL/F: Apparent clearance
o
V/F: Apparent volume of distribution
Secondary Analyses
Clinical Outcomes
Clinical outcome measures are secondary endpoints for the study. Clinical outcome measures will be based on 
5 efficacy evaluation periods: the overall treatment period (Day 0 through Day 364), Treatment Period A (Day 0 
through Day 182), Treatment Period B (Day 183 through Day 364), an overall presumed steady state period (Day 70 
through Day 364), and the presumed steady state period for Treatment Period A (Day 70 through Day 182).
The primary clinical outcome endpoint will be the normalized number of investigator-confirmed HAE attacks for 
the overall treatment period. 
The other clinical outcome endpoints are as follows:

Normalized number of investigator-confirmed HAE attacks for each efficacy evaluation period other than the 
overall treatment period.

Time to the first attack, ie, duration that a subject is attack-free until their first attack for each efficacy 
evaluation period.

Normalized number of investigator-confirmed HAE attacks requiring acute therapy use for each efficacy 
evaluation period. 

Normalized number of moderate or severe investigator-confirmed HAE attacks for each efficacy evaluation 
period.

Normalized number of high morbidity investigator-confirmed HAE attacks for each efficacy evaluation period.

Characteristics of investigator-confirmed HAE attacks for each efficacy evaluation period, including duration, 
severity, attack location, and rescue medication use. 

Achievement of attack-free status for each efficacy evaluation period.
Pharmacodynamics
The following PD measure is the secondary endpoint for the study:

Plasma kallikrein activity (as measured by cHMWK level).
Immunogenicity 
Immunogenicity as measured by presence or absence of neutralizing or non-neutralizing anti-drug antibody (ADA) 
in plasma is a secondary endpoint for the study.
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Sample Size 
The sample size for the proposed pediatric study is driven by feasibility considerations as enrollment of pediatric 
patients 2 to <12 years old is expected to be difficult. Statistical analyses will be descriptive in nature. The primary 
emphasis will be to assess the safety and PK of lanadelumab in this age group, but also to generate data on clinical 
outcomes if subjects have sufficient baseline attack frequency for evaluation. 
At least 20 subjects will be enrolled (including at least 5 subjects in each age group of 2 to <9 years of age and 9 to 
<12 years of age) to ensure a minimum of 15 subjects complete 1 year (52 weeks) of treatment on the study. Given 
the limited number of pediatric subjects with HAE who will fall within this age category and have a history of 
angioedema attacks appropriate to meet study inclusion criteria (Caballero, 2013), this number is considered a 
reasonable target at study initiation with respect to the ability to enroll eligible subjects.
Statistical Methodology
Clinical Outcomes
The analysis of clinical outcomes will be conducted using the Safety Analysis Set, which is defined as all subjects 
who received any study drug. Data will be summarized by dose group and overall during each treatment period, 
partitioned by dose regimen for subjects with dose modifications. This study is not designed for statistical 
hypothesis testing, and given the small sample size and the primary study objective (PK and safety), only descriptive 
analysis will be done, and the following will apply:

Continuous clinical outcome endpoints (eg, HAE attack rates) will be analyzed using descriptive statistics 
including number of subjects, mean, standard deviation (SD), median, minimum, and maximum. Whenever 
appropriate, clinical outcome endpoints will be summarized for the observation period, each efficacy evaluation 
period, and each efficacy evaluation period change from observation period by treatment. The baseline is 
defined as the last non-missing value prior to initial dose of study drug.

Categorical clinical outcome endpoints (eg, attack severity) will be summarized by the number of subjects in 
each category and the percentage of subjects out of the total in the respective analysis set.

Time-to-event endpoint (eg, time to the first HAE attack) will be analyzed using Kaplan-Meier estimates. 
Summaries will include median time and quartiles, if estimable, and corresponding 95% confidence intervals.
Safety
Safety endpoints will be analyzed based on the Safety Analysis Set, which is defined as all subjects who received 
any study drug. Data will be summarized by dose group and treatment period, partitioned by dose regimen for 
subjects with dose modifications.

Continuous endpoints (eg, change in laboratory parameters) will be summarized using number of subjects (n), 
mean, SD, median, minimum value, and maximum value. As appropriate, raw (actual) values, changes from 
baseline, and percent changes from baseline will be summarized overall and at each scheduled time point. 

Categorical endpoints (eg, presence or absence of an outcome measure) will be summarized using counts and 
percentages. Summaries will include but are not limited to: number and percentage of subjects with an outcome 
measure and laboratory shift tables (categorical change from baseline). 

Only treatment emergent AEs (TEAEs) will be analyzed. The number and percentage of subjects reporting any 
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TEAEs, SAEs, and TEAEs related to the investigational product, TEAEs leading to withdrawal, severe TEAEs 
and absolute count of events will be summarized by treatment group, overall and by preferred term and system 
organ class. 

All AEs (TEAEs and non-TEAEs) will be provided in the AE subject listing.  All safety data, including derived 
data, will be presented in subject data listings.

Clinical laboratory tests and vital signs will be summarized by treatment group and visit. Potentially clinically 
important findings will also be summarized or listed
Pharmacokinetics/Pharmacodynamics
A descriptive summary analysis will be performed for plasma concentrations of lanadelumab, as appropriate, using 
nominal time points. 
A descriptive summary analysis will be performed for cHMWK levels, 
, as appropriate, using 
nominal time points. 
The PK and PD properties of lanadelumab (including PK parameters, cHMWK, 
, and 
 
 as appropriate) will be evaluated by a population modeling and a simulation approach using data from 
this study and from all other studies in the lanadelumab clinical development program. A separate clinical 
pharmacology statistical analysis plan will support the population PK and PD analysis and the analysis results will 
be reported separately.  
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1.2
Schema
Figure 1:
Study Design
*An individual subject’s dose frequency may be modified based on a benefit-risk assessment and recommendation from the treating physician. Consultation with and approval by 
the sponsor's medical monitor is required. For example, subjects 6 to <12 years of age may administer lanadelumab 150 mg q4wks in Treatment Period B at the investigator’s 
discretion and sponsor’s medical monitor approval, if they are well controlled (eg, attack free) for 26 weeks with lanadelumab treatment in this study.
Note: An interim clinical study report summarizing data up to Treatment Period A and a final clinical study report summarizing data from the entire study duration will be 
prepared.
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1.3
Schedule of Activities
Table 1:
Schedule of Activities- Screening and Baseline Observation Period
Procedures
Screeninga
(up to 4 
weeks)
End of 
Screening 
Site 
Contacta
BASELINE OBSERVATION PERIOD (by week; up to 12 weeks)b
See protocol 
section below 
for details 
1
2
3
4
5
6
7
8
9
10
11
12
Informed consent (written 
permission and assent)
X
Section 8.2.1
Demographics, medical history, 
and HAE history
X
Section 8.2.3
Eligibility review 
X
Section 8.1.1
Discontinue long-term 
prophylactic therapya
X
Section 8.1.1
Telephone contactc
X
X
X
X
X
X
Vital signsd
X
Section 8.2.5.2
Physical examinatione
X
Section 8.2.5.1
Tanner stagingf
X
Section 8.2.5.1
Hematology, serum chemistry, 
and coagulation tests
X
Section 8.2.5.4
Virology testing: HBsAg, HCV, 
and HIV (serologies)g
X
Section 8.2.5.4
C1-INH, C1q, and C4 testingh
X
Section 8.2.6.4
Within 24 hours after the onset of symptoms of an HAE attack, if applicable
Section 8.2.6.5
HAE attack data
(subject HAE attack diary and 
site monitoring)i
X----------------------------------------------------------------------------------------------------------X
Appendix 5
Prior/current medications, 
therapies, and proceduresj
X
X----------------------------------------------------------------------------------------------------------X
Section 6.6
Adverse events/serious adverse 
events
X
X----------------------------------------------------------------------------------------------------------X
Sections 8.2.5.5, 
8.2.5.6
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Table 1:
Schedule of Activities- Screening and Baseline Observation Period
Procedures
Screeninga
(up to 4 
weeks)
End of 
Screening 
Site 
Contacta
BASELINE OBSERVATION PERIOD (by week; up to 12 weeks)b
See protocol 
section below 
for details 
1
2
3
4
5
6
7
8
9
10
11
12
C1-INH=C1 esterase inhibitor; HAE=hereditary angioedema; HbsAg = Hepatitis B Surface Antigen; HCV=Hepatitis C Virus; HIV=Human Immunodeficiency Virus
a Subjects should complete all screening procedures within 4 weeks. After confirming that a subject meets all eligibility criteria, the site will contact the subject and 
parent/caregiver to notify them of study eligibility. The site will instruct that the subject must discontinue long-term prophylactic therapy (if applicable) prior to the baseline 
observation period and begin the HAE attack diary on the first day of the baseline observation period.
b Subjects must stay in the observation period for at least 4 weeks except for those subjects who report more than 2 HAE attacks within the first 2 weeks that are confirmed by the 
investigator and agreed with the sponsor’s medical monitor. Subjects may exit the observation period after reporting 1 investigator confirmed attack after 4 weeks in the 
observation period; subjects will then enter the treatment period. 
c Study personnel will contact the parent/caregiver on Weeks 2, 4, 6, 8, 10, and 12 to discuss study compliance (ie, completion of the diary) and to evaluate the subject’s HAE 
attacks and other adverse events that may have occurred since the last contact. The preferred method of site contact is a telephone call; however, an alternate method of contact 
may be considered as site policies permit. Site contacts will be documented in the source notes at the clinical site.
d Vital signs, including sitting or supine blood pressure (BP), heart rate (HR), body temperature, and respiratory rate (RR).
e Complete physical examination, including height and body weight. Tanner staging may also be required for premenarchal female subjects (see footnote f).
f Tanner staging will be required at screening for female subjects who are premenarchal and ≥9 years of age, to confirm that contraception is not required during the study 
(Section 5.4.1).
g HIV (Inno-Lia) and hepatitis (hepatitis B surface antigen, hepatitis C antibody) will be tested only at the screening visit.
h C1-INH, C1q, and C4 testing is required at screening from the sponsor-approved central laboratory.
i During the baseline observation period, parents/caregivers will use a diary to daily record the subject’s symptoms or occurrences of HAE attacks, and any medications taken for 
the management of these attacks. HAE attacks will be monitored daily and recorded as they occur.  Parents/caregivers will also be instructed to notify and report details of an 
attack to the study site within 72 hours of the onset of an HAE attack, in accordance with HAARP (Appendix 5).
j Includes medications, therapies, and procedures administered/occurring prior to the first dose of lanadelumab.
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2.
INTRODUCTION
2.1
Disease Etiology and Pathophysiology
Hereditary angioedema (HAE) is a serious, severely debilitating, and life-threatening condition 
caused by mutations in the C1 inhibitor (also known as C1 esterase inhibitor [C1-INH]) 
SERPING1 gene (Tosi, 1998), leading to the heterozygous deficiency (Type I HAE) or 
dysfunction (Type II HAE) of C1-INH plasma protein (Zuraw et al., 2013) and results in a 
dysregulated plasma kallikrein-kinin pathway. Dysregulated pKal is recognized as the key 
pathophysiologic defect responsible for the development of angioedema attacks in patients with 
HAE (Zuraw and Christiansen, 2016). The critical components of the plasma kallikrein-kinin 
pathway (or contact system) consists of 3 essential proteins: coagulation factor XII (Hageman 
factor), prekallikrein (Fletcher factor), and high molecular weight kininogen (HMWK, Fitzgerald 
factor). Factor XII autoactivation initiates a cascade of events leading to pKal generation from 
prekallikrein (Figure 2). Plasma kallikrein, in turn, acts on HMWK to generate cleaved HMWK 
(cHMWK) and release bradykinin, a potent vasodilator. Bradykinin binds to the B2 receptor on 
endothelial cells, causing vascular permeability and resultant tissue edema recognized as 
swelling (Leeb-Lundberg et al., 2005). Normal levels of C1 inhibitor regulate the activity of 
pKal as well as a variety of other proteases, including C1r, C1s, factor XIa, and factor XIIa. In 
patients with Types I and II HAE, C1-INH levels are insufficient for the regulation of pKal 
activity, which leads to pathologic levels of bradykinin and results in bradykinin-mediated 
angioedema (Davis, 2005). 
HAE manifests clinically as unpredictable, intermittent attacks of subcutaneous (SC) or 
submucosal edema of the face, upper airway (larynx), gastrointestinal tract, limbs and/or 
genitalia (Zuraw, 2008; Zuraw et al., 2013). Frequency of recurrences varies between patients 
and within the same patient. Swelling may last up to 5 or more days; patients can range from 
asymptomatic to suffering 3 attacks per week. Mortality related to upper airway attacks is 
significant at 30% and is considerably higher (almost 3-fold to 9-fold) in patients who remain 
undiagnosed (Bork et al., 2012). Triggers of angioedema attacks in patients with HAE can 
include stress, physical trauma, medical or dental procedures, and estrogen exposure, although 
most attacks appear to occur spontaneously (Bork, 2014a;Bork, 2014b).
HAE affects all ethnic populations, adults and children, and both genders (Nzeako et al., 2001). 
Symptoms often begin in childhood and typically worsen during puberty. The unpredictability of 
attacks results in significant decrements in vocational and school achievement (Caballero et al., 
2014). Additionally, due to the chronic, recurrent nature of HAE attacks and the ever present risk 
of death from asphyxiation, HAE considerably affects patient quality of life (Caballero et al., 
2014; Fouche et al., 2014a; Lumry et al., 2014;Fouche et al., 2014b).
There is no evidence that there are significant differences in HAE etiology and pathophysiology 
based on age and, overall, clinical aspects of pediatric and adult HAE are quite similar. However, 
frequency and severity of attacks are variable amongst individuals, and some differences have 
been noticed between pediatric and adult populations. Children appear to have less frequent and 
less severe symptoms than adults or adolescents and life-threatening attacks are less common in 
the pediatric population than in adults (Read et al., 2014). 
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Although the genetic defect (SERPING1 gene mutation) of HAE Type I and II is present at birth, 
symptoms are uncommon during neonatal age or infancy. The symptoms may occur at any age, 
but usually begin in childhood or adolescence (World Allergy Organization [WAO]/European 
Academy of Allergy and Clinical Immunology [EAACI] guidelines-2017 revision and update; 
(Maurer et al., 2018). 
Several studies examined the natural history of HAE in children. Reported median age of first 
symptom onset varies in the literature. While these studies have been based on small sample 
sizes, they demonstrate the rarity of HAE symptoms among children younger than 6 years of 
age. It has been acknowledged that while angioedema episodes may occur at any age, they 
usually begin between 5 and 11 years of age (Farkas, 2010). Per the WAO/EAACI guidelines 
revised in 2017, the median age of symptom onset is approximately 12 years of age. 
Subcutaneous edema is the most common earliest symptom. However, abdominal symptoms 
may be unrecognized and often misdiagnosed in infants with Type 1 or II HAE. Asphyxia may 
ensue rapidly in children, and earliest occurrence was described in one 4-week old boy (Maurer 
et al., 2018). Erythema marginatum as a prodromal sign is more frequent in the pediatric 
population. The frequency and severity of symptoms may increase during puberty and 
adolescence (Maurer et al., 2018), possibly because endocrine factors seem to have a great 
impact on the manifestation of the disease (Frank et al., 1976). Bork et al. reported that 90% of 
patients had symptom onset before age 20 (Bork et al., 2006a). Very few cases of HAE attacks 
have been reported in children younger than 3 years of age (Bygum et al., 2011;El-Hachem et al., 
2005; Nanda et al., 2015; Roche et al., 2005). 
2.2
Disease Diagnosis in the Pediatric Population 
Diagnosis of HAE is difficult, particularly challenging in children, and often delayed. It is often 
misdiagnosed or diagnosed several years after the initial attack because of its rarity and the 
potential lack of family history due to spontaneous mutations (Agostoni and Cicardi, 1992;Roche 
et al., 2005). With autosomal dominant inheritance, the offspring of a patient with HAE I or II 
stands a 50% chance of inheriting the disease. Therefore, it is important to establish the diagnosis 
as early as possible (WAO/EAACI guidelines-2017 revision and update; Maurer et al., 2018). As 
HAE shares similar symptoms with "allergic" conditions, misdiagnosis is frequent. Delay is 
often reduced when patients present family history of swelling (Read et al., 2014). The WAO 
guidelines recommend testing children from HAE-affected families as soon as possible and all 
offspring of an affected parent be tested (Maurer et al., 2018).
Some of the reasons that could explain the difficulty in diagnosing HAE are detailed as follows:

Normal reference ranges for C1-INH concentrations and activity have not been 
established for children under 1 year of age (Gompels et al., 2005b;Gompels et al., 
2005a).

Testing for C1-INH level and activity conducted prior to 1 year of age should be repeated 
after age 1 (Bowen et al., 2008) because the complement and kallikrein/kinin systems do 
not reach adult maturity levels until later (from 6 to 36 months; Davis et al., 1979;Nielsen 
et al., 1994). 
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
The prevalence of patients who have symptoms of HAE, and especially HAE attacks, is 
extremely low in the pediatric population under 6 years of age, as median age for first 
symptom onset reported from large studies is generally higher than 6 years of age (Bork 
et al., 2006a;Bygum et al., 2011;Farkas, 2010;Roche et al., 2005).

In many cases there is a lack of family history that would otherwise have aided in 
diagnosis of the disease. 

Up to 25% of HAE cases are due to new or spontaneous mutations (Agostoni and 
Cicardi, 1992;Zuraw, 2008;Pappalardo et al., 2000). 

Abdominal attacks are particularly difficult to diagnose in children and can be confused 
with acute abdominal emergencies and other abdominal events, such as appendicitis or 
intussusception (Agostoni and Cicardi, 1992).
Patients who present with HAE symptoms need laboratory tests to confirm HAE diagnosis. 
Measurements of C1-INH antigen (protein), C1-INH functional (activity) level, and C4 level are 
advisable in all children with angioedema without urticaria (WAO/EAACI guideline for the 
management of HAE- 2017 revision and update; Maurer et al., 2018). In practice, it is common 
to test C1-INH function levels initially, establishing HAE directly, in order to avoid, for 
example, problematic repeated blood draws in children.
2.3
Epidemiology in the Pediatric Population
Hereditary angioedema is an orphan disorder and its exact prevalence is unknown, but current 
estimates range from 1 per 10,000 to 1 per 50,000 persons (Bygum, 2009; Goring et al., 1998; 
Lei et al., 2011; Lumry, 2013; Nordenfelt et al., 2014; Roche et al., 2005). Although genetically 
present at birth, the disease may be clinically observable only many years later. In addition, 
variability of presentation and difficulty in diagnosis of the disease often lead to delayed 
recognition of the disorder. This, in turn, translates to difficulty in estimating the prevalence of 
symptomatic HAE, especially in the pediatric population, with any degree of certainty.
Attempts to estimate the prevalence of HAE attacks in pediatric patients can be made from case 
series and case reports of adult patients who report the age at which they first had symptoms or 
severe attacks. It is acknowledged that age of onset may be biased because the accuracy is 
wholly dependent upon the patient’s recollection. Patients tend to remember their attacks of 
severe laryngeal edema more readily than their intestinal, skin or extremity edema episodes 
(Bork et al., 2006a; Bork et al., 2006b)
Epidemiological studies of HAE that provide information on pediatric patients report that this 
population includes approximately 10% to 28% of the total HAE patient population, although 
some of these pediatric patients were asymptomatic at the time of the report (Agostoni et al., 
2004; Bygum, 2009; Farkas et al., 2002; Jolles et al., 2014; Nordenfelt et al., 2014; Stray-
Pedersen et al., 2017). For example, based on the available information, it can be estimated that 
pediatric patients in the United States represent approximately 22.8% of the overall HAE patient 
population. This corresponds to a prevalence of 0.24 per 10,000 persons <18 years of age, or an 
estimated 1766 to 1798 pediatric patients (diagnosed and undiagnosed) with HAE in the United 
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States. Similarly, if we examine the pediatric population ≤12 years of age in the United States, 
then we have an estimated 1268-1286 patients (diagnosed and undiagnosed) with HAE, thus 
translating to an HAE prevalence of 0.24 per 10,000 persons ≤12 years of age in the United 
States. Based on the available information, it can be estimated that pediatric patients represent 
approximately 20% of the overall HAE patient population, which would correspond to <5,124 
total pediatric patients in the European Union based on the overall prevalence of less than 0.5 per 
10,000 persons (ie, <25,619 total HAE patients in the European Union, plus Iceland, 
Liechtenstein, and Norway, based on overall European population of 512,384,164 inhabitants on 
01 Jan 2014 [EUROSTAT, 2015]) identified in the orphan drug designation in the EU for 
lanadelumab (EU/3/15/1551). Overall, the prevalence of patients who have HAE attacks is 
extremely low in the pediatric population under 6 years of age, as the median age for first 
symptom onset reported from large studies is generally higher than 6 years of age (Bork et al., 
2006a; Bygum et al., 2011; Farkas, 2010; Roche et al., 2005).
2.4
Indication and Current Treatment Options 
Management of HAE has evolved over the last 10 years from underdiagnosed disability and 
higher risk of death from asphyxiation if undiagnosed, towards self-administration and 
independence from inpatient treatment. Effective management of HAE, including optimization 
of therapy, may reduce the clinical burden and have an overall favorable impact on the quality of 
life for individual HAE patients and their families (Banerji, 2013; Caballero et al., 2014). HAE 
International treatment guidelines state that the goal of prophylactic treatment is to reduce the 
frequency and severity of attacks and thus to increase patients’ quality of life (Cicardi et al., 
2012;Craig et al., 2012b). Current prophylactic options for HAE have improved the lives of HAE 
patients, but have significant limitations (Longhurst, 2017). The treatment guidelines recommend 
C1-INH or attenuated androgens as the standard of care over antifibrinolytic agents (Cicardi et 
al., 2012;Craig et al., 2012b). The most recent WAO & EAACI guidelines recommend C1-INH 
as first-line long-term prophylactic therapy (androgens as second-line). Antifibrinolytics are not 
recommended due to the lack of efficacy in long-term prophylaxis (LTP) (Maurer et al., 2018). 
Given the serious morbidity and mortality associated with HAE, including a 50% lifetime chance 
of experiencing a life-threatening laryngeal attack (Bork et al., 2003; Bork et al., 2006a), 
improved prophylactic treatments are needed for patients with HAE.
A patient with HAE, regardless of age, is a candidate for a prophylactic regimen if a number of 
criteria are met which may include: events in life that are associated with increased disease 
activity, attack frequency or severity, history of laryngeal attacks, impact on quality of life 
including work and school performance, proximity to emergency care, physiological or 
psychological stress, etc. (Craig et al., 2009; Maurer et al., 2018). Like adults, children with 
HAE can suffer from recurrent and debilitating attacks. Symptoms may present very early in 
childhood, and upper airway angioedema has been reported in patients with HAE as young as the 
age of 3 years (Bork et al., 2003), and an earliest occurrence described in one 4-week old boy 
(Maurer et al., 2018). There is an unmet medical need for safe, effective and convenient 
prophylactic therapies for children <12 years of age with HAE (Craig et al., 2012a). Treatments 
available for adult HAE patients have been evaluated in a limited number of children (Frank et 
al., 2016). In the European Union (EU), few treatments are approved for use in pediatric patients 
under the age of 12 years: Firazyr (icatibant) for acute attacks in only; Berinert (C1 esterase 
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inhibitor [human]) for acute attacks and pre-procedure prevention for patients under 12 years of 
age, and Cinryze (C1 esterase inhibitor [human]), for acute treatment and pre-procedure 
prevention for patients at 2-17 years of age and for prevention of attacks for patients at 6-17 
years of age with intravenous (IV) administration twice a week. In the United States, IV Berinert 
is available for acute treatment for children under the age of 12, and Cinryze has recently been 
approved for routine prophylaxis for children 6 to <12 years of age with IV administration twice 
a week. An unmet medical need still exists, especially for an effective and more convenient (eg, 
no venous access required or less frequent administration) prophylactic treatment for HAE in 
children <12 years of age. 
Lanadelumab, a first-in-class monoclonal antibody inhibitor of active plasma kallikrein, may 
provide significant benefit to patients across age ranges, based on the results of a 26-week 
prevention study in adolescents and adults with HAE. Lanadelumab has a convenient dosing 
schedule with a recommended starting dose of 300 mg every 2 weeks (q2wks) and a dosing 
interval of every 4 weeks (q4wks) if the patient is well controlled or stably attack free (eg, for 
more than 6 months) in adolescent and adults; a similar a convenient dosing interval of q2wks or 
q4wks has been proposed for the pediatric population in this study as well. In addition, 
lanadelumab has a favorable route of administration (SC) and demonstrated efficacy in 
preventing HAE attacks, achieving a high proportion of patients being attack free while 
improving health related quality of life (HRQoL). 
The targeted indication of lanadelumab (SHP643, DX-2930) is for prophylaxis to prevent attacks 
of HAE in patients aged 12 years and older. 
Refer to the latest version of the lanadelumab investigator’s brochure [IB] for details. 
2.5
Product Background and Clinical Information
2.5.1
Drug Information
Mechanism of Action
Lanadelumab is a fully human, immunoglobulin G1 (IgG1) kappa light chain monoclonal 
antibody expressed in Chinese hamster ovary (CHO) cells. It is a potent (inhibition 
constant=125 pM) and specific inhibitor of active plasma kallikrein (pKal) activity that binds 
both soluble and membrane-bound forms of the enzyme (Kenniston et al., 2014). Lanadelumab 
was designed to specifically bind active pKal as opposed to prekallikrein, the zymogen form of 
the enzyme mainly present in plasma. This specificity of lanadelumab for active pKal indicates 
that the main form of the antibody in the circulation is free to inhibit the excess amount of pKal 
generated during an attack enabling near normal levels of enzyme activity prior to reversible 
inhibition by the antibody. Nonclinical data demonstrates that the specific inhibition of pKal by 
lanadelumab prevents the release of bradykinin from HMWK. Inhibition of bradykinin 
generation prevents the vascular leak and swelling during an angioedema attack initiated when 
bradykinin binds to the B2 receptor (Figure 1). The pharmacokinetic (PK) properties of 
lanadelumab offer the potential for a long-acting and sustained therapeutic effect (administration 
q2wks or q4wks) through the control of pKal activity, limiting both contact system activation as 
well as the generation of bradykinin in patients with HAE. 
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Figure 2:
Lanadelumab Specifically Inhibits Plasma Kallikrein (pKal)
The kallikrein-kinin system (KKS or contact system) is initiated by the autoactivation of the Factor XII zymogen to XIIa 
following contact with a negatively charged surface (1), leading to the conversion of prekallikrein to active pKal (2), which
cleaves HWMK to generate cleaved HMWK (2-chain or cleaved HMWK) and bradykinin (3). In addition, pKal will activate 
more FXII (dotted arrow) and FXIIa can initiate coagulation via the intrinsic pathway (dashed arrow). Bradykinin binds and 
activates the bradykinin B2 receptor (4) and following plasma exoprotease generation of des-Arg9 bradykinin (5), the bradykinin 
B1 receptor. The KKS is dysregulated in HAE patients that are deficient in C1-INH (6), an endogenous inhibitor of active pKal 
and FXIIa. Lanadelumab (7) is a potent and specific, fully human antibody inhibitor of pKal engineered to restore normalized 
pKal regulation in HAE due to C1-INH through the lack of binding to prekallikrein, which is expected to permit low levels of 
pKal activity prior to being reversibly inhibited (Adapted from Kenniston et al., 2014). 
Dosage Form 
The drug product is a sterile, preservative-free, ready-to-use solution with a lanadelumab 
concentration of 150 mg/mL provided in a single-use 2 mL glass vial (150 mg/1 mL).
For use in children less than 12 years, the same formulation and presentation used for 
adolescents and adults aged 12 years and above are planned. The proposed presentation is a 
solution in vial (150 mg/mL) where the full 1 mL (150 mg) dose will be withdrawn from the vial 
and administered to the subject. 
Route of Administration
Lanadelumab is formulated as a liquid for injection and is intended for SC administration in the 
abdomen, thigh, or upper arm.
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2.5.2
Nonclinical Studies with Lanadelumab
The completed nonclinical safety studies evaluating SC administration of lanadelumab for up to 
6 months in cynomolgus monkeys adequately support the pediatric patient population ages ≥2 to 
<12 years (refer to the latest version of the lanadelumab IB).
The nonclinical program conducted to date indicated no safety signal or toxicity with SC 
administered lanadelumab at doses of up to and including the highest tested dose (50 mg/kg, 
once weekly) for 6 months in cynomolgus monkeys. At the no-observed-adverse-effect-level 
(NOAEL) in the 6-month cynomolgus monkey study, exposure margins based on maximum 
observed concentration (Cmax) occurring at tmax and area under the drug concentration-time curve 
(AUC) were approximately 22- and 23-fold higher, respectively, than those observed at the 
clinical dosage of 300 mg q2wks (Study DX-2930-03).
The battery of genotoxicity studies routinely conducted for pharmaceuticals is not applicable to 
biotechnology-derived pharmaceuticals and therefore was not conducted. Carcinogenicity studies 
were not conducted. A weight-of-evidence approach indicates a low risk for carcinogenicity in 
humans as lanadelumab is a fully human immunoglobulin molecule that does not target any 
hormonal or cell proliferation pathways; the pharmacologic mechanism of action does not pose 
an increased risk for carcinogenicity, nor is there evidence from any of the preclinical studies for 
an increased risk of hyperplasia, preneoplasia, or neoplastic lesions. 
Nonclinical juvenile toxicology studies were not performed. However, the range of ages of 
cynomolgus monkeys used in the completed repeat-dose toxicity studies correspond to 
juvenile/adolescents to adults in human (Baldrick, 2010; Morford et al., 2011). Furthermore, no 
effects on development parameters were noted in an enhanced pre-and post-natal development 
(ePPND) study conducted in cynomolgus monkeys. In the ePPND study in pregnant cynomolgus 
monkeys administered once weekly SC doses, there were no lanadelumab-related effects on 
pregnancy and parturition or embryo-fetal development. In the infants maintained for 3 months 
post-partum, exposure to lanadelumab was dose-proportional to maternal dose and no 
lanadelumab-related defects on survival, growth, and/or postnatal development were noted. It is 
expected that the exposure of infants to lanadelumab during the fetal period and during the first 3 
to 6 months of postnatal life covers many critical periods relevant to human development (Martin 
and Weinbauer, 2010). Since no specific target organ toxicity or toxicity relevant for developing 
organ systems was observed in cynomolgus monkeys administered lanadelumab, no additional 
nonclinical studies are planned to support the administration of lanadelumab in the pediatric 
population in clinical trials. 
2.5.3
Clinical Studies with Lanadelumab
The proposed indication of lanadelumab for routine prophylaxis to prevent attacks of HAE in 
patients 12 years and older is primarily supported by the efficacy results from a double-blind, 
placebo-controlled Phase 3 study (DX-2930-03). Supportive data, including durability of 
response and long-term safety, are provided from the open-label, Phase 3 study (DX-2930-04) 
and the proof of concept, Phase 1b, multiple ascending dose study (DX-2930-02). Prior to 
evaluating lanadelumab in subjects with HAE, a randomized, double-blind, placebo-controlled, 
Phase 1a, single ascending dose study evaluated the safety, tolerability, and PK of a single dose 
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of lanadelumab in healthy adult subjects (DX-2930-01). Refer to the latest version of the 
lanadelumab IB for more details on the outcome from these 4 clinical studies.
Clinical study DX-2930-01 evaluated the safety, tolerability, and PK of a single dose of 
lanadelumab (0.1, 0.3, 1.0, or 3.0 mg/kg) in healthy subjects. The data demonstrated that 
lanadelumab was well tolerated by healthy subjects up to doses of 3.0 mg/kg without evidence of 
dose-limiting toxicity. The PK profile demonstrated linear, dose-dependent exposure with a 
mean half-life of approximately 17 to 21 days across dose groups. The exposure was dose 
proportional and the half-life was consistent across the dose groups.
Clinical study DX-2930-02 evaluated the safety, tolerability, and PK of 2 doses of lanadelumab 
(30, 100, 300, or 400 mg) separated by 14 days in HAE subjects and demonstrated that 
lanadelumab was well tolerated following 2 doses up to 400 mg. There were no deaths, serious 
adverse events (SAEs), discontinuations due to an adverse event (AE), or safety signals 
following lanadelumab treatment. One SAE of pneumonia was reported in a placebo-treated 
subject. Two subjects treated with lanadelumab tested positive for anti-drug antibodies (ADAs), 
which were not classified as neutralizing. The PK profile of lanadelumab is consistent and 
predictable, with a half-life of approximately 14 days in HAE subjects. Pharmacodynamic (PD) 
activity of lanadelumab was associated with plasma drug levels. Doses of 300 and 400 mg 
suppressed pKal activity and reduced kininogen cleavage to the levels observed in healthy 
subjects. In a prespecified efficacy analysis, a statistically significant finding of HAE attack 
prevention by lanadelumab was observed. Specifically, in comparison to placebo, attack rate was 
reduced by 100% and 88% in the 300 and 400 mg lanadelumab treatment groups, respectively. 
The effects on HAE attacks were associated with drug exposure. Safety results from the 
multiple-ascending dose study in HAE patients, in conjunction with results from the 
single-ascending dose study in healthy subjects and the current nonclinical data package, 
supported the continued clinical development of lanadelumab in patients with HAE.
Lanadelumab clinical development program has 2 Phase 3 clinical studies in adolescent (≥12 to 
<18 years old) and adult subjects with documented diagnosis of Type I or Type II HAE: the 
completed pivotal, double-blind Study DX-2930-03 and the ongoing open-label extension 
Study DX-2930-04.
Study DX-2930-03 (HELP Study™) was a multicenter, randomized, double-blind, 
placebo-controlled, parallel group efficacy and safety study to evaluate lanadelumab for LTP 
against acute attacks of HAE. Adolescent and adult patients with Type I or Type II HAE who 
experienced at least 1 attack per 4 weeks during the run-in period were included in this study. 
Based on PD bioactivity, PK, safety, and efficacy of lanadelumab from the Phase 1 clinical 
studies and nonclinical studies, the dosing regimens identified for this study were: 300 mg 
q2wks, 300 mg q4wks, and 150 mg q4wks. The 3 proposed dose-regimen combinations provide 
a 6-fold range of steady-state trough concentrations and leverage both the biomarker and efficacy 
data generated in study DX-2930-02. Evaluation of the lanadelumab plasma concentrations at the 
time of attacks reported by lanadelumab-treated subjects in DX-2930-02 suggested that the 3 
planned dosing regimens would provide a meaningful range of clinical response. 
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The primary objective of the study was to evaluate the efficacy of lanadelumab in preventing 
HAE attacks. The secondary objective was evaluation of the safety of repeated SC administration 
of lanadelumab. Each subject underwent a treatment period consisting of 13 doses of blinded 
investigational medicinal product (IMP) for a period of 26 weeks from the date of the first dose 
on Day 0 through 2 weeks after the final dose (for the 150 mg q4wks and 300 mg q4wks 
regimens, every second dose was placebo). Over the 26-week treatment period, all 
3 lanadelumab dose regimens, 150 mg q4wks, 300 mg q4wks, and 300 mg q2wks, resulted in a 
highly statistically significant percentage reduction in the least squares mean investigator-
confirmed HAE attack rate compared with placebo of 76%, 73%, and 87% (adjusted p<0.001), 
respectively, for the primary endpoint. During the estimated steady-state 16-week period (Day 70 
through Day 182), the percentage reduction in the mean monthly HAE attack rates for 
lanadelumab-treated subjects compared with placebo was 78% in the 150 mg q4wks arm, 81% in 
the 300 mg q4wks arm, and 91% in the 300 mg q2wks arm. Furthermore, all 3 lanadelumab 
regimens demonstrated highly statistically significant attack rate reductions compared with 
placebo for all secondary efficacy analyses (adjusted p<.001 for all comparisons): attacks 
requiring acute treatment (74% to 87%), moderate or severe attacks (70% to 83%), and attacks 
from Day 14 through Day 182 (75% to 89%). The mean reduction in HAE attack rate was 
consistently higher across the lanadelumab treatment arms compared with placebo regardless of 
the baseline history of LTP therapy, laryngeal attacks, or attack rate during the run-in period. 
Notably, the magnitude of the treatment effect was consistently the largest across all endpoints in 
the lanadelumab 300 mg q2wks treatment arm compared with the lanadelumab q4wks arms. 
Lanadelumab treatment resulted in a high proportion of subjects being attack free during the 
26-week treatment period and it is notable that once steady state was achieved, especially for the 
300 mg q2wks group, 77% of subjects were attack free for 16 weeks. The evidence of prevention 
of HAE attacks was indicated by sustained decreased frequency of attacks, decreased severity of 
attacks, reduced need for rescue medication (acute treatment), and improved health-related 
quality of life (HRQoL) based on angioedema quality of life (AE-QoL) scores. Lower cleaved 
high molecular weight kininogen (cHMWK) levels corresponded with higher lanadelumab 
plasma concentrations and lower investigator-confirmed HAE attack rate 
(attacks/month/4 weeks), thus corroborating the outcome of the primary efficacy analysis. 
Lanadelumab was generally well tolerated over the 26-week treatment period; no 
treatment-related SAEs or deaths were reported. No discernible dose-response pattern or 
dose-related toxicity was observed for any related treatment-emergent AE (TEAE). Two subjects 
(1 lanadelumab treated and 1 placebo) discontinued the study due to a TEAE. The overall 
incidence of ADA in the pivotal study was 11.9% in lanadelumab-treated subjects and 4.9% in 
placebo-treated subjects. No subject discontinued treatment due to the presence of ADA. All 
ADA-positive samples were of low titer (range: 20-1280), and a few (3.2%; 2 subjects in 
lanadelumab 150 mg q4wks treatment arm) tested positive for antibodies classified as 
neutralizing. The development of ADA including neutralizing antibodies did not appear to 
impact PK, PD, efficacy, or safety profiles.
Study DX-2930-04 (HELP Study ExtensionTM) is an open-label, long-term safety and efficacy 
extension study of DX-2930-03 to evaluate the IMP, lanadelumab, in preventing acute 
angioedema attacks in patients with Type I or Type II HAE. 
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The open-label extension study DX-2930-04 is currently ongoing and has completed enrollment; 
the study enrolled 212 total subjects, including 109 who rolled over from DX-2930-03 and 
103 nonrollover subjects. At the time of the interim analysis based on the data cutoff date of 
31 August 2018, the safety profile in this study was consistent with the pivotal 
Study DX-2930-03 and previous interim analysis (data cutoff date of 01 Sep 2017) for the global 
marketing license or authorization applications for lanadelumab. No treatment-related SAEs or 
deaths were reported. Treatment-emergent AEs for most subjects were mild or moderate in 
severity with few reported severe events considered related to lanadelumab treatment. 
Lanadelumab 300 mg q2wks remained highly effective during this extension study for rollover 
and nonrollover subjects. Efficacy was maintained and shown to be durable with over 12 months 
of lanadelumab exposure across Study DX-2930-03 and Study DX-2930-04 for rollover subjects. 
Improved HRQoL based on AE-QoL scores were observed for rollover and nonrollover subjects. 
In addition, a Phase 1 clinical study, SHP643-101, evaluated the PK properties and the safety of 
lanadelumab administered as a single subcutaneous dose of 300 mg in healthy male and female 
adult volunteer subjects of Japanese descent and matched non-Hispanic, Caucasian healthy male 
and female volunteer subjects. The data indicated that the peak and systemic exposure to 
lanadelumab (Cmax, AUC0-last, and AUC0-∞) in healthy Japanese subjects was similar to that 
observed in healthy Caucasian subjects. Lanadelumab was generally safe and well tolerated by 
both ethnic groups. 
2.5.4
Adolescent Clinical Trial Experience
The Phase 3 clinical studies for lanadelumab, pivotal Study DX-2930-03 and the ongoing open-
label extension Study DX-2930-04, evaluated the adult and adolescent population; inclusion of 
adolescents in these studies was justified based on the similarity of the pathophysiology and 
clinical presentation of HAE in adults and adolescents, as well as by the lack of any safety signal 
identified in nonclinical and clinical studies to date. As of the data cut for the global marketing 
license or authorization application for lanadelumab, the 23 unique adolescent subjects across the 
2 Phase 3 studies received a total of 413 doses of lanadelumab, most of which were 300 mg 
Both Phase 3 studies demonstrated superior efficacy compared to placebo or baseline and 
well-tolerated safety profiles in both adolescent and adult populations. In the pivotal Study 
DX-2930-03, although the number of adolescent subjects was low (150 mg q4wks=1; 300 mg 
q4wks=3; 300 mg q2wks=2, placebo = 4), overall, a lower mean (SD) HAE attack rate during 
the treatment period was observed in the 6 lanadelumab-treated pediatric subjects (0.254 [0.284]) 
compared to the mean (SD) HAE attack rate in the 4 placebo-treated pediatric subjects (0.917 
[0.992]), and the results were consistent with the results observed in the well-represented age 
groups ≥18 to <40 and ≥40 to <65 years. A similar observation was made for <18 years of age 
(N=8) in the rollover population in Study DX-2930-04 and for the nonrollover subjects who 
were <18 years of age (N=13). All pediatric subjects had >50% reduction in HAE attack rate 
relative to the run-in period or the pretreatment baseline.
Lanadelumab was generally well-tolerated by subjects across the clinical development program. 
The pediatric study in patients with HAE, <12 years of age, is being initiated after the 
completion of the 26-week long pivotal Phase 3 study and a mean (SD) duration of exposure of 
19.98 (4.942) months with a maximum of 26.1 months of data from the Phase 3 long-term safety 
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clinical study in patients with HAE, including adolescents (Study DX-2930-04 Interim Analysis 
2 data cutoff on 31 August 2018). 
In the 23 unique adolescent subjects who participated across Phase 3 Studies DX-2930-03 and 
DX-2930-04, no relevant differences between the TEAE profile for pediatric subjects and that 
reported for adult subjects were identified. The most frequently reported treatment-related TEAE 
was injection site pain. No adolescent subjects had reported investigator-confirmed AESIs in 
Study DX-2930-03 or at the time of the interim analysis data cut of 31 August 2018 in 
Study DX-2930-04. One adolescent subject in the lanadelumab treatment arms in 
Study DX-2930-03 had 1 unrelated severe, serious TEAE of catheter site infection. As of the 
data cut of 31 August 2018, one rollover adolescent subject in Study DX-2930-04 had 1 
unrelated severe, serious TEAE of suicidal ideation. There were no deaths or discontinuations in 
adolescent subjects due to TEAEs during the treatment period in the pivotal Phase 3 study or its 
open-label extension study. 
No safety signals were identified in terms of clinical laboratory hematology or coagulation, 
laboratory test abnormalities, vital signs, physical examination or ECGs. Overall, the safety and 
tolerability of lanadelumab were similar in the pediatric population (12 to <18 years old) and 
adults (≥18 years old).
Based on analyses of PK parameters for adolescents and adults in Phase 3 studies, no influence 
of age was apparent on clearance (CL/F) of lanadelumab after correcting for body weight. Based 
on the evaluation of PK, efficacy and safety, no dosing regimen adjustment has been 
recommended for adolescents (12 to < 18 years). Refer to the latest lanadelumab investigator’s 
brochure.
2.6
Study Rationale
No safety signal has been identified in nonclinical and clinical studies of lanadelumab, to date, 
which supports the administration of lanadelumab in the pediatric population ≥2 to <12 years of 
age in the proposed clinical study.
A significant unmet medical need for effective and safe treatment options exist among children 
(2 to <12 years of age) with HAE (see Section 2.4 for current treatment options). Like adults, 
children with HAE can experience recurrent, debilitating, and life-threatening upper airway 
attacks. The unpredictable nature of HAE attacks in children results in significant decrements in 
vocational and school achievement, which impact the overall quality of life (Caballero et al., 
2014). Prophylactic treatment with lanadelumab may be beneficial for children based on 
demonstrated efficacy, safety, and tolerability in adults and adolescents with the reduced 
treatment burden of a low volume, infrequent, SC administration. 
Proteins in the complement and the plasma kallikrein-kinin systems reach adult maturity levels at 
6 to 36 months of age, the occurrence of which may precede or coincide with the early onset of 
symptoms in patients with HAE (Davis et al., 1979; Nielsen et al., 1994; Bork, 2013). The 
similarity of pathophysiology and clinical symptoms for HAE attacks between adults and 
children suggest the involvement of plasma kallikrein and bradykinin in both groups of patients, 
with similar treatment recommendations (Maurer et al., 2018; Sabharwal and Craig, 2017; 
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Kuhlen and Banerji, 2015). The specificity of lanadelumab was engineered to maintain basal 
plasma kallikrein activity, as observed in the Phase 3 studies (DX-2930-03 and DX-2930-04) 
using the PD biomarker cHMWK, which approximated or slightly exceeded that of healthy 
controls (Banerji et al., 2017). Thus, lanadelumab should provide significant benefit to young 
children suffering from HAE.
2.7
Benefit/Risk Assessment 
Clinical studies with lanadelumab demonstrated the improved efficacy and safety for routine 
prophylaxis to prevent and control symptoms of HAE in patients 12 years and older 
(Sections 2.5.3 and 2.5.4; refer to the latest version of the lanadelumab IB).
From a benefit/risk perspective, lanadelumab was generally well tolerated by subjects with HAE 
across the clinical program and has not shown safety limitations. There were no deaths and few 
subjects withdrew due to TEAEs. There were no discontinuations of treatment due to TEAEs in 
adolescent subjects in any of the Phase 3 studies (until the interim data cut of 01 Sep 2017).
In the pivotal study (DX-2930-03), lanadelumab was generally well tolerated over the 26-week 
treatment period. No discernible dose-response pattern or dose-dependent or limiting toxicity 
was observed for any related TEAEs. The safety profile in the ongoing Phase 3 open-label study 
(DX-2930-04) was consistent with the pivotal study. Across both Phase 3 studies, changes in 
hematology, coagulation, and chemistry laboratory parameters over time were small and no 
clinically relevant trends were observed, especially in adolescent subjects. Overall, there were no 
clinically meaningful changes in vital signs and physical findings. No subject receiving treatment 
with lanadelumab had an abnormal, clinically significant ECG result. 
Across both Phase 3 studies, 5.0% of lanadelumab-treated subjects reported SAEs, and none of 
them were related to lanadelumab treatment. There was no discernible pattern or commonality to 
the events reported as SAEs. One adolescent subject randomized to 300 mg q2wks treatment arm 
in pivotal Study DX-2930-03 had a serious, severe TEAE of catheter site infection that required 
hospitalization 138 days after the first dose of the investigational product. No action was taken 
with the investigational product due to the SAE. Treatment for the SAE included acetaminophen, 
vancomycin, ibuprofen, and piperacillin/tazobactam and removal of the catheter. The event was 
not considered related to the investigational product and resolved after a duration of 3 days. The 
subject completed the study and enrolled in the extension study (DX-2930-04). No serious or 
severe TEAEs were reported in the adolescent population until the interim data cut of 01 Sep 
2017 for the open-label extension Study DX-2930-04.
In Study DX-2930-03, most frequently reported TEAEs in lanadelumab-treated adolescent 
subjects were in the following system organ class (SOC): general disorders and administration 
site conditions (4 subjects, 66.7%), infections and infestations (3 subjects, 50.0%), and skin and 
SC tissue disorders (3 subjects, 50.0%). In Study DX-2930-04, the most frequently reported 
TEAEs in lanadelumab-treated pediatric subjects were in the following SOCs: infections and 
infestations (11 subjects, 52.4%), general disorders and administration site conditions 
(9 subjects, 42.9%), gastrointestinal disorders (5 subjects, 23.8%), and nervous system disorders 
(2 subjects, 9.5%). Overall, 3 lanadelumab-treated adolescent subjects (50.0%) had a total of 13 
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treatment-related non-HAE TEAEs, all of which were in the SOC of general disorders and 
administration site conditions in Study DX-2930-03. The most common preferred term (PT) was 
injection site pain (3 subjects, 50.0%). Similarly, in Study DX-2930-04, overall, 9 adolescent 
subjects (42.9%) had a total of 65 treatment-related TEAEs. Treatment-emergent AEs were most 
frequently reported in the SOC of general disorders and administration site conditions 
(8 subjects, 38.1%). The most frequently reported treatment-related TEAE was injection site pain 
(8 subjects, 38.1%). All other treatment-related TEAEs occurred in only 1 subject each.
Prespecified identified risks associated with the use of lanadelumab or other monoclonal 
antibodies include injection site reactions (ISRs) (identified risk) and hypersensitivity (important 
identified risk).
The most frequently reported non-HAE TEAEs in the overall lanadelumab-treated population 
were ISRs. Most (90.8%) ISRs were considered related to treatment and were mild or moderate 
in intensity. No subject reported an ISR that was serious, severe, or that resulted in 
discontinuation of treatment. The majority (66.4%) of ISRs were ≤0.5 hour duration, with 89.2% 
of all ISR AEs ≤1 day duration. Analyses of TEAEs by duration of exposure showed no 
evidence of dose-limiting toxicity, repetitive events, or late-emergent safety concerns (eg, more 
serious events or AESIs) with longer term exposure. 
An important identified risk was hypersensitivity. Hypersensitivity reactions were prespecified 
AESIs due to the theoretical risk associated with monoclonal antibodies, including anaphylactoid 
events or anaphylaxis. The incidence of hypersensitivity was low (1.8%) in lanadelumab-treated 
population and there were no events of anaphylaxis observed in both phase 3 studies. It was at 
the investigator’s discretion the PT used to report the AESI AEs. Few investigator-defined 
AESIs were reported in the pivotal study: 1 subject in the 300 mg q2wks arm had 2 related 
events reported as hypersensitivity reactions (1 mild and 1 moderate in severity), which included 
symptoms of tingling, itchiness, and discomfort of the tongue, dry cough, and mild headache and 
3 lanadelumab-treated subjects from 1 clinical site (1 in each dosing arm) had a total of 5 related 
events (all mild in severity) that were investigator-defined AESI, with the PTs of ISR, erythema, 
or induration (all “delayed or recall ISR” according to the principal investigator). No anaphylaxis 
or anaphylactoid events were reported and none of the subjects with these AESIs developed 
ADAs. No investigator-defined AESI of hypersensitivity were reported in the placebo group. 
In the open-label Phase 3 extension study (DX-2930-04), 7 investigator-reported hypersensitivity 
AESIs occurred in 6 subjects (4 in rollover subjects and 3 in nonrollover subjects). Three 
hypersensitivity reactions and 4 ISRs in 3 subjects were classified as hypersensitivity. All of the 
hypersensitivity AESIs were classified as related to treatment, and 3 of the subjects discontinued 
(hypersensitivity reactions [rash at site of injection and slight swelling under the eyes; edema, 
wheals and joint pain] and ISR papules). One AESI of hypersensitivity was classified as related 
and severe because it coincided with an HAE attack and ongoing disease. However, no 
anaphylaxis and no anaphylactoid reactions were observed and none of the subjects with these 
AESIs developed ADAs. 
Besides hypersensitivity, disordered coagulation (bleeding events or hypercoagulable events 
potentially associated with the mechanism of action of lanadelumab, an active plasma kallikrein 
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inhibitor) was a prespecified AESI. One adult subject in Study DX-2930-03 diagnosed with 
gastroesophageal reflux had an investigator-reported AESI, 1 mild event of microcytic anemia, 
although screening hemoglobin and hematocrit were below the normal range and there was no 
actual event of “bleeding” reported. Two subjects had 4 investigator-reported AESIs of vaginal 
bleeding in Study DX-2930-04 (1 subject had uncontrolled hypothyroidism and the other subject 
had comorbidity of uterine adenomyosis). None of these 4 events were related to lanadelumab 
treatments or required dosing interruption. 
No adolescent subject across both Phase 3 studies had any investigator-reported AESI of 
hypersensitivity, or AESIs with PT of ISRs, or disordered coagulation, until the interim analysis 
data cut on 01 Sep 2017.
An important potential risk associated with the use of lanadelumab or other monoclonal 
antibodies includes immunogenicity. The overall incidence of ADA in the pivotal study was 
11.9% in lanadelumab-treated subjects and 4.9% in placebo-treated subjects. Pre-existing ADA 
of low titer was observed in 3 lanadelumab-treated subjects and 1 placebo-treated subject at 
baseline. No subject discontinued treatment due to the presence of ADA. All ADA-positive 
samples were of low titer (range: 20-1280), and 2/84 or 2.4% lanadelumab-treated subjects tested 
positive for antibodies classified as neutralizing. The overall prevalence of ADAs in treated 
subjects in Study DX-2930-04 was 9.0% (19 of 212 subjects), which included 12 rollover and 7 
nonrollover subjects. Six subjects developed ADAs classified as neutralizing. All titers were low 
(between 20 and 320). Formation of ADAs or neutralizing antibodies had no observable effect 
on the PK, PD, efficacy or safety profiles.
In Study DX-2930-03, one 12-year-old adolescent subject in lanadelumab 300 mg q4wks 
treatment arm was positive for transient, low titer non-neutralizing ADA with no apparent 
clinical consequence. This subject rolled over to Study DX-2930-04 and was positive for low 
titer (titer =80) ADA classified as neutralizing with no apparent clinical consequence. Another 
13-year old adolescent rollover subject previously treated with placebo was positive for transient 
low titer (titer=80) non-neutralizing ADA in Study DX-2930-04 with no apparent clinical 
consequence.
Overall, the safety and tolerability of lanadelumab are similar in adolescent population 12-17 
years old and adults (≥18 years old). Although the number of adolescent subjects aged ≥12 to 
<18 years was small (N=23) across pivotal Phase 3 study and its open-label extension), no 
relevant differences between the TEAE profile for adolescent subjects and that reported for adult 
subjects were identified.
In summary, the known biology of the drug target, does not identify any particular safety risks 
for the pediatric population. Safety signals have not emerged from all available clinical and 
nonclinical data to date for systemically administered lanadelumab. The proposed pediatric study 
is being initiated after completion of one 26-week long pivotal study and after obtaining 16 
months of safety data from the ongoing long-term safety study patients with HAE, including 
adolescents 12 to 17 years of age. This development program has thus enabled the safety of 
chronic lanadelumab therapy to be characterized first in this broader population before exposing 
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children younger than 12 years old to lanadelumab. Frequent safety assessments will be 
conducted throughout this pediatric study (see Schedule of Activities, Table 2 and Table 3).
Always refer to the latest version of the lanadelumab IB for the overall benefit/risk assessment 
and the most accurate and current information regarding drug metabolism, pharmacokinetics, 
efficacy, and safety of lanadelumab. 
2.8
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; ICH E6 R2, 2016), 
Title 21 of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 
2005/28/EC), and applicable national and local regulatory requirements.
The responsibilities of the study sponsor and investigator(s) are described fully in Appendix 1.
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3.
OBJECTIVES AND ENDPOINTS
3.1
Study Objectives
3.1.1
Primary Objective
The primary objective of the study is to evaluate the safety and PK of lanadelumab in children 
(2 to <12 years of age) with HAE. 
3.1.2
Secondary Objectives
The secondary objectives of the study are:

To evaluate the clinical activity/outcomes (hereafter referred to as clinical outcomes) of 
lanadelumab in preventing HAE attacks in children (2 to <12 years of age) with HAE.

To characterize the PD of lanadelumab in children (2 to <12 years of age) with HAE.

To assess the immunogenicity of chronically administered lanadelumab and its effect on 
PK, PD, clinical outcomes, and safety in children (2 to <12 years of age) with HAE.
3.2
Study Endpoints
A list of endpoints which support the study objectives are tabulated below. A detailed description 
of endpoints and the planned statistical analysis are provided in Section 9.
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Table 4:
Objectives and Endpoints
Objective
Endpoint(s)
Primary
1.
To evaluate the safety of 
lanadelumab in children (2 to 
<12 years of age) with HAE. 
Measures of safety include:

Adverse events including SAEs and AESI.

Clinical laboratory testing (hematology, clinical chemistry, coagulation)

Vital signs including blood pressure, heart rate, body temperature, and 
respiratory rate.
2.
To evaluate the 
pharmacokinetics (PK) of 
lanadelumab in children (2 to 
<12 years of age) with HAE.
Measures of PK include:

Plasma concentrations of lanadelumab over the treatment period

PK parameters in plasma, by age group, will be estimated by a 
population modelling and simulation approach and reported separately:
o
Cmax,ss: Maximum observed concentration at steady state
o
Cavg,ss: Average concentration over dosing interval at steady state
o
Ctrough,ss: Predose concentration at steady state
o
tmax: Time to reach Cmax in plasma
o
AUCtau,ss: Area under the concentration-time curve over the dosing 
interval at steady state
o
t½: Terminal half-life
o
CL/F: Apparent clearance
o
V/F: Apparent volume of distribution
Secondary
1.
To evaluate the clinical 
activity/outcomes (hereafter 
referred to as clinical 
outcomes) of lanadelumab in 
preventing HAE attacks in 
children (2 to <12 years of age) 
with HAE.
Clinical outcome measures are secondary endpoints for the study.
The primary clinical outcome endpoint will be the normalized number of 
investigator-confirmed HAE attacks for the overall treatment period. 
The other clinical outcome endpoints are:

Normalized number of investigator-confirmed HAE attacks for each 
efficacy evaluation period other than the overall treatment period.

Time to the first attack, ie, duration that a subject is attack-free until 
their first attack for each efficacy evaluation period.

Normalized number of investigator-confirmed HAE attacks requiring
acute therapy use for each efficacy evaluation period.

Normalized number of moderate or severe investigator-confirmed HAE 
attacks for each efficacy evaluation period. 

Normalized number of high morbidity investigator-confirmed HAE 
attacks for each efficacy evaluation period.

Characteristics of investigator-confirmed HAE attacks for each efficacy 
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4.
STUDY DESIGN
4.1
Overall Design
Study SHP643-301 targets to enroll at least 20 pediatric subjects (2 to <12 years of age; at least 
5 subjects in each age group of 2 to <9 years of age and 9 to <12 years of age) to ensure that a 
minimum of 15 subjects complete 1 year (52 weeks) of treatment on the study. All subjects must 
have a diagnosis of HAE (Type I or II) with a history of ≥1.0 angioedema attacks per 3 months 
(12 weeks). 
Subjects meeting all eligibility criteria will be enrolled and enter the observation period for up to 
12 weeks; all subjects must discontinue LTP before entering the observation period. The attack 
rate in the observation period will serve as the baseline for the study. Subjects who experience 
≥1.0 angioedema attacks per 3 months during the 12-week baseline observation period and who 
remain eligible per study criteria will enter the lanadelumab treatment period for 52 weeks. 
Subjects must stay in the observation period for a minimum of 4 weeks except for those subjects 
who report more than 2 HAE attacks (confirmed by the investigator and agreed with the 
sponsor’s medical monitor) within the first 2 weeks of the observation period. Subjects may exit 
the observation period after reporting one investigator-confirmed attack after 4 weeks in the 
observation period; subjects will then enter the treatment period.
The 52-week treatment period will comprise a 26-week Treatment Period A and a 26-week 
Treatment Period B. Subjects who complete Treatment Period A will immediately continue into 
Treatment Period B. 
The proposed dose regimens for pediatric subjects 2 to <12 years are shown below, and are 
based on population PK modeling and simulation, the similarity of etiology of HAE between 
adult, adolescent, and pediatric subjects with HAE, and body weight distribution information on 
the related age groups. Dosing regimen will be determined based on a subject’s age at the date of 
informed consent, and subjects will remain in the same age category throughout the study.

6 to <12 years: lanadelumab 150 mg q2wks

2 to <6 years: lanadelumab 150 mg q4wks 
Subjects 6 to <12 years will receive lanadelumab 150 mg q2wks in Treatment Period A and may 
remain on the same dose regimen in Treatment B or, if the subject has been well controlled (eg, 
attack free) for 26 weeks with lanadelumab treatment in this study, the subject may switch to a 
dose of 150 mg q4wks at the discretion of the investigator and following approval by the 
sponsor’s medical monitor. Subjects 2 to <6 years will receive lanadelumab 150 mg q4wks in 
both Treatment Period A and Treatment Period B.
Section 4.3 provides justification for the dosing regimen proposed for this study.  See the 
following for more details: 

Section 2.5.1 for the route of administration for the study

Section 2.6 for the rationale for this study
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
Section 4.2 for the discussion around the study design

Section 6.2.3 for dosing frequency and timing

Appendix 5 for HAE attack collection

Section 8.2.6.7 for administration of lanadelumab by a subject (aged 6 years or older) or 
parent/caregiver (hereafter referred to as self-administration)
After completion of the second 26-week treatment period (Treatment Period B), subjects will be 
followed for an additional 4 weeks. 
Acute HAE attacks during the treatment period will be managed in accordance with the 
investigator’s usual care of their patients, including use of individualized acute therapy that the 
investigator deems medically appropriate. C1-INH will be permitted as an acute attack therapy 
but not as a long-term prophylactic therapy during the study.
After 5 subjects receive at least 5 doses of lanadelumab, an interim PK analysis will be 
conducted to evaluate the proposed dose regimens using available data for this study (see 
Section 6.2.5).
Individual subject participation from screening through the completion of safety follow-up visit 
will be approximately 72 weeks (up to 4-week screening visit, up to 12-week baseline 
observation period, 52-week treatment period, and 4-week post-treatment safety follow-up visit). 
An overview of the study design is provided in Figure 2 .
4.2
Scientific Rationale for Study Design
At this time no safety signal has been identified in nonclinical (see Section 2.5.2) and clinical 
studies of lanadelumab, including 26-week long repeat-dose treatment in Phase 3 clinical studies 
with adolescent and adults subjects with HAE (see Section 2.5.3 and Section 2.5.4), which 
supports the administration of lanadelumab in the pediatric population 2 to <12 years of age in 
this open-label, uncontrolled Phase 3 study. Study SHP643-301 aims to provide knowledge on 
the safety, PK, PD and clinical outcomes of lanadelumab for prevention of attacks in children 
aged 2 to <12 years with Type I or Type II HAE. 
Hereditary angioedema is usually diagnosed in the first or second decade of age as disease 
symptoms appear. While occasional severe attacks have been reported, children overall have less 
severe symptoms than adults or adolescents (Bork et al., 2006a;Bygum et al., 2011). The severity 
of HAE increases at puberty (Bork et al., 2006a;Bygum et al., 2011;Farkas, 2010;Roche et al., 
2005;Gompels et al., 2005b). 
As mentioned in Section 2.3 (epidemiology in pediatric population), the prevalence of patients 
who experience HAE attacks is extremely low in the pediatric population under 6 years of age; 
the mean age for first symptom onset reported from large studies is 6 to 12 years of age (Bork et 
al., 2006a;Bygum et al., 2011;Farkas, 2010;Roche et al., 2005). The low prevalence of HAE 
symptoms in children younger than 6 years of age also leads to particularly difficult diagnosis of 
this pathology and corresponds to an extremely small potentially treatable population. Long-term 
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prophylactic treatment is seldom necessary for the pediatric population under the age of 6 years 
old because frequent HAE symptoms are rare before this age (Farkas, 2010; Jolles et al., 2014; 
MacGinnitie, 2014), and international treatment guidelines currently recommend that on-demand 
therapy for attacks in children is preferable, as opposed to LTP, unless the patient has frequent, 
severe attacks that disrupt education and family life (Craig et al., 2012b; Farkas, 2010; Farkas et 
al., 2007). Therefore, although enrollment will be open to children 2 to <12 years of age, the 
target enrollment is at least 5 subjects in the 2 to <9 year age group and at least 5 subjects in the 
9 to <12 year age group. 
Definitive diagnosis of HAE in patients under the age of 2 years is difficult given clinical and 
unreliable diagnostic challenges. Serum levels of complement system components, including C4 
and C1-INH, which form the basis for the diagnosis of HAE, do not stabilize until up to 3 years 
of age (Davis et al., 1979;Roach et al., 1981). The proportion of patients under 2 years of age 
who manifest symptoms and have a confirmed diagnosis of HAE requiring treatment for HAE 
attacks is not known and it is difficult to estimate. However, it is likely to be a very small 
subpopulation. Giving prophylactic treatments to patients for whom a diagnosis of HAE is not 
properly confirmed would result in exposing this younger population to suboptimal prophylactic 
therapy. Therefore, patients <2 years of age are not planned to be included in this pediatric study.
For this pediatric study, PK/PD modelling and simulations were employed to inform pediatric 
lanadelumab dosing regimens in 2 to <12 years old, using an aggregate of available data from 
clinical studies of lanadelumab in adults and adolescents (see Sections 2.5.3 and 2.5.4). As 
characterized by modeling and simulation, lanadelumab exposure, as seen with other monoclonal 
antibodies, is associated with body weight. A weight-adjusted modeling approach for dose 
selection is reasonable and has been conducted. Currently available safety and nonclinical 
toxicity data support a wide safety margin for dosing. See Section 4.3 for further details on the 
rationale for the planned pediatric dosing regimens.
Extrapolation of efficacy data from adults to pediatrics is reasonable, given that there are no 
known differences in the clinical presentation (other than a lower frequency and severity of 
attacks in pre-adolescent children) or differences in underlying pathophysiology for HAE 
between the two populations. PK and PD data from the Phase 1b study (DX-2930-02), together 
with additional data from the 26-week long Phase 3 studies (DX-2930-03 and DX-2930-04 
[interim analysis data]), provide a robust dataset against which the PK and PD data obtained 
from the pediatric study will be assessed in extrapolating efficacy. The extrapolation may be 
supplemented by clinical outcomes data from this pediatric study if subjects have sufficiently 
high baseline attack frequencies, which will provide additional supportive clinical efficacy. This 
study applies the endpoint measures similar to those used in the Phase 3 studies in adults and 
adolescents. 
Initial feasibility evaluations, together with the well-recognized rarity of disease (particularly in 
pre-adolescent patients who have less frequent and less severe attacks), indicate that the number 
of subjects who may realistically enroll in this study will be low. Broadening the range of attack 
rate frequency in the entry criteria will be helpful towards recruiting subjects for the study. The 
proposed enrollment number will be sufficient to facilitate meaningful PK assessment, efficacy 
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extrapolation and long-term safety evaluation (duration of subject participation exceeds 
12 months, including a 52-week long treatment period).
In summary, this open-label, uncontrolled, study aims to provide knowledge on the safety, PK, 
PD and clinical outcomes of lanadelumab for prevention of attacks in children aged 2 to <12 
years with HAE. 
4.3
Justification for Dose
Based on the population PK modeling and simulation using the previously established population 
PK model, the similarity of etiology of HAE between adult, adolescent, and pediatric subjects 
with HAE, and body weight distribution information on the related age groups, the proposed 
dose regimens for pediatric subjects 2 to <12 years are:

6 to <12 years: 150 mg q2wks

2 to <6 years: 150 mg q4wks
The above-proposed lanadelumab dose regimens for pediatric subjects are expected to provide 
similar exposure to lanadelumab 300 mg q2wks, the recommended dose regimen in the 
lanadelumab prescribing information for adults and adolescents with HAE based on the results of 
the pivotal Phase 3 HELP Study® (Study DX-2930-03). The Phase 3 clinical studies for 
lanadelumab, pivotal Study DX-2930-03 and open-label extension Study DX-2930-04, evaluated 
the adult and adolescent population; inclusion of adolescents in these studies was justified based 
on the similarity of the pathophysiology and clinical presentation of HAE in adults and 
adolescents (Bork et al., 2003; Farkas, 2010; Bennett and Craig, 2015; Zuraw, 2008) which was 
confirmed in the clinical trial, as well as the lack of any safety signal identified in nonclinical and 
clinical studies to date. In the two Phase 3 studies, DX-2930-03 and DX-2930-04, PK, PD, and 
exposure-response data were available in a total of 6 and 21 adolescents (including rollovers 
from Study DX-2930-03), respectively. Overall, the efficacy and safety profile of lanadelumab in 
adolescents was similar to that in adults. Based on post-hoc analyses of PK parameters for 
adolescents (12 to <18 years, N=21) and adults (18 to 65 years, N=180) in Study DX-2930-04 
for up to 1 year of treatment, no influence of age was CL/F of lanadelumab after correcting for 
body weight. Based on mean estimated PK parameters, as expected, an approximately 37% 
higher exposure (area under the concentration-time curve over the dosing interval at steady state 
[AUCtau,ss]) in adolescents than adults (18 to 65 years), was observed. Based on the evaluation of 
PK, efficacy, and safety, no dosing regimen adjustment has been recommended for adolescents 
(12 to <18 years).
The dose regimens proposed for children 6 to <12 years old and 2 to <6 years old are based on 
population PK modeling and simulation using the final population PK model, and similarity of 
etiology of HAE between adult, adolescent and pediatric subjects with HAE (Farkas, 2010; 
Bennett and Craig, 2015). Using the final population PK model and the Centers for Disease 
Control and Prevention information on the body weight distribution, the exposure to 
lanadelumab in these age groups (N=1000 per age group; body weight range: 8.99 to 76.1 kg) 
have been simulated and estimated. The results show that the proposed fixed-dose regimen of 
lanadelumab 150 mg q2wks for children 6 to <12 years of age and lanadelumab 150 mg q4wks 
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for children 2 to <6 years of age (see Table 5 and Table 6) are expected to provide similar 
exposure to lanadelumab 300 mg q2wks observed in adults and adolescents, the fixed-dose 
regimen which demonstrated the optimal benefit-risk profile in Phase 3 studies. Hence, these 
simulation results are expected to support the fixed-dose regimens proposed to be tested in 
pediatric subjects 2 to <12 years. Notably, lanadelumab 300 mg q2wks provides exposure 
approximately above the maximal inhibitory concentration (IC90) of cHMWK, EAUC90 for 
clinical response in the majority of subjects across a large range of body weight (46.8-150 kg), 
and the safety profile supports lanadelumab 300 mg q2wks as the recommended fixed-dose 
regimen, including adolescent population. Meanwhile, understanding the need for clinicians to 
individualize therapy, including an opportunity for flexible dosing regimen, and thus, extending 
the dosing interval beyond every 2 weeks, to every four weeks, represents a 
 
 benefit for patients and would be considered if the subjects are well controlled (eg., attack 
free for 26 weeks) on the recommended dose.
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Table 5:
Lanadelumab Exposure in Virtual Pediatric Patients (6 to <12 years, 150 mg 
q2wks) Relative to Patients with HAE ≥12 years (300 mg q2wks)
Age Group
Descriptive
Statistics 
AUC0-2week,ss 
(µg•day/mL)
Cavg,ss
(ng/mL)
Cmax,ss
(ng/mL)
Cmin,ss
(ng/mL)
CL/F
(L/h)
Vc/F
(L)
t1/2 
(h) 
6-<12 years
150 mg 
q2wks
n
1416
1416
1416
1416
1416
1416
1416
Mean (SD)
505 (130)
36100 
(9310)
40400 
(10200)
29600 
(7950)
0.0132 
(0.00356)
7.68 
(1.65)
408 
(20.8)
CV%
25.8
25.8
25.3
26.9
26.9
21.5
5.11
Median
499
35600
39900
29200
0.0125
7.38
409
Min
233
16600
18900
13200
0.0066
4.42
352
Max
944
67400
74500
56600
0.0268
13.6
463
≥12 years
300 mg 
q2wks
n
211
211
211
211
211
211
211
Mean (SD)
474 (166)
33800 
(11800)
38700 
(13500)
26900 
(9530)
0.0292 
(0.0112)
14.4 
(4.09)
354 
(45.1)
CV%
34.9
34.9
34.9
35.4
38.5
28.4
12.7
Median
469
33400
38000
26800
0.0261
13.3
349
Min
121
8670
10400
7590
0.0123
7.52
247
Max
1050
74800
84900
60500
0.0822
31.3
507
Ratio
6-<12 years 
versus
≥12 years
Median
1.06
1.07
1.05
1.09
0.479
0.553
1.17
Min
0.496
0.497
0.498
0.491
0.253
0.331
1.01
Max
2.01
2.02
1.96
2.11
1.03
1.02
1.33
AUC0-2week,ss=area under the curve over 2 weeks at steady state; Cave,ss=average concentrations at steady state; CL/F=apparent 
clearance; Cmax,ss=maximum observed concentration at steady state; Cmin,ss=minimum observed concentration at steady state; 
t1/2=terminal elimination half-life; Vc/F=apparent volume of distribution 
Note: Descriptive statistics for ratios were derived by dividing individual PK parameters in children by the median value in 
patients with HAE ≥12 years.
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Table 6:
Lanadelumab Exposure in Virtual Pediatric Patients (2 to <6 years, 150 mg 
q4wks) Relative to Patients with HAE ≥12 years (300 mg q2wks)
Age Group
Descriptive
Statistics 
AUC0-4 week,ss 
(µg•day/mL)
Cavg,ss
(ng/mL)
Cmax,ss
(ng/mL)
Cmin,ss
(ng/mL)
CL/F
(L/h)
Vc/F
(L)
t1/2 
(h) 
2-<6 years
150 mg q4wks
n
584
584
584
584
584
584
584
Mean
(SD)
969
(186)
34600
(6660)
45600
(8320)
22000
(4650)
0.00668
(0.00130)
4.44
(0.692)
464
(17.4)
CV%
19.2
19.2
18.3
21.1
19.4
15.6
3.75
Median
958
34200
45100
21700
0.00651
4.36
465
Min
535
19100
26000
11400
0.00400
2.95
415
Max
1560
55600
71600
36900
0.0117
6.98
511
≥12 years 
300 mg q2wks
n
211
211
211
211
211
211
211
Mean
(SD)
949
(331)
33800
(11800)
38700
(13500)
26900
(9530)
0.0292
(0.0112)
14.4
(4.09)
354
(45.1)
CV%
34.9
34.9
34.9
35.4
38.5
28.4
12.7
Median
937
33400
38000
26800
0.0261
13.3
349
Min
242
8670
10400
7590
0.0123
7.52
247
Max
2100
74800
84900
60500
0.0822
31.3
507
Ratio
2-<6 years/≥12 years
Median
1.02
1.02
1.19
0.810
0.249
0.327
1.33
Min
0.57
0.571
0.682
0.426
0.153
0.221
1.19
Max
1.66
1.66
1.88
1.38
0.447
0.523
1.46
AUC0-4week, ss=area under the curve over 4 weeks at steady state; Cavg, ss=average concentrations at steady state; CL/F=apparent 
clearance; Cmax, ss=maximum observed concentration at steady state; Cmin, ss=minimum observed concentration at steady state; 
t1/2=terminal elimination half-life; Vc/F=apparent volume of distribution 
Note: Descriptive statistics for ratios were derived by dividing individual PK parameters in children by the median value in 
patients with HAE ≥12 years.
4.4
Duration of Subject Participation and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 72 weeks.  
Individual subject participation from screening through the completion of safety follow-up visit 
will include: up to 4-week screening period, up to 12- week baseline observation period, 52-
week treatment period, and 4-week post-treatment safety follow-up visit. The study will be 
completed in approximately 72 weeks. 
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The Study Completion Date is defined as the date on which the last subject in the study 
completes the final protocol-defined assessment(s). This includes the follow-up visit or contact, 
whichever is later (refer to Section 8.1.4 for the defined follow-up period for this protocol).
The Study Completion Date is used to ascertain timing for study results posting and reporting.
4.5
Sites and Regions
This is a multicenter study. Approximately 18 sites in North America (United States, Canada) 
and Europe (Germany, Spain, Hungary) will participate.
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5.
STUDY POPULATION
At least 20 pediatric subjects (male or female) age 2 to <12 years of age with HAE Type I or II 
are planned to be enrolled and treated with lanadelumab, including at least 5 subjects in each age 
group of 2 to <9 years and 9 to <12 years. Each subject must participate in the informed consent 
process and provide written informed consent/assent before any procedures specified in the 
protocol are performed. Inclusion and exclusion criteria for enrolling subjects in this study are 
presented in Section 5.1 and Section 5.2, respectively.
5.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Be a child (male or female) 2 to <12 years of age at the time of screening.
2. Documented diagnosis of HAE (Type I or II) based upon both of the following:

Documented clinical history consistent with HAE (SC or mucosal, nonpruritic swelling 
episodes without accompanying urticaria);

Diagnostic testing results obtained during screening from a sponsor-approved central 
laboratory that confirm C1-INH functional level <40% of the normal level. Subjects with 
functional C1-INH level 40-50% of the normal level may be enrolled if they also have a 
C4 level below the normal range. With prior sponsor approval, subjects may be retested 
during the baseline observation period if results are incongruent with clinical history or 
believed by the investigator to be confounded by recent C1 inhibitor use.
3. A historical baseline HAE attack rate of at least 1 attack per 3 months. Note: In addition, 
subjects who experience ≥1.0 angioedema attacks per three months during the 12-week 
baseline observation period and who remain eligible per the inclusion criteria will enter the 
lanadelumab treatment period.
4. Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
5. Have a parent(s)/legal guardian who is informed of the nature of the study and can provide 
written informed consent for the child to participate in the study before any study-specific 
procedures are performed (with assent from the child when appropriate).
6. Females of childbearing potential must agree to be abstinent or agree to comply with the 
applicable contraceptive requirements of this protocol through the duration of the study from 
screening through 70 days after the final study visit.
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5.2
Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met. 
1. Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired 
angioedema (AAE), HAE with normal C1-INH, idiopathic angioedema, or recurrent 
angioedema associated with urticaria.
2. Dosing with an investigational drug or exposure to an investigational device within 4 weeks 
prior to screening.
3. Be pregnant or breastfeeding. 
4. Have initiated androgen treatment (eg, stanozolol, danazol, oxandrolone, methyltestosterone, 
and testosterone) within 2 weeks prior to entering the observation period.
5. Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing 
medications with systemic absorption (such as oral contraceptives or hormonal replacement 
therapy) within 4 weeks prior to screening. 
6. Have any active infectious illness or fever defined as an oral temperature >38°C (100.4°F), 
tympanic >38.5°C (101.3°F), axillary >38°C (100.4°F), or rectal/core >38.5°C (101.3°F) 
within 24 hours prior to the first dose of study drug in Treatment Period A.
7. Have any HAE attack that is not resolved prior to the first dose of study drug in Treatment 
Period A.
8. Have any of the following liver function test abnormalities: alanine aminotransferase (ALT) 
>3x upper limit of normal (ULN), or aspartate aminotransferase (AST) >3x ULN, or total 
bilirubin >2x ULN (unless the bilirubin elevation is a result of Gilbert’s syndrome).
9. Have any condition (any surgical or medical condition) that, in the opinion of the investigator 
or sponsor, may compromise their safety or compliance, preclude the successful conduct of 
the study, or interfere with interpretation of the results (eg, significant pre-existing illness or 
other major comorbidity that the investigator considers may confound the interpretation of 
study results).
10. Subject has a known hypersensitivity to the investigational product or its components.
5.3
Restrictions 
5.3.1
Medical Interventions
Medical interventions deemed necessary by the investigator for the health and well-being of the 
subjects will not be excluded during this study.
5.3.2
Fluid and Food Intake
There are no restrictions on fluid and food intake. Subjects may continue their usual dietary 
regimens.
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5.3.3
Activity
There are no activity restrictions. Subjects may continue their usual activity regimens.
5.4
Reproductive Potential
A study of lanadelumab in cynomolgus monkeys does not indicate effects on embryo-fetal 
development (see the latest version of lanadelumab IB). Lanadelumab has not been studied in 
pregnant women, and there are limited data from its use in pregnant women. However, a risk to 
the pregnant woman or developing fetus cannot be excluded. Therefore, a decision should be 
made whether to initiate or discontinue treatment with lanadelumab, taking into account the 
risk/benefit of therapy.
No evidence of testicular toxicity or adverse effects on male fertility or teratogenicity 
transferable to a fetus/embryo from animal studies were observed (see the latest version of 
lanadelumab IB). 
5.4.1
Female Contraception
Female subjects should be either:

Premenarchal and either Tanner stage 1 or less than age 9 years, or

Females of childbearing potential with a negative urine beta-human chorionic 
gonadotropin (β-hCG) pregnancy test prior to first dose on Study Day 0 (Visit 1). 
Females of childbearing potential must agree to abstain from sexual activity that could 
result in pregnancy or agree to use acceptable methods of contraception. 
Sexually active females of childbearing potential should use a medically acceptable form of 
contraception. Females of childbearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 70 days following the last dose of 
investigational product. If used, hormonal contraceptives should be administered according to 
the package insert. Any female of childbearing potential who is not currently sexually active 
must agree to use acceptable contraception, as defined below, if she becomes sexually active 
during the study and for 70 days following the last dose of investigational product. 
Acceptable methods of contraception include the following:

Intrauterine devices (IUD, all types) or intrauterine hormone releasing systems (IUS) plus 
condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Progestin-only contraceptive associated with inhibition of ovulation (oral, depot, patch, 
injectable, or vaginal ring), stabilized for at least 30 days prior to the screening visit, 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.
Note: estrogen-containing medications with systemic absorption are not allowed in the study.
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5.4.2
Male Contraception
The study population includes male children <12 years of age. Therefore, male contraception is 
not required in this study.
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6.
STUDY INTERVENTION
6.1
Investigational Product
6.1.1
Identity of Investigational Product
The investigational product is lanadelumab, which will be provided as solution in a vial 
(150 mg/mL) where the full 1 mL (150 mg) dose will be withdrawn from the vial and 
administered to the subject. Additional information regarding the dosage forms is provided in the 
latest version of the lanadelumab IB or the medication guide. 
6.1.2
Blinding the Treatment Assignment
Not applicable. This is an open-label study. 
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
An Interactive Response Technology (IRT) vendor will be used for this study to manage 
packaged IMP supply, IMP shipments, receipt of IMP at clinical sites, assignment of IMP to 
subjects, expiry tracking, IMP returns, and IMP accountability.
6.2.2
Allocation of Subjects to Treatment 
This is an open-label study. Subject numbers are assigned to all subjects as they consent to take 
part in the study. Within each site (numbered uniquely within a study), the subject number is 
assigned to subjects according to the sequence of presentation for study participation. 
The Medication Identification Number (MedID) represents a unique number corresponding to 
investigational product allocated to the subject, once eligibility has been determined. Individual 
subject treatment is automatically assigned by the IRT.
6.2.3
Dosing
Lanadelumab injection will be administered SC in the abdomen, thigh, or upper arm. 
The lanadelumab dose regimens are: 

150 mg q2wks for subjects 6 to <12 years old; a total of 27 doses over the 52-week 
treatment period, and 

150 mg q4wks for subjects 2 to <6 years old; a total of 14 doses over 52-week treatment 
period. 
A subject’s dosing regimen will be determined based on the subject’s age at enrollment (ie, date 
of informed consent), and subjects will remain in the same age category throughout the study.
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Modification of these dosing regimens may be considered for subjects in one or both age groups 
following an interim PK analysis, and modification of the dosing regimen for individual subjects 
may be considered based on a benefit-risk assessment; refer to Section 6.2.5 for details.
The presentation is a solution in vial (150 mg/mL) where the full 1 mL (150 mg) dose will be 
withdrawn and administered to the subject.
Table 7 presents the frequency and timing of dose administration.
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Table 7:
Treatment Period Dosing Schedule
Lanadelumab 150 mg
every 2 weeksa
(for subjects 6 to <12 years)b
Lanadelumab 150 mg
every 4 weeks
(for subjects 2 to <6 years)b
Dose Number
Study Visit/Study 
Day/Study Week
Dose Number
Study Visit/Study 
Day/Study Week
Treatment Period A
1
Visit 1/Day 0/Week 0
1
Visit 1/Day 0/Week 0
2
Visit 3/Day 14/Week 2
3
Visit 4/Day 28/Week 4
2
Visit 4/Day 28/Week 4
4
Visit 6/Day 42/Week 6
5
Visit 8/Day 56/Week 8
3
Visit 8/Day 56/Week 8
6
Visit 10/Day 70/Week 10
7
Visit 12/Day 84/Week 12
4
Visit 12/Day 84/Week 12
8
Visit 14/Day 98/Week 14
9
Visit 16/Day 112/Week 16
5
Visit 16/Day 112/Week 16
10
Visit 18/Day 126/Week 18
11
Visit 20/Day 140/Week 20
6
Visit 20/Day 140/Week 20
12
Visit 22/Day 154/Week 22
13
Visit 24/Day 168/Week 24
7
Visit 24/Day 168/Week 24
14
Visit 26/Day 182/Week 26
Treatment Period B
15
Visit 28/Day 196/Week 28
8
Visit 28/Day 196/Week 28
16
Visit 30/Day 210/Week 30
17
Visit 32/Day 224/Week 32
9
Visit 32/Day 224/Week 32
18
Visit 34/Day 238/Week 34
19
Visit 36/Day 252/Week 36
10
Visit 36/Day 252/Week 36
20
Visit 38/Day 266/Week 38
21
Visit 40/Day 280/Week 40
11
Visit 40/Day 280/Week 40
22
Visit 42/Day 294/Week 42
23
Visit 44/Day 308/Week 44
12
Visit 44/Day 308/Week 44
24
Visit 46/Day 322/Week 46
25
Visit 48/Day 336/Week 48
13
Visit 48/Day 336/Week 48
26
Visit 50/Day 350/Week 50
27
Visit 52/Day 364/Week 52
14
Visit 52/Day 364/Week 52
a Subjects 6 to <12 years of age may administer lanadelumab 150 mg q4wks in Treatment Period B at the investigator’s discretion 
and sponsor’s medical monitor approval, if they are well controlled (eg, attack free) for 26 weeks with lanadelumab treatment in 
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Table 7:
Treatment Period Dosing Schedule
Lanadelumab 150 mg
every 2 weeksa
(for subjects 6 to <12 years)b
Lanadelumab 150 mg
every 4 weeks
(for subjects 2 to <6 years)b
Dose Number
Study Visit/Study 
Day/Study Week
Dose Number
Study Visit/Study 
Day/Study Week
this study.
b A subject’s dosing regimen will be determined based on the subject’s age at enrollment (ie, date of informed consent), and 
subjects will remain in the same age category throughout the study.
6.2.4
Unblinding the Treatment Assignment
Not applicable. This is an open-label study.
6.2.5
Dose Modification
The decision to continue with the proposed dose regimen or proceed with another dose regimen 
(either an increase or a decrease in the dose and/or dosing frequency) will be made by the 
sponsor’s study team after 5 subjects receive at least 5 doses of lanadelumab, and an interim PK 
analysis is conducted to evaluate the dose regimens using available data. 
An individual subject’s dose frequency may also be modified based on a benefit-risk assessment 
and recommendation from the treating physician. Consultation with and approval by the 
sponsor's medical monitor is required. For example, subjects 6 to <12 years of age may 
administer lanadelumab 150 mg q4wks in Treatment Period B at the investigator’s discretion and 
sponsor’s medical monitor approval, if they are well controlled (eg., attack free) for 26 weeks 
with lanadelumab treatment in this study. Other modifications may be considered at the 
discretion of the investigator in consultation with the sponsor’s medical monitor.
6.3
Labeling, Packaging, Storage, and Handling of Investigational Product
6.3.1
Packaging and Labeling
The open-label lanadelumab will be supplied by the sponsor and pre-packaged in a study kit for 
the study. Each study kit will contain 1 vial of investigational product. Both the vial and carton 
(kit) will be appropriately labeled according to local regulations and bear the unique study drug 
kit number. The investigative site will provide ancillary supplies including syringes, needles, and 
alcohol wipes to subjects. The site has the option of using needles of a different gauge to aid 
subject comfort with each SC injection. 
Detailed instructions on preparation and administration of investigational product will be 
provided to the clinical sites in a Pharmacy Manual.
Subjects (aged 6 years or older) or parents/caregivers who elect to self-administer investigational 
product, where permitted per protocol (see Section 8.2.6.7), will be provided the following 
supplies as applicable:

1 dose supply of investigational product
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
Ancillary supplies, and a container for sharps disposal

Subject accountability form to record investigational product administration details
All used and unused vials should be returned to the study kit cartons/boxes and transported to the 
site for drug accountability. Written instructions on lanadelumab handling and 
self-administration procedures will be provided to the trained subject (aged 6 years or older) or
parent/caregiver prior to initiating self-administration. Refer to the Pharmacy Manual for 
additional details on lanadelumab and its administration.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
Labels containing study information and pack identification are applied to the investigational 
product(s) container. 
All investigational product is labeled with a minimum of the following: protocol number, MedID 
number, lot number, expiry date, dosage form, directions for use, storage conditions, the 
sponsor's name, address, and telephone number, the statements “For clinical trial use only” and 
"Keep out of sight and reach of children". Any additional labeling requirements for participating 
countries will also be included on the label.
Space is allocated on the label so that the site representative can record the site number and 
subject number.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Storage and Handling
Lanadelumab should be stored in a refrigerator at 2 to 8°C (36–46°F). Vials should be removed 
from refrigeration and allowed to get to room temperature before administration. Do not freeze. 
The vial should be protected from light in the original carton. Refer to the latest version of the IB 
for current stability data.
Before use, each vial of study drug should be inspected for appearance. Any vial containing 
visible particles or discoloration should not be used (any such issues should be reported to the 
sponsor as per the instructions on the Product Quality Complaints page of this protocol). Avoid 
shaking or vigorous agitation of the vial. 
Any unused contents of a vial of study medication should be discarded in accordance with local 
requirements for investigational materials. Intact vials of study medication that are not used 
during the course of the clinical study should be returned according to direction from the 
sponsor.
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 
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team member will enter the unique subject number on the investigational product vial/carton 
labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering and dispensing investigational 
product (for dosing by site personnel and self-administration, respectively). Where permissible, 
tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately trained in the 
protocol and who works under the direct supervision of the investigator. This delegation must be 
documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer/dispense the investigational product only to 
subjects included in this study following the procedures set out in the study protocol. Each 
subject will be given only the investigational product carrying his/her treatment assignment. All 
administered/dispensed medication will be documented in the subject’s source and/or other 
investigational product record. The investigator is responsible for ensuring the retrieval of all 
study supplies from subjects. Due to the health/safety concerns with returning the investigational 
product container, the investigator must request that subjects keep the empty investigational 
product packaging after use and return it to the site for drug accountability purposes.
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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.
With the written agreement of the sponsor, at the end of the study all unused stock, 
subject-returned investigational product, and empty/used investigational product packaging may 
be destroyed at the site or a local facility. In this case, destruction records identifying what was 
destroyed, when and how, must be obtained with copies provided to the sponsor. Destruction of 
investigational product must be in accordance with local, state, and national laws.
If the sponsor has not provided written agreement for destruction at the site or a local facility 
then, at the end of the study or as instructed by the sponsor, all unused stock, subject-returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational product being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (or designated CRO). For unused supplies where the original supplied tamper-evident 
feature is verified as intact, the tamper-evident feature must not be broken and the labeled 
amount is to be documented in lieu of counting. Shipment return forms, when used, must be 
signed prior to shipment from the site. Validated electronic return systems (ie, IRT) do not 
require a shipment form. Returned investigational product must be packed in a tamper-evident 
manner to ensure product integrity. Contact the sponsor for authorization to return any 
investigational product prior to shipment. Shipment of all returned investigational product must 
comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Subjects must be instructed to bring unused investigational product and empty/used 
investigational product packaging to every visit. Drug accountability must be assessed at the 
container/packaging level for unused investigational product that is contained within the original 
tamper-evident sealed container (vials) or at the individual count level for opened 
containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.
6.6
Prior and Concomitant Therapy
All non-study treatment including but not limited to all prescriptions, over-the counter 
medications, herbal treatments, vitamins and supplements, behavioral treatment, non-
pharmacological treatments and procedures (such as psychotherapy, surgical, diagnostic, or 
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dental), as appropriate, received within 28 days (4 weeks) prior to the screening visit (or PK 
equivalent of 5 half-lives, whichever is longer) and through the final study contact (including 
protocol-defined follow-up period) must be recorded in the subject’s source document following 
informed consent. 
6.6.1
Prior Treatment 
Prior treatment includes all non-study treatments received within 28 days (4 weeks) prior to 
screening visit (or PK equivalent of 5 half-lives, whichever is longer) up to the date of first dose 
of investigational product. 
6.6.2
Concomitant Treatment
Concomitant treatment refers to all non-study treatments taken between the dates of the first dose 
of investigational product and the end of the follow-up period, inclusive.
Parents or caregivers should record in the subject's diary any medications taken by the subject for 
the management of HAE attacks during the baseline observation period and during the treatment 
period.
6.6.3
Permitted Treatment 
The following concomitant therapies are allowed during the study:

Therapies for co-existing conditions, including those for acute attacks of HAE, are 
permitted if not excluded during the study (see Section 6.6.4). Acute HAE attacks during 
the study will be managed in accord with the investigator’s usual care of their patients, 
including use of individualized acute therapy that the investigator deems as medically 
appropriate. Use of C1-INH will be permitted as an acute attack therapy but not as LTP. 
Administration of lanadelumab and study procedures will continue without alteration to 
the protocol-specified study schedule, even if the subject has symptoms of an HAE attack 
the day of lanadelumab administration and/or receives treatment for an HAE attack. The 
administration of lanadelumab can also be re-scheduled as long as the minimum and 
maximum timeframe between doses are met based on subject preference or physician 
discretion.

The use of short-term prophylactic treatment for HAE will be permitted if medically 
indicated. Short-term prophylaxis is defined as C1-INH, attenuated androgens, or 
antifibrinolytics used to avoid angioedema complications from medically indicated 
procedures.

Therapies to treat any AEs the subject experienced during the study will be permitted.
6.6.4
Prohibited Treatment
Use of the following treatments will not be permitted during the study:

Long-term prophylaxis for HAE (eg, use of C1-INH for LTP, attenuated androgens, or 
antifibrinolytics) from the time that LTP is discontinued prior to the baseline observation 
period and during the study.
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
Angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to screening and 
during the study.

Estrogen-containing medications with systemic absorption within 4 weeks prior to 
screening and during the study.

Use of androgens (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) 
for non-HAE related medical conditions or for HAE, from discontinuation of these 
androgens at least 2 weeks prior to entering the observation period and throughout the 
study.

Any other investigational drug or device.
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7.
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Treatment
Subjects who prematurely discontinue investigational product, regardless of the reason, should 
undergo the end of study (EOS) visit procedures specified for Study Day 392 (Visit 56) 
whenever possible (see Section 8.1.4). Comments (spontaneous or elicited) or complaints made 
by the subject must be recorded in the source documents. The reason for discontinuation of 
investigational product, date of discontinuation of the investigational product, and the total 
amount of investigational product administered must be recorded in the source documents.
Subjects who prematurely discontinue investigational product will not be replaced. 
7.2
Reasons for Discontinuation 
The reason for discontinuation (from treatment and/or the study) must be determined by the 
investigator and recorded in the subject’s source document: subject’s medical record and on the 
case report form (CRF). If a subject is discontinued for more than 1 reason, each reason should 
be documented in the source and the most clinically relevant reason should be indicated. 
Reasons for discontinuation of study include, but are not limited to:

Withdrawal of consent (by a parent or both parents/legal guardian for pediatric subjects)

Adverse event (must specify on the CRF)

Protocol deviation (eg, lack of compliance, use of experimental drug) 

Pregnancy

Sponsor decision (must specify on the CRF)

Investigator decision (must specify on the CRF)

Death

Lost to follow-up

Lack of efficacy

Other (must specify on the CRF)
7.3
Withdrawal from the Study
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution, or may be withdrawn at any 
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.
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7.4
Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject who is lost to 
follow-up at any time point prior to the last scheduled contact (office visit or site contact). At 
least 1 of these documented attempts must include a written communication sent to the subject’s 
last known address via courier or mail (with an acknowledgement of receipt request) asking that 
the subject return to the site for final safety evaluations and return any unused investigational 
product.
7.5
Stopping Rules 
7.5.1
Study Level Stopping Rules
Study data, including SAEs and AESI (as defined in Section 8.2.5.6), will be monitored regularly 
throughout the duration of the study. If any potential safety signal is identified as a result of 
monitoring in this study, the sponsor may take actions as deemed appropriate, including 
suspending dosing in the study, while the potential risk is evaluated and a course of action has 
been determined.
7.5.2
Individual Stopping Rules
Dosing for any individual subject will be discontinued if the subject experiences a 
lanadelumab-related SAE (or a lanadelumab-related, clinically-significant, non-serious AE) that, 
in the assessment of the investigator, warrants discontinuation from further dosing for that 
subject’s well-being. The investigator has the ability to contact and consult with the medical 
monitor on such matters. Subjects who prematurely discontinue investigational product should 
undergo the EOS visit procedures specified for Study Day 392 (Visit 56) (see Section 8.1.4), 
unless they request to be discontinued from the study..
7.5.3
Follow-Up for Subjects Meeting Stopping Criteria
Subjects that develop either an SAE or other toxicity considered clinically relevant 
(AE, laboratory, physical examination, or vital sign finding) will be carefully monitored until 
resolution, which may include the following:

Additional clinical laboratory tests and/or other clinical investigations

Additional visits or extended duration of follow-up

Obtaining a specialist consultation
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8.
STUDY ASSESSMENTS AND PROCEDURES
8.1
Study Periods
Refer to Table 1, Table 2, and Table 3 for the schedule of study activities. Study assessments are 
detailed in Section 8.2.
8.1.1
Screening Period (up to 4 weeks)
Informed consent must be obtained before any study specific procedures are performed.
As indicated in Table 1, following procedures and assessments are to be performed during 
Screening:

Informed consent 

Demographics, medical history, and HAE history

Prior/current medications, therapies and procedures 

Vital signs including blood pressure (BP), heart rate (HR), body temperature, and 
respiratory rate (RR) 

Complete physical examination, including documentation of height and weight.

Tanner staging (for female subjects who are premenarchal and ≥9 years of age; see 
Section 5.4.1).

Clinical laboratory testing including hematology, coagulation, and serum chemistry 

Functional C1-INH, C4, and C1q testing

Virology testing for Hepatitis B surface antigen (HbsAg), Hepatitis C Virus (HCV), and 
Human Immunodeficiency Virus (HIV)

Adverse events collection; pre-existing signs and symptoms
At the in-clinic visit of the screening period, the subject and their parent/caregiver should be 
given an HAE Attack Diary.
A subject should complete all screening procedures within 4 weeks. Eligibility review may be 
conducted by the site as screening data become available. A final eligibility review will be 
conducted prior to Day 0, after a subject has completed all screening procedures and all results 
are available.
A screen failure is a subject who has given informed consent and failed to meet all inclusion 
criteria and/or has met at least 1 of the exclusion criteria and has not been administered 
investigational product(s). Once a subject has been designated as a screen failure, the subject 
may be rescreened at the discretion of the investigator and following discussion with the sponsor 
medical monitor.
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parent/caregivers, in the event the subject is <18 years old or is incapacitated) will be instructed 
to report details of the HAE attack to the study site within 72 hours of the onset of the attack.
The collection, reporting and assessment of HAE attacks in this study will be done in accordance 
with the HAE Attack Assessment and Reporting Procedures (HAARP) provided in Appendix 5
of this protocol. Site personnel will be trained on HAARP prior to screening subjects at their site.
A high morbidity HAE attack is defined as any attack that has at least one of the following 
characteristics: severe, results in hospitalization (except hospitalization for observation <24 
hours), hemodynamically significant (systolic blood pressure <90, requires IV hydration or 
associated with syncope or near-syncope) or laryngeal.
8.2.4.2
Management of Acute Hereditary Angioedema Attacks
As mentioned in Section 4.1, acute HAE attacks during the study are to be managed in accord 
with the investigator’s usual care of their patients, including use of acute attack therapies that the 
investigator deems as medically appropriate. Use of C1-INH will be permitted as an acute attack 
therapy but not as LTP. 
Administration of the investigational product and study procedures will continue without 
alteration to the protocol specified study schedule, even if the subject receives any treatment for 
an HAE attack.
8.2.5
Safety
8.2.5.1
Physical Examination
A physical examination (including body weight) will be performed by the investigator or his/her 
qualified designee according to the Study Schedule of Activities (Table 1, Table 2, and Table 3). 
The date and time of each examination will be recorded on the source documents and electronic 
CRF (eCRF). Adverse events emerging from any physical examination will be recorded on the 
source document and eCRF. 
The physical examination will be performed in accordance with standards at the site. The 
physical examination will include, at a minimum, assessments of the body systems listed below:

Weight 

General appearance

Ears, nose, and throat

Head and Neck

Ophthalmological

Respiratory

Cardiovascular

Abdomen

Neurological
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
Extremities

Dermatological

Lymphatic
In addition, height will be measured at the screening visit and Day 1 only.
The screening physical examination will also include Tanner staging for premenarchal female 
subjects who are ≥9 years of age. For such subjects, Tanner staging may also be performed 
during other physical examination assessments at the discretion of the investigator if clinically 
indicated.
Abnormalities identified at the screening visit and at subsequent study visits will be recorded in 
the subject’s source documents.  
8.2.5.2
Vital Signs
Vital signs will be assessed by the investigator or his/her qualified designee according to the 
Study Schedule of Activities in Table 1, Table 2, and Table 3. Routine vital sign assessments 
will be taken with the subject in the sitting or supine position after 5 minutes at rest and will 
include body temperature, HR, BP, and RR. Blood pressure should be determined using the same 
arm and the same equipment, and the same position for each assessment throughout the study. 
During the study, additional vital signs measurements will be performed if clinically indicated. 
Vital signs performed on dosing days should be obtained prior (within 60 minutes) to the start of 
the injection and 30 minutes (± 15 minutes) after completion of the injection of study drug. 
Every effort should be made to measure and record vital signs prior to any blood sample 
collection. 
The investigator will assess whether a change from baseline (predose, Visit 1/Day 0) in vital 
signs may be deemed clinically significant and whether the change should be considered and 
recorded as an AE.
8.2.5.3
Pregnancy Test 
For all females who have reached menarche, pregnancy testing (β-hCG) will be performed at the 
time points specified in Schedule of Activities in Table 2 and Table 3; if pregnancy is suspected; 
or on withdrawal (early termination visit) of the subject from the study. Pregnancy testing at 
Day 0 will be urine-based. All other pregnancy testing in this study may be urine or serum based. 
8.2.5.4
Clinical Laboratory Tests for Safety Assessments
A complete list of clinical laboratory tests to be performed to assess general safety parameters is 
provided in Appendix 2.
All clinical laboratory tests will be performed according to the laboratory’s standard procedures, 
using established and validated methods. Reference ranges will be supplied by the laboratory and 
used to assess the results for clinical significance and out-of-range changes which may be 
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associated with, or constitute, an AE. The investigator should assess out-of-range clinical 
laboratory values for clinical significance, indicating if the value(s) is/are not clinically 
significant or clinically significant. Abnormal clinical laboratory values, which are unexpected or 
not explained by the subject’s clinical condition, may, at the discretion of the investigator or 
sponsor, be repeated as soon as possible until confirmed, explained, or resolved.
All safety laboratory assessments will be performed at a central laboratory. The clinical 
laboratory values will be reported to the investigator who will review them for clinical 
significance and consideration of abnormal values as potential AEs.
8.2.5.5
Adverse Events
Each subject will be monitored for the occurrence of AEs, including SAEs and AESIs, from 
signing of the informed consent form through the final follow-up visit:

Subjects will be questioned and/or examined by the investigator or a qualified designee 
for evidence of AEs. The questioning of subjects with regard to the possible occurrence 
of AEs will be generalized such as, "How have you been feeling since your last visit?”  
The presence or absence of specific AEs should not be elicited from subjects. 

The clinical outcomes endpoint, HAE attacks, will also be captured as AEs in this study 
(see details below).

Subjects having treatment-emergent AEs (TEAEs) will be monitored until resolution with 
relevant clinical assessments and laboratory tests, as determined by the investigator. AEs, 
actions taken as a result of AEs, and follow-up results must be recorded in the eCRF as 
well as in the subject's source documentation. Follow-up laboratory results should be 
filed with the subject's source documentation. 

For any SAEs or AEs that require the subject to be discontinued from dosing, relevant 
clinical assessments and laboratory tests will be repeated as clinically appropriate, until 
final resolution or stabilization of the event(s). Subjects who discontinue treatment will 
complete EOS visit procedures as described in Section 7.1.
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All AEs, regardless of seriousness, severity, or causal relationship to study drug, will be recorded 
on the AE page of the eCRF (see exception below for HAE attack AEs). Any AE meeting 
criteria for an SAE, as defined in Appendix 3, must also be reported to the sponsor using the 
SAE Reporting Form within 24 hours of the site becoming aware of the event. All AESIs, as 
defined in Section 8.2.5.6, must also be reported to the sponsor using the same timelines as 
described for SAE reporting.
Further information on AE definitions, collection time frame, assessment of causality and 
severity, and safety reporting is provided in Appendix 3, Appendix 3.2, and Appendix 3.3, 
Appendix 3.4, respectively. Information on SAE collection time frame, onset/resolution dates, 
and SAEs with a fatal outcome is presented in Appendix 3.5, Appendix 3.6, and Appendix 3.7, 
respectively. 
The clinical outcomes endpoint, HAE attacks, will also be captured as AEs in this study. To 
avoid complicating the interpretation of safety, 2 mutually exclusive subgroups of AEs will be 
defined based on whether the AE is (or is not) identified in the eCRF as a subject-reported HAE 
attack: 

Non-HAE attack AEs will include the subset of AEs that are not identified in the eCRF as 
a subject-reported HAE attack. Essentially, this will be AEs excluding the subject-
reported HAE attack events. These non-HAE attack AEs will be reported on the AE 
page of the eCRF. The severity of these AEs will be assessed according to the Division 
of Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Table (Appendix 6). 

HAE attack AEs will include the subset of AEs identified in the eCRF as a 
subject-reported HAE attack. This will include, but will not be limited to, 
investigator-confirmed HAE attacks. These HAE attack AEs will be reported on the 
designated angioedema attack page of the eCRF. Severity of the HAE attack will be 
assessed in accordance with HAARP (Appendix 5), which includes an assessment using 
HAARP criteria and an assessment using DMID criteria.
For all SAEs that are reported as HAE attacks, the investigator will review the event within 
24 hours of initial notification and, in accordance with HAARP, evaluate if it represented a 
confirmed HAE attack. For all non-serious AEs that are reported as HAE attacks, the investigator 
will review the event within 7 days of initial notification and, in accordance with HAARP, 
evaluate if it represented a confirmed HAE attack. If necessary for the evaluation, the 
investigator or designee may contact the subject for additional information. Any subject-reported 
attack not confirmed by the investigator must have an alternate AE diagnosis recorded. All 
subject-reported and investigator-confirmed HAE attacks will be recorded in the eCRF. Note: 
Hereditary angioedema is the indication for treatment and should be considered expected as the 
events are considered disease related (progression of underlying disease) and not subject to 
expedited reporting.
Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
will be captured in the eCRF.
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8.2.5.6
Adverse Events of Special Interest (AESI)
Adverse events of special interest (AESI) will be captured and monitored during this study. 
Investigators will report all AESI to the sponsor, regardless of causality, using the same 
timelines as described for SAE reporting. The following describe the AESI and the criteria for 
reporting AESI. 
Hypersensitivity Reactions
As hypersensitivity reactions have been observed for monoclonal antibodies as a class, these 
events are considered AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with hypersensitivity 
reactions, regardless of causality, within 24 hours from the time of study drug administration. 
Investigators will report hypersensitivity reactions that occur after 24 hours, only if the reactions 
are suspected to be related to study drug. 
Events of Disordered Coagulation
Bleeding AESI
Although activated partial thromboplastin time (aPTT) prolongation due to plasma kallikrein 
inhibition is an artifactual in vitro phenomenon, as a precautionary measure in evaluating the 
safety of lanadelumab, bleeding events will be reported as AESI for this study. Investigators will 
report all diagnoses, or signs and symptoms when diagnoses cannot be determined, that are 
consistent with a clinical event of bleeding. Coagulation testing (aPTT, PT, INR) should be 
performed when possible, and when temporally reasonable, with any reports of bleeding or for 
clinical conditions possibly indicative of bleeding.
Hypercoagulable AESI
Investigators will report all diagnoses, or signs and symptoms when diagnoses cannot be 
determined, that are consistent with a thrombotic or embolic etiology. 
8.2.6
Other 
8.2.6.1
Clinical Pharmacology 
Blood samples for the measurement of plasma lanadelumab concentration will be obtained at the 
study days specified in Table 2 and Table 3. Samples should be obtained at pre-dose (ie, within 
2 hours prior to dosing), with the exception of Day 4, Day 14 (for q4wks dose regimen only), 
and Day 182, when the samples may be collected at any time of the scheduled day. 
 
8.2.6.2
Pharmacodynamics 
Blood samples for the measurement of cHMWK, 
 will be obtained at the study 
days specified in Table 2 and Table 3. Samples should be obtained at pre-dose (ie, within 2 hours 
prior to dosing), with the exception of Day 4, Day 14 (for q4wks dose regimen only), and 
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8.2.6.6
Healthcare Resource Utilization 
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8.2.6.7
Self-administration of Lanadelumab
Self-administration of lanadelumab is defined as administration by a subject (aged 6 years or 
older) or parent/caregiver, either at the clinic or in an offsite location. Self-administration of 
lanadelumab by the subject is only permitted for those aged 6 years or older who have 
demonstrated the necessary skills for self-treatment, as assessed the investigator. Subjects less 
than 6 years of age must have a parent/caregiver self-administer lanadelumab in this study.
Self-administration by the subject (aged 6 years or older) or parent/caregiver is allowed after the 
subject (aged 6 years or older) or parent/caregiver has received appropriate training by the 
investigator or designee and their understanding is confirmed. The subject (aged 6 years or older) 
or parent/caregiver may initiate self-administration in an offsite setting after the subject has 
received the first 2 doses of lanadelumab at the study site (administered by study personnel or 
health care provider) and may continue to self-administer all subsequent doses. The subject is 
required to return to the clinic for visits as outlined in the schedule of events. At these in-clinic 
visits, the subject (aged 6 years or older) or parent/caregiver may opt to continue to self-
administer lanadelumab or opt for administration by study personnel or health care provider.
The investigator or designee will train subjects (aged 6 years or older) or parents/caregivers who 
elect to self-administer lanadelumab on the following:

The parent/caregiver’s transportation of investigational product using a sponsor-provided 
cooler, and the recommended storage conditions of investigational product when stored at 
an offsite location. 

Maintenance of accurate records regarding each administration of investigational product 
including supply identification (ie, lot/kit number), date and time of injection, injection 
site location, infusion time, and if applicable, any reason the self-administration could not 
be completed as instructed.

Retention of all used and unused vials of investigational product for drug accountability 
purposes.

Additional information, as provided in the Pharmacy Manual. 
Site check-in will occur throughout the treatment period as specified in Table 2 and Table 3. If a 
subject does not have a scheduled on-site visit on study days specified in these tables, site 
personnel will perform a site check-in (within 3 days of the study day) to collect AEs and 
concomitant medications, ensure all HAE attacks have been appropriately documented and, if 
applicable, ensure that self-administration of lanadelumab (by the subject [aged 6 years or older] 
or parent/caregiver) has occurred as scheduled. The preferred method of site check-in is a 
telephone call; however, an alternate method of contact may be considered as site policies 
permit.
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Table 8:
Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samplesa
2.5
15
37.5
Pharmacodynamic (cHMWK, 
) 
samples
2.7
15
40.5
HBsAg, HIV, HCV (virology)
6
1
6
C1-INH, C4, C1q at screening
5
1
5 
Anti-drug antibody testing samples
2.5
10
25
Safety
Clinical Chemistry
1
13
13
Coagulation
2.7
13
35.1
Hematology
1
13
13
Total
23.4
81b
175.1
C1-INH=C1 esterase inhibitor; cHMWK=cleaved high molecular weight kininogen; HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; PK=pharmacokinetic.
a The first 0.25 mL will be discarded if a catheter is used, after which, withdraw 2.25 mL and dispense into the appropriate tube 
for PK sampling. A total of 2.5 mL of blood drawn has been used in determination of sample volume.
b This represents the total number of samples collected during the study. The number of samples drawn at any given study visit is 
expected to range from 3 to 7.
8.2.8
Blood Sample Collection, Storage, and Shipping
Blood samples for laboratory assessments will be collected at the site by a trained site staff 
designated and/or approved by the study investigator. Details for the collection, processing, 
storage and shipment of samples for all laboratory determinations will be provided in the 
Laboratory Manual. Biological material will be stored and secured in a manner that assures that 
unauthorized access is prohibited and the samples are not lost, allowed to deteriorate, or 
accidentally or illegally destroyed.
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9.
STATISTICAL CONSIDERATIONS
9.1
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the clinical outcomes and safety data, as well as describe the approaches to be taken 
for summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock.
All statistical analyses will be performed using SASVersion 9.3 or higher (SAS Institute, Cary, 
NC 27513). 
9.2
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
Interim analyses of study data will be undertaken as described below. No adaptive design or data 
monitoring committee (DMC) is planned for this study. 
After 5 subjects receive at least 5 doses of lanadelumab, an interim PK analysis will be 
conducted to evaluate the proposed dose regimens using available data for this study.
A formal interim data analysis to support the supplemental marketing application submission 
will summarize the safety, PK, PD, clinical outcomes, 
, and immunogenicity of the first 
26 weeks of treatment with lanadelumab in children 2 to <12 years of age with HAE (Treatment 
Period A).
An interim clinical study report summarizing data up to Treatment Period A and a final clinical 
study report summarizing data from the entire study duration will be prepared.
9.3
Sample Size and Power Considerations
The sample size for this pediatric study is driven by feasibility considerations as enrollment of 
pediatric patients 2 to <12 years old is expected to be difficult. Statistical analyses will be 
descriptive in nature. The primary emphasis will be to assess the safety and PK of lanadelumab 
in this age group, but also to generate data on clinical outcomes if subjects have sufficient 
baseline attack frequency for evaluation. 
At least 20 subjects will be enrolled to ensure a minimum of 15 subjects complete 1 year (52 
weeks) of treatment on the study. Given the limited number of pediatric subjects with HAE who 
will fall within this age category and have a history of angioedema attacks appropriate to meet
the study inclusion criteria (Caballero, 2013), this number is considered a reasonable target at 
study initiation with respect to the ability to enroll eligible subjects.
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9.4
Statistical Analysis Set(s)
Safety Analysis Set is defined as all subjects who receive any study drug.
Pharmacokinetic Set (PK Set) is defined as all subjects in the Safety Analysis Set who have at 
least 1 evaluable post dose PK concentration value. 
Pharmacodynamic Set (PD Set) is defined as all subjects in the Safety Analysis Set who have at 
least 1 evaluable post dose PD value.
9.5
Analysis Set Description and Exposure
9.5.1
Subject Disposition
The numbers of subjects treated with study drug, completed the study, and discontinued 
prematurely by reason will be summarized for each analysis population.
9.5.2
Demographics and Other Baseline Characteristics
Baseline and demographic variables will be summarized for each analysis population.
9.5.3
Medical History
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by SOC and PT for each analysis population.
9.5.4
Treatment Exposure and Compliance
Treatment compliance and the extent of exposure to study drug will be described by the 
percentage of planned doses received by the subject, total number of doses received by the 
subject, and the number and percentage of subjects that received at least 80% of planned doses, 
summarized for each analysis population.
9.5.5
Prior and Concomitant Medications
Concomitant medications will be coded using the World Health Organization-Drug Dictionary. 
The number and percentage of subjects with prior or concomitant medications will be 
summarized by therapeutic class and PT for each analysis population. A separate, similar table 
will be provided for the subset of concomitant medications classified as rescue medications.
9.6
Clinical Outcome Analyses
The clinical outcomes analysis is a secondary study objective and will be conducted using the 
Safety Analysis Set. Data will be summarized by dose group and overall during each treatment 
period, partitioned by dose regimen for subjects with dose modifications. This study is not 
designed for statistical hypothesis testing, and given the small sample size and the primary study 
objective (PK and safety), only descriptive analysis will be done, and the following will apply:

Continuous clinical outcome endpoints (eg, HAE attack rates) will be analyzed using 
descriptive statistics including number of subjects, mean, standard deviation (SD), 
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median, minimum, and maximum. Whenever appropriate, clinical outcome endpoints 
will be summarized for the observation period, each efficacy evaluation period, and each 
efficacy evaluation period change from observation period by treatment. The baseline is 
defined as the last non-missing value prior to initial dose of study drug.

Categorical clinical outcome endpoints (eg, attack severity) will be summarized by the 
number of subjects in each category and the percentage of subjects out of the total in the 
respective analysis set.

Time-to-event endpoint (eg, time to the first HAE attack) will be analyzed using Kaplan-
Meier estimates. Summaries will include median time and quartiles, if estimable, and 
corresponding 95% confidence intervals.
Clinical outcome endpoints will be evaluated for each of the following 5 efficacy evaluation 
periods: 

Overall treatment period (Day 0 [after study drug administration] through Day 364 
[Week 52])

Treatment Period A (Day 0 [after study drug administration] through Day 182 [Week 
26])

Treatment Period B (Day 183 through Day 364 [Week 52])

Overall presumed steady state period (Day 70 [Week 10] through Day 364 [Week 52])

Presumed steady state period for Treatment Period A (Day 70 [Week 10] through 
Day 182 [Week 26])
9.6.1
Primary Clinical Outcome Endpoint
Clinical outcome measures are secondary endpoints for the study.
9.6.2
Secondary Clinical Outcome Endpoints
The primary clinical outcome endpoint will be the normalized number of investigator-confirmed 
HAE attacks for the overall treatment period.
The other clinical outcome endpoints are as follows:

Normalized number of investigator-confirmed HAE attacks for each efficacy evaluation 
period other than the overall treatment period.

Time to the first attack, ie, duration that a subject is attack-free until their first attack for 
each efficacy evaluation period.

Normalized number of investigator-confirmed HAE attacks requiring acute therapy use
for each efficacy evaluation period.

Normalized number of moderate or severe investigator-confirmed HAE attacks for each 
efficacy evaluation period.
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
Normalized number of high morbidity investigator-confirmed HAE attacks for each 
efficacy evaluation period.

Characteristics of investigator-confirmed HAE attacks for each efficacy evaluation 
period, including duration, severity, attack location, and rescue medication use.

Achievement of attack-free status for each efficacy evaluation period.
9.6.2.1
Normalized Number of Investigator-confirmed Hereditary Angioedema Attacks 
The normalized number of investigator-confirmed HAE attacks during each efficacy evaluation 
period will be expressed as a monthly HAE attack rate and will be analyzed using the Safety 
Analysis Set.
The normalized investigator-confirmed HAE attack rate during each efficacy evaluation period 
will be calculated for each subject as the number of investigator-confirmed HAE attacks 
occurring during the efficacy evaluation period divided by the number of days the subject 
contributed to the efficacy evaluation period multiplied by 28 days. The total number of attacks 
as well as the subject-time in months, where a month is defined as 28 days, will also be 
presented.
The baseline investigator-confirmed HAE attack rate will be calculated for each subject as the 
number of investigator-confirmed HAE attacks occurring during the observation period divided 
by the number of days the subject contributed to the observation period multiplied by 28 days.
The baseline investigator-confirmed attack rate, as well as the investigator-confirmed attack rate, 
change from baseline, and percent change from baseline for each efficacy evaluation period will 
be summarized for the Safety Analysis Set. In addition to the descriptive statistics for attack 
rates, the summary will include the total number of investigator-confirmed HAE attacks reported 
during each period and subject-time in months that each subject contributed to each period. 
Figures will be created for the Safety Analysis Set by plotting the on-study investigator-
confirmed HAE attacks reported during each efficacy evaluation period relative to Day 0 for 
each subject.
The number of investigator-confirmed HAE attacks per month will be summarized by month 
(per 28-day interval) for the Safety Analysis Set. The summary will include descriptive statistics 
for baseline investigator-confirmed attack rate, as well as monthly investigator-confirmed attack 
rates, monthly change from baseline, and monthly percent change from baseline for each 
efficacy evaluation period. Investigator-confirmed HAE attacks will be grouped into 28-day 
intervals using the start date of the HAE attack. The date of the first exposure to study drug in 
this study will be used as the start of the first interval and end of the interval will be the date of 
first exposure to study drug in this study plus 28 days. Each successive interval will start the last 
day of the prior interval plus 1 day and end 28 days later.
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Similar summary tables will be presented for the following clinical outcome measures for the 
Safety Analysis Set:

Normalized number of investigator-confirmed HAE attacks requiring acute treatment 

Normalized number of moderate or severe investigator-confirmed HAE attacks 

Normalized number of high-morbidity investigator-confirmed HAE attacks 
9.6.2.2
Time to First Attack
The time to the first investigator-confirmed HAE attack (days) for each efficacy evaluation 
period will be calculated from the date and time of the first dose of lanadelumab for that efficacy 
evaluation period to the date and time of the first investigator-confirmed HAE attack after the 
first open-label dose for that efficacy evaluation period. Subjects who do not experience any 
attacks during the efficacy evaluation period will be censored at the date and time of the end of 
the period. Subjects who discontinue the study during the efficacy evaluation period prior to 
experiencing their first on-study investigator-confirmed HAE attack will be censored at the date 
and time of study discontinuation. Time to the first investigator-confirmed HAE attack will be 
summarized using the Kaplan-Meier method.
9.6.2.3
Characteristics of Investigator-confirmed Hereditary Angioedema Attacks
Characteristics of investigator-confirmed HAE attacks will be summarized for each efficacy 
evaluation period at both the subject level and event level. The calculations described below will 
be conducted for clinical outcomes data partitioned within each efficacy evaluation period.
Subject level HAE attack characteristics:

HAE Attack Duration: For each subject, the mean duration of all investigator-confirmed 
HAE attacks will be calculated in hours and summarized. The subject-level average 
attack duration will be categorized into 12-hour intervals and tabulated by category (<12 
hours, 12-24 hours, >24-48 hours, and >48 hours).  

HAE Attack Severity: For each subject, the mean and maximum severity of all 
investigator-confirmed HAE attacks will be calculated using a numerical rating and 
summarized. The number and percentage of subjects will be tabulated by maximum 
attack severity (no attacks, mild, moderate, and severe).  
Event level HAE attack characteristics:

HAE Attack Location: The number and percentage of subjects with attacks, as well as the 
total number of attacks, will be tabulated by the primary attack location (peripheral, 
abdominal, and laryngeal) as determined by the investigator. Additionally, the attack 
location will be re-classified and summarized with an emphasis on the laryngeal attack. 
In this summary, an attack with either the primary or secondary location(s) identified as 
laryngeal will be considered as a laryngeal attack; otherwise attacks will be classified by 
their reported primary attack location.  
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
Rescue Medication Use: The number and percentage of subjects with rescue medication 
use for an HAE attack, as well as the number of rescue medications, will be tabulated by 
rescue medication by type (ecallantide, icatibant, nano-filtered C1-INH, plasma-derived 
C1-INH, recombinant C1-INH, fresh frozen plasma, and other) as reported in the AE 
CRF.
9.6.2.4
Achievement of Attack-free Status
The number and percentage of subjects that are attack-free will be summarized for each efficacy 
evaluation period. For subjects that discontinue treatment during the efficacy evaluation period, 
only the period of time for which the subject was on treatment will be used to evaluate attack-
free status for that efficacy evaluation period. 
9.7
Safety Analyses
Safety endpoints will be analyzed based on the Safety Analysis Set. Data will be summarized by 
dose group and treatment period, partitioned by dose regimen for subjects with dose 
modifications.

Continuous endpoints (eg, change in laboratory parameters) will be summarized using 
number of subjects (n), mean, SD, median, minimum value, and maximum value. As 
appropriate, raw (actual) values, changes from baseline, and percent changes from 
baseline will be summarized overall and at each scheduled time point. 

Categorical endpoints (eg, presence or absence of an outcome measure) will be 
summarized using counts and percentages. Summaries will include but are not limited to: 
number and percentage of subjects with an outcome measure and laboratory shift tables 
(categorical change from baseline). 
9.7.1
Adverse Events
Adverse events will be coded using the MedDRA coding dictionary.
Treatment-emergent AEs are defined as AEs with onset at the time of or following the first 
exposure to lanadelumab in this study, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. For AEs with partial onset times, non-missing date parts will be used to determine if 
the AE is treatment-emergent or not. If a determination cannot be made using the non-missing 
date as to when the AE occurred relative to study drug administration, then the AE will be 
classified as treatment-emergent.
The analyses described in this section will be based on treatment-emergent AEs; plainly referred 
to as AEs in this section for brevity.
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Related AEs are AEs classified as related to study drug by the investigator. Severe AEs are AEs 
classified as severe (grade 3) or life threatening (grade 4) by the investigator.
For this analysis, AEs will be classified to one of two analysis periods:

Treatment Period AEs will include all AEs starting at or after the first exposure to 
lanadelumab in this study to those starting before or at the subject’s last visit date during 
the treatment period in this study (AEs starting at or after treatment on Day 0 through 
Day 364 visit).  Treatment Period AEs will be further summarized for Treatment Period 
A (Day 0 through Day 182), Treatment Period B (Day 183 through Day 364), and overall 
for the entire Treatment Period (Day 0 through Day 364).

Follow-up Period AEs will include all AEs starting at or after the subject’s last visit date 
of the treatment period in this study (AEs starting after the Day 364 visit).
The number and percentage of subjects with any AE, any related AE, any SAE, any related SAE, 
any severe AE, any related severe AE, and any investigator-reported AESI, as well as the total 
number of events for each category will be summarized for each analysis period. The number of 
deaths due to an AE, hospitalization due to an AE and study discontinuation due to an AE will be 
summarized for each analysis period.
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by SOC, and PT for each analysis period. This tabulation will be repeated for 
related AEs, SAEs, related SAEs, severe AEs, related severe AEs, and investigator-reported 
AESI for treatment period and follow-up period AEs.
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by PT for treatment period AEs only. This tabulation will be repeated for related 
AEs and serious AEs for treatment period AEs.
All AEs will be provided in subject listings. Listings will be presented separately for each 
analysis period. In addition, subject listings of AEs causing discontinuation of study medication, 
AEs leading to death, SAEs, related AEs, severe AEs, and AESIs will be produced.
Adverse events of special interest for this study are hypersensitivity reactions and disordered 
coagulation (hypercoagulability events and bleeding events). Standardized MedDRA Queries 
(SMQ) for each AESI will be performed using the study data. The number an percentage of 
subjects with an AESI, as well as the total number of AESIs, will be summarized by SOC and PT 
for each analysis period. Separate summary tables will be created for each AESI and for those 
events with the SMQs classified as related, serious, related serious, severe, and related severe. A 
listing detailing the PT within the SMQ will be provided.
9.7.2
Laboratory Test Results
Baseline is defined as the last non-missing value prior to the first exposure to lanadelumab. 
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Actual values and change from baseline clinical laboratory tests will be summarized by study 
visit. If more than one laboratory result is reported per study visit per parameter, the last non-
missing result will be selected for analysis.
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the investigator. The number of subjects with a non-missing result, 
and the number and percentage of subjects with a clinically significant result less than the lower 
limit of normal (LLN), non-clinically significant result less than the LLN, within the normal 
range, non-clinically significant result more than the ULN, and clinically significant result more 
than the ULN will be summarized by study visit. If more than one laboratory result is reported 
per study visit per parameter, the result yielding the most severe classification will be selected 
for analysis.
Categorical laboratory test results will be summarized by study visit. If more than one laboratory 
result is reported per study visit per parameter, the result yielding the most severe classification 
will be selected for analysis. Subjects with clinically significant abnormal laboratory test results 
will be listed. This listing will include all results of the laboratory parameter that was abnormal 
and determined to be clinically significant by the investigator for a subject across study visit to 
identify any trends.
9.7.3
Vital Signs
Baseline is defined as the last non-missing value prior to the first exposure to lanadelumab. 
Actual values and changes from baseline in vital signs will be summarized by study visit and 
study time point. All vital sign data will be presented in subject listings.
Vital sign values will be classified according to clinical significance as determined by the 
investigator. The number of subjects with a non-missing result, and the number and percentage 
of subjects with a non-clinically significant result and clinically significant result will be 
summarized by study visit and study time point. If more than one vital sign result is reported per 
study visit and study time point per parameter, the result yielding the most severe classification 
will be selected for analysis.
Subjects with clinically significant vital sign values will be listed. This listing will include all 
results of the vital sign parameter that was determined by the investigator to be clinically 
significant for a subject across study time points to identify any trends.
9.8
Other Analyses
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9.8.2
Pharmacokinetic/Pharmacodynamic Analyses
A descriptive summary analysis will be performed for plasma concentrations of lanadelumab, as 
appropriate, using nominal time points. 
A descriptive summary analysis will be performed for cHMWK levels, 
, as 
appropriate, using nominal time points. 
The PK and PD properties of lanadelumab (including PK parameters, cHMWK, 
, 
and 
 as appropriate) will be evaluated by a population modeling and a 
simulation approach using data from this study and from all other studies in the lanadelumab 
clinical development program. A separate clinical pharmacology SAP will support the 
population PK and PD analysis and the analysis results will be reported separately. 
9.8.3
Immunogenicity Analyses
Immunogenicity will be evaluated based on the number and percentage of subjects with positive 
ADAs and whether they were neutralizing or non-neutralizing. Data will be summarized by 
study visit and overall.
9.9
Statistical/Analytic Considerations
9.9.1
Multiplicity Adjustment
No adjustment for multiple comparisons will be performed. Any statistical testing will be 
considered exploratory.
9.9.2
Handling of Missing Data
All available data will be included in the analysis. No imputation of missing data will be 
performed except for the handling of partial or missing AE start dates as described in 
Section 9.7.1.
9.9.3
Multicenter Studies
Data from all study sites that participate in this protocol will be combined so that an adequate 
number of subjects will be available for analyses.
9.9.4
Subgroup Analyses
Subgroup analyses are planned for the number of investigator-confirmed HAE attacks during the 
efficacy evaluation period and AEs using the Safety Analysis Set.  
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The following subgroups will be used:

Age Group: (2 to <9 (years), 9 to <12 (years))
9.10
Sensitivity Analyses
The following sensitivity analysis will be performed on the number of investigator-confirmed 
HAE attacks during each efficacy evaluation period for the Safety Analysis Set to evaluate the 
robustness of the results. Data summaries will parallel those described for the number of 
investigator-confirmed HAE attacks during each efficacy evaluation period.
The analysis will be repeated using all subject-reported HAE attacks instead of limiting the 
analysis to those attacks that were investigator confirmed.
To evaluate the impact of treatment discontinuation on the achievement of attack-free status for 
each efficacy evaluation period, 2 sensitivity analyses will be conducted.  The first will be based 
only on the subset of subjects that complete the efficacy evaluation period.  The second will 
include all subjects in the analysis set, but attribute subjects that discontinue treatment during the 
efficacy evaluation period as not attack-free.
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
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APPENDIX 1
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS
Appendix 1.1
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.
Appendix 1.2
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 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 of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO, as necessary.
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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 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. 
The sponsor will provide the ECs with a copy of the same summary.
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
Appendix 1.3
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.
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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.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), 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.
Documentation and Retention of Records
Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
CRF.
The final, clean CRFs with subject data must be approved (signed-off in EDC) by the 
investigator prior to database lock
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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, subject diary cards, 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 
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 1.4
Data Management Considerations 
Data Collection
The investigators’ authorized site personnel must enter into the CRF the information required by 
the study protocol, according to the CRF Completion Guidelines or similar. A study monitor will 
visit each site in accordance with the monitoring plan and review the CRF data against the source 
data for completeness and accuracy. Discrepancies between source data and data entered on the 
CRF will be addressed by qualified site personnel. When a data discrepancy warrants correction, 
the correction will be made by authorized site personnel. Data collection procedures will be 
discussed with the site at the site initiation visit and/or at the investigator’s meeting. 
Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
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 documented in an auditable manner.
Appendix 1.5
Ethical Considerations 
Informed Consent
It is the responsibility of the investigator to obtain written informed consent (and assent, where 
applicable) from all study subjects prior to any study-related procedures including screening 
assessments. All consent (and assent) 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 (and assent) 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.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form (and assent form, 
where applicable) that was reviewed by the IRB/EC and received their favorable 
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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 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 investigator agreement. 
Investigational product supplies will not be released until the sponsor has 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.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol 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 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 
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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, 
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 
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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 2
CLINICAL LABORATORY TESTS
The following clinical laboratory assessments will be performed as mentioned in Section 8.2.5.4: 
Chemistry

Albumin

Alkaline phosphatase

Alanine aminotransferase (ALT; SGPT)

Aspartate aminotransferase (AST; 
SGOT)

Bilirubin (total and direct)

Blood urea nitrogen (BUN)

Calcium

Carbon dioxide (CO2)

Chloride

Creatinine

Creatine phosphokinase (CPK)

Glucose

Phosphate

Magnesium

Potassium

Sodium

Total protein

Uric acid
Hematology

Hemoglobin

Hematocrit

Red blood cell (RBC) count

White blood cell (WBC) count with differential

Mean corpuscular volume (MCV)

Mean corpuscular hemoglobin (MCH)

Mean corpuscular hemoglobin concentration (MCHC)

Absolute platelet count
Coagulation

Prothrombin time

Activated partial thromboplastin time (aPTT)

International Normalized Ratio (INR)
Virology (at screening only)
Hepatitis B Surface Antigen (HbsAg); Hepatitis C Virus (HCV); Human Immunodeficiency 
Virus (HIV)
See Section 8.2.7 for volume of blood to be drawn.
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APPENDIX 3
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING
Appendix 3.1
Adverse Event Definitions
An adverse event (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 a clinically significant laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
causality is suspected (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 clinical manifestation of signs, symptoms or 
outcomes (whether considered related to investigational product or not and 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 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:
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
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.

Reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), 
hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E 
virus (HEV), or parvovirus B19 (B19V)
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 latest version of the IB 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 latest version of the IB 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 from 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
Symptoms of the Disease under Study 
As discussed in Section 8.2.5.5 of this protocol, HAE attacks will be captured as AEs in this 
study and will be evaluated in accordance with HAARP (Appendix 5).
Clinical Laboratory and Other Safety Assessment
A change in the value of a clinical laboratory or vital sign measure 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 warning of an already clinically 
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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 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.
In general, laboratory abnormalities are not considered AEs unless they are associated with 
clinical signs or symptoms, or require medical intervention. A clinically significant laboratory 
abnormality that is independent from a known underlying medical condition and that requires 
medical or surgical intervention, or leads to lanadelumab interruption or discontinuation, will be 
considered an AE.
When laboratory abnormalities are considered to be AEs, the severity of these AEs will be 
assessed according to the DMID Pediatric Toxicity Table (Appendix 6).
Where discrepancies in the upper limit of normal (ULN) and lower limit of normal (LLN) of 
laboratory ranges occur between those included in the DMID tables and those of the laboratory 
that performs the assays, the values provided by the laboratory will be used for assignment of 
severity grade. Clinical significance of individual laboratory AEs will be determined by the 
investigator with input from the medical monitor as needed. 
The following is an exception to defining clinically significant, abnormal laboratory values as 
AEs: 

aPTT prolongation in the absence of any associated bleeding or other evidence of clinical 
relevance will not be considered a clinically significant laboratory abnormality or AE. In 
the appropriate physiologic setting, such as IV heparin therapy, aPTT can be used to 
monitor bleeding risk. However, as noted in the investigators brochure, aPTT 
prolongation due to plasma kallikrein inhibition is an artifactual in vitro phenomenon. 
Although plasma kallikrein drives fibrin formation in the aPTT assay, plasma kallikrein-
driven coagulation does not appear to have hemostatic or other physiologically important 
functions in vivo. It is well documented that, in humans, deficiency of factor XII or 
prekallikrein (and thus plasma kallikrein) is not associated with abnormal bleeding, either 
spontaneous or during surgical procedures (Renne and Gruber, 2012). Despite the lack of 
clinical effect, deficiency of either protein is associated with marked prolongation of the 
aPTT.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel) or vital sign 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 or vital sign parameter is clinically 
significant and represents an AE.
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Appendix 3.2
Collection of Adverse Events
All AEs/SAEs are collected from the time the informed consent document is signed until the 
defined follow-up period stated in Section 8.1.4. 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.
Appendix 3.3
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 a 
new AE of severe dyspepsia (with the appropriate date of onset) should be documented in the 
source.
In this study, the severity of all AEs will be assessed according to the DMID Pediatric Toxicity 
Table (Appendix 6). HAE attacks are also captured as AEs in this study; HAE attacks assessed 
as described in HAARP (Appendix 5), which includes an assessment using HAARP criteria and 
an assessment using DMID criteria.
For abnormalities not specifically found in the Toxicity Tables, the following general scale will 
be used to estimate grade of severity:

GRADE 1 (Mild): Transient or mild discomfort; no medical intervention/therapy required

GRADE 2 (Moderate): Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required

GRADE 3 (Severe): Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible 

GRADE 4 (Life-threatening): Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
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The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe nausea). This is not the same as “serious,” which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning.
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.
The following additional guidance may be helpful: 
The causal relationship between lanadelumab and the AE will be assessed using one of the 
following categories:
Not Related: Factors consistent with an assessment of Not Related include:

Temporal relationship is lacking (eg, the event did not occur within a reasonable time 
frame following administration of lanadelumab); or

Other causative factors more likely explain the event (eg, a pre-existing condition, other 
concomitant treatments).
Related: Factors consistent with an assessment of Related include:

A positive temporal relationship (eg, the event occurred within a reasonable time frame 
following administration of lanadelumab); or

The AE is more likely explained by administration of lanadelumab than by another cause 
(ie, the AE shows a pattern consistent with previous knowledge of lanadelumab or the 
class of lanadelumab).
Outcome Categorization
The outcome of AEs must be documented in the source during the course of the study. Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved
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
Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown
If applicable, action taken (ie, dose increased, dose not changed, dose reduced, drug interrupted, 
drug withdrawn, not applicable, or unknown) will also be recorded on the AE CRF. 
Appendix 3.4
Safety Reporting
Reference Safety Information
The RSI for this study is the lanadelumab latest investigator’s brochure, 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 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 3.9) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire “Clinical Study Adverse Event Form for 
Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol”, 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 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.
Appendix 3.5
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 8.1.4 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 reported first becoming aware of the event.
Appendix 3.6
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 
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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.
The investigator is required to follow SAEs until resolution regardless of whether the subjects 
are still participating in the study. SAE resolution is defined as:

Resolved with or without residual effects.

A return to baseline for a pre-existing condition.

Laboratory values have returned to baseline or stabilized.

The investigator does not expect any further improvement or worsening of the event.

Fatal outcome (see Appendix 3.7)—if an autopsy is performed; the autopsy report is 
requested to be provided to the sponsor as soon as it is available.
Appendix 3.7
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). The 
investigational product action of withdrawn should not be selected solely as a result of the 
subject’s death.
Appendix 3.8
Pregnancy 
All pregnancies are reported from the time informed consent is signed until the defined follow-
up period stated in Section 8.1.4.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Drug Safety Department using the Clinical Study Pregnancy Report Form. 
A copy of the Clinical Study 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.
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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 Clinical Study Pregnancy Report 
Form. The test date of the first positive serum/urine β-hCG test or ultrasound result will 
determine the pregnancy onset date.
Appendix 3.9
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 3. 
Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of investigational product higher 
than the protocol-prescribed dose

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
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All investigational product provided to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.
Appendix 3.10
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.
Appendix 3.11
Regulatory Agency, Institutional Review Board, Ethics Committee and 
Site Reporting
The sponsor and the clinical CRO are responsible for notifying the relevant regulatory authorities 
of related, unexpected SAEs. The clinical CRO is responsible for notifying the relevant US and 
Canada central and local IRBs and EU central ECs 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 that occur at his or her site as required by IRB/EC procedures (see Appendix 1.5).
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HAEATTACKASSESSMENTANDREPORTING PROCEDURES (HAARP)
Title:
HAE Attack Assessment and Reporting Procedures (HAARP)
Product Name:
TAK743 / SHP643, lanadelumab (formerly DX-2930)
Sponsor:
Dyax Corp. (a wholly-owned, indirect subsidiary of Shire plc) (Shire plc, a wholly-
owned subsidiary of Takeda Pharmaceutical Company Limited)
300 Shire Way, Lexington, MA 02421 USA
Original Date 
(v1.0)
14 September 2015
Version 2.0:
29 June 2017
Version 3.0:
06 May 2019
Confidentiality Statement
This document is the property of Shire. The information in this document contains trade secrets and commercial
information that are privileged or confidential and may not be disclosed without the express written permission
of the sponsor unless required by federal or state lawor regulations. Any person to whom the information is
disclosed must be informed that the information is privileged or confidential and may not be further disclosed by
them. These restrictions on disclosure will apply equally to all future information supplied to you that is
indicated as privileged or
confidential.
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TABLE OF CONTENTS
HAEATTACKASSESSMENTANDREPORTINGPROCEDURES (HAARP).............................1
TABLE OF CONTENTS..................................................................................................................2
LIST OF ABBREVIATIONS ..........................................................................................................3
1.
PURPOSE.................................................................................................................................4
2.
DEFINITION OF AN ATTACK ..............................................................................................4
3.
REPORTING AND ASSESSMENT OF ATTACK DATA .....................................................5
3.1
Subject (or Parent/Caregiver) Reported Symptoms...................................................5
3.1.1
Attack Information...................................................................................................5
3.1.2
Worsening Symptoms..............................................................................................6
3.1.3
Subject Training.......................................................................................................6
3.1.4
Reporting Multiple Attacks......................................................................................6
3.1.5
Subject (or Parent/Caregiver) Contact with Sites....................................................6
3.2
Site Contact with the Subject .....................................................................................6
3.2.1
Review, Documenting, and Assessing a Reported Attack.......................................7
3.2.2
Site Training.............................................................................................................8
3.3
Hereditary Angioedema Attacks as Adverse Events..................................................8
4.
INVESTIGATOR ATTACK ASSESSMENT........................................................................10
2
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LIST OF ABBREVIATIONS
AE
adverse event
eCRF
electronic case report form
HAARP
HAE Attack Assessment and Reporting Procedures
HAE
hereditary angioedema
SAE
serious adverse event
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1. PURPOSE
This document applies to clinical trials that involve investigator adjudication/assessment of 
angioedema attacks. The purpose of this document is to provide a definition of a hereditary 
angioedema (HAE) attack and to define a standardized set of procedures for the subject (or 
parent/caregiver) reporting and investigator assessment of events reported by subjects to 
determine whether those events meet the criteria of an angioedema attack as defined in this 
document. 
2. DEFINITION OF AN ATTACK
To be confirmed as an HAE attack, the event must have symptoms or signs consistent with an 
attack in at least 1 of the following locations:

Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region

Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea

Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx
Despite the presence of these symptoms, the investigator may still determine clinically that the 
event did not represent an HAE attack if there are features that strongly refute such a diagnosis. 
For example, the reported event is accompanied by symptoms that are not consistent with an 
angioedema attack (eg, urticaria), the reported event persists well beyond the typical time course 
of an attack (eg, ˃7 days), or there is a likely alternate etiology for the event (eg, the subject’s 
abdominal symptoms are attributable to a viral gastroenteritis outbreak in the household).
To be counted as a unique attack distinct from their previous attack, the new symptoms must 
occur at least 24 hours after complete resolution of the prior attack’s symptoms.
Attacks that progress from 1 body site (physical location on the body) to another will be 
considered a single attack. Attacks that begin to regress and then worsen before complete 
resolution will be considered 1 attack.
Attack resolution is defined as when the subject no longer has symptoms of the attack. 
Prodromal symptoms by themselves are not considered an attack.
Subject (or parent/caregiver) report of use of acute HAE attack treatment for an attack by itself is 
not confirmation that an attack met HAE attack criteria. 
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3. REPORTING AND ASSESSMENT OF ATTACK DATA
At screening for applicable clinical trials, subject HAE attack history will be collected by the site 
for entry into the clinical database. Information collected will include any prior history of 
laryngeal attacks, attack frequency, average severity, predominant location(s), average duration, 
acute attack therapy use, and history of long-term prophylaxis.
During the relevant study periods, as defined in the applicable study protocol, subjects (or 
parents/caregivers) will be instructed to contact the site within 72 hours of the start of symptoms 
of an attack. In the situation that a subject (or parent/caregiver) is incapacitated and is unable to 
contact the site, another family member or other individual with detailed knowledge of the event 
can provide the information. 
Site personnel will review the information provided by the subject (or parent/caregiver) and 
solicit additional information as necessary to document the attack. Information will be 
documented in the HAE Attack Source Worksheet by the site and will be considered source for 
the study.
A designated individual at the site (the collector) will contact the subject (or parent/caregiver) on 
a regular basis as defined in the study protocol, regardless of whether or not the subject has 
reported any attacks, in order to solicit for any attacks that may have occurred but were not 
reported or updates to previously reported attacks. In addition, during each study visit, site 
personnel will solicit for any new attack information that was not provided through previous 
contact with the subject (or parent/caregiver).
The investigator or designee (the assessor) will review the attack information and evaluate if the 
event represents a confirmed HAE attack. If necessary for the evaluation, the investigator or 
designee may contact the subject (or parent/caregiver) to receive additional information.
3.1
Subject (or Parent/Caregiver) Reported Symptoms
Subjects (or parents/caregivers) will use the sponsor-provided Daily HAE Attack Diary. Diaries 
will include a daily response documenting whether or not the subject experienced an HAE 
attack. On days a subject experiences an attack, additional information will be captured in the 
HAE Attack Worksheet that is part of the diary. Subjects (or parents/caregivers) will contact the 
study site as soon as possible, but no later than 72 hours (3 full days) after the first symptoms 
appear, to report the information. The study site will utilize the sponsor-provided HAE Attack 
Source Worksheet to document the reported attack. 
3.1.1
Attack Information
The following information should be provided by the subject (or parent/caregiver) at the time 
they are reporting an attack to the site:

Date and time symptoms of an attack were first experienced

Description of symptoms experienced, including triggers and location(s)
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
Impact on activity and whether any assistance or medical intervention was required, 
including hospitalizations or emergency department visits

Any medications used to treat the attack, including both acute therapies and other 
medications.

If the attack resolved, date and time the subject was no longer experiencing symptoms

Any other pertinent information related to the attack
Subjects (or parents/caregivers) do not have to wait for their symptoms to completely resolve to 
report an attack. Information about ongoing symptoms can be obtained by the site during the 
check-in call and/or at a scheduled study visit. Subjects (or parents/caregivers) should not 
withhold or delay any treatment that would normally be received by the subject to treat their 
attack in order to contact the site.
3.1.2
Worsening Symptoms
The site may request the subject call them back if they experience worsening symptoms and/or 
new symptoms for a reported attack. Otherwise, the new information will be captured during the 
next check-in call or scheduled study visit. Subjects (or parents/caregivers) may contact the site 
on their own to provide information about any worsening symptoms.
3.1.3
Subject Training
During screening, site personnel will train subjects (and/or parents/caregivers) on identifying 
symptoms of an attack, the requirements for reporting attacks, and the information they will be 
expected to provide. The subject (or parent/caregiver) will confirm their understanding of what is 
required of them for reporting attacks to the site. Sites will assess the subject’s (or 
parent’s/caregiver's) compliance with the reporting requirements throughout the study and may 
retrain the subject (or parent/caregiver) if necessary in order to maintain the integrity of the data 
provided to the site.
3.1.4
Reporting Multiple Attacks
If a subject experiences symptoms that he/she attributes to more than 1 unique attack, the subject 
(or parent/caregiver) may report this as multiple attacks to the site. Based on the definition of an 
attack, it will be the determination of the investigator or designee as to whether events reported 
as being separate are confirmed as separate attacks or not.
3.1.5
Subject (or Parent/Caregiver) Contact with Sites
Site personnel will establish a recommended method and time window for each subject (or 
parent/caregiver) to contact the site to report any symptoms of an attack. Sites will establish a 
primary contact person and, if possible, a back-up person, with contact information. Back-up 
plans, including call backs and/or use of back-up contacts, should be established in case the 
subject (or parent/caregiver) is unable to reach someone at the site.
3.2
Site Contact with the Subject
Sites will establish a recommended day and time window for check-in calls between study visits, 
as outlined in the study protocol. The date and time for check-ins can be modified based on when 
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the last contact with the subject (or parent/caregiver) was made. When the site is contacted by a 
subject (or parent/caregiver) reporting symptoms of an attack. The site should make sure they 
have the ability to record the information provided in a complete and accurate way. Back-up 
plans should be established in case the subject (or parent/caregiver) misses a call from the site. A 
study schedule for each subject’s on-site visits will be provided to the subject (or 
parent/caregiver) by the site.
3.2.1
Review, Documenting, and Assessing a Reported Attack
During contact with the subject (or parent/caregiver), whether initiated by the subject (or 
parent/caregiver) or at a regular check-in, site personnel should ask the subject (or 
parent/caregiver) to provide them information about new or ongoing HAE attacks experienced 
by the subject.
The site will try to obtain all information necessary to document the attack completely. Missing 
information may impact the assessment of an attack and should be avoided whenever possible.
Complete and accurate documentation of each reported attack is important to making an 
investigator assessment of the attack. The site should document the following information about 
each attack reported by the subject (or parent/caregiver):

Date and time of contact with the subject (or parent/caregiver)

Date and time the subject first experienced symptoms

Description of symptoms experienced, including location(s)

Description of any HAE attack triggers

Impact on daily activity and whether any assistance was required

If the attack has resolved or is ongoing. If the attack has resolved, the date and time the 
subject was no longer experiencing any symptoms of the attack.

Names and dates and times of any medications used to treat the attack including HAE 
acute therapy or other non-HAE treatments. 

If hospitalization occurred

If a trip to the emergency department occurred
Additional probing questions about what the subject experienced to determine:

If the subject only experienced prodromal symptoms

If the subject experienced anything different than their typical attack

If there were any possible alternative etiologies of the symptoms. For example, a viral 
gastroenteritis outbreak in the household could explain abdominal symptoms
The overall severity of the subject’s attack will be determined by the site using the following 
definitions (per HAARP):

Mild: Transient or mild discomfort

Moderate: Mild to moderate limitation in activity - some assistance may be needed

Severe: Marked limitation in activity, assistance required
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The site will also document the date and time of investigator or designee review, the official 
designation of the event as an attack or not, and if applicable, the reason why an event is not 
considered an attack.
All reported attacks will be entered by site personnel into the electronic case report form (eCRF).
3.2.2
Site Training
Site personnel responsible for collecting attack information about subject HAE attacks will need 
to pass a “collector” training assessment covering the following:

Definition of an HAE attack

Requirements of subjects (or parents/caretakers) for reporting attacks

Reporting worsening symptoms and multiple attacks

Information to be collected from subjects (or parents/caregivers) as well as the additional 
probing questions to gather context for the attack information provided

Assessment of attack severity

Entry of the attack data into the eCRF

Reporting HAE attacks as adverse events

Requirements for investigator assessment of attacks
Trainings will be conducted prior to sites screening subjects. Trainings will be documented in the 
Trial Master File. Investigators and designees will be trained on these procedures as well and 
must pass an “assessor” training in order to officially assess attacks for this study.
All responsible persons involved in assessing attacks must be listed on FDA Form 1572 or 
regulatory equivalent document as applicable.
3.3
Hereditary Angioedema Attacks as Adverse Events
At the time of each contact, including scheduled study visits, site personnel will ask if the subject 
experienced any adverse events (AEs) or changes to the medications they are taking.
All AEs, regardless of seriousness, severity, or causal relationship to study drug, will be recorded 
in the eCRF.
Any AE reported to the site meeting criteria for a serious adverse event (SAE) must be reported 
to the sponsor using the SAE Reporting Form within 24 hours of the site staff becoming aware of 
the event. Sites should also complete the appropriate AE form in the electronic data capture 
system as well. For all SAEs that are reported as HAE attacks, the principal investigator or 
physician designee will review the event within 24 hours of initial notification and, in 
accordance with HAARP, evaluate if it represented a confirmed HAE attack.
For all non-serious AEs that are reported as HAE attacks, the principal investigator or physician 
designee will review the event within 7 days of initial notification and, in accordance with 
HAARP, evaluate if it represented a confirmed HAE attack. If necessary for the evaluation, the 
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investigator or designee may contact the subject for additional information. Any subject-reported 
attack not confirmed by the investigator must have an alternate AE diagnosis recorded in the 
source documents and eCRF. All subject-reported and investigator-confirmed HAE attacks will 
also be recorded in the source documents and eCRF.
Hereditary angioedema attacks will be captured as AEs; however, all HAE attacks will be 
recorded on the designated angioedema attack page of the eCRF and not on the AE page of the 
eCRF. 
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4. INVESTIGATOR ATTACK ASSESSMENT
The principal investigator for a study site may identify a physician designee to assess patient 
angioedema symptom information and make attack determinations. Sites should be limited to 2 
individuals responsible for assessing attacks, one of them being the principal investigator.
Assessors must be experienced with HAE and familiar with the study subject’s disease history.
The assessor must review the relevant, subject-reported information and determine whether the 
event meets the criteria of an angioedema attack or not. If needed, the assessor can contact the 
subject (and/or parent/caregiver) to clarify information or ask for any additional detail. The 
determination will be documented in the source documents,  along with the date and time the 
determination was made. Any angioedema event reported by the subject (and/or 
parent/caregiver) deemed not an angioedema acute attack by the investigator must be 
accompanied by an explanation and alternative diagnosis assigned by the assessor.
When reviewing subject information, the assessor will follow the definitions of an attack as 
outlined in these procedures and, taking all available information about the event into 
consideration, will determine if it is a confirmed attack. The assessment of the attack is the 
investigator or designee’s own, and not the opinion of the subject (or parent/caregiver) or any 
other site personnel. Assessors may consult with one another about a particular subject’s attack 
but only 1 assessor makes the documented determination. It is possible for both the principal 
investigator and physician designee to assess different attacks for the same subject.
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT
1
Note:  The following toxicity table is a DRAFT and designed to provide general guidance 
on parameters for monitoring safety in clinical trials.  This toxicity table is not comprehensive and should 
not be applied directly to all trials.   
When selecting a toxicity table, the following are some of the items that must be taken into consideration: 
•
The population being studied
o
Does the clinical trial evaluate healthy subjects, subjects with a particular disease or 
condition?
•
The stage of test article development
o
Is the clinical trial a Phase I (is it for the fisrt time in human subjects?) , II, III or IV?
•
The type of test article
o
Does the clinical trial evaluate a drug, device, vaccine or other biologic agent?
•
The prior human and preclinical experience with the test article 
o
Are there any specific findings that require adjustment of the toxicity table?
o
Has it been approved for this indication in adult population?
Single site clinical trials evaluating healthy subjects should conform to the laboratory normal values at the 
single site. Multi-center clinical trials should reconcile among their laboratory normal values when 
evaluating a healthy volunteer population. 
Please confer with the DMID protocol team and DMID's Office of Clinical Research Affairs when selecting 
or developing a toxicity table for a DMID-sponsored trial. 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
2
 
 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal             LLN = Lower Limit of Normal 
Rx  = Therapy                                         Req = Required 
Mod = Moderate                                     IV  = Intravenous 
ADL = Activities of Daily Living          Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
GRADE 1 
Mild  
 
Transient or mild discomfort  
 
(< 48 hours); no medical intervention/therapy required 
GRADE 2 
Moderate 
 
Mild to moderate limitation in activity - 
some assistance may be needed; no or minimal medical 
intervention/therapy required 
GRADE 3 
Severe  
 
Marked 
limitation 
in 
activity, 
some 
assistance usually required; medical intervention/therapy required, 
hospitalizations possible 
GRADE 4 
Life-threatening 
Extreme limitation in activity, significant 
assistance required; significant 
medical 
intervention/therapy 
required, hospitalization or hospice care probable 
GRADE 5                              Death 
 
SERIOUS OR LIFE-THREATENING AEs 
 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event.  Clinical events considered to be serious or life-threatening include, 
but are not limited to:  seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common 
Toxicity Criteria (CTC), and World Health Organization (WHO)) have been adapted for 
use by the Division of Microbiology and Infectious Diseases (DMID) and modified to 
better meet the needs of participants in DMID trials. 
 
•  
For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide For Estimating Severity Grade”  located above. 
 
• 
Criteria are generally grouped by body system. 
 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supercede the use of these tables for specified criteria. 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
3 
(Selected Values for children less than or equal  
to 3 months of age – does not apply for preterm infants)  
 
 
For all parameters not listed on this table, please refer 
 to the DMID Toxicity Table for children > 3 months of age. 
HEMATOLOGY  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hemoglobin 
1-7 days old 
13.0-14.0 gm/dL 
12.0-12.9 gm/dL 
<12 gm/dL 
Cardiac Failure  
secondary to Anemia 
8-21 days old 
12.0-13.0 gm/dL 
10.0-11.9 gm/dL 
<10.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
22-35 days old 
9.5-10.5 gm/dL 
8.0-9.4 gm/dL 
<8.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
36-60 days old 
8.5-9.4 gm/dL 
7.0-8.4 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
61-90 days old 
9.0-9.9 gm/dL 
7.0-8.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
Abs Neutrophil Ct 
1 day old 
5000-7000/mm3 
3000-4999/mm3 
1500-2999/mm3 
<1500/mm3 
2-6 days old 
1750-2500/mm3 
1250-1749/mm3 
750-1249/mm3 
<750/mm3 
7-60 days old 
1200-1800/mm3 
900-1199/mm3 
500-899/mm3 
<500/mm3 
61-90 days old 
750-1200/mm3 
400-749/mm3 
250-399/mm3 
<250/mm3 
Bilirubin (Fractionated bilirubin test must be preformed when total bilirubin is elevated) 
<7 days old 
. 
20-25mg/dL 
26-30 mg/dL 
>30 mg/dL 
7-60 days old 
1.1-1.9xN 
2.0-2.9Xn 
3.0-7.5xN 
>7.5xN 
61-90 days old 
1.1-1.9xN 
2.0-2.9xN 
3.0-7.5xN 
>7.5xN 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
4
(Selected Values for children less than or equal  
to 3 months of age)  
 
 
HEMATOLOGY (continued) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Creatinine 
<7 days old 
1.0-1.7 mg/dL 
1.8-2.4 mg/dL 
2.5-3.0 mg/dL 
>3.0 mg/dL 
7-60 days old 
0.5-0.9 mg/dL 
1.0-1.4 mg/dL 
1.5-2.0 mg/dL 
>2.0 mg/dL 
61-90 days old 
0.6-0.8 mg/dL 
0.9-1.1 mg/dL 
1.2-1.5 mg/dL 
>1.5 mg/dL 
Cr Clearance 
<7 days old 
35-40 ml/min 
30-34 ml/min 
25-29 ml/min 
<25 ml/min 
7-60 days old 
45-50 ml/min 
40-44 ml/min 
35-39 ml/min 
<35 ml/min 
61-90 days old 
60-75 ml/min 
50-59 ml/min 
35-49 ml/min 
<35 ml/min 
Hypocalcemia 
<7 days old 
6.5–6.9 mEq/L 
6.0-6.4 mEq/L 
5.5-5.9 mEq/L 
<5.5 mEq/L 
7-60 days old 
7.6-8.0 mEq/L 
7.0-7.5 mEq/L 
6.0-6.9 mEq/L 
<6.0 mEq/L 
61-90 days old 
7.8-8.4 mEq/L 
7.0-7.7 mEq/L 
6.0-6.9 mEq/L 
<6.0 mEq/L 
Hypercalcemia 
<7 days old 
12.0-12.4 mEq/L 
12.5-12.9 mEq/L 
13.0-13.5 mEq/L 
>13.5 mEq/L 
7-60 days old 
10.5-11.2 mEq/L 
11.3-11.9 mEq/L 
12.0-13.0 mEq/L 
>13.0 mEq/L 
61-90 days old 
10.5-11.2 mEq/L 
11.3-11.9 mEq/L 
12.0-13.0 mEq/L 
>13.0 mEq/L 
 
 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
5
 
 (Greater than 3 months of age) 
 
LOCAL REACTIONS 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Induration 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Erythema 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Edema 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Rash at Injection Site 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Pruritus 
Slight itching at 
injection site 
Moderate itching at 
injection extremity 
Itching at injection 
extremity and other 
sites 
Itching over entire 
body 
 
HEMATOLOGY  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hemoglobin for 
children greater than 
months and less than 
2 years of age 
9.0-9.9 gm/dL 
7.0-8.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to anemia 
Hemoglobin for 
children greater that 2 
years of age 
10-10.9 gm/dL 
7.0-9.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to anemia 
Absolute Neutrophil 
Count 
750-1200/mm3  
400-749/mm3 
250-399/mm3 
<250/mm3 
Platelets 
------- 
50,000-75,000/mm3 
25,000-49,999/mm3 
<25,000/mm3 
Prothrombin Time 
(PT) 
1.1-1.2 x ULN 
1.3 -1.5 x ULN 
1.6 -3.0 x ULN 
>3.0 x ULN 
Partial 
Thromboplastin Time 
(PTT) 
1.1-1.6 x ULN 
1.7-2.3 x ULN 
2.4 -3.0 x ULN 
>3.0 x ULN 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
6
 (Greater than 3 months of age)  
 
GASTROINTESTINAL  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Bilirubin (when 
accompanied by any 
increase in other liver 
function test) 
 
1.1 - <1.25 x ULN 
 
1.25 - <1.5 x ULN 
 
1.5 – 1.75 x ULN 
 
> 1.75 x ULN 
Bilirubin (when other 
liver function are in 
the  normal range) 
 
1.1 - <1.5 x ULN 
 
1.5 - <2.0 x ULN 
 
2.0 – 3.0 x ULN 
 
> 3.0 x ULN 
AST (SGOT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
ALT (SGPT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
GGT 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
Pancreatic Amylase 
1.1-1.4 x ULN 
1.5-1.9 x ULN 
2.0-3.0 x ULN 
>3.0 x ULN 
Uric Acid 
7.5-9.9mg/dL 
10-12.4 mg/dL 
12.5-15.0 mg/dL 
>15.0 mg/dL 
CPK 
See Neuromuscular Toxicity 
Appetite 
----------------- 
Decreased appetite 
Appetite very 
decreased, no solid 
food taken 
No solid or liquid taken  
Abdominal Pain 
Mild 
Moderate-  
No Treatment Needed 
Moderate-  
Treatment Needed 
Severe-  
Hospitalized for treatment 
Diarrhea 
Slight change in 
consistency and/or 
frequency of stools 
Liquid stools 
Liquid stools greater 
that 4x the amount or 
number normal for 
this child 
Liquid stools greater than 8x 
the amount or number 
normal for this child  
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
7
 (Greater than 3 months of age)  
 
GASTROINTESTINAL (continued) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Constipation 
Slight change in the 
consistency/frequency 
of stool 
Hard, dry stools with 
a change in frequency 
Abdominal pain 
Distention and 
Vomiting 
Nausea 
Mild 
Moderate-  
Decreased oral intake 
Severe-Little  
oral intake 
Unable to ingest food  
or fluid for more than 
24 hours 
Vomiting 
1 episode/day 
2-3 episodes  
per day 
4-6 episodes per day  
Greater than 6 episodes 
per day or Intractable 
Vomiting 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
8
 (Greater than 3 months of age)  
 
ELECTROLYTES 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
CREATININE  
3 Months -2 Years of 
age  
0.6-0.8 x ULN 
0.9-1.1 x ULN 
1.2-1.5 x ULN 
>1.5 x ULN 
2 Years- 12 Years of 
age 
0.7-1.0 x ULN 
1.1-1.6 x ULN 
1.7-2.0 x ULN 
>2.0 x ULN 
Greater than  
12 Years of age 
1.0-1.7 x ULN 
1.8-2.4 x ULN 
2.5-3.5 x ULN 
>3.5 x ULN 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
9
 (Greater than 3 months of age)  
 
ELECTROLYTES  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hypernatremia 
 
<145-149 mEq/L 
150-155 mEq/L 
>155 mEq/L or 
abnormal sodium 
AND mental status 
changes 
Hyponatremia 
 
130-135 mEq/L 
129-124 mEq/L 
<124 mEq/L or 
abnormal sodium 
AND mental status 
changes 
Hyperkalemia 
5.0-5.9 mEq/L 
6.0-6.4 mEq/L 
6.5-7.0 mEq/L 
>7.0 mEq/L or 
abnormal potassium 
AND cardiac 
arrhythamia 
Hypokalemia 
3.0-3-5 mEq/L 
2.5-2.9 mEq/L 
2.0-2.4 mEq/L 
<2.0 mEq/L or 
abnormal potassium 
AND cardiac 
arrhythmia 
Hypercalcemia 
10.5-11.2mg/dL 
11.3-11.9 mg/dL 
12.0-12.9 mg/dL 
>13.0 mg/dL 
Hypocalcemia 
7.8-8.4 mg/dL 
7.0-7.7 mg/dL 
6.0-6.9 mg/dL 
<6.0 mg/dL 
Hypomagnesemia 
1.2-1.4 mEq/L 
0.9-1.1 mEq/L 
0.6-0.8 mEq/L 
<0.6 mEq/L or 
abnormal magnesium 
AND cardiac 
arrhythmia 
Hypoglycemia 
55-65 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or 
abnormal glucose 
AND mental status 
changes 
Hyperglycemia 
116-159 mg/dL 
160-249 mg/dL 
250-400 mg/dL 
>400 mg/dL or 
ketoacidosis 
Proteinuria 
Tr-1+  
or 
 <150 mg/day 
2+  
or 
150-499 mg/day 
3+  
or  
500-1000 mg/day 
4+ 
 or 
 Nephrotic syndrome 
>1000 mg/day 
Hematuria 
Microscopic <25 
Microscopic >25 
 
Gross hematuria 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
10 
cells/hpf 
cells/hpf 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
11 
 (Greater than 3 months of age) 
 
CENTRAL NERVOUS SYSTEM (CNS) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Generalized CNS 
Symptoms 
 
 
Dizziness 
Hypotonic, 
hyporesponsive 
episodes;   
Seizures; 
Apnea/Bradycardia; 
Inconsolable crying > 
3 hrs; 
Headache  
Mild 
Moderate, Responds 
to non-narcotic 
analgesia 
Moderate to Severe,  
Responds to narcotic 
analgesia 
Intractable 
Level of Activity 
 
Slightly irritable OR 
slightly subdued 
Very irritable OR 
Lethargic 
Inconsolable OR 
Obtunded 
Visual 
 
Blurriness, diplopia, 
or horizontal 
nystagmus of < 1 
hour duration, with 
spontaneous 
resolution 
More than 1 episode 
of Grade 2 
symptoms per week, 
or an episode of 
Grade 2 symptoms 
lasting more than  
1 hour with 
spontaneous 
resolution by 4 
hours or vertical 
nystagmus 
Decrease in visual 
acuity, visual field 
deficit, or oculogyric 
crisis  
Myelopathy 
 
None 
None 
Myelopathic/spinal 
cord symptoms, such 
as: pyramidal tract 
weakness and 
disinhibition, sensory 
level, loss of 
proprioception, 
bladder/bowel 
dysfunction 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
12 
(Greater than 3 months of age) 
 
PERIPHERAL NERVOUS SYSTEM  
PARAMETER 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Neuropathy/  
Lower Motor 
Neuropathy 
 
Mild transient  
Paresthesia only 
Persistent or 
progressive 
paresthesias, burning 
sensation in feet, or 
mild dysesthesia; no 
weakness; mild to 
moderate deep 
tendon reflex 
changes; no sensory 
loss 
Onset of significant 
weakness, decrease or 
loss of DTRs, sensory 
loss in "stocking 
glove" distribution, 
radicular sensory loss, 
multiple cranial nerve 
involvement; bladder 
or bowel dysfunction, 
fasciculations, 
respiratory 
embarrassment from 
chest wall weakness. 
Myopathy or 
Neuromuscular 
Junction Impairment 
Normal or mild 
 (<2 x ULN) CPK 
elevation 
Mild proximal 
weakness and/or 
atrophy not affecting 
gross motor function. 
Mild myalgias, +/- 
mild CPK elevation 
(<2 x ULN)  
Proximal muscle 
weakness and/or 
atrophy affecting 
motor function +/- 
CPK elevation; or 
severe myalgias with 
CPK >2 x ULN;  
Onset of myasthenia-
like symptoms 
(fatigable weakness 
with external, variable 
ophthalmoplegia 
and/or ptosis), or 
neuromuscular 
junction blockade 
(acute paralysis) 
symptoms 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
13 
 (Greater than 3 months of age)  
 
OTHER  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Allergy 
Pruritus without Rash 
Pruritic Rash 
Mild Urticaria 
Severe Urticaria  
Anaphylaxis, 
Angioedema 
Drug Fever (Rectal) 
. 
38.5-40C 
101.3 – 104.0F 
Greater than 40.0C 
Greater than 104.0F 
Sustained Fever:  
Equal or greater than 
40C (104.0F) for 
longer than 5 days 
Cutaneous 
Localized rash 
Diffuse 
maculopapular 
Rash 
Generalized urticaria 
Stevens-Johnson 
Syndrome or Erythema 
multiforme 
Stomatitis 
Mild discomfort 
Painful, difficulty 
swallowing, but able 
to eat and drink  
Painful: unable to 
swallow solids 
Painful:  unable to 
swallow liquids; 
requires IV fluids 
Clinical symptoms 
not otherwise 
specified in this table 
No therapy; monitor 
condition 
May require minimal 
intervention and 
monitoring 
Requires medical care 
and possible 
hospitalization 
Requires active 
medical intervention, 
hospitalization, or 
hospice care 
Laboratory values not 
otherwise specified in 
this table 
Abnormal, but 
requiring no 
immediate 
intervention; follow 
Sufficiently abnormal 
to require evaluation 
as to causality and 
perhaps mild 
therapeutic 
intervention, but not 
of sufficient severity 
to warrant immediate 
changes in study drug 
Sufficiently severe to 
require evaluation 
and treatment, 
including at least 
temporary suspension 
of study drug 
Life-threatening 
severity; Requires 
immediate evaluation, 
treatment, and usually 
hospitalization; Study 
drug must be stopped 
immediately and 
should not be restarted 
until the abnormality is 
clearly felt to be 
caused by some other 
mechanism that study 
drug 
 
 
 
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APPENDIX 7
ABBREVIATIONS
AAE
acquired angioedema
ACE
angiotensin-converting enzyme
ADA
Anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
AE-QoL
angioedema quality of life
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC0-2week,ss
area under the concentration-time curve over 2 weeks at 
steady state
AUC0-4week,ss
area under the concentration-time curve over 4 weeks at 
steady state
AUCtau,ss
area under the concentration-time curve over the dosing 
interval at steady state
-hCG
beta-human chorionic gonadotropin
BP
blood pressure
Cavg, ss
average concentration over dosing interval at steady-state
C1-INH
C1 esterase inhibitor
CFR
Code of Federal Regulations
cHMWK
cleaved high molecular weight kininogen
CHO
Chinese hamster ovary
CL/F
apparent clearance 
Cmax
maximum observed concentration
Cmax,ss
maximum observed concentration at steady state
Cmin,ss
minimum observed concentration at steady state
Ctrough,ss
predose concentration at steady state
CRF
case report form
EAACI
European Academy of Allergy and Clinical Immunology 
EAUC90
Area under the concentration-time curve at 90% maximal 
effect
eCRF
electronic case report form
age 
2
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EOS
end of study
ET
early termination
EU
European Union
EUDRA
European Union Drug Regulatory Authorities
EUDRACT
European Union clinical trials database
FDA
Food and Drug Administration
FIM
Family Impact Module
GCP
Good Clinical Practice
HAARP
HAE Attack Assessment and Reporting Procedures
HAE
hereditary angioedema
HIV
human immunodeficiency virus
HMWK
high molecular weight kininogen
HR
heart rate
HRQoL
Health-related quality of life
IC90
90% inhibitory concentration
ICH
International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IEC
independent ethics committee
IgG1
immunoglobulin G1
IMP
investigational medical product
IND
Investigational New Drug
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
ISR
injection site reaction
IV
intravenous(ly) 
LLN
lower limit of normal
LTP
long-term prophylaxis
MCH
mean corpuscular hemoglobin
MCHC 
mean corpuscular hemoglobin concentration 
MCID
minimal clinically important difference
MCV
mean corpuscular volume
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MedDRA
Medical Dictionary for Regulatory Activities
NA
not applicable
NOAEL
no-observed-adverse-effect-level
PD
pharmacodynamics(s)
PK
pharmacokinetic(s)
pKal
plasma kallikrein 
PT
preferred term
q2wks
every 2 weeks
q4wks
every 4 weeks
RBC
red blood cell
RR
respiratory rate
RSI
reference safety information
SAE
serious adverse event
SAP
statistical analysis plan
SAS
statistical analysis system
SC
subcutaneous(ly)
SD
standard deviation
SOC
system organ class
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
t1/2
terminal elimination half life
tmax
time to reach maximum observed plasma concentration
UK
United Kingdom
ULN
upper limit of normal
US(A)
United States
WAO
World Allergy Organization
WBC
white blood cell 
V/F or Vc/F
apparent volume of distribution
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11.
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