Conditions: Hereditary Angioedema
Keywords: Lanadelumab
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
The main aims of this study are to learn how lanadelumab moves through a child's body and if the children have any medical problems from lanadelumab. Other aims are to learn if prophylactic treatment with lanadelumab reduces the number and severity of HAE attacks in children, how lanadelumab affects the child's body, and if the children develop antibodies to lanadelumab.

The study doctors will treat acute HAE attacks according to their standard practice.

Participants will receive lanadelumab for up to 52 weeks. When they start treatment, participants will visit their clinic every week for the first 4 weeks. Then, they will visit their clinic every 4 weeks during treatment.

Detailed description:
This study will consists of 52-week treatment period and a 2 or 4-weeks follow-up period (depending on the treatment schedule). 52-week treatment period comprises of a 26-week treatment period A (Day 0 to Day 182) and a 26-week treatment period B (Day 183 to Day 364). Participants who complete treatment period A will immediately continue into treatment period B.

Arms:
arm 1: Participants aged 2 to \<6 years received lanadelumab subcutaneous (SC) injection at a dose of 150 milligrams (mg) for every 4 weeks (q4wks) over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). arm 2: Participants aged 6 to \<12 years received lanadelumab SC injection at a dose of 150 mg for every 2 weeks (q2wks) over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator's discretion and sponsor's medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.Participants aged 6 to \<12 years received lanadelumab SC injection at a dose of 150 mg for every 2 weeks (q2wks) over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator's discretion and sponsor's medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.

Interventions: intervention 1: Lanadelumab
Intervention descriptions: intervention 1: Participants will receive 150 mg dose of lanadelumab every 2 or 4 weeks, depending on the participants age, over the 52-week treatment period.

Protocol document:
Prot_002.pdf: 
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 2: 
22 Jun 2021 
 
 


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
Amendment 1.1 (Germany): 15 Oct 2019
Amendment 1.2 (Germany): 5 Dec 2019
Amendment 2.0: 22 June 2021 
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


For non-commercial use only


Shire
CONFIDENTIAL
Page 4
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
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
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: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 5
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 6
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION..................................3
EMERGENCY CONTACT INFORMATION................................................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF APPENDICES................................................................................................................10
1.
PROTOCOL SUMMARY......................................................................................................11
1.1
Synopsis ...................................................................................................................11
1.2
Schema .....................................................................................................................18
1.3
Schedule of Activities ..............................................................................................19
2.
INTRODUCTION..................................................................................................................28
2.1
Disease Etiology and Pathophysiology....................................................................28
2.2
Disease Diagnosis in the Pediatric Population.........................................................29
2.3
Epidemiology in the Pediatric Population................................................................30
2.4
Indication and Current Treatment Options...............................................................31
2.5
Product Background and Clinical Information ........................................................32
2.5.1
Drug Information ...................................................................................................32
2.5.2
Nonclinical Studies with Lanadelumab .................................................................34
2.5.3
Clinical Studies with Lanadelumab .......................................................................34
2.5.4
Adolescent Clinical Trial Experience....................................................................37
2.6
Study Rationale ........................................................................................................38
2.7
Benefit/Risk Assessment..........................................................................................39
2.8
Compliance Statement..............................................................................................42
3.
OBJECTIVES AND ENDPOINTS........................................................................................43
3.1
Study Objectives ......................................................................................................43
3.1.1
Primary Objective..................................................................................................43
3.1.2
Secondary Objectives.............................................................................................43
43
3.2
Study Endpoints .......................................................................................................43
4.
STUDY DESIGN ...................................................................................................................46
4.1
Overall Design..........................................................................................................46
4.2
Scientific Rationale for Study Design......................................................................47
4.3
Justification for Dose ...............................................................................................49
4.4
Duration of Subject Participation and Study Completion Definition ......................52
4.5
Sites and Regions .....................................................................................................53
For non-commercial use only


Shire
CONFIDENTIAL
Page 7
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
5.
STUDY POPULATION.........................................................................................................54
5.1
Inclusion Criteria......................................................................................................54
5.2
Exclusion Criteria.....................................................................................................55
5.3
Restrictions...............................................................................................................55
5.3.1
Medical Interventions ............................................................................................55
5.3.2
Fluid and Food Intake............................................................................................55
5.3.3
Activity ..................................................................................................................56
5.4
Reproductive Potential .............................................................................................56
5.4.1
Female Contraception............................................................................................56
5.4.2
Male Contraception................................................................................................57
6.
STUDY INTERVENTION ....................................................................................................58
6.1
Investigational Product.............................................................................................58
6.1.1
Identity of Investigational Product.........................................................................58
6.1.2
Blinding the Treatment Assignment......................................................................58
6.2
Administration of Investigational Product ...............................................................58
6.2.1
Interactive Response Technology for Investigational Product Management ........58
6.2.2
Allocation of Subjects to Treatment ......................................................................58
6.2.3
Dosing....................................................................................................................58
6.2.4
Unblinding the Treatment Assignment..................................................................60
6.2.5
Dose Modification .................................................................................................60
6.3
Labeling, Packaging, Storage, and Handling of Investigational Product.................60
6.3.1
Packaging and Labeling.........................................................................................60
6.3.2
Storage and Handling.............................................................................................61
6.4
Drug Accountability.................................................................................................62
6.5
Subject Compliance..................................................................................................63
6.6
Prior and Concomitant Therapy...............................................................................64
6.6.1
Prior Treatment ......................................................................................................64
6.6.2
Concomitant Treatment .........................................................................................64
6.6.3
Permitted Treatment...............................................................................................64
6.6.4
Prohibited Treatment .............................................................................................65
7.
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL..........................................................................66
7.1
Discontinuation of Study Treatment ........................................................................66
7.2
Reasons for Discontinuation ....................................................................................66
7.3
Withdrawal from the Study......................................................................................66
7.4
Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit..............................67
7.5
Stopping Rules .........................................................................................................67
7.5.1
Study Level Stopping Rules...................................................................................67
For non-commercial use only


Shire
CONFIDENTIAL
Page 8
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
7.5.2
Individual Stopping Rules......................................................................................67
7.5.3
Follow-Up for Subjects Meeting Stopping Criteria...............................................67
8.
STUDY ASSESSMENTS AND PROCEDURES..................................................................68
8.1
Study Periods............................................................................................................68
8.1.1
Screening Period (up to 4 weeks) ..........................................................................68
8.1.2
Baseline Observation Period (up to 12 weeks)......................................................69
8.1.3
Treatment Period....................................................................................................69
8.1.3.1
Study Visit 1; Study Day 0.....................................................................69
8.1.3.2
Study Visit 2-Visit 52; Study Day 4- Study Day 364 ............................70
8.1.3.3
Final Treatment Visit (Study Visit 52; Study Day 364).........................71
8.1.4
Follow-up Period ...................................................................................................72
8.1.5
Early Termination..................................................................................................73
8.1.6
Additional Care of Subjects after the Study ..........................................................73
8.2
Study Assessments ...................................................................................................73
8.2.1
Informed Consent...................................................................................................73
8.2.2
Eligibility Review..................................................................................................73
8.2.3
Demographic and Other Baseline Characteristics .................................................73
8.2.3.1
Medical and Medication History............................................................73
8.2.4
Clinical Outcomes..................................................................................................74
8.2.4.1
Collection of Hereditary Angioedema Attacks ......................................74
8.2.4.2
Management of Acute Hereditary Angioedema Attacks .......................74
8.2.5
Safety .....................................................................................................................74
8.2.5.1
Physical Examination.............................................................................74
8.2.5.2
Vital Signs..............................................................................................75
8.2.5.3
Pregnancy Test .......................................................................................75
8.2.5.4
Clinical Laboratory Tests for Safety Assessments.................................75
8.2.5.5
Adverse Events.......................................................................................76
8.2.5.6
Adverse Events of Special Interest (AESI)............................................77
8.2.6
Other ......................................................................................................................78
8.2.6.1
Clinical Pharmacology...........................................................................78
8.2.6.2
Pharmacodynamics.................................................................................78
8.2.6.3
Immunogenicity (Anti-drug Antibody Testing).....................................78
8.2.6.4
Biomarkers .............................................................................................79
79
8.2.6.6
Healthcare Resource Utilization.............................................................80
8.2.6.7
Self-administration of Lanadelumab......................................................81
8.2.6.8
Injection Report and Subcutaneous Administration Survey ..................82
8.2.7
Volume of Blood to Be Drawn from Each Subject ...............................................82
For non-commercial use only


Shire
CONFIDENTIAL
Page 9
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
8.2.8
Blood Sample Collection, Storage, and Shipping..................................................83
9.
STATISTICAL CONSIDERATIONS ...................................................................................84
9.1
Statistical Analysis Process......................................................................................84
9.2
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......84
9.3
Sample Size and Power Considerations...................................................................84
9.4
Statistical Analysis Set(s).........................................................................................84
9.5
Analysis Set Description and Exposure ...................................................................85
9.5.1
Subject Disposition................................................................................................85
9.5.2
Demographics and Other Baseline Characteristics................................................85
9.5.3
Medical History .....................................................................................................85
9.5.4
Treatment Exposure and Compliance....................................................................85
9.5.5
Prior and Concomitant Medications ......................................................................85
9.6
Clinical Outcome Analyses......................................................................................85
9.6.1
Primary Clinical Outcome Endpoint......................................................................86
9.6.2
Secondary Clinical Outcome Endpoints................................................................86
9.6.2.1
Normalized Number of Investigator-confirmed Hereditary 
Angioedema Attacks ..............................................................................87
9.6.2.2
Time to First Attack ...............................................................................88
9.6.2.3
Characteristics of Investigator-confirmed Hereditary Angioedema 
Attacks....................................................................................................88
9.6.2.4
Achievement of Attack-free Status ........................................................89
89
9.7
Safety Analyses........................................................................................................89
9.7.1
Adverse Events ......................................................................................................89
9.7.2
Laboratory Test Results.........................................................................................90
9.7.3
Vital Signs..............................................................................................................91
9.8
Other Analyses .........................................................................................................91
91
9.8.2
Pharmacokinetic/Pharmacodynamic Analyses ......................................................92
9.8.3
Immunogenicity Analyses .....................................................................................92
9.9
Statistical/Analytic Considerations ..........................................................................92
9.9.1
Multiplicity Adjustment.........................................................................................92
9.9.2
Handling of Missing Data......................................................................................92
9.9.3
Multicenter Studies................................................................................................92
9.9.4
Subgroup Analyses ................................................................................................92
9.10
Sensitivity Analyses .................................................................................................93
10. REFERENCES .......................................................................................................................94
11. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .........99
For non-commercial use only


Shire
CONFIDENTIAL
Page 10
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
LIST OF TABLES
Table 1
Schedule of Activities- Screening and Baseline Observation Period............19
Table 2
Schedule of Activities- Treatment Period A (Day 0 [Week 1] to Day 
182 [Week 26])..............................................................................................21
Table 3
Schedule of Activities- Treatment Period B (Day 183 [Week 27] 
through Day 364 [Week 52]) and Follow-up Period.....................................24
Table 4
Objectives and Endpoints..............................................................................44
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) ...........................................................................................................51
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) ...........................................................................................................52
Table 7
Treatment Period Dosing Schedule...............................................................59
Table 8
Volume of Blood to Be Drawn from Each Subject.......................................83
LIST OF FIGURES
Figure 1
Study Design .................................................................................................18
Figure 2
Lanadelumab Specifically Inhibits Plasma Kallikrein (pKal).......................33
LIST OF APPENDICES
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations ..........................100
Appendix 2
Clinical Laboratory Tests ............................................................................108
Appendix 3
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .......................................................109
118
Appendix 5
Hereditary Angioedema Attack Assessment and Reporting Procedures 
(HAARP).....................................................................................................119
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)................................................................................120
Appendix 7
Abbreviations ..............................................................................................121
Appendix 8
Protocol History...........................................................................................124
For non-commercial use only


Shire
CONFIDENTIAL
Page 11
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 12
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
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. 
Subjects who complete Treatment Period A will immediately continue into Treatment Period B. Subjects 6 to <12 
For non-commercial use only


Shire
CONFIDENTIAL
Page 13
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
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.
An individual subject’s maximum duration of 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. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 14
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
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: 2 or 4 weeks (depending on the treatment schedule)
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 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
For non-commercial use only


Shire
CONFIDENTIAL
Page 15
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 16
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021
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). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 17
SHP643-301 Protocol Amendment 2.0 
Lanadelumab (SHP643)
22 Jun 2021

Only treatment emergent AEs (TEAEs) will be analyzed. The number and percentage of subjects reporting 
any 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.  
For non-commercial use only


Shire
CONFIDENTIAL
Page 18
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 19
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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
Section 8.2.5.5, 
Section 8.2.5.6
For non-commercial use only


Shire
CONFIDENTIAL
Page 20
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 28
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 29
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 30
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021

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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 31
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
(diagnosed and undiagnosed) with HAE in the United 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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 32
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
(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 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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 33
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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. 
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. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 34
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Route of Administration
Lanadelumab is formulated as a liquid for injection and is intended for SC administration in the 
abdomen, thigh, or upper arm.
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 35
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 
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 
pivotal, double-blind Study DX-2930-03 and the 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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 36
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
time of attacks reported by lanadelumab-treated subjects in DX-2930-02 suggested that the 
3 planned dosing regimens would provide a meaningful range of clinical response. 
The primary objective of the study was to evaluate the efficacy of lanadelumab in preventing 
HAE attacks. The secondary objective was evaluation of the safety of repeated SC administration 
of lanadelumab. Each subject underwent a treatment period consisting of 13 doses of blinded 
investigational medicinal product (IMP) for a period of 26 weeks from the date of the first dose 
on Day 0 through 2 weeks after the final dose (for the 150 mg q4wks and 300 mg q4wks 
regimens, every second dose was placebo). Over the 26-week treatment period, all 
3 lanadelumab dose regimens, 150 mg q4wks, 300 mg q4wks, and 300 mg q2wks, resulted in a 
highly statistically significant percentage reduction in the least squares mean investigator-
confirmed HAE attack rate compared with placebo of 76%, 73%, and 87% (adjusted p<0.001), 
respectively, for the primary endpoint. During the estimated steady-state 16-week period (Day 70 
through Day 182), the percentage reduction in the mean monthly HAE attack rates for 
lanadelumab-treated subjects compared with placebo was 78% in the 150 mg q4wks arm, 81% in 
the 300 mg q4wks arm, and 91% in the 300 mg q2wks arm. Furthermore, all 3 lanadelumab 
regimens demonstrated highly statistically significant attack rate reductions compared with 
placebo for all secondary efficacy analyses (adjusted p<.001 for all comparisons): attacks 
requiring acute treatment (74% 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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 37
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Study DX-2930-04 (HELP Study ExtensionTM) was an open-label, long-term safety and efficacy 
extension study of DX-2930-03 to evaluate the IMP, lanadelumab, in preventing acute 
angioedema attacks in patients with Type I or Type II HAE. 
The open-label extension study DX-2930-04 has been completed. The study enrolled 212 total 
subjects, including 109 who rolled over from DX-2930-03 and 103 nonrollover subjects. 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 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, 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 
DX2930-03, 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 DX2930-04 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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 38
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 39
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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; 
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 
(Section 2.5.3 and Section 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 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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 40
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 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 non-rollover 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. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 41
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 
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 non-rollover 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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 42
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
is being initiated after completion of one 26-week long pivotal study and after obtaining 
16 months of safety data from the 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 
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 43
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 44
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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. 
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 46
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 47
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021

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 2 or 4 weeks (depending on the treatment schedule). 
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).
An individual subject’s maximum duration of 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 a 2 or 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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 48
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
population. Long-term 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 Section 2.5.3 and Section 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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 49
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 50
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 51
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 52
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 a 2 or 4-week post-treatment safety follow-up visit. The study 
will be completed in approximately 72 weeks. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 53
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 54
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 55
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 56
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 57
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Note: estrogen-containing medications with systemic absorption are not allowed in the study.
5.4.2
Male Contraception
The study population includes male children <12 years of age. Therefore, male contraception is 
not required in this study.
For non-commercial use only


Shire
CONFIDENTIAL
Page 58
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 59
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 60
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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
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 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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 61
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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

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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 62
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 63
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer/dispense the investigational product only to 
subjects included in this study following the procedures set out in the study protocol. Each 
subject will be given only the investigational product carrying his/her treatment assignment. All 
administered/dispensed medication will be documented in the subject’s source and/or other 
investigational product record. The investigator is responsible for ensuring the retrieval of all 
study supplies from subjects. Due to the health/safety concerns with returning the investigational 
product container, the investigator must request that subjects keep the empty investigational 
product packaging after use and return it to the site for drug accountability purposes.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 64
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 65
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021

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.

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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 66
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 67
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 immediately discontinued from the study without additional 
assessments.
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 68
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 74
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
8.2.4
Clinical Outcomes
8.2.4.1
Collection of Hereditary Angioedema Attacks 
HAE attack information will be solicited by site personnel during scheduled study visits and site 
check-ins, as shown in Table 1, Table 2, and Table 3. In addition, study subjects (or 
parent/caregivers, in the event the subject is <18 years old or is incapacitated) will be instructed 
to report details of the HAE attack to the study site within 72 hours of the onset of the attack.
The collection, reporting and assessment of HAE attacks in this study will be done in accordance 
with the 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
For non-commercial use only


Shire
CONFIDENTIAL
Page 75
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021

Cardiovascular

Abdomen

Neurological

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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 76
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
All clinical laboratory tests will be performed according to the laboratory’s standard procedures,
using established and validated methods. Reference ranges will be supplied by the laboratory and 
used to assess the results for clinical significance and out-of-range changes which may be 
associated with, or constitute, an AE. The investigator should assess out-of-range clinical 
laboratory values for clinical significance, indicating if the value(s) is/are not clinically 
significant or clinically significant. Abnormal clinical laboratory values, which are unexpected or 
not explained by the subject’s clinical condition, may, at the discretion of the investigator or 
sponsor, be repeated as soon as possible until confirmed, explained, or resolved.
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.
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, 
For non-commercial use only


Shire
CONFIDENTIAL
Page 77
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 78
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 
Day 182, when the samples may be collected at any time of the scheduled day. 
 
8.2.6.3
Immunogenicity (Anti-drug Antibody Testing)
Immunogenicity will be measured based on the presence or absence of neutralizing or 
non-neutralizing ADA in plasma. Blood samples will be collected at the study days specified in 
Table 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. 
 
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 80
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
8.2.6.6
Healthcare Resource Utilization 
Not applicable.
For non-commercial use only


Shire
CONFIDENTIAL
Page 81
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 83
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 84
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
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.
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. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 85
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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), 
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 86
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021

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.

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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 87
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 88
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.  

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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 89
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
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 non-commercial use only


Shire
CONFIDENTIAL
Page 90
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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. 
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 91
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 92
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.  
The following subgroups will be used:

Age Group: (2 to <9 (years), 9 to <12 (years))
For non-commercial use only


Shire
CONFIDENTIAL
Page 93
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 94
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
10.
REFERENCES
Agostoni, A., Aygoren-Pursun, E., Binkley, K. E., Blanch, A., Bork, K., Bouillet, L., Bucher, C., 
Castaldo, A. J., Cicardi, M., Davis, A. E., De Carolis, C., Drouet, C., Duponchel, C., 
Farkas, H.and Fay, K. 2004. Hereditary and acquired angioedema: Problems and 
progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. 
Journal of Allergy and Clinical Immunology, The, 114, S51-S131.
Agostoni, A.and Cicardi, M. 1992. Hereditary and acquired C1-inhibitor deficiency: Biological 
and clinical characteristics in 235 patients. Medicine, 71, 206-215.
Baldrick, P. 2010. Juvenile animal testing in drug development - Is it useful? Regulatory 
Toxicology and Pharmacology, 57, 291-299.
Banerji, A. 2013. The burden of illness in patients with hereditary angioedema. Ann Allergy 
Asthma Immunol, 111, 329-36.
Banerji, A., Busse, P., Shennak, M., Lumry, W., Davis-Lorton, M., Wedner, H. J., Jacobs, J., 
Baker, J., Bernstein, J. A., Lockey, R., Li, H. H., Craig, T., Cicardi, M., Riedl, M., Al-
Ghazawi, A., Soo, C., Iarrobino, R., Sexton, D. J., TenHoor, C., Kenniston, J. A., 
Faucette, R., Still, J. G., Kushner, H., Mensah, R., Stevens, C., Biedenkapp, J. C., 
Chyung, Y.and Adelman, B. 2017. Inhibiting Plasma Kallikrein for Hereditary 
Angioedema Prophylaxis. N Engl J Med, 376, 717-728.
Bennett, G.and Craig, T. 2015. Hereditary angioedema with a focus on the child. Allergy Asthma 
Proc, 36, 70-3.
Bork, K. 2013. Hereditary Angioedema with Normal C1 Inhibitor. Immunology and Allergy 
Clinics of North America, 33, 457-470.
Bork, K. 2014a. Current drugs in early development for hereditary angioedema: potential for 
effective treatment. Expert Opin Investig Drugs, 23, 887-91.
Bork, K. 2014b. An evidence based therapeutic approach to hereditary and acquired angioedema.
Current Opinion in Allergy and Clinical Immunology, 14, 354-362.
Bork, K., Hardt, J., Schicketanz, K. H.and Ressel, N. 2003. Clinical studies of sudden upper 
airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor 
deficiency. Arch Intern Med, 163, 1229-35.
Bork, K., Hardt, J.and Witzke, G. 2012. Fatal laryngeal attacks and mortality in hereditary 
angioedema due to C1-INH deficiency. J Allergy Clin Immunol, 130, 692-7.
Bork, K., Meng, G., Staubach, P.and Hardt, J. 2006a. Hereditary angioedema: New findings 
concerning symptoms, affected organs, and course. American Journal of Medicine, 119, 
267-274.
Bork, K., Staubach, P., Eckardt, A. J.and Hardt, J. 2006b. Symptoms, course, and complications 
of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J 
Gastroenterol, 101, 619-27.
For non-commercial use only


Shire
CONFIDENTIAL
Page 95
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Bowen, T., Cicardi, M., Bork, K., Zuraw, B., Frank, M., Ritchie, B., Farkas, H., Varga, L., 
Zingale, L. C., Binkley, K., Wagner, E., Adomaitis, P., Brosz, K., Burnham, J., 
Warrington, R., Kalicinsky, C., Mace, S., McCusker, C., Schellenberg, R., Celeste, L., 
Hebert, J., Valentine, K., Poon, M. C., Serushago, B., Neurath, D., Yang, W., Lacuesta, 
G., Issekutz, A., Hamed, A., Kamra, P., Dean, J., Kanani, A., Stark, D., Rivard, G. E., 
Leith, E., Tsai, E., Waserman, S., Keith, P. K., Page, D., Marchesin, S., Longhurst, H. J., 
Kreuz, W., Rusicke, E., Martinez-Saguer, I., Aygoren-Pursun, E., Harmat, G., Fust, G., 
Li, H., Bouillet, L., Caballero, T., Moldovan, D., Spath, P. J., Smith-Foltz, S., Nagy, I., 
Nielsen, E. W., Bucher, C., Nordenfelt, P.and Xiang, Z. Y. 2008. Hereditary angiodema: 
a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus 
Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann 
Allergy Asthma Immunol, 100, S30-40.
Bygum, A. 2009. Hereditary angio-oedema in Denmark: a nationwide survey. The British 
journal of dermatology, 161, 1153-8.
Bygum, A., Fagerberg, C. R., Ponard, D., Monnier, N., Lunardi, J.and Drouet, C. 2011. 
Mutational spectrum and phenotypes in Danish families with hereditary angioedema 
because of C1 inhibitor deficiency. Allergy, 66, 76-84.
Caballero, T. 2013. Angio-oedema due to hereditary C1 inhibitor deficiency in children. Allergol 
Immunopathol (Madr), 41, 45-53.
Caballero, T., Aygoren-Pursun, E., Bygum, A., Beusterien, K., Hautamaki, E., Sisic, Z., Wait, 
S.and Boysen, H. B. 2014. The humanistic burden of hereditary angioedema: results from 
the Burden of Illness Study in Europe. Allergy Asthma Proc, 35, 47-53.
Cicardi, M., Bork, K., Caballero, T., Craig, T., Li, H. H., Longhurst, H., Reshef, A.and Zuraw, 
B. 2012. Evidence-based recommendations for the therapeutic management of 
angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an 
International Working Group. Allergy, 67, 147-57.
Craig, T., Aygoren-Pursun, E., Bork, K., Bowen, T., Boysen, H., Farkas, H., Grumach, A., 
Katelaris, C. H., Lockey, R., Longhurst, H., Lumry, W., Magerl, M., Martinez-Saguer, I., 
Ritchie, B., Nast, A., Pawankar, R., Zuraw, B.and Maurer, M. 2012a. WAO Guideline for 
the Management of Hereditary Angioedema. World Allergy Organ J, 5, 182-99.
Craig, T., Pursun, E. A., Bork, K., Bowen, T., Boysen, H., Farkas, H., Grumach, A., Katelaris, C. 
H., Lockey, R., Longhurst, H., Lumry, W., Magerl, M., Martinez-Saguer, I., Ritchie, B., 
Nast, A., Pawankar, R., Zuraw, B.and Maurer, M. 2012b. WAO Guideline for the 
Management of Hereditary Angioedema. World Allergy Organ J, 5, 182-199.
Craig, T. J., Levy, R. J., Wasserman, R. L., Bewtra, A. K., Hurewitz, D., Obtulowicz, K., Reshef, 
A., Ritchie, B., Moldovan, D., Shirov, T., Grivcheva-Panovska, V., Kiessling, P. C., 
Keinecke, H. O.and Bernst 2009. Efficacy of human C1 esterase inhibitor concentrate 
compared with placebo in acute hereditary angioedema attacks. Journal of Allergy and 
Clinical Immunology, The, 124, 801-808.
Davis, A. E. 2005. The pathophysiology of hereditary angioedema. Clinical Immunology, 114, 3-
9.
Davis, C. A., Vallota, E. H.and Forristal, J. 1979. Serum complement levels in infancy: age 
related changes. Pediatr Res, 13, 1043-6.
El-Hachem, C., Amiour, M., Guillot, M.and Laurent, J. 2005. Hereditary angioneurotic edema: a 
case report in a 3-year-old child. Archives de pédiatrie, 12, 1232-6.
For non-commercial use only


Shire
CONFIDENTIAL
Page 96
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Farkas, H. 2010. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma 
Clin Immunol, 6, 18.
Farkas, H., Harmat, G., Fust, G., Varga, L.and Visy, B. 2002. Clinical management of hereditary 
angio-oedema in children. Pediatr Allergy Immunol, 13, 153-61.
Farkas, H., Varga, L., Szeplaki, G., Visy, B., Harmat, G.and Bowen, T. 2007. Management of 
hereditary angioedema in pediatric patients. Pediatrics, 120, e713-22.
Fouche, A. S., Saunders, E. F. H.and Craig, T. 2014a. Depression and anxiety in patients with 
hereditary angioedema. Annals of Allergy, Asthma & Immunology, 112, 371-375.
Fouche, C., Kenealy, T., Mace, J.and Shaw, J. 2014b. Practitioner perspectives from seven health 
professional groups on core competencies in the context of chronic care. J Interprof 
Care, 28, 534-40.
Frank, M. M., Gelfand, J. A.and Atkinson, J. P. 1976. Hereditary angioedema: the clinical 
syndrome and its management. Ann Intern Med, 84, 580-93.
Frank, M. M., Zuraw, B., Banerji, A., Bernstein, J. A., Craig, T., Busse, P., Christiansen, S., 
Davis-Lorton, M., Li, H. H., Lumry, W. R.and Riedl, M. 2016. Management of Children 
With Hereditary Angioedema Due to C1 Inhibitor Deficiency. Pediatrics, 138, 
e20160575-e20160575.
Gompels, M. M., Lock, R. J., Abinun, M., Bethune, C. A., Davies, G., Grattan, C., Fay, A. C.,
Longhurst, H. J., Morrison, L., Price, A., Price, M.and Watters, D. 2005a. C1 inhibitor 
deficiency: consensus document. Clin Exp Immunol, 139, 379-94.
Gompels, M. M., Lock, R. J., Abinun, M., Bethune, C. A., Davies, G., Grattan, C., Fay, A. C., 
Longhurst, H. J., Morrison, L., Price, A., Price, M.and Watters, D. 2005b. C1 inhibitor 
deficiency: consensus document. Clinical and Experimental Immunology, 139, 379-94.
Goring, H. D., Bork, K., Spath, P. J., Bauer, R., Ziemer, A., Hintner, H.and Wuthrich, B. 1998.
Hereditary angioedema in the German-speaking region. Hautarzt, 49, 114-22.
Jolles, S., Williams, P., Carne, E., Mian, H., Huissoon, A., Wong, G., Hackett, S., Lortan, J., 
Platts, V., Longhurst, H., Grigoriadou, S., Dempster, J., Deacock, S., Khan, S., Darroch, 
J.and Simon, C. 2014. A UK national audit of hereditary and acquired angioedema. 
Clinical & Experimental Immunology, 175, 59-67.
Kenniston, J. A., Faucette, R. R., Martik, D., Comeau, S. R., Lindberg, A. P., Kopacz, K. J., 
Conley, G. P., Chen, J., Viswanathan, M., Kastrapeli, N., Cosic, J., Mason, S., DiLeo, M., 
Abendroth, J., Kuzmic, P., Ladner, R. C., Edwards, T. E., TenHoor, C., Adelman, B. A., 
Nixon, A. E.and Sexton, D. J. 2014. Inhibition of plasma kallikrein by a highly specific 
active site blocking antibody  J Biol Chem 289  23596-608
Kuhlen, J. L., Jr.and Banerji, A. 2015. Hereditary angioedema: Special consideration in children, 
women of childbearing age, and the elderly. Allergy and Asthma Proceedings, 36, 425-
432.
For non-commercial use only


Shire
CONFIDENTIAL
Page 97
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Leeb-Lundberg, L. M. F., Marceau, F., Müller-Esterl, W., Pettibone, D. J.and Zuraw, B. L. 2005. 
International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: 
from Molecular Mechanisms to Pathophysiological Consequences. Pharmacological 
Reviews, 57, 27-77.
Lei, W. T., Shyur, S. D., Huang, L. H., Kao, Y. H.and Lo, C. Y. 2011. Type I hereditary 
angioedema in Taiwan -- clinical, biological features and genetic study. Asian Pac J 
Allergy Immunol, 29, 327-31.
Longhurst, H. J. 2017. Kallikrein Inhibition for Hereditary Angioedema. New England Journal 
of Medicine, The, 376, 788-789.
Lumry, W. R. 2013. Overview of epidemiology, pathophysiology, and disease progression in 
hereditary angioedema. American journal of managed care, The, 19, s103-10.
MacGinnitie, A. J. 2014. Pediatric hereditary angioedema. Pediatr Allergy Immunol, 25, 420-7.
Martin, P. L.and Weinbauer, G. F. 2010. Developmental Toxicity Testing of Biopharmaceuticals 
in Nonhuman Primates. International Journal of Toxicology, 29, 552-568.
Maurer, M., Magerl, M., Ansotegui, I., Aygoren Pursun, E., Betschel, S., Bork, K., Bowen, T., 
Balle Boysen, H., Farkas, H., Grumach, A., Hide, M., Katelaris, C., Lockey, R., 
Longhurst, H., Lumry, W., Martinez-Saguer, I., Moldovan, D., Nast, A., Pawankar, R., 
Potter, P., Riedl, M., Ritchie, B., Rosenwasser, L., Sanchez-Borges, M., Zhi, Y., Zuraw, 
B.and Craig, T. 2018. The international WAO/EAACI guideline for the management of 
hereditary angioedema - the 2017 revision and update. Allergy.
Morford, L. L., Bowman, C. J., Blanset, D. L., Bogh, I. B., Chellman, G. J., Halpern, W. G., 
Weinbauer, G. F.and Coogan, T. P. 2011. Preclinical safety evaluations supporting 
pediatric drug development with biopharmaceuticals: strategy, challenges, current 
practices. Birth Defects Res B Dev Reprod Toxicol, 92, 359-80.
Nanda, M. K., Elenburg, S., Bernstein, J. A.and Assa'ad, A. H. 2015. Clinical features of 
pediatric hereditary angioedema. J Allergy Clin Immunol Pract, 3, 392-5.
Nielsen, E. W., Johansen, H. T., Holt, J.and Mollnes, T. E. 1994. C1 inhibitor and diagnosis of 
hereditary angioedema in newborns. Pediatric Research, 35, 184-7.
Nordenfelt, P., Dawson, S., Wahlgren, C. F., Lindfors, A., Mallbris, L.and Bjorkander, J. 2014. 
Quantifying the burden of disease and perceived health state in patients with hereditary 
angioedema in Sweden. Allergy Asthma Proc, 35, 185-90.
Nzeako, U. C., Frigas, E.and Tremaine, W. J. 2001. Hereditary angioedema, a broad review for 
clinicians. Archives of Internal Medicine, 161, 2417-2429.
Pappalardo, E., Cicardi, M., Duponchel, C., Carugati, A., Choquet, S., Agostoni, A.and Tosi, M. 
2000. Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients 
with angioedema. Journal of Allergy and Clinical Immunology, The, 106, 1147-1154.
Read, N., Lim, E., Tarzi, M. D., Hildick-Smith, P., Burns, S.and Fidler, K. J. 2014. Paediatric 
hereditary angioedema: a survey of UK service provision and patient experience. Clin 
Exp Immunol, 178, 483-8.
Renne, T.and Gruber, A. 2012. Plasma kallikrein: novel functions for an old protease. Thromb 
Haemost, 107, 1012-3.
Roach, B., Kim, Y., Jerome, E.and Michael, A. F. 1981. Influence of age and sex on serum 
complement components in children. Am J Dis Child, 135, 918-20.
For non-commercial use only


Shire
CONFIDENTIAL
Page 98
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Roche, O., Blanch, A., Caballero, T., Sastre, N., Callejo, D.and Lopez-Trascasa, M. 2005. 
Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to 
the prevalence in Spain. Ann Allergy Asthma Immunol, 94, 498-503.
Sabharwal, G.and Craig, T. 2017. Pediatric hereditary angioedema: an update. F1000Research,
6.
Stray-Pedersen, A., Sorte, H. S., Samarakoon, P., Gambin, T., Chinn, I. K., Coban Akdemir, Z. 
H., Erichsen, H. C., Forbes, L. R., Gu, S., Yuan, B., Jhangiani, S. N., Muzny, D. M., 
Rodningen, O. K., Sheng, Y., Nicholas, S. K., Noroski, L. M., Seeborg, F. O., Davis, C. 
M., Canter, D. L., Mace, E. M., Vece, T. J., Allen, C. E., Abhyankar, H. A., Boone, P. 
M., Beck, C. R., Wiszniewski, W., Fevang, B., Aukrust, P., Tjonnfjord, G. E., Gedde-
Dahl, T., Hjorth-Hansen, H., Dybedal, I., Nordoy, I., Jorgensen, S. F., Abrahamsen, T. 
G., Overland, T., Bechensteen, A. G., Skogen, V., Osnes, L. T. N., Kulseth, M. A., 
Prescott, T. E., Rustad, C. F., Heimdal, K. R., Belmont, J. W., Rider, N. L., Chinen, J., 
Cao, T. N., Smith, E. A., Caldirola, M. S., Bezrodnik, L., Lugo Reyes, S. O., Espinosa 
Rosales, F. J., Guerrero-Cursaru, N. D., Pedroza, L. A., Poli, C. M., Franco, J. L., Trujillo 
Vargas, C. M., Aldave Becerra, J. C., Wright, N., Issekutz, T. B., Issekutz, A. C., Abbott, 
J., Caldwell, J. W., Bayer, D. K., Chan, A. Y., Aiuti, A., Cancrini, C., Holmberg, E., 
West, C., Burstedt, M., Karaca, E., Yesil, G., Artac, H., Bayram, Y., Atik, M. M., 
Eldomery, M. K., Ehlayel, M. S., Jolles, S., Flato, B., Bertuch, A. A., Hanson, I. C., 
Zhang, V. W., Wong, L. J., Hu, J., Walkiewicz, M., Yang, Y., Eng, C. M., Boerwinkle, 
E., Gibbs, R. A., Shearer, W. T., Lyle, R., Orange, J. S.and Lupski, J. R. 2017. Primary 
immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian 
disorders. J Allergy Clin Immunol, 139, 232-245.
Zuraw, B.and Christiansen, S. 2016. HAE Pathophysiology and Underlying Mechanisms. 
Clinical Reviews in Allergy & Immunology, 51, 216-229.
Zuraw, B. L. 2008. Clinical practice. Hereditary angioedema. N Engl J Med, 359, 1027-36.
Zuraw, B. L., Bernstein, J. A., Lang, D. M., Craig, T., Dreyfus, D., Hsieh, F., Khan, D., Sheikh, 
J., Weldon, D., Bernstein, D. I., Blessing-Moore, J., Cox, L., Nicklas, R. A., 
Oppenheimer, J., Portnoy, J. M., Randolph, C. R., Schuller, D. E., Spector, S. L., Tilles, 
S. A., Wallace, D., American Academy of Allergy, A., Immunology, American College 
of Allergy, A.and Immunology 2013. A focused parameter update: hereditary 
angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme 
inhibitor-associated angioedema. J Allergy Clin Immunol, 131, 1491-3.
For non-commercial use only


Shire
CONFIDENTIAL
Page 99
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
For non-commercial use only


Shire
CONFIDENTIAL
Page 100
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 101
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 102
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 103
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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).
For non-commercial use only


Shire
CONFIDENTIAL
Page 104
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 105
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 106
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 107
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 108
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 109
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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:
For non-commercial use only


Shire
CONFIDENTIAL
Page 110
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021

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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 111
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 112
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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. If the subject experiences a 
change in the severity of an AE, the event should be captured once with the maximum severity 
recorded. 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
For non-commercial use only


Shire
CONFIDENTIAL
Page 113
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 114
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021

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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 115
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 116
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 117
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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).
For non-commercial use only


Shire
CONFIDENTIAL
Page 118
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
For non-commercial use only


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.
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 119
For non-commercial use only


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
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 120
For non-commercial use only


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
3
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 121
For non-commercial use only


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. 
4
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 122
For non-commercial use only


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)
5
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 123
For non-commercial use only



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 
6
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 124
For non-commercial use only


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
7
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 125
For non-commercial use only


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 
8
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 126
For non-commercial use only


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. 
9
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 127
For non-commercial use only


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.
10
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 128
For non-commercial use only


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. 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 129
For non-commercial use only


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. 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 130
For non-commercial use only


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 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 131
For non-commercial use only


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 
 
 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 132
For non-commercial use only


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 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 133
For non-commercial use only


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  
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 134
For non-commercial use only


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 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 135
For non-commercial use only


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 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 136
For non-commercial use only


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 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 137
For non-commercial use only


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
10 
cells/hpf 
cells/hpf 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 138
For non-commercial use only


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 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 139
For non-commercial use only


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 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 140
For non-commercial use only


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 
 
 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
Page 141
For non-commercial use only


Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
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
Page 142
For non-commercial use only


Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
eCRF
electronic case report form
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
Page 143
For non-commercial use only


Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 2.0
Lanadelumab (SHP643)
22 Jun 2021
MCV
mean corpuscular volume
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
Page 144
For non-commercial use only


For non-commercial use only

SAP_003.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
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 
 
 
SAP Version and Date:  
Version 2.0:  27 September 2021 
 


Shire is a wholly owned subsidiary of Takeda Pharmaceutical Company Limited 
Statistical Analysis Plan 
for 
Full Analysis 
Lanadelumab 
Phase 3 
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 
Protocol Identifier: SHP643-301 
Study Sponsor(s): 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 
Author: 
, 
Protocol: 
Amendment 2.0: 22 June 2021 
SAP Version #: 
V2.0 
SAP Date: 
27 Sep 2021 
Status: 
Final 
Confidentiality Statement 
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


Shire 
CONFIDENTIAL 
Page 2 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
VERSION HISTORY 
Version 
Issue Date 
Summary of Changes 
1.0 
May 26, 2021 
New Document 
2.0 
Sep 27, 2021 
1) Updated based on PA 2: 
a) Individual subject participation duration 
was revised to clarify that maximum 
duration for study participation is 72 
weeks in Section 3.1. Subjects receiving 
treatment q2wks may complete the study 
in 70 weeks. 
b) Revised follow-up period to 2-4 weeks in 
Section 3.1 as follow-up period depends on 
the treatment schedule. Subjects receiving 
treatment q2wks will have a 2 week 
follow-up period (EOS Visit at Day 378); 
subjects receiving treatment q4wks will 
have a 4-week follow-up period (EOS 
Visit at Day 392). 
c) The text about the interim analysis 
summarizing data up to Treatment Period 
A has been removed from Section 3.1 and 
Sec 11 as it is no longer planned. 
d) EOS/ET visit in footnote “a” was 
incorrectly written as Day 292. This has 
been corrected to Day 392 in Appendix 1, 
Schedule of Activities. 
e) Removed the text in Section 14 as the PA 
2 has addressed the previous changes. 
 
2) Updated section 7.1 for all AEs summaries 
that summarized by SOC and PT, will be 
presented by the dose regimen the subject 
actually received and separated to Treatment 
Period A, Treatment Period B, overall 
treatment period, and Follow-up period. 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 3 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
TABLE OF CONTENTS 
VERSION HISTORY ....................................................................................................... 2 
LIST OF IN-TEXT TABLES ........................................................................................... 6 
LIST OF IN-TEXT FIGURES ......................................................................................... 6 
LIST OF APPENDICES................................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................... 8 
1. INTRODUCTION ...................................................................................................... 10 
2. OBJECTIVES, ESTIMANDS, AND ENDPOINTS.................................................... 10 
2.1 Objectives ............................................................................................................. 10 
2.1.1 Primary Objective .......................................................................................... 10 
2.1.2 Secondary Objective(s) ................................................................................... 10 
10 
2.2 Estimands ............................................................................................................. 10 
2.3 Endpoints.............................................................................................................. 14 
2.3.1 Primary Endpoint(s) ...................................................................................... 14 
2.3.2 Secondary Endpoint(s) ................................................................................... 14 
5 
3. STUDY DESIGN ........................................................................................................ 16 
3.1 General Description.............................................................................................. 16 
3.2 Randomization ..................................................................................................... 18 
3.3 Blinding ................................................................................................................ 18 
3.4 Sample Size and Power Considerations ............................................................... 18 
4. STATISTICAL ANALYSIS SETS ............................................................................. 18 
4.1 Screened Set ......................................................................................................... 18 
4.2 Safety Analysis Set................................................................................................ 18 
4.3 Pharmacokinetic Set ............................................................................................. 18 
4.4 Pharmacodynamic Set .......................................................................................... 19 
5. STUDY SUBJECTS .................................................................................................... 19 
5.1 Disposition of Subjects.......................................................................................... 19 
5.2 Protocol Deviations............................................................................................... 19 
5.3 Demographic and Other Baseline Characteristics ............................................... 19 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 4 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
5.4 Medical History .................................................................................................... 21 
5.5 Prior and Concomitant Medication...................................................................... 21 
5.6 Treatment Exposure and Compliance.................................................................. 22 
6. CLINICAL OUTCOME (EFFICACY) ANALYSES ................................................. 25 
6.1 Analyses of Primary Clinical Outcome Endpoint(s) ............................................ 26 
6.2 Analyses of Secondary Clinical Outcome Endpoint(s) ......................................... 26 
6.2.1 Normalized Number of Investigator-confirmed HAE Attacks....................... 27 
6.2.2 Time to First Attack ....................................................................................... 30 
6.2.3 Characteristics of Investigator-confirmed HAE ............................................ 30 
6.2.4 Achievement of Attack-free Status ................................................................. 31 
6.2.5 Sensitivity Analyses ........................................................................................ 31 
6.3 Subgroup Analyses ............................................................................................... 32 
7. SAFETY ANALYSIS.................................................................................................. 32 
7.1 Adverse Events ..................................................................................................... 33 
7.1.1 SMQ-defined Adverse Events of Special Interest (AESI) .............................. 34 
7.1.2 Injection Site Reaction (ISR) Adverse Events ................................................ 35 
7.2 Clinical Laboratory Data ..................................................................................... 35 
7.2.1 Additional Laboratory Analyses .................................................................... 36 
7.3 Vital Signs............................................................................................................. 40 
8. PHARMACOKINETIC/ PHARMACODYNAMIC ANALYSIS............................... 40 
9. IMMUNOGENICITY DATA ..................................................................................... 40 
10. OTHER ANALYSES ................................................................................................ 40 
 
 
 
 
10.1.4 Coronavirus Pandemic ................................................................................. 42 
10.2 Healthcare Resource Utilization ......................................................................... 42 
11. INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE .......... 42 
12. DATA HANDLING CONVENTIONS ..................................................................... 43 
12.1 General Data Reporting Conventions ................................................................ 43 
12.2 Definition of Baseline .......................................................................................... 43 
12.3 Definition of Visit Windows................................................................................ 43 
12.4 Derived Efficacy Endpoints ................................................................................ 43 
12.5 Repeated or Unscheduled assessments of Safety Parameters............................. 43 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 5 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
12.6 Handling of Missing, Unused, and Spurious Data .............................................. 44 
12.6.1 Missing Date of Last Dose of Study drug ..................................................... 44 
12.6.2 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) ................................................................................. 44 
12.6.2.1 Incomplete Start Date/Time ................................................................... 44 
12.6.2.2 Incomplete Stop Date/Time .................................................................... 45 
12.6.3 Missing Date Information for Adverse Events ............................................. 45 
12.6.4 Missing Severity assessment for Adverse Events.......................................... 46 
12.6.5 Missing Relationship to Study drug for Adverse Events .............................. 46 
12.6.6 Character Values of Clinical Laboratory Variables..................................... 46 
12.7 Handling Below Quantitation Limit (BQL) Values ............................................ 46 
13. ANALYSIS SOFTWARE ......................................................................................... 47 
14. CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ..................................... 47 
15. REFERENCES ......................................................................................................... 48 
16. APPENDIX ............................................................................................................... 49 
 
 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 6 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
LIST OF IN-TEXT TABLES 
Table 1 Intercurrent Event Types .................................................................................. 11 
Table 2 List of Estimands ............................................................................................... 12 
Table 3 Treatment Exposure Intervals for Subjects with No Dose Modifications ......... 23 
Table 4 Actual Treatment is 150 mg every 2 weeks........................................................ 23 
Table 5 Actual Treatment is 150 mg every 4 weeks........................................................ 23 
Table 6 Actual Treatment is 150 mg every 4 weeks........................................................ 24 
Table 7 Actual Treatment is 150 mg every 2 weeks........................................................ 24 
Table 8. Defining Treatment Months ............................................................................. 28 
Table 9. SMQs Used to Identify AESI ............................................................................ 35 
Table 10. Criteria for Potentially Clinically Significant Laboratory Tests .................... 38 
Table 11. Examples for Coding of Special Character Values for Clinical Laboratory 
Variables .................................................................................................................... 46 
Table 12 LTP Prior to Study Enrollment ....................................................................... 63 
Table 13 LTP Subgroup ................................................................................................. 63 
Table 14 Dose Modification Example ............................................................................. 65 
 
 67 
 
 69 
 71 
Table 18 List of Planned Tables ..................................................................................... 72 
Table 19 List of Planned Figures .................................................................................... 89 
Table 20 List of Planned Listings ................................................................................... 90 
  
 
LIST OF IN-TEXT FIGURES 
Figure 1. Study Design.................................................................................................... 17 
 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 7 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
LIST OF APPENDICES 
Appendix 1 Schedule of Activities .................................................................................. 50 
Appendix 2 Handling of HAE Attack Data .................................................................... 59 
Appendix 3 Clinical Significance Attributions for Laboratory Results ......................... 62 
Appendix 4 Algorithm to Identify LTP Use at Baseline ................................................. 63 
Appendix 5 Actual Dose Regimen .................................................................................. 64 
Appendix 6 Injection Site Reaction AEs......................................................................... 66 
 67 
Appendix 8 List of Statistical Outputs............................................................................ 72 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 8 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BMI 
Body Mass Index 
C1-INH 
C1 esterase inhibitor 
cHMWK 
cleaved high molecular weight kininogen 
CRF 
case report form 
eCRF 
electronic case report form 
FIM 
Family Impact Module 
HAARP 
HAE Attack Assessment and Reporting Procedures 
HAE 
hereditary angioedema 
 
 
IP 
study drug 
IcEv 
intercurrent event 
IMP 
investigational medicinal product 
ISR 
Injection Site Reaction 
KM 
Kaplan-Meier 
LLN 
lower limit of normal 
LOE 
lack of efficacy 
LTP 
long-term prophylaxis 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamic(s) 
  
 
PK 
pharmacokinetic(s) 
PT 
preferred term 
PY 
patient-year 
Q2WKS 
every 2 weeks 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 9 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Abbreviation 
Definition 
Q4WKS 
every 4 weeks 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SMQ 
standardized MedDRA® query 
SOC 
system organ class 
SY 
subject-year 
ULN 
upper limit of normal 
 
 
WHO 
World Health Organization 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 10 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
1. INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of safety, pharmacokinetic (PK)/pharmacodynamic (PD), clinical outcomes, 
 
 and immunogenicity as described in the study protocol amendment version 
1.0 dated 12 Aug 2019. Specifications for tables, figures, and listings are contained in a separate 
document. This SAP contains detailed information to aid in the implementation of the statistical 
analysis of the study data for use in the clinical study report (CSR) and publication. 
2. OBJECTIVES, ESTIMANDS, AND ENDPOINTS 
2.1 Objectives 
2.1.1 Primary Objective 
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. 
2.1.2 Secondary Objective(s) 
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. 
2.2 Estimands 
The types of intercurrent events are described in Table 1. The primary and secondary estimands 
are described in Table 2. The treatment conditions are always “Treatment with Lanadelumab 
(150 mg s.c. q2wks for subjects 6 to <12 years old and q4wks for subjects 2 to <6 years old)”. 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 11 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Table 1 Intercurrent Event Types 
Label 
Intercurrent Event Type 
IcEv1 (IMP-related 
Discontinue) 
Discontinuation of IMP due to a reason linked to the IMP (lack of 
efficacy or treatment related treatment-emergent AE or 
tolerability issue) 
IcEv2 (IMP-unrelated 
Discontinue) 
Discontinuation of IMP due to a reason not linked to IMP such as 
an unrelated intercurrent illness, logistical reason (e.g. COVID19 
lock-down, personal circumstances) 
IcEv3 (IMP Interruption) Interruption in dosing (delayed dose) 
IcEv4 (Meds) 
Use of rescue medications (ecallantide, icatibant, nano-filtered 
C1-INH, plasma-derived, C1-INH, recombinant C1-INH, fresh 
frozen plasma) 
 
 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 12 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
 
Table 2 List of Estimands 
 
 
 
Attributes 
Estimand 
Definition 
A:  
Population 
B:  
Variable  
(or endpoint) 
C:  
Strategy for addressing 
intercurrent event 
D:  
Population-level 
summary 
Primary 
Proportion of pediatric patients 
with HAE who would develop 
treatment-emergent AE 
(including each AESI 
[hypersensitivity reactions, 
hypercoagulability events and 
bleeding events] and all 
serious events) if exposed to 
Lanadelumab.     
Pediatric 
patients (aged 
2 to <6, 6 to 
<12 and 
overall) with 
HAE 
Occurrence of 
treatment-
emergent AEs 
following first 
Lanadelumab 
dose 
IcEv1 (IMP-related 
Discontinue): While on 
Treatment: Count 
subjects with treatment-
emergent AEs 
IcEv2 (IMP-unrelated 
Discontinue): While on 
Treatment: Count 
subjects with treatment-
emergent AEs 
IcEv3 (IMP 
Interruption): Treatment 
Policy (ignoring the 
interruption) 
IcEv4 (Meds): Treatment 
Policy: AEs are included 
regardless of the use of 
other medications 
Number and 
proportion of 
patients who 
experience 
treatment-
emergent AEs 
Primary 
Average number of treatment-
emergent AEs per patient year 
(including each AESI 
[hypersensitivity reactions, 
hypercoagulability events and 
Pediatric 
patients (aged 
2 to <6, 6 to 
<12 and 
overall) with 
HAE 
Number of 
treatment-
emergent AEs 
while on 
treatment.  
IcEv1 (IMP-related 
Discontinue): While on 
Treatment: Count 
treatment-emergent AEs  
IcEv2 (IMP-unrelated 
Discontinue): While on 
Number of 
treatment-
emergent AEs, 
normalized by 
exposure time 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 13 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
bleeding events] and all 
serious events).  
Treatment: Count 
treatment-emergent AEs 
IcEv3 (IMP 
Interruption): Treatment 
Policy (ignoring the 
interruption) 
IcEv4 (Meds): Treatment 
Policy: AEs are included 
regardless of the use of 
other medications 
(patient year) 
over all patients 
Secondary 
Normalized number of 
investigator-confirmed HAE 
attacks per 4 weeks, while on 
treatment  
Pediatric 
patients (aged 
2 to <6, 6 to 
<12 and 
overall) with 
HAE 
Number of 
investigator-
confirmed HAE 
attacks 
IcEv1 (IMP-related 
Discontinue): While on 
treatment: Count attacks 
through end of Treatment 
Period B 
IcEv2 (IMP-unrelated 
Discontinue): While on 
treatment: Count attacks 
through end of Treatment 
Period B 
IcEv3 (IMP 
Interruption): Treatment 
policy (ignoring the 
interruption) 
IcEv4 (Meds): Treatment 
policy: Attacks are 
included regardless of the 
use of other medications 
Normalized 
number of 
investigator-
confirmed HAE 
attack per 4 
weeks during 
Treatment 
Period and 
comparison to 
normalized 
number of 
investigator-
confirmed HAE 
attack per 4 
weeks during 
baseline 
observation 
period. 
Notes: For ease of reading, the endpoints in the estimand definitions are italicized.  
Generally, the treatment policy strategy implies the analysis ignores the occurrence of the IcEv, and is selected to estimate what is expected to occur under the 
same conditions as those of the trial. 
Abbreviations: FU=follow-up; IcEv=intercurrent event; IMP=investigational medical product. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 14 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
2.3 Endpoints 
2.3.1 Primary Endpoint(s) 
The primary endpoint for this study is safety and PK. 
The safety measures 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. 
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 and reported separately: 
- 
Cmax,ss: Maximum observed concentration at steady state 
- 
Cavg,ss: Average concentration over dosing interval at steady state 
- 
Ctrough,ss: Predose concentration at steady state 
- 
tmax: Time to reach Cmax in plasma 
- 
AUCtau,ss: Area under the concentration-time curve over the dosing interval at 
steady state 
- 
t½: Terminal half-life 
- 
CL/F: Apparent clearance 
- 
V/F: Apparent volume of distribution 
2.3.2 Secondary Endpoint(s)  
Clinical outcome measures are secondary endpoints for the study.  
Clinical outcome measures are 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). 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 15 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
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. 
The other secondary endpoints are as follows: 
• PD measurements: Plasma kallikrein activity (as measured by cHMWK level). 
• 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. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 16 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
3. STUDY DESIGN 
3.1 General Description 
This is an open-label, multicenter study to evaluate the safety, PK, and PD of Lanadelumab for 
prevention against acute attacks of hereditary angioedema (HAE) in pediatric subjects 2 to <12 
years of age.  
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 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 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 
Dose group is defined based on the planned dose regimen:  
• “lanadelumab 150 mg every 2 weeks” consistents of subjects with planned dosing 
regimen of lanadelumab 150 mg q2wks 
• “lanadelumab 150 mg every 4 weeks” consistents of subjects with planned dosing 
regimen of lanadelumab 150 mg q4wks 
For non-commercial use only


For non-commercial use only


Shire 
CONFIDENTIAL 
Page 18 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
*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. 
**The follow-up period for this protocol is 14 to 28 days (2-4 weeks). For subjects receiving treatment q2wks, the 
follow-up period is 2 weeks. At the end of the 2-week follow-up period, a scheduled on-site EOS visit will be on 
Study Day 378 (Visit 54) to query for SAEs and AEs, concomitant treatments, and perform the assessments and 
procedures described for the EOS assessment (there is no site check-in call). For subjects receiving treatment q4wks, 
the follow-up period is 4 weeks, a site check-in call will occur on Study Day 378 (Visit 54). 
3.2 Randomization 
Not applicable. This is an open-label study and randomization is not conducted. 
3.3 Blinding 
Not applicable. This is an open-label study. 
3.4 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.  
4. STATISTICAL ANALYSIS SETS 
4.1 Screened Set  
The Screened Set will consist of all subjects who have signed informed consent. 
4.2 Safety Analysis Set  
The Safety Analysis Set will consist of all subjects who receive any study drug.  
4.3 Pharmacokinetic Set  
The Pharmacokinetic (PK) Set is defined as all subjects in the Safety Analysis Set who have at 
least 1 evaluable post dose PK concentration value. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 19 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
4.4 Pharmacodynamic Set  
The Pharmacodynamic (PD) Set is defined as all subjects in the Safety Analysis Set who have at 
least 1 evaluable post dose PD value. 
5. STUDY SUBJECTS 
All summary for treatment compliance and exposure will be conducted according to the actual 
dose regimen received. Other summary for disposition, protocol deviation, demographic and 
baseline characteristics, medical history, prior and concomitant medication will be conducted 
according to the dose regimen assigned at Visit 1 Day 0.  
5.1 Disposition of Subjects 
A listing of all screen failures (i.e., subjects who were screened but not enrolled) will be 
presented along with reasons for screen fail and details of any AEs. The listing will include the 
first screening data for re-screened subjects. 
The number of subjects who were included in each defined analysis set (i.e., Screened, Safety) 
will be summarized by dose group and overall, except for the Screened Set, which will be 
summarized only overall. 
The number and percentage of subjects who completed 3 months, completed treatment period A, 
completed treatment period B, completed the study and prematurely discontinued the study will 
be presented by dose group and overall for the Safety Analysis Set. Reasons for premature 
discontinuation as recorded on the termination page of the eCRF will be summarized (number 
and percentage) by dose group and overall for the Safety Analysis Set. All subjects who 
prematurely discontinued the study will be listed by discontinuation reason for Safety Analysis 
Set. 
5.2 Protocol Deviations 
Protocol deviations will be collected at both the site and subject level. Deviations at the site level 
will be applied to all subjects who were enrolled at that site at the time of the deviation.  
Summary tables of protocol deviations by dose group and overall will be provided for the Safety 
Analysis Set. All protocol deviations will be included in a subject listing. A separate listing will 
list the deviations for inclusion/exclusion criteria. The protocol deviations related to COVID-19 
will be listed separately for the Safety Analysis Set. 
5.3 Demographic and Other Baseline Characteristics 
Baseline and demographic variables will be descriptively summarized by dose group and overall 
for the Safety Analysis Set, the PK set and the PD set. 
The baseline and demographic characteristics will be summarized in the following order in the 
tables:  
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 20 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
• Age (years) 
• Age group 1 (2 to <6 years and 6 to <12 years) 
Age group 2 (2 to <9 years and 9 to <12 years) 
• Sex 
• Ethnicity 
• Race 
• Race group (White, Other) 
• Geographic region (US, Canada, Europe) 
• Weight (kg) 
• Weight percentile group (Underweight: <5th percentile, Healthy or Overweight: 5th – <95th 
percentile, Obese: ≥ 95th percentile) 
• Height (cm) 
• BMI (kg/m2) 
• BMI percentile group (Underweight: <5th percentile, Healthy or Overweight: 5th – <95th 
percentile, Obese: ≥ 95th percentile) 
• Prior long-term prophylactic (LTP) treatment (Yes or No) 
• LTP therapy use (C1-INH, Androgens, Anti-fibrinolytics, or not on LTP) 
• Type of LTP therapy (C1-INH, Oral Therapy, C1-INH and Oral Therapy, not on LTP) 
Age will be calculated as the date of birth minus the date of informed consent + 1 day with 1 
decimal place. If date of birth is partial date, age recorded on the CRF page will be used. 
The LTP therapy use and type of LTP therapy are defined in Appendix 4. 
Height and weight will be used to calculate BMI using the formula below: 
BMI = weight [kg] / (height [m])2 
A SAS program for the 2000 CDC Growth Charts will be used to derive the BMI percentiles and 
weight percentiles (Kuczmarski, R. J. et al. 2000 CDC Growth Charts).  
A separate table will be created for HAE attack history and will include: 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 21 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
• Age at onset of angioedema symptoms 
• HAE type (Type I, Type II, Unspecified-Type I or Type II) 
• History of laryngeal attack 
• Primary attack locations 
• Number of attacks in the last 1, 3, and 12 months 
• Average severity of HAE attacks in the last 12 months 
• Severity of HAE attacks in the last 3 months 
• Average duration of HAE attacks in the last 3 and 12 months 
• Baseline HAE attack rate (attacks during baseline observation period) (refer to Section 
6.2.1 for a definition of the baseline HAE attack rate).  
• Baseline HAE attack rate group (>0 to <1, 1 to <2, 2 to <3, ≥3 attacks/month) 
All baseline and demographic data will be presented in subject listings. 
5.4 Medical History 
Medical history will be collected at the Screening Visit and will be coded using MedDRA 
Version 22.0 or newer. A listing will be provided using the Safety Analysis Set.  
The medical history will be summarized by system organ class (SOC) and preferred term (PT) 
by dose group and overall for each analysis population. Tabulations will be presented sorted by 
SOC in alphabetical order and by PT within each SOC by descending frequency of the overall 
population. 
5.5 Prior and Concomitant Medication  
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary dated March 2019 or newer.  
Prior medication is defined as any medication with the start date prior to the date of the first dose 
of study drug.  
Concomitant medication is defined as any medication with a start date prior to the date of the 
first dose of study drug and continuing after the first dose of study drug or with a start date from 
the date of the first dose of study drug until end of study, inclusive. 
Rescue medication is defined as any medication identified by the investigator as given for an 
HAE attack. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 22 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
For medications with partial onset times, non-missing date parts will be used to determine 
whether the medication is concomitant or prior medication. If a determination cannot be made 
using the non-missing date parts as to when the medication occurred relative to study drug 
administration, then the medication will be classified as concomitant. 
The number and percentage of subjects with prior or concomitant medications excluding rescue 
medications will be summarized by therapeutic class and preferred term by dose group and 
overall for each analysis population. Therapeutic class will be based on the Therapeutic 
Subgroup corresponding to level 2 of the Anatomic Therapeutic Chemical (ATC) classification 
system. Tabulations will be presented sorted by therapeutic class in alphabetical order and by PT 
within each therapeutic class by descending frequency in the overall group. A separate, similar 
table will be provided for the subset of prior or concomitant medications classified as rescue 
medications for each analysis population. Concomitant medications will be summarized by 
Treatment Period A, Treatment Period B, and Overall Study Period (including follow-up period). 
Prior and concomitant therapies/procedures will be coded using MedDRA Version 22.0 or 
newer. The number and percentage of subjects with prior or concomitant therapies/procedures 
will be summarized per system organ class and preferred term by the dose regimen assigned at 
Visit 1 Day 0 and overall for each analysis population. 
All medications/therapies/procedures will be presented in subject listings for the Safety Analysis 
Set. 
5.6 Treatment Exposure and Compliance 
All planned study drug administrations will be recorded in the eCRF, including whether the 
injection was given by parent/caregiver at home, parent/caregiver administered in clinic, study 
staff in clinic, self-administered in clinic, or self-administered at home; whether a full, partial, or 
no dose was given; date and time of dose; and location of the injection.  
The number of planned doses is the number of doses a subject is scheduled to receive based on 
the actual dosing regimen.  Treatment compliance 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 by actual dose 
regimen and overall during the treatment period A, treatment period B and overall treatment 
period for each analysis population.  
For each actual dose regimen and overall, exposure to the study treatment will be summarized 
using total dose (mg) received by the subject, time on study, and total patient-years during 
Treatment Period A, Treatment Period B and overall treatment period for each analysis 
population. Exposure will be calculated and summarized by actual dose regimen.   
Treatment Exposure for Subjects with No Dose Modifications 
Treatment exposure intervals and formulas of time on study (month) are presented below in 
Table 3 for subjects with no dose modifications. These formulas can be applied to subjects 
assigned to either dose group. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 23 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Table 3 Treatment Exposure Intervals for Subjects with No Dose Modifications 
Treatment 
Period 
Treatment Exposure 
Interval 
Formula of Time on Study (month) 
A 
[first dose date, date of Visit 26 Day 
182] 
(date of Visit 26 Day 182 – first dose date + 
1)/28 days 
B 
[date of Visit 26 Day 182 + 1, last 
date of the treatment period*] 
(last date of the treatment period* - (date of 
Visit 26 Day 182 + 1) + 1)/28 days 
Overall 
[first dose date, last date of the 
treatment period*] 
(last date of the treatment period*- first dose 
date + 1)/28 days 
*The last date of the treatment period is defined as the earliest of the date of early study discontinuation or the end date 
of the treatment period. 
Treatment Exposure for Subjects with Dose Modifications 
Dose modifications were allowed during Treatment Period B as mentioned in section 6.2.5 of the 
protocol. 
Subjects Assigned to 150 mg every 2 weeks 
Treatment exposure intervals and formulas of time on study (month) for the actual 150 mg every 
2 weeks regimen and actual 150 mg every 4 weeks regimen are detailed in Table 4 and Table 5, 
respectively, for subjects assigned to the 150 mg every 2 weeks dosing regimen with dose 
modification once.  
These subjects are assigned to the 150 mg every 2 weeks dosing regimen in Treatment Period A, 
but have their dose regimen modified to 150 mg every 4 weeks during Treatment B. Table 4 
details the exposure interval and formula for the actual time on the 150 mg every 2 weeks 
regimen. Table 5 details the exposure interval and formula for the actual time on the 150 mg 
every 4 weeks regimen. 
Table 4 Actual Treatment is 150 mg every 2 weeks 
Treatment 
Period 
Treatment Exposure for Actual 150 mg every 2 weeks Regimen 
Interval 
Time on Regimen (months) 
A 
[first dose date, date of Visit 26 Day 
182] 
(date of Visit 26 Day 182 – first dose date + 
1)/28 days 
B 
[date of Visit 26 Day 182 + 1, date of 
first q4wk dose - 1] 
((date of first q4wk dose -1) - (date of Visit 26 
Day 182 + 1) + 1)/28 days 
Overall 
[first dose date, date of first q4wk 
dose - 1] 
((date of first q4wk dose -1) - first dose date + 
1)/28 days 
 
Table 5 Actual Treatment is 150 mg every 4 weeks 
Treatment 
Period 
Treatment Exposure for Actual 150 mg every 4 weeks Regimen 
Interval 
Time on Regimen (month) 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 24 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
A 
NA 
 
NA 
 
B 
[date of first q4wk dose, last date of 
the treatment period*] 
(last date of the treatment period* - date of 
first q4wk dose + 1)/28 days 
Overall 
[date of first q4wk dose, last date of 
the treatment period*] 
(last date of the treatment period*- date of 
first q4wk dose + 1)/28 days 
*The last date of the treatment period is defined as the earliest of the date of early study discontinuation or the end date 
of the treatment period. 
Subjects Assigned to 150 mg every 4 weeks 
Treatment exposure intervals and formulas of time on study (month) for the actual 150 mg every 
4 weeks regimen and 150 mg every 2 weeks regimen are detailed in Table 6 and Table 7, 
respectively, for subjects assigned to the 150 mg every 4 weeks dosing regimen with dose 
modification once.  
These subjects are assigned to the 150 mg every 4 weeks dosing regimen in Treatment Period A, 
but have their dose regimen modified to 150 mg every 2 weeks during Treatment B. Table 6 
details the exposure interval and formula for the actual time on the 150 mg every 4 weeks 
regimen. Table 7 details the exposure interval and formula for the actual time on the 150 mg 
every 2 weeks regimen.  
Table 6 Actual Treatment is 150 mg every 4 weeks 
Treatment 
Period 
Treatment Exposure for Actual 150 mg every 4 weeks Regimen 
Interval 
Time on Regimen (month) 
A 
[first dose date, date of Visit 26 Day 
182] 
(date of Visit 26 Day 182 – first dose date + 
1)/28 days 
B 
[date of Visit 26 Day 182 + 1, date of 
first q2wk dose - 1] 
((date of first q2wk dose - 1) - (date of Visit 26 
Day 182 + 1) + 1)/28 days 
Overall 
[first dose date, date of first q2wk 
dose - 1] 
((date of first q2wk dose - 1) - first dose date + 
1)/28 days 
 
 
 
Table 7 Actual Treatment is 150 mg every 2 weeks 
Treatment 
Period 
Treatment Exposure for Actual 150 mg every 2 weeks Regimen 
Interval 
Time on Regimen (month) 
A 
NA 
 
NA 
 
B 
[date of first q2wk dose, last date of 
the treatment period*] 
(last date of the treatment period* - date of 
first q2wk dose + 1)/28 days 
Overall 
[date of first q2wk dose, last date of 
the treatment period*] 
(last date of the treatment period*- date of first 
q2wk dose + 1)/28 days 
*The last date of the treatment period is defined as the earliest of the date of early study discontinuation or the end date 
of the treatment period. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 25 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
In general, for subjects who had dose modifications in Treatment Period B, assuming only one 
modification occurred during the study, the interval of time on the planned treatment assignment 
in Treatment Period B and overall treatment period is defined as [start date of treatment period, 
start date of modified dosing regimen – 1 day] and the interval of time on the modified dosing 
regimen is [start date of modified dosing regimen, last date of the treatment period].    
However, if there are subsequent dose modifications in Treatment Period B, the intervals of time 
on the 1st modified dosing regimen in Treatment Period B and overall treatment period are 
defined as [start date of 1st modified dosing regimen, start date of subsequent modified dosing 
regimen – 1 day].  Furthermore, the intervals of time on the subsequent dose modifications in 
Treatment Period B and overall treatment period is defined as [start date of subsequent modified 
dosing regimen, last date of the treatment period]. Treatment exposure for a dose regimen will be 
summed across a subject to represent the total exposure time a subject experienced for each dose 
regimen. 
The duration of participation will be categorized by <1 month, 1-<3 months, 3-<7 months, and 
≥7 months during Treatment Period A and Treatment Period B, and it will be categorized by <1 
month, 1-<3 months, 3-<6 months, 6-<13 months, and ≥13 months during overall treatment 
period for each analysis population. Summaries will also be provided by dose group of the total 
number of doses received, percentage of injections that were given by parent/caregiver at home,  
parent/caregiver administered in clinic, study staff in clinic, self-administered in clinic, or self-
administered at home during Treatment Period A, Treatment Period B and overall treatment 
period for each analysis population. 
A listing of study administrations will be created by subject number and giving the date and time 
of dose administration using the Safety Analysis Set. 
6. CLINICAL OUTCOME (EFFICACY) ANALYSES  
All clinical outcome analyses will be based on the Safety Analysis Set. Data will be summarized 
by the dose regimen the subject actually received (refer to Appendix 5) and overall during each 
treatment period except where otherwise indicated.  
• 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.  
• 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 (KM) estimates. Summaries will include median time and quartiles, if estimable, 
and corresponding 95% confidence intervals. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 26 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
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]) 
6.1 Analyses of Primary Clinical Outcome Endpoint(s) 
The primary objective for this study is safety and PK. All clinical outcome endpoints are 
secondary endpoints. 
6.2 Analyses of Secondary Clinical Outcome Endpoint(s)  
The secondary endpoints are as follows: 
• Normalized number of investigator-confirmed HAE attacks for each efficacy evaluation 
period. 
• Time to the first attack, i.e., 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. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 27 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
6.2.1 Normalized Number of Investigator-confirmed HAE 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 baseline investigator-confirmed HAE attack rate will be calculated for each subject as the 
number of investigator-confirmed HAE attacks occurring during the baseline observation period 
divided by the number of days the subject contributed to the observation period multiplied by 28 
days. 
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. 
For subject’s with dose modifications, the attack rate is calculated as the number of investigator-
confirmed attacks occurring during the actual dosing regimen divided by the number of days on 
the actual dosing regimen multiplied by 28 days.  In the total column, the HAE attack rage will 
be calculated for each subject as the number of investigator-confirmed HAE attacks occurring 
during the efficacy evaluation period divided by the number of days the subject contributed to 
the efficacy evaluation period multiplied by 28 days. 
The baseline investigator-confirmed 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. 
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. For the overall treatment period and Treatment 
Period A, the date of the first exposure to study drug in this study will be used as the start of the 
first interval. For Treatment Period B, the (visit date of Visit 26 Day 182 + 1 day) will be used as 
the start of the first interval. For the presumed steady state period and presumed steady state 
period for Treatment Period A, the Day 70 will be used as the start of the first interval. The end 
of the interval will be the start of the interval plus 27 days. Each successive interval will start the 
last day of the prior interval plus 1 day and end 28 days later, refer to Table 8. 
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 Visit 1 Day 0 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 28 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
for each subject in Safety Analysis Set. Figures will be presented by the dose regimen assigned 
at Visit Day 0. 
All HAE attacks will be presented in a listing. 
Table 8. Defining Treatment Months 
Efficacy Evaluation 
Period 
Month 
Study Day (Study Schedule in Appendix 1) 
Overall Treatment 
Period 
1 
0-27 
2 
28-55 
3 
56-83 
4 
84-111 
5 
112-139 
6 
140-167 
7 
168-195 
8 
196-223 
9 
224-251 
10 
252-279 
11 
280-307 
12 
308-335 
13 
336-363 
14 
364- visit date of Visit 52 Day 364 
Treatment Period A 
1 
0-27 
2 
28-55 
3 
56-83 
4 
84-111 
5 
112-139 
6 
140-167 
7 
168- visit date of Visit 26 Day 182 
Treatment Period B 
1 
(visit date of Visit 26 Day 182+1) - (visit date of Visit 26 
Day 182+28) 
2 
(visit date of Visit 26 Day 182+29) - (visit date of Visit 26 
Day 182+56) 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 29 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Efficacy Evaluation 
Period 
Month 
Study Day (Study Schedule in Appendix 1) 
3 
(visit date of Visit 26 Day 182+57) - (visit date of Visit 26 
Day 182+84) 
4 
(visit date of Visit 26 Day 182+59) - (visit date of Visit 26 
Day 182+112) 
5 
(visit date of Visit 26 Day 182+113) - (visit date of Visit 26 
Day 182+140) 
6 
(visit date of Visit 26 Day 182+141) - (visit date of Visit 26 
Day 182+168) 
7 
(visit date of Visit 26 Day 182+169) - visit date of Visit 52 
Day 364 
Overall Presumed 
Steady State Period 
1 
70-97 
 
2 
98-125 
 
3 
126-153 
 
4 
154-181 
 
5 
182-209 
 
6 
210-237 
 
7 
238-265 
 
8 
266-293 
 
9 
294-321 
 
10 
322-349 
 
11 
350- visit date of Visit 52 Day 364 
Presumed Steady 
State Period for 
Treatment Period A 
1 
70-97 
2 
98-125 
3 
126-153 
4 
154-181 
5 
182- visit date of Visit 26 Day 182 
Similar summary tables for each efficacy evaluation period will be presented for the following 
clinical outcome measures for the Safety Analysis Set: 
• Normalized number of investigator-confirmed HAE attacks requiring acute treatment 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 30 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
• Normalized number of moderate or severe investigator-confirmed HAE attacks 
• Normalized number of high-morbidity investigator-confirmed HAE attacks 
A high morbidity investigator-confirmed HAE attack is defined as any investigator-confirmed 
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. 
A subject level listing will be presented to list the HAE attack rate for each efficacy evaluation 
period. A separate listing will be presented for subjects who have dose regimen changes.  
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 start date and time of that efficacy evaluation period to the 
date and time of the first investigator-confirmed HAE attack after the start date and time of that 
efficacy evaluation period. Time to first attack analyses will be presented by dose group (dose 
regimen the subject assigned at Visit 1 Day 0). 
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 for each efficacy 
evaluation period using the Kaplan-Meier (KM) method by the dose regimen assigned at Visit 
Day 0. The KM plots will be produced for the Safety Analysis Set. Each subject’s censoring 
status and time to event will be provided in a subject level efficacy listing.  
6.2.3 Characteristics of Investigator-confirmed HAE 
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 (No attacks, 
>0-<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 (refer to 
Appendix 2) and summarized. The number and percentage of subjects will be tabulated by 
maximum attack severity (no attack, mild, moderate, and severe). 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 31 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
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. 
• 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 (no use, ecallantide, icatibant, nano-filtered C1-INH, plasma-
derived C1-INH, recombinant C1-INH, and fresh frozen plasma) as reported in the AE 
CRF. 
• Supportive Medication Use: The number and percentage of subjects with supportive 
medication use for an HAE attack, as well as the number of supportive medications, will 
be tabulated by rescue medication by type (no use, IV fluids, pain medication, oxygen, 
anti-emetic, and other) as reported in the AE CRF. 
6.2.4 Achievement of Attack-free Status 
The number and percentage of subjects that are attack-free of investigational-confirmed HAE 
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. Subjects 
who discontinued treatment during the efficacy evaluation period but are attack-free for the time 
observed, will be counted as attack-free in the analysis. 
A subject level listing will be presented to list the subject level HAE characteristics and Attack-
free days for each efficacy evaluation period. A separate listing will be presented for subjects 
who have dose regimen changes. 
6.2.5 Sensitivity Analyses 
The following sensitivity analysis will be performed to evaluate the robustness of the results.  
The analysis of normalized investigator-confirmed HAE attack rate during each efficacy 
evaluation will be repeated using all subject-reported HAE attacks. The baseline all HAE attack 
rate, as well as HAE attack rate, change from baseline, and percent change from baseline using 
all subject-reported HAE attacks for each efficacy evaluation period will be summarized for the 
Safety Analysis Set. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 32 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Two sensitivity analyses will be conducted to evaluate the impact of treatment discontinuation 
on the achievement of attack-free status for each efficacy evaluation period. The first will be 
based only on the subset of subjects that complete each 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. 
6.3 Subgroup Analyses 
Subgroup analyses are planned for the number of investigator-confirmed HAE attacks during 
each efficacy evaluation period using the Safety Analysis Set. The same subgroup will be used 
for the overall AE summary table and summary table by SOC and PT (all treatment-emergent 
AEs, related Treatment-emergent AEs and severe Treatment-emergent AEs) on non-HAE attack 
reported AEs using the Safety Analysis Set.  
The following subgroups will be used: 
• Age group 1 (2 to <6 years and 6 to <12 years) 
Age group 2 (2 to <9 years and 9 to <12 years) 
• Sex  
• Race group (White, Other) 
• Geographic region (US, Canada, Europe)  
• Weight percentile group (Underweight, Healthy or Overweight, Obese) 
• BMI percentile group (Underweight, Healthy or Overweight, Obese) 
• Baseline HAE attack rate group (>0 to <1, 1 to <2, 2 to <3, ≥3 attacks/month) 
• Type of LTP therapy (C1-INH, Oral Therapy, C1-INH and Oral Therapy, not on LTP) 
• HAE Type (Type I, Type II, Unspecified-Type I or Type II) 
• History of laryngeal HAE attack (history of laryngeal attack, no history of laryngeal attack) 
7. SAFETY ANALYSIS  
The safety analysis will be performed using the Safety Analysis Set. Safety variables include 
AEs, clinical laboratory variables and vital signs. For each safety variable, the last value 
collected before the first dose of study drug will be used as baseline for all analyses of that safety 
variable. The safety variables will be summarized in the tables and all available data will be 
shown in the listings.  
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 33 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
The safety analyses for AEs will be conducted according to the dose regimen the subject actually 
received (refer to Appendix 5) and overall. The safety analyses for other safety variables will be 
conducted according to the dose group (dose regimen the subject assigned at Visit 1 Day 0) and 
overall. 
• 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). 
7.1 Adverse Events  
Adverse events will be coded using MedDRA Version 22.0 or newer. 
Treatment-emergent AEs are defined as AEs with onset at the time of or following the first 
exposure to lanadelumab in this study, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. For AEs with partial onset times, non-missing date parts will be used to determine if 
the AE is treatment-emergent or not. If a determination cannot be made using the non-missing 
date as to when the AE occurred relative to study drug administration, then the AE will be 
classified as treatment-emergent.  
The analyses described in this section will be based on treatment-emergent AEs; plainly referred 
to as AEs in this section for brevity.  
Related AEs are AEs classified as related to study drug by the investigator. Severe AEs are AEs 
classified as severe (grade 3) or life threatening (grade 4) by the investigator using DMID 
criteria. 
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 Visit 1 Day 0 
through Visit 52 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 Visit 52 Day 364). 
The number and percentage of subjects with any AE, any related AE, any SAE, any related SAE, 
any severe AE, any related severe AE, any investigator-reported AESI, and hospitalization due to 
an AE as well as the total number of events for each category will be summarized in the overall 
summary table. The number of deaths due to an AE and study discontinuation due to an AE will 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 34 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
be summarized in the overall summary table. The total patient-years will be included in the 
overall summary table. The overall summary table will be repeated by HAE attack reported AEs, 
non-HAE attack reported AEs and investigator-reported AESI.  
The number and percentage of subjects with an AE, as well as the total number of AEs and the 
rate of number of AEs by total patient-years will be summarized by SOC, and PT. This 
tabulation will be repeated for related AEs, SAEs, related SAEs, severe AEs, related severe AEs, 
and investigator-reported AESI. Tabulations will be presented sorted by SOC in alphabetical 
order and by PT within each SOC by descending frequency in the total column of the Safety 
Analysis Set. This summary table will be separated by HAE attack reported AEs and non-HAE 
attack reported AEs. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by PT on non-HAE attack reported AEs. This tabulation will be repeated for related 
non-HAE attack reported AEs and serious non-HAE attack reported AEs. 
All AEs summaries that summarized by SOC, and PT will be presented by the dose regimen the 
subject actually received (Refer to Appendix 5) and separated to Treatment Period A, Treatment 
Period B, overall treatment period, and Follow-up period. All other AEs summaries will be 
presented by the dose regimen the subject actually received (Refer to Appendix 5) and separated 
to Treatment Period A, Treatment Period B and overall study period.  The overall study period 
will include Follow-up period AEs. 
All AEs will be provided in subject listings. In addition, subject listings of AEs causing 
discontinuation of study medication, AEs leading to death, SAEs, related AEs, severe AEs, and 
AESI will be produced. All follow-up period AEs will be provided in a separate listing.  
7.1.1 SMQ-defined Adverse Events of Special Interest (AESI) 
Adverse events of special interest for this study are hypersensitivity reactions and disordered 
coagulation (hypercoagulability events and bleeding events). Investigators are required to 
document any potential AESI AEs on the CRF page. In addition to investigator-reported AESI, 
standardized MedDRA Queries (SMQ) for each AESI category will be performed using the 
study data. The preferred terms from MedDRA 22.0 or newer version SMQ will be used to 
identify an SMQ-defined AESI, refer to Table 9.  
For each dose regimen the subject actually received, the number and percentage of subjects with 
an AESI, as well as the total number of AESIs and the rate of number of AEs by total patient-
years will be summarized by SOC and PT. This tabulation will be created for each AESI and for 
those events with the SMQs classified as related, serious, related serious, severe, and related 
severe. Tabulations will be presented sorted by SOC in alphabetical order and by PT within each 
SOC by descending frequency in the total column of the Safety Analysis Set.  
Listings detailing the PT within the SMQ will be provided.  
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 35 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Table 9. SMQs Used to Identify AESI 
AESI  
SMQ  
Hypersensitivity  
Hypersensitivity  
Hypercoagulable  
Embolic and thrombotic events, arterial  
Embolic and thrombotic events, venous  
Embolic and thrombotic events, vessel type unspecified and 
mixed arterial and venous  
Bleeding  
Haemorrhage laboratory terms  
Haemorrhage terms (excl laboratory terms)  
7.1.2 Injection Site Reaction (ISR) Adverse Events 
Injection site reaction (ISR) AEs are AEs with the preferred terms (PT) starting with “Injection 
site”, “Application site”, or “Administration site”. 
The number and percentage of subjects with any ISR AE, any related ISR AE, any severe ISR 
AE, any related severe ISR AE, any ISR SAE, and any related ISR SAE, as well as the total 
number of events for each category, will be summarized. The number of deaths due to an ISR 
AE, hospitalization due to an ISR AE, and study discontinuation due to an ISR AE will be 
summarized. The total patient-years will be included in the overall summary table. 
The number and percentage of subjects with an ISR AE, as well as the total number of ISR AEs 
and the rate of number of AEs by total patient-years will be summarized by dose regimen the 
subject actually received, SOC and PT. The separate table will be created for ISR AEs by dose 
regimen the subject actually received, SOC, PT and maximum severity. Tabulations will be 
presented sorted by SOC in alphabetical order and by PT within each SOC by descending 
frequency in the total column of the Safety Analysis Set. 
The number of injections, number of injection site reactions, and the percent of injections with 
ISR AEs will be summarized by the administration type of the injection and location of the 
injection. The duration of ISR AEs overall and by PT will be summarized numerically (summary 
statistics) and categorically (0 - 0.5 hour, >0.5 - 1 hour, >1- 12 hours, >12 – 24 hours, ≤1 day – 
unclear, >1 – 14 days, and >14 days). Definition of the duration of ISR is provided in Appendix 
6.  
A listing of ISR AEs will be provided. 
7.2 Clinical Laboratory Data 
Descriptive statistics for clinical laboratory values (in conventional units) and changes from 
baseline at each scheduled study visit, combined all scheduled study visits, combined all 
unscheduled visits, and combined all visits including both scheduled and unscheduled visits will 
be presented by dose group and overall for the following clinical laboratory variables in the 
Safety Analysis Set. If more than one laboratory result is reported per scheduled study visit per 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 36 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
parameter, the last non-missing result will be selected for analysis. The non-standard laboratory 
results will be converted to numeric values using the rules shown in Table 11. Baseline is 
defined as the last non-missing value prior to the first exposure to lanadelumab. 
Hematology 
Hemoglobin, hematocrit, red blood cells (RBC) count, absolute platelet 
count, white blood cell count – total and differential (WBC), mean 
corpuscular hemoglobin concentration (MCHC), mean corpuscular 
hemoglobin (MCH), and mean corpuscular volume (MCV). 
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. 
Coagulation 
Prothrombin time, activated partial thromboplastin time (aPTT), 
international normalized ratio (INR). 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the investigator. See Appendix 3 for details on handling clinical 
significance attribution for laboratory values. The number of subjects with a non-missing result, 
and the number and percentage of subjects with a clinically significant result below the lower 
limit of normal (LLN), clinically non-significant result below the LLN, within the normal range, 
clinically non-significant result above the upper limit of normal (ULN), and clinically significant 
result above 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. In the event of a tie, the earlier measurement will be used.  
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 visits to identify any trends. All 
laboratory data will be provided in subject listings by panel type. 
7.2.1 Additional Laboratory Analyses 
For the Safety Analysis Set, additional analyses will be conducted on liver function tests and 
selected hematology, chemistry and coagulation tests using the highest pre-treatment and highest 
treatment period measurements. The number and percentage of subjects with highest results 
falling into the categories of < LLN, normal, >1-<3 x ULN, 3-5 x ULN, and > 5 x ULN on the 
liver function tests for ALT and AST will be summarized for all pre-treatment measurements, 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 37 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
treatment period A measurements, treatment period B assessments, and overall study period 
assessments which include follow-up assessments. ALP will be summarized by the number and 
percentage of subjects with highest results fall into the categories of ≤ 3 x ULN and > 3 x ULN 
for all pre-treatment measurements, treatment period A measurements, treatment period B 
assessments, and overall study period assessments. Total bilirubin will be summarized by the 
number and percentage of subjects with highest results fall into the categories of ≤ 2 x ULN and 
> 2 x ULN for all pre-treatment measurements, treatment period A measurements, treatment 
period B assessments, and overall study period assessments. This table will be repeated for 
hematology, chemistry, and coagulation using the categories defined in Table 10. 
Additionally, for the Safety Analysis Set, a shift table summarizing the shift in categories from 
highest pre-treatment measurements to the highest treatment period A measurements, treatment 
period B assessments, and overall study period assessments will be created for the liver function 
tests including ALT, AST, ALP and total bilirubin. For ALT and AST, the categories are < LLN, 
normal, >1-<3 x ULN, 3-5 x ULN, and > 5 x ULN; for ALP, the categories are ≤ 3 x ULN and > 
3 x ULN; for total bilirubin, the categories are ≤ 2.0 x ULN and > 2.0 x ULN. Also, for the 
Safety Analysis Set, shift tables will be repeated for hematology, chemistry, and coagulation 
using the categories defined in Table 10. 
Additional laboratory parameters may be evaluated as identified by the study physician.  
 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
Page 38 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Table 10. Criteria for Potentially Clinically Significant Laboratory Tests 
Parameter  
Criteria Categories  
 
Liver Function Tests  
 
ALT (U/L)  
< LLN 
 Normal 
>1-<3 x ULN  
3-5 x ULN  >5 x ULN  
AST (U/L)  
< LLN 
Normal 
>1-<3 x ULN  
3-5 x ULN  >5 x ULN  
ALP (U/L) 
≤3.0 x ULN  
>3.0 x ULN  
- 
- 
- 
Total Bilirubin (mg/dL)  ≤2.0 x ULN  
>2.0 x ULN  
-  
- 
- 
Chemistry  
 
Albumin (g/dL)  
Low (<0.6 x LLN)  
Normal (≥0.6 x LLN)  
-  
-  
-  
Creatinine (mg/dL)  
Normal (≤1.5 x ULN)  High (>1.5 x ULN)  
-  
-  
-  
Glucose (mg/dL)  
Low (<0.6 x LLN)  
Normal (0.6 x LLN - 3.5 x 
ULN)  
High (>3.5 x ULN)  -  
-  
Potassium (mEq/L)  
Low (<0.85 x LLN)  
Normal (0.85 x LLN - 1.2 x 
ULN)  
High (>1.2 x ULN)  -  
-  
Urea Nitrogen (mg/dL)  Normal (≤3.0 x ULN)  High (>3.0 x ULN)  
-  
-  
-  
Hematology  
 
Eosinophils/Leukocyte
s  
Normal (≤4.0 x ULN)  High (>4.0 x ULN) 
-  
-  
- 
Hematocrit  
Low (<0.6 x LLN)  
Normal (0.6 x LLN - 1.3 x 
ULN)  
High (>1.3 x ULN)  -  
-  
Hemoglobin (g/dL)  
Low (< 0.6 x LLN)  
Normal (0.6 x LLN - 1.3 x 
ULN)  
High (>1.3 x ULN)  -  
-  
Leukocytes (10^3/uL)  
Low (<0.5 x LLN)  
Normal (0.5 x LLN – 2.0 x 
ULN)  
High (>2.0 x ULN)  -  
-  
Neutrophils (10^3/uL)  
Low (<0.5 x LLN)  
Normal (≥0.5 x LLN)  
-  
-  
-  
Platelets (10^3/uL)  
Low (<0.4 x LLN)  
Normal (0.4 x LLN – 2.0 x 
ULN)  
High (>2.0 x ULN)  -  
- 
Coagulation  
 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
Page 39 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Activated Partial 
Thromboplastin Time 
(sec)  
≤ 1.5 x ULN  
> 1.5 x ULN  
-  
-  
-  
Prothrombin Intl. 
Normalized Ratio  
≤ 2 x ULN  
> 2 x ULN  
-  
-  
-  
Prothrombin Time 
(sec)  
≤ 1.5 x ULN  
> 1.5 x ULN  
-  
-  
- 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 40 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
7.3 Vital Signs 
Vital signs will be summarized by dose group and overall using the Safety Analysis Set 
including body temperature, heart rate, blood pressure, and respiratory rate.  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. 
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 (within 60 minutes pre-dose and 30 minutes (± 15 minutes) post-dose).  
All vital sign data will be presented in subject listings. 
8. PHARMACOKINETIC/ PHARMACODYNAMIC ANALYSIS  
A descriptive summary analysis will be performed for plasma concentrations of lanadelumab, as 
appropriate, using nominal time points in the PK Set. A listing of plasma concentrations of 
lanadelumab will be provided. 
A descriptive summary analysis will be performed for plasma kallikrein activity (cHMWK 
levels), 
, as appropriate, using nominal time points in the PD Set. A listing of 
cHMWK levels, 
 will be provided. 
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. IMMUNOGENICITY DATA 
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 at each 
scheduled study visit, overall Treatment Period A, overall Treatment Period B, and overall study 
period (including follow-up period) by dose group and overall using the Safety Analysis Set. 
All immunogenicity data will be provided in subject listings for the Safety Analysis Set. 
10. OTHER ANALYSES 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 41 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 42 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
10.1.4 Coronavirus Pandemic 
COVID-19 pandemic since 2019 poses risks to the safety of subjects enrolled in clinical trials, 
and may impact the availability and interpretability of data from those trials. The protocol 
deviations related to COVID-19 as reported in the protocol deviation log will be listed for the 
Safety Analysis Set. The study disruptions related to COVID-19 as reported on the visit eCRF 
page will be listed for the Safety Analysis Set. 
10.2 Healthcare Resource Utilization 
Not applicable. 
11. INTERIM ANALYSIS/ DATA MONITORING (REVIEW) 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. The details 
of the analysis will be described in a separate document. 
A separate clinical pharmacology SAP will support the population PK and PD analysis and the 
analysis results will be reported separately. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 43 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
12. DATA HANDLING CONVENTIONS  
12.1 General Data Reporting Conventions  
Continuous variables will be summarized using the following descriptive statistics:  n, mean, 
median, standard deviation, minimum, maximum. Categorical and count variables will be 
summarized by the number of subjects (n) and the percent of subjects in respective analysis set.  
Unless specified otherwise, min/max will be presented to the same decimal places as the raw 
data. Percentage, mean and median will be presented to 1 more decimal places than the raw data. 
Standard deviation and standard error will be presented to 2 more decimal places than the raw 
data.  
BMI should be rounded to 1 decimal place for reporting. 
 
Averaged lab and vital sign results should be rounded to 1 decimal place for reporting. 
12.2 Definition of Baseline  
Baseline HAE attack rate for all efficacy analyses is defined as the monthly HAE attacks during 
baseline observation period.  
For safety variables and immunogenicity variables, the last value collected before the first dose 
of study drug will be used as baseline. 
 
12.3 Definition of Visit Windows  
Study day will be calculated as follows: 
• 
If the assessment date is on or after the date of first dose of IP:  
Study day = assessment date – first dosing date + 1 
• 
If the assessment date is before the date of first dose of IP: 
Study day = assessment date – first dosing date 
 
12.4 Derived Efficacy Endpoints  
Refer to Section 6.2 and Appendix 1 for derivation instructions of efficacy endpoints. 
12.5 Repeated or Unscheduled assessments of Safety Parameters  
If a subject has repeated assessments before the start of study drug, then the results from the final 
assessment made prior to the start of study drug will be used as baseline. If end of study 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 44 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
assessments are repeated or unscheduled, the last post-baseline assessment will be used as the 
end of study assessment for generating descriptive statistics. If a subject has unscheduled 
assessments between the start of investigational product in the treatment period and the end of 
study visit, the assessments of unscheduled visits will be excluded in the table summary unless 
specified. However, all assessments will be presented in the data listings. 
12.6 Handling of Missing, Unused, and Spurious Data  
No imputation for missing data (e.g., last observation carried forward) will be applied except for 
the missing date/time for HAE attacks, the partial dates for AEs and prior/concomitant 
medications, the missing severity for AEs and the missing relationship to study drug for AEs. 
Imputed dates will not be presented in the listings. The original missing date/time will be 
presented in the listings.  
12.6.1 Missing Date of Last Dose of Study drug 
When the date of the last dose of study drug is missing for a subject in the Safety Analysis Set, 
all efforts should be made to obtain the date from the investigator. If it is still missing after all 
efforts, then the last non-missing dose date of study drug will be used in the calculation of 
treatment duration. 
12.6.2 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) 
For prior or concomitant medications (and/or therapies/procedures), including rescue 
medications, incomplete (i.e., partially missing) start date and/or stop date will be imputed. 
When the start date/time and the stop date/time are both incomplete for a subject, the start 
date/time will be imputed first. 
12.6.2.1 Incomplete Start Date/Time 
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
12.6.2.1.1 Missing Time 
• If the start time is missing and the start date is equal to the date of first dose of 
study drug (before or after imputation), then the time of first dose of study drug 
will be assigned to the missing time. 
• For any other cases, the missing time will be imputed as 0:00. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 45 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
12.6.2.1.2 Missing Day and Month 
• If the year of the incomplete start date is the same as the year of the date of the 
first dose of study drug, then the day and month of the date of the first dose of 
study drug will be assigned to the missing fields. 
• If the year of the incomplete start date is before the year of the date of the first 
dose of study drug, then December 31 will be assigned to the missing fields. 
• If the year of the incomplete start date is after the year of the date of the first dose 
of study drug, then 01 January will be assigned to the missing fields. 
12.6.2.1.3 Missing Month Only 
• The day will be treated as missing and both month and day will be replaced 
according to the above procedure. 
12.6.2.1.4 Missing Day Only 
• If the month and year of the incomplete start date are the same as the month and 
year of the date of the first dose of study drug, then the day of the date of the first 
dose of study drug will be assigned to the missing day 
• If either the year is before the year of the date of the first dose of study drug or if 
both years are the same but the month is before the month of the date of the first 
dose of study drug, then the last day of the month will be assigned to the missing 
day 
• If either the year is after the year of the date of the first dose of study drug or if 
both years are the same but the month is after the month of the date of the first 
dose of study drug, then the first day of the month will be assigned to the missing 
day. 
12.6.2.2 Incomplete Stop Date/Time  
Not applicable. 
12.6.3 Missing Date Information for Adverse Events  
For AEs with partial start date/time, non-missing date/time parts will be used to determine if the 
AE is treatment-emergent or not. If a determination cannot be made using the non-missing 
date/time parts as to when the AE occurred relative to study drug administration, e.g. AE start 
year and month are the same as the year and month of the first dose of study drug, then the AE 
will be classified as treatment-emergent. Refer to Section 7.1. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 46 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
To facilitate categorization of AEs as treatment emergent, imputation of start date/time will be 
used. Stop date/time will not be imputed. 
12.6.3.1.1 Incomplete Start Date/Time 
Follow the same rule as in section 12.6.2.1. 
12.6.3.1.2 Incomplete Stop Date/Time 
Not applicable. 
12.6.4 Missing Severity assessment for Adverse Events  
If severity is missing for an AE starting prior to the date of the first dose of study drug, then a 
severity of “Mild” will be assigned. If the severity is missing for an AE starting on or after the 
date of the first dose of study drug, then a severity of “Severe” will be assigned. The imputed 
values for severity assessment will be used for incidence summaries, while the actual values will 
be used in data listings. 
12.6.5 Missing Relationship to Study drug for Adverse Events  
If the relationship to study drug is missing for an AE starting on or after the date of the first dose 
of study drug, a causality of “Related” will be assigned. The imputed values for relationship to 
study drug will be used for incidence summaries, while the actual values will be presented in 
data listings. 
12.6.6 Character Values of Clinical Laboratory Variables 
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis due 
to, for example, that a character string is reported for a numerical variable. The appropriately 
determined coded value will be used in the statistical analysis. However, the actual values as 
reported in the database will be presented in data listings. 
Table 11. Examples for Coding of Special Character Values for Clinical Laboratory 
Variables 
Non-Standard Lab Values  
Standardized Numeric Values  
<0.2  
Deduct 0.01 from the reference value. i.e., 0.19  
<0.1  
Deduct 0.01 from the reference value. i.e., 0.09  
>1.045  
Add 0.001 to the reference value. i.e. 1.046  
12.7 Handling Below Quantitation Limit (BQL) Values 
For PK analysis, the plasma concentration below the lower limit of quantitation (LLOQ) will be 
imputed to zero in the table. The BQL plasma concentrations will not be imputed in the data 
listings. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 47 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
13. ANALYSIS SOFTWARE  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS® on a suitably 
qualified environment. 
14. CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL 
The following change to the analysis specified in Protocol Amendment 2 dated 22 Jun 2021 
(final version 1.0 dated 06 May 2019, Amendment 1 dated 12 Aug 2019) has been made: 
• The SAP added the definition of Screened Set. 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 48 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
15. REFERENCES 
Caballero, T. 2013. Angio-oedema due to hereditary C1 inhibitor deficiency in children. Allergol 
Immunopathol (Madr), 41, 45-53. 
Kuczmarski, R. J. et al. 2000 CDC Growth Charts for the United States: methods and 
development. Vital Health Stat 11, 1–190 (2002). 
https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm  
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 49 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
16. APPENDIX 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 50 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
Appendix 1 Schedule of Activities  
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 
EQ-5D-Y 
 
 
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 
Section 8.2.5.5, 
Section 8.2.5.6 
C1-INH=C1 esterase inhibitor; HAE=hereditary angioedema; HbsAg = Hepatitis B Surface Antigen; HCV=Hepatitis C Virus; HIV=Human Immunodeficiency Virus 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 51 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
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 co ntraception 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 als o 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. 
 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 52 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
Schedule of Activities- Treatment Period A (Day 0 [Week 1] to Day 182 [Week 26]) 
  
Treatment Period 
 Shaded columns: scheduled on-site visits 
Non-Shaded columns: potential subject-elected offsite activity  
Study Week 
1-2 
3-4 
5-8 
9-12 
13-16 
17-20 
21-24 
25-26 
See Protocol 
Section below for 
details 
Study Visit (± 4 days) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 
20 
21 22 23 24 25 
26 
Study Day 
0 
4 
14 
28 
35 
42 
49 
56 
63 
70 
77 
84 
91 
98 105 112 119 126 133 140 147 154 161 168 175 
182 
Confirmation of 
eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.2 
Prior/current 
medications, therapies, 
and procedures 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.6 
Vital signsa 
X 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Section 8.2.5.2 
Physical examinationb 
X 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Section 8.2.5.1 
Hematology, serum 
chemistry, and 
coagulation tests 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Section 8.2.5.4 
Pregnancy testingc 
X 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
Section 8.2.5.3 
Plasma PK sampled 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Section 8.2.6.1 
Plasma PD (cHMWK) 
sampled 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Section 8.2.6.2 
Plasma PD (
 
) sampled 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Section 8.2.6.2  
Plasma anti-drug 
antibody sampled 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Section 8.2.6.3 
Lanadelumab 
administration  
(6 to <12 years old) 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Table 7  
Lanadelumab 
administration  
(2 to <6 years old) 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Table 7 
Site check-in calle 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Injection report  
(6 to <12 years)f 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Section 8.2.6.8 
Injection report  
(2 to <6 years old)f  
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Section 8.2.6.8 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 53 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
Schedule of Activities- Treatment Period A (Day 0 [Week 1] to Day 182 [Week 26]) 
  
Treatment Period 
 Shaded columns: scheduled on-site visits 
Non-Shaded columns: potential subject-elected offsite activity  
Study Week 
1-2 
3-4 
5-8 
9-12 
13-16 
17-20 
21-24 
25-26 
See Protocol 
Section below for 
details 
Study Visit (± 4 days) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 
20 
21 22 23 24 25 
26 
Study Day 
0 
4 
14 
28 
35 
42 
49 
56 
63 
70 
77 
84 
91 
98 105 112 119 126 133 140 147 154 161 168 175 
182 
SC administration 
surveyg  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Section 8.2.6.8 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Section 8.2.6.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Section 8.2.6.5 
X 
Within 24 hours after the onset of symptoms of an HAE attack, if applicable 
X 
Section 8.2.6.5 
HAE attack data 
(subject HAE attack 
diary and site 
monitoring)i  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Appendix 5 
Concomitant therapies, 
medications, 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 6.6 
Adverse events/serious 
adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.2.5.5, 
Section 8.2.5.6 
; ;  HAE=hereditary angioedema; PD=pharmacodynamic; 
 
; PK=pharmacokinetic; SC=subcutaneous 
Note: Permissible assessment window during treatment period and follow-up period: Study Visit Day ±4 days 
a Vital signs, including sitting or supine blood pressure (BP), heart rate (HR), body temperature, and respiratory rate (RR), will be measured using standard methods at each stu dy 
site. On dosing days, vital signs will be obtained prior (within 60 minutes) to the injection of lanadelumab and 30 minutes ( ± 15 minutes) after completion of the injection of 
lanadelumab. Additional vital signs measurements will be performed if clinically indicated. 
b Complete physical examination, including body weight (and height at Day 1 only). Additional physical examination will be targeted based on reporting of adverse events; 
symptom-oriented physical examinations other than protocol-specified examinations will be performed when clinically indicated in accordance with standard at the site. For 
premenarchal female subjects, the physical examination may also include Tanner staging at the discretion of the investigator, if clinically indicated. 
c Pregnancy testing will be performed for females who have reached menarche. Tests performed on Day 0 must be urine-based to confirm eligibility prior to first dose. Tests 
performed at the indicated visits after Day 0 may be serum or urine-based. 
d Blood samples for testing PK, PD and formation of antibodies to lanadelumab will be obtained predose. Note: On Study Days 4, 14 (for q4wks dose regimen), and 182, PK and 
PD samples can be collected at any time of the day. All sample collection and dosing time should be accurately recorded in th e eCRF (as date, hours, and minutes).
 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 54 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
e If a subject does not have a scheduled on-site visit on the indicated study day, site personnel will perform a site check-in (within 3 days of the study day) to collect AEs and 
concomitant medications, to ensure all HAE attacks have been appropriately documented and, if applicable, to 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. 
f Collect the injection reports assessing the subject’s experience with SC lanadelumab administration. An injection report must be completed by the subject’s parent/caregiver after 
each dose of lanadelumab.  
g The subject’s parent/caregiver will complete the SC Administration survey at the indicated visits.  
h 
 
 
 
i During the treatment and follow-up 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). Any parent/caregiver-reported attack not confirmed by the 
investigator must have an alternate AE diagnosis reported. 
 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 55 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
Schedule of Activities- Treatment Period B (Day 183 [Week 27] through Day 364 [Week 52]) and Follow-up Period 
Treatment Period 
Shaded columns: scheduled on-site visits 
Non-Shaded columns: potential subject-elected offsite activity  
Follow-up 
Period 
 
Study Week 
27-28 
29-32 
33-36 
37-40 
41-44 
45-48 
49-52 
53-56 
 
Study Visit (± 
4 days) 
27 28 29 30 31 
32 
33 34 35 36 37 38 39 40 
41 42 43 44 45 
46 47 48  49 50 51 52 a 53 54 55 
56 
EOS/ 
ETn 
See Protocol 
Section 
below for 
details 
Study Day 
189 196 203 210 217 224 231 238 245 252 259 266 273 280 287 294 301 308 315 322 329 336 343 350 357 364 a 371 378 385 392 
Vital signsb 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Section 
8.2.5.2 
Physical 
examinationc 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Section 
8.2.5.1 
Hematology, 
serum 
chemistry, and 
coagulation 
testsd 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Section  
8.2.5.4 
Pregnancy 
testinge 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Section 
8.2.5.3 
Plasma PK 
samplef 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Section 
8.2.6.1 
Plasma PD 
(cHMWK) 
samplef 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Section 
8.2.6.2 
Plasma PD 
(
 
) samplef 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Section 
8.2.6.2  
Plasma anti-
drug antibody 
samplef 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Section 
8.2.6.3 
Lanadelumab 
administration  
(6 to <12 years 
old) 
 
X 
 
Xl 
 
X 
 
Xl 
 
X 
 
Xl 
 
X 
 
Xl 
 
X 
 
Xl 
 
X 
 
Xl 
 
X 
 
 
 
 
Table 7 
Lanadelumab 
administration  
(2 to <6 years 
old) 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Table 7 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 56 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
Schedule of Activities- Treatment Period B (Day 183 [Week 27] through Day 364 [Week 52]) and Follow-up Period 
Treatment Period 
Shaded columns: scheduled on-site visits 
Non-Shaded columns: potential subject-elected offsite activity  
Follow-up 
Period 
 
Study Week 
27-28 
29-32 
33-36 
37-40 
41-44 
45-48 
49-52 
53-56 
 
Study Visit (± 
4 days) 
27 28 29 30 31 
32 
33 34 35 36 37 38 39 40 
41 42 43 44 45 
46 47 48  49 50 51 52 a 53 54 55 
56 
EOS/ 
ETn 
See Protocol 
Section 
below for 
details 
Study Day 
189 196 203 210 217 224 231 238 245 252 259 266 273 280 287 294 301 308 315 322 329 336 343 350 357 364 a 371 378 385 392 
Site check-ing 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Xo 
 
 
 
Injection report 
(6 to <12 years 
old)h 
 
X 
 
Xl 
 
X 
 
Xl 
 
X 
 
Xl 
 
X 
 
Xl 
 
X 
 
Xl 
 
X 
 
Xl 
 
X 
 
 
 
 
Section  
8.2.6.8 
Injection report 
(2 to <6 years 
old)h 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Section  
8.2.6.8 
SC 
administration 
surveyi 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Section  
8.2.6.8 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Section 
8.2.6.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Section 
8.2.6.5 
Within 24 hours after the onset of symptoms of an HAE attack, if applicablej  
X 
 
 
 
X 
Section 
8.2.6.5 
HAE attack 
data 
(subject HAE 
attack diary  
and site 
monitoring)k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X Appendix 5 
Concomitant 
therapies, 
medications, 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
Section 6.6 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 57 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
Schedule of Activities- Treatment Period B (Day 183 [Week 27] through Day 364 [Week 52]) and Follow-up Period 
Treatment Period 
Shaded columns: scheduled on-site visits 
Non-Shaded columns: potential subject-elected offsite activity  
Follow-up 
Period 
 
Study Week 
27-28 
29-32 
33-36 
37-40 
41-44 
45-48 
49-52 
53-56 
 
Study Visit (± 
4 days) 
27 28 29 30 31 
32 
33 34 35 36 37 38 39 40 
41 42 43 44 45 
46 47 48  49 50 51 52 a 53 54 55 
56 
EOS/ 
ETn 
See Protocol 
Section 
below for 
details 
Study Day 
189 196 203 210 217 224 231 238 245 252 259 266 273 280 287 294 301 308 315 322 329 336 343 350 357 364 a 371 378 385 392 
Adverse 
events/serious 
adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
Section  
8.2.5.5, 
Section 
8.2.5.6 
End of study 
Visitm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Section 
8.1.4 
EOS=End of Study; ET=Early Termination; HAE= hereditary angioedema; PD=pharmacodynamic; PK=pharmaco kinetic; q2wks=every 2 weeks; 
q4wks=every 4 weeks 
Note: Permissible assessment window during treatment period and follow-up period: Study Visit Day ±4 days 
a End of Treatment (Section 8.1.3.3) will occur on Day 364/Visit 52 for subjects who complete Treatment Period B. Subjects who prematurely discontinue study treatment should 
complete the End-of-Study (EOS) / Early Termination (ET) visit procedures at Day 392/Visit 56, whenever feasible (Section 8.1.4). 
b Vital signs, including sitting or supine blood pressure (BP), heart rate (HR), body temperature, and respiratory rate (RR), will be measured using standard methods at each study 
site. On dosing days, vital signs will be obtained prior (within 60 minutes) to the injection of lanadelumab and 30 minutes ( ± 15 minutes) after completion of the injection of 
lanadelumab. Additional vital signs measurements will be performed if clinically indicated. 
c Complete physical examination, including body weight. Additional physical examination will be targeted based on reporting of adverse events; symptom-oriented physical 
examinations other than protocol-specified examinations will be performed when clinically indicated in accordance with standard at the site. 
d Clinical laboratory testing including hematology, serum chemistry, and coagulation. 
e Pregnancy testing will be performed on females who have reached menarche. Tests performed at the indicated visits may be serum o r urine-based. 
f Blood samples for testing PK, PD, and formation of antibodies to lanadelumab will be obtained predose. Note: The End of Study (EOS) PK and PD sample may be collected at 
any time of the day. All sample collection and dosing time should be accurately recorded in the eCRF (as date, hours, and min utes). 
 
. 
g If a subject does not have a scheduled on-site visit on the indicated study day, 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. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 58 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
h Collect the injection reports assessing the subject’s experience with lanadelumab SC administration. An injection report must be completed by the parent/caregiver after each dose 
of lanadelumab.  
i The subject’s parent/caregiver will complete the SC Administration survey at the indicated visits. 
 
 
 
 
k During the treatment and follow-up 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). Any parent/caregiver-reported attack not confirmed by the 
investigator must have an alternate AE diagnosis reported. 
l 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 q4wk s 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. 
m Subjects who terminate from the study early (ET) will undergo (if possible) all of the assessments and procedures at Day 392 (EOS) at their final study visit. 
n The EOS visit on Study Day 392 (Visit 56) will occur only for subjects receiving treatment q4wks; the EOS visit for subjects receiving treatment q2wks will occur on Study Day 
378 (Visit 54) (see Section 8.1.4) 
o For subjects receiving treatment q4wks only. 
 
 
 
 
 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 59 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Appendix 2 Handling of HAE Attack Data 
The following rules apply to the handling of HAE attack data for efficacy analyses only. HAE 
attacks starting prior to the baseline observation period are not processed by these rules. For 
safety analyses, HAE attacks will be analyzed as reported.  
Imputing Missing Start or End Date and Time for HAE Attacks  
In general, missing start time will be imputed as 0:00 and missing end time will be imputed as 
23:59. However, the following rules will be applied for the attacks satisfying the corresponding 
conditions, in order to conservatively classify the attacks as separate, distinct attacks with at least 
24 hours in-between:  
• For HAE attacks with a missing start time and a non-missing start date one calendar day 
after the end date of the previous attack, the start time will be imputed using the end time 
of the previous HAE attack to ensure there are 24 hours in between the two attacks.  
• For HAE attacks with a missing start time and a non-missing end date/time within 24 
hours from the end date/time of the previous attack, the attack should be considered as 
one attack with the previous attack. 
• For HAE attacks with missing end time and a non-missing end date one calendar day 
before the start date of the next attack, the end time will be imputed as the start time of 
the next HAE attack to ensure there are 24 hours in between the two attacks.  
• For HAE attacks with a missing end time and non-missing start date/time within 24 hours 
from the start date/time of the next attack, the attack should be considered as one attack 
with the next attack. 
For HAE attacks with a non-missing start date and time and a missing end date and time:  
• If the event is not indicated as ongoing, the end date and time will be imputed as start 
date and time + 48 hours or 24 hours before the start date and time of the next attack, 
whichever is earlier.  
• If the event is indicated as ongoing, the end date and time will be imputed as the earlier 
of the following two date and time:  
- 
Start date and time + 48 hours or study completion date and the end time of 23:59, 
whichever is later.  
- 
24 hours before the start date and time of the next attack.  
Unique HAE Attacks  
To be counted as a unique attack distinct from the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms. 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 60 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Specifically, there must be at least 24 hours between the end date/ time of the first event and the 
start date/time of the next event, for the attacks to be considered distinct. If there is less than 24 
hours between the end date/time of the first event and the start date/time of the next event, the 
events will be counted as one attack.  
When two or more attacks are combined for efficacy analysis, the parameters of the attacks will 
be conservatively chosen. The start date and time of the combined attack will take the earliest 
start date and time from the individual attacks; and the end date and time of the combined attack 
will take the latest end date and time of the individual attacks. The severity of the combined 
attack will take the highest severity from the individual attacks. The primary location of the 
combined attack will be determined by the primary location of the individual attacks, and by 
following the hierarchy of laryngeal attack, abdominal attack, and peripheral attack. One primary 
location will be taken; and all the other primary location(s) and secondary locations will be 
considered as secondary location for the combined attack. The rescue medications and 
supportive treatment for the combined attack will include all the records from individual attacks. 
Also, the combined attack will be considered as an investigator-confirmed attack if any of the 
individual attack being combined is an investigator-confirmed attack. 
In order to assign the actual dose regimen for an HAE attacks that need to be combined for 
efficacy analyses, the HAE attack will be combined first, then the start date/time will be used for 
consideration of the actual dosing regimen after the HAE attack has been combined.  See 
Appendix 5 for the algorithm of actual dose regimen assignment. 
HAE Attack Duration  
The duration of an HAE attack is calculated as stop date/time – start date/time.  
Investigator-confirmed HAE Attacks Requiring Acute Therapy  
Investigator-confirmed HAE attacks requiring acute therapy are those attacks identified as 
‘treated for HAE attack with acute therapy’ on the CRF.  
Moderate and Severe Investigator-confirmed HAE Attacks  
Moderate and severe investigator-confirmed HAE attacks are those attacks that were classified as 
of moderate or severe according to the HAARP defined severity and reported as such on the 
CRF.  
HAE Attack Severity  
The overall severity of the subject’s attack was to be determined by the investigator using the 
following definitions provided as part of HAARP:  
• Mild: Transient or mild discomfort  
• Moderate: Mild to moderate limitation in activity - some assistance needed  
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 61 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
• Severe: Marked limitation in activity, assistance required  
The average attack severity will be calculated per subject by attributing a numeric value to each 
severity as follows: 1=Mild, 2=Moderate, and 3=Severe. Higher values will indicate more severe 
attacks, while lower values will indicate less severe attacks. 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 62 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Appendix 3 Clinical Significance Attributions for Laboratory Results 
The EDC system design permitted attribution of clinical significance for all laboratory values, 
not just those that are outside of the reference range. Therefore, many data points have an 
attribution of clinical significance when none is expected.  
The laboratory results will be programmatically classified for analysis due to the database 
limitation using the following algorithm:  
• Lab results within the reference range will be classified as Normal.  
• Lab results outside of the reference range will be classified as a) CS Low, b) NCS Low, c) 
NCS High, or d) CS High using a combination of the CS/NCS classification by the 
investigator and the Low/High classification based on the central lab reference range.  
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 63 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Appendix 4 Algorithm to Identify LTP Use at Baseline  
The LTP (C1-INH, Androgens, or Anti-fibrinolytics) treatment a subject was on prior to study 
enrollment will be determined by applying the algorithm presented in Table 12 to prior 
medications (i.e., medications with start and stop date prior to study enrollment) reported for that 
subject that lasted for ≥4 days. 
Table 12 LTP Prior to Study Enrollment 
LTP 
Algorithm to Identify Medications  
C1-INH 
ATC level 4 in (‘B06AC’) and preferred drug term not in 
(‘icatibant’, ‘ecallantide’, ‘icatibant acetate’)  
Androgens 
ATC level 4 in (‘G03BA’, ‘G03BB’, ‘A14AA’) or preferred drug 
term in (‘danazol’, ‘oxandrolone’)  
Anti-fibrinolytics 
ATC level 4 in (‘B02AA’, ‘B02AB’)  
Subjects will be further classified into four LTP subgroups, based on the LTP use prior to study 
enrollment. Table 13 provides the algorithm to classify subjects by type of LTP use prior to 
study enrollment. 
Table 13 LTP Subgroup 
LTP 
Algorithm to Identify Medications  
C1-INH 
Subjects who took only C1-INH as LTP  
Oral Therapy 
Subjects who took either androgens and/or anti-fibrinolytics as 
LTP  
C1-INH and Oral Therapy Subjects who took C1-INH and androgens and/or anti-
fibrinolytics as LTP 
Not on LTP 
Subjects who didn’t take any LTP medications prior to first dose 
of study drug 
 
                
 
                   
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 64 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Appendix 5 Actual Dose Regimen 
Dose modification is mentioned in section 6.2.5 of the protocol. A subject’s dose regimen may 
be modified based on an interim PK analysis or a benefit-risk assessment or recommendation 
from the treating physician. For example, in Treatment Period B, subjects in the 6 to <12 years 
age group may administer lanadelumab 150 mg q4wks 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.  
The actual dosing regimen is the dosing regimen the subject is on when the assessment/event 
occurs. 
Because there were no dose modifications in Treatment Period A, efficacy/safety 
assessments/events will be attributed to the dose regimen assigned to the subject at Visit 1 Day 0. 
For dose modifications, the start date/time of the assessment/event will be compared to the visit 
date/time at which the dose modification occurred to assign the assessment/event to the 
appropriate dose regimen.  For HAE attacks that are combined for efficacy analyses, the start 
date/time of the combined HAE attack will be used to assign to the appropriate dose regimen.  
For example, if a subject has a dose modification at Visit 28 Day 196 which reduces dosing 
frequency from q2wks to q4wks, then assessments/events with start date/time prior to the Visit 
28 Day 196 will be attributed to the q2wks dosing regimen and assessments/events with start 
date/time on or after the Visit 28 Day 196 will be attributed to the q4wks dosing regimen (see 
schematic in Table 14). The last dose on the q2wks regimen will be considered the first dose of 
the q4wks regimen.  
For concomitant medications, adverse events, and HAE attacks, if the start date/time of 
assessment/event is partially missing, the start date/time after imputation per section 12.6 will be 
used to assign the actual dose regimen. For other assessments/events, if the start date/time of 
assessment/event is partially missing, non-missing date parts will be used to determine the dose 
regimen. If a determination cannot be made using the non-missing date parts or the start date is 
missing, the actual dose regimen will be set to dose regimen the subject assigned at Visit 1 Day 
0. Note, that in general, assessment dates should not be missing.  It is anticipated that missing 
dates could arise from assessments performed on a continual basis like adverse events. 
Additionally, if a subject had a dose modification on Visit 48/ Day 336 which increases the 
dosing frequency from q4wks to q2wks, then assessments/events with start date/time on or after 
the Visit 48/Day 336 will be attributed to the q2wks dosing regimen (see schematic in Table 14). 
For by visit assessments such as clinical laboratory data, vital signs, PK/PD, immunogenicity, 
, the assessment date will be used to assign the actual 
dose regimen instead of date and time.  
 
 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 65 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Table 14 Dose Modification Example 
 
Lanadelumab 150 mg Every 2 Weeksa 
(for subjects 6 to <12 years)b 
Treatment Period 
Dose Number 
Study Visit/Study Day/Study Week 
A 
1 
Visit 1/Day 0/Week 0 
2 
Visit 3/Day 14/Week 2 
3 
Visit 4/Day 28/Week 4 
4 
Visit 6/Day 42/Week 6 
5 
Visit 8/Day 56/Week 8 
6 
Visit 10/Day 70/Week 10 
7 
Visit 12/Day 84/Week 12 
8 
Visit 14/Day 98/Week 14 
9 
Visit 16/Day 112/Week 16 
10 
Visit 18/Day 126/Week 18 
11 
Visit 20/Day 140/Week 20 
12 
Visit 22/Day 154/Week 22 
13 
Visit 24/Day 168/Week 24 
14 
Visit 26/Day 182/Week 26 
B 
15 
Visit 28/Day 196/Week 28 
16 
Visit 32/Day 224/Week 32 
 
 
17 
Visit 36/Day 252/Week 36 
18 
Visit 40/Day 280/Week 40 
19 
Visit 44/Day 308/Week 44 
20 
Visit 48/Day 336/Week 48 
21 
Visit 50/Day 350/Week 50 
22 
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 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. 
 
Dosing Regimen:  
Every 2 weeks 
Dose Modification 
Dose Modification 
Dosing Regimen: 
Every 4 weeks 
Dosing Regimen: 
Every 2 weeks 
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 66 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
v2.0 27 Sep 2021 
 
 
Appendix 6 Injection Site Reaction AEs  
Injection site reaction (ISR) AEs will be identified by adverse events with the preferred terms 
starting with ‘Injection site’, ‘Application site’, or ‘Administration site’. 
Duration of ISR AEs is calculated as "stop date/time – start date/time" for the ISR AEs with non-
missing start and stop date/time.  
The missing start or stop date/time for ISR AEs will not be imputed. ISR AEs with missing start 
or stop date/time will be excluded from the summary statistics analysis and reported as number 
missing in the continuous analysis of ISR AE duration. For the categorical analyses on ISR AE 
duration, the following rules will be applied:  
• ISR AE with non-missing start and stop date/time: duration of the AE will be calculated 
as ‘stop date/time – start date/time’ and mapped to a duration category.  
• ISR AE with non-missing start and stop dates and missing time: duration of the AE will 
be calculated as ‘stop date – start date +1’. If the calculated duration is 1 day, then the 
duration category for this AE is ≤ 1 day - unclear. If the calculated duration is greater 
than 1 day, then it will be mapped to a >1 Day category.  
• ISR AE with missing start or stop date: The ISR AE will be excluded from the 
categorical analyses on duration.  
 
 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 67 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 68 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 69 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 70 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 71 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 72 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Appendix 8 List of Statistical Outputs  
Table 18 List of Planned Tables 
Table No. 
Title 
14.1.1.1  
Subject Disposition by Treatment Group (Screened Set) 
14.1.2  
Protocol Deviations by Treatment Group (Safety Set) 
14.1.4.1.1  
Demographic and Baseline Characteristics (Safety Set) 
14.1.4.1.2  
Demographic and Baseline Characteristics (PK Set) 
14.1.4.1.3  
Demographic and Baseline Characteristics (PD Set) 
14.1.4.2  
Baseline HAE Attack History (Safety Set) 
14.1.4.3  
Medical History by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.1.4.4  
Prior Medications (Excluding Medications taken for an HAE Attack) (Safety Set) 
14.1.4.5  
Prior Medications taken for an HAE Attack (Safety Set) 
14.1.4.6  
Concomitant Medications (Excluding Therapies/Procedures taken for an HAE Attack) (Safety Set) 
14.1.4.7  
Concomitant Medications taken for an HAE Attack (Rescue Medications) (Safety Set) 
14.1.4.8  
Prior Therapies/Procedures (Safety Set) 
14.1.4.9 
Concomitant Therapies/Procedures (Safety Set) 
14.1.4.10 
Medical History by System Organ Class, Preferred Term and Treatment Group (PK Set) 
14.1.4.11 
Prior Medications (Excluding Medications taken for an HAE Attack) (PK Set) 
14.1.4.12 
Prior Medications taken for an HAE Attack (PK Set) 
14.1.4.13 
Concomitant Medications (Excluding Therapies/Procedures taken for an HAE Attack) (PK Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 73 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.1.4.14 
Concomitant Medications taken for an HAE Attack (Rescue Medications) (PK Set) 
14.1.4.15 
Prior Therapies/Procedures (PK Set) 
14.1.4.16 
Concomitant Therapies/Procedures (PK Set) 
14.1.4.17 
Medical History by System Organ Class, Preferred Term and Treatment Group (PD Set) 
14.1.4.18 
Prior Medications (Excluding Medications taken for an HAE Attack) (PD Set) 
14.1.4.19 
Prior Medications taken for an HAE Attack (PD Set) 
14.1.4.20 
Concomitant Medications (Excluding Therapies/Procedures taken for an HAE Attack) (PD Set) 
14.1.4.21 
Concomitant Medications taken for an HAE Attack (Rescue Medications) (PD Set) 
14.1.4.22 
Prior Therapies/Procedures (PD Set) 
14.1.4.23 
Concomitant Therapies/Procedures (PD Set) 
14.2.1.1.1  
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Treatment Group During 
Treatment Period A (Safety Set) 
14.2.1.1.2  
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Treatment Group During 
Presumed Steady State Period for Treatment Period A (Safety Set) 
14.2.1.1.3 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Treatment Group During 
Treatment Period B (Safety Set) 
14.2.1.1.4 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Treatment Group During 
Overall Treatment Period (Safety Set) 
14.2.1.1.5 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Treatment Group During 
Overall Presumed Steady State Period (Safety Set) 
14.2.1.1.6 
Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During Treatment Period A 
(Safety Set) 
14.2.1.1.7 
Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During Presumed Steady State 
Period for Treatment Period A (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 74 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.2.1.1.8 
Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During Treatment Period B 
(Safety Set) 
14.2.1.1.9 
Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During Overall Treatment Period 
(Safety Set) 
14.2.1.1.10 
Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During Overall Presumed Steady 
State Period (Safety Set) 
14.2.1.1.11 
Summary of Normalized Number of All Reported HAE Attacks by Treatment Group During Treatment 
Period A (Safety Set) 
14.2.1.1.12 
Summary of Normalized Number of All Reported HAE Attacks by Treatment Group During Presumed 
Steady State Period for Treatment Period A (Safety Set) 
14.2.1.1.13 
Summary of Normalized Number of All Reported HAE Attacks by Treatment Group During Treatment 
Period B (Safety Set) 
14.2.1.1.14 
Summary of Normalized Number of All Reported HAE Attacks by Treatment Group During Overall 
Treatment Period (Safety Set) 
14.2.1.1.15 
Summary of Normalized Number of All Reported HAE Attacks by Treatment Group During Overall 
Presumed Steady State Period (Safety Set) 
14.2.1.1.16 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Age Group and Treatment 
Group During Treatment Period A (Safety Set) 
14.2.1.1.17 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Age Group and Treatment 
Group During Presumed Steady State Period for Treatment Period A (Safety Set) 
14.2.1.1.18 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Age Group and Treatment 
Group During Treatment Period B (Safety Set) 
14.2.1.1.19 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Age Group and Treatment 
Group During Overall Treatment Period (Safety Set) 
14.2.1.1.20 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Age Group and Treatment 
Group During Overall Presumed Steady State Period (Safety Set) 
14.2.1.1.21 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Sex and Treatment Group 
During Treatment Period A (Safety Set) 
14.2.1.1.22 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Sex and Treatment Group 
During Presumed Steady State Period for Treatment Period A (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 75 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.2.1.1.23 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Sex and Treatment Group 
During Treatment Period B (Safety Set) 
14.2.1.1.24 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Sex and Treatment Group 
During Overall Treatment Period (Safety Set) 
14.2.1.1.25 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Sex and Treatment Group 
During Overall Presumed Steady State Period (Safety Set) 
14.2.1.1.26 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Race Group and Treatment 
Group During Treatment Period A (Safety Set) 
14.2.1.1.27 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Race Group and Treatment 
Group During Presumed Steady State Period for Treatment Period A (Safety Set) 
14.2.1.1.28 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Race Group and Treatment 
Group During Treatment Period B (Safety Set) 
14.2.1.1.29 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Race Group and Treatment 
Group During Overall Treatment Period (Safety Set) 
14.2.1.1.30 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Race Group and Treatment 
Group During Overall Presumed Steady State Period (Safety Set) 
14.2.1.1.31 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Geographic Region and 
Treatment Group During Treatment Period A (Safety Set) 
14.2.1.1.32 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Geographic Region and 
Treatment Group During Presumed Steady State Period for Treatment Period A (Safety Set) 
14.2.1.1.33 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Geographic Region and 
Treatment Group During Treatment Period B (Safety Set) 
14.2.1.1.34 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Geographic Region and 
Treatment Group During Overall Treatment Period (Safety Set) 
14.2.1.1.35 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Geographic Region and 
Treatment Group During Overall Presumed Steady State Period (Safety Set) 
14.2.1.1.36 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Weight Percentile Group and 
Treatment Group During Treatment Period A (Safety Set) 
14.2.1.1.37 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Weight Percentile Group and 
Treatment Group During Presumed Steady State Period for Treatment Period A (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 76 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.2.1.1.38 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Weight Percentile Group and 
Treatment Group During Treatment Period B (Safety Set) 
14.2.1.1.39 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Weight Percentile Group and 
Treatment Group During Overall Treatment Period (Safety Set) 
14.2.1.1.40 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Weight Percentile Group and 
Treatment Group During Overall Presumed Steady State Period (Safety Set) 
14.2.1.1.41 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by BMI Percentile Group and 
Treatment Group During Treatment Period A (Safety Set) 
14.2.1.1.42 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by BMI Percentile Group and 
Treatment Group During Presumed Steady State Period for Treatment Period A (Safety Set) 
14.2.1.1.43 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by BMI Percentile Group and 
Treatment Group During Treatment Period B (Safety Set) 
14.2.1.1.44 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by BMI Percentile Group and 
Treatment Group During Overall Treatment Period (Safety Set) 
14.2.1.1.45 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by BMI Percentile Group and 
Treatment Group During Overall Presumed Steady State Period (Safety Set) 
14.2.1.1.46 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Baseline HAE Attack Rate 
Group and Treatment Group During Treatment Period A (Safety Set) 
14.2.1.1.47 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Baseline HAE Attack Rate 
Group and Treatment Group During Presumed Steady State Period for Treatment Period A (Safety Set) 
14.2.1.1.48 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Baseline HAE Attack Rate 
Group and Treatment Group During Treatment Period B (Safety Set) 
14.2.1.1.49 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Baseline HAE Attack Rate 
Group and Treatment Group During Overall Treatment Period (Safety Set) 
14.2.1.1.50 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Baseline HAE Attack Rate 
Group and Treatment Group During Overall Presumed Steady State Period for Treatment Period (Safety Set) 
14.2.1.1.51 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Type of LTP Therapy and 
Treatment Group During Treatment Period A (Safety Set) 
14.2.1.1.52 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Type of LTP Therapy and 
Treatment Group During Presumed Steady State Period for Treatment Period A (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 77 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.2.1.1.53 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Type of LTP Therapy and 
Treatment Group During Treatment Period B (Safety Set) 
14.2.1.1.54 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Type of LTP Therapy and 
Treatment Group During Overall Treatment Period (Safety Set) 
14.2.1.1.55 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by Type of LTP Therapy and 
Treatment Group During Overall Presumed Steady State Period (Safety Set) 
14.2.1.1.56 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by HAE Type and Treatment 
Group During Treatment Period A (Safety Set) 
14.2.1.1.57 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by HAE Type and Treatment 
Group During Presumed Steady State Period for Treatment Period A (Safety Set) 
14.2.1.1.58 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by HAE Type and Treatment 
Group During Treatment Period B (Safety Set) 
14.2.1.1.59 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by HAE Type and Treatment 
Group During Overall Treatment Period (Safety Set) 
14.2.1.1.60 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by HAE Type and Treatment 
Group During Overall Presumed Steady State Period (Safety Set) 
14.2.1.1.61 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by History of Laryngeal HAE 
Attack and Treatment Group During Treatment Period A (Safety Set) 
14.2.1.1.62 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by History of Laryngeal HAE 
Attack and Treatment Group During Presumed Steady State Period for Treatment Period A (Safety Set) 
14.2.1.1.63 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by History of Laryngeal HAE 
Attack and Treatment Group During Treatment Period B (Safety Set) 
14.2.1.1.64 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by History of Laryngeal HAE 
Attack and Treatment Group During Overall Treatment Period (Safety Set) 
14.2.1.1.65 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks by History of Laryngeal HAE 
Attack and Treatment Group During Overall Presumed Steady State Period (Safety Set) 
14.2.1.2.1   
Summary of Normalized Number of Investigator-Confirmed HAE Attacks Requiring Acute Treatment by 
Treatment Group During Treatment Period A (Safety Set) 
14.2.1.2.2   
Summary of Normalized Number of Investigator-Confirmed HAE Attacks Requiring Acute Treatment by 
Treatment Group During Presumed Steady State Period for Treatment Period A (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 78 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.2.1.2.3 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks Requiring Acute Treatment by 
Treatment Group During Treatment Period B (Safety Set) 
14.2.1.2.4 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks Requiring Acute Treatment by 
Treatment Group During Overall Treatment Period (Safety Set) 
14.2.1.2.5 
Summary of Normalized Number of Investigator-Confirmed HAE Attacks Requiring Acute Treatment by 
Treatment Group During Overall Presumed Steady State Period (Safety Set) 
14.2.1.2.6 
Investigator-Confirmed HAE Attack Rate Requiring Acute Treatment by Month and Treatment Group 
During Treatment Period A (Safety Set) 
14.2.1.2.7 
Investigator-Confirmed HAE Attack Rate Requiring Acute Treatment by Month and Treatment Group 
During Presumed Steady State Period for Treatment Period A (Safety Set) 
14.2.1.2.8 
Investigator-Confirmed HAE Attack Rate Requiring Acute Treatment by Month and Treatment Group 
During Treatment Period B (Safety Set) 
14.2.1.2.9 
Investigator-Confirmed HAE Attack Rate Requiring Acute Treatment by Month and Treatment Group 
During Overall Treatment Period (Safety Set) 
14.2.1.2.10 
Investigator-Confirmed HAE Attack Rate Requiring Acute Treatment by Month and Treatment Group 
During Overall Presumed Steady State Period (Safety Set) 
14.2.1.3.1   
Summary of Normalized Number of Moderate or Severe Investigator-Confirmed HAE Attacks by Treatment 
Group During Treatment Period A (Safety Set) 
14.2.1.3.2   
Summary of Normalized Number of Moderate or Severe Investigator-Confirmed HAE Attacks by Treatment 
Group During Presumed Steady State Period for Treatment Period A (Safety Set) 
14.2.1.3.3 
Summary of Normalized Number of Moderate or Severe Investigator-Confirmed HAE Attacks by Treatment 
Group During Treatment Period B (Safety Set) 
14.2.1.3.4 
Summary of Normalized Number of Moderate or Severe Investigator-Confirmed HAE Attacks by Treatment 
Group During Overall Treatment Period (Safety Set) 
14.2.1.3.5 
Summary of Normalized Number of Moderate or Severe Investigator-Confirmed HAE Attacks by Treatment 
Group During Overall Presumed Steady State Period (Safety Set) 
14.2.1.3.6 
Moderate or Severe Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During 
Treatment Period A (Safety Set) 
14.2.1.3.7 
Moderate or Severe Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During 
Presumed Steady State Period for Treatment Period A (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 79 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.2.1.3.8 
Moderate or Severe Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During 
Treatment Period B (Safety Set) 
14.2.1.3.9 
Moderate or Severe Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During 
Overall Treatment Period (Safety Set) 
14.2.1.3.10 
Moderate or Severe Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During 
Overall Presumed Steady State Period (Safety Set) 
14.2.1.4.1   
Summary of Normalized Number of High-Morbidity Investigator-Confirmed HAE Attacks by Treatment 
Group During Treatment Period A (Safety Set) 
14.2.1.4.2   
Summary of Normalized Number of High-Morbidity Investigator-Confirmed HAE Attacks by Treatment 
Group During Presumed Steady State Period for Treatment Period A (Safety Set) 
14.2.1.4.3 
Summary of Normalized Number of High-Morbidity Investigator-Confirmed HAE Attacks by Treatment 
Group During Treatment Period B (Safety Set) 
14.2.1.4.4 
Summary of Normalized Number of High-Morbidity Investigator-Confirmed HAE Attacks by Treatment 
Group During Overall Treatment Period (Safety Set) 
14.2.1.4.5 
Summary of Normalized Number of High-Morbidity Investigator-Confirmed HAE Attacks by Treatment 
Group During Overall Presumed Steady State Period (Safety Set) 
14.2.1.4.6 
High-Morbidity Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During Treatment 
Period A (Safety Set) 
14.2.1.4.7 
High-Morbidity Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During Presumed 
Steady State Period for Treatment Period A (Safety Set) 
14.2.1.4.8 
High-Morbidity Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During Treatment 
Period B (Safety Set) 
14.2.1.4.9 
High-Morbidity Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During Overall 
Treatment Period (Safety Set) 
14.2.1.4.10 
High-Morbidity Investigator-Confirmed HAE Attack Rate by Month and Treatment Group During Overall 
Presumed Steady State Period (Safety Set) 
14.2.1.5.1   
Time to First Investigator-confirmed HAE Attack Using Kaplan-Meier Method by Treatment Group During 
Treatment Period A (Safety Set) 
14.2.1.5.2 
Time to First Investigator-confirmed HAE Attack Using Kaplan-Meier Method by Treatment Group During 
Presumed Steady State Period for Treatment Period A (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 80 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.2.1.5.3 
Time to First Investigator-confirmed HAE Attack Using Kaplan-Meier Method by Treatment Group During 
Treatment Period B (Safety Set) 
14.2.1.5.4 
Time to First Investigator-confirmed HAE Attack Using Kaplan-Meier Method by Treatment Group During 
Overall Treatment Period (Safety Set) 
14.2.1.5.5 
Time to First Investigator-confirmed HAE Attack Using Kaplan-Meier Method by Treatment Group During 
Overall Presumed Steady State Period (Safety Set) 
14.2.2.1.1   
Subject Level Characteristics of Investigator-Confirmed HAE Attacks by Treatment Group During Treatment 
Period A (Safety Set) 
14.2.2.1.2   
Subject Level Characteristics of Investigator-Confirmed HAE Attacks by Treatment Group During Presumed 
Steady State Period for Treatment Period A (Safety Set) 
14.2.2.1.3 
Subject Level Characteristics of Investigator-Confirmed HAE Attacks by Treatment Group During Treatment 
Period B (Safety Set) 
14.2.2.1.4 
Subject Level Characteristics of Investigator-Confirmed HAE Attacks by Treatment Group During Overall 
Treatment Period (Safety Set) 
14.2.2.1.5 
Subject Level Characteristics of Investigator-Confirmed HAE Attacks by Treatment Group During Overall 
Presumed Steady State Period (Safety Set) 
14.2.2.1.6 
Event Level Characteristics of Investigator-Confirmed HAE Attacks by Treatment Group During Treatment 
Period A (Safety Set) 
14.2.2.1.7 
Event Level Characteristics of Investigator-Confirmed HAE Attacks by Treatment Group During Presumed 
Steady State Period for Treatment Period A (Safety Set) 
14.2.2.1.8 
Event Level Characteristics of Investigator-Confirmed HAE Attacks by Treatment Group During Treatment 
Period B (Safety Set) 
14.2.2.1.9 
Event Level Characteristics of Investigator-Confirmed HAE Attacks by Treatment Group During Overall 
Treatment Period (Safety Set) 
14.2.2.1.10 
Event Level Characteristics of Investigator-Confirmed HAE Attacks by Treatment Group During Overall 
Presumed Steady State Period (Safety Set) 
14.2.3.1.1   
Achievement of Investigator-Confirmed HAE Attack-Free by Treatment Group During Efficacy Evaluation 
Period (Safety Set) 
14.2.3.2.1   
Achievement of Investigator-Confirmed HAE Attack-Free Excluding Subjects Who Discontinued Treatment 
by Treatment Group During Efficacy Evaluation Period (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 81 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.2.3.3.1   
Achievement of Investigator-Confirmed HAE Attack-Free with Subjects Who Discontinued Treatment as 
Not Attack-free by Treatment Group During Efficacy Evaluation Period (Safety Set) 
14.2.3.4.1  
Subject Listing of Efficacy Parameters - Part 1 (Safety Set) 
14.2.3.4.2  
Subject Listing of Efficacy Parameters - Part 2 (Safety Set) 
14.2.3.4.3 
Subject Listing of Efficacy Parameters for Subjects Who Changed Dose Regimen - Part 1 (Safety Set) 
14.2.3.4.4 
Subject Listing of Efficacy Parameters for Subjects Who Changed Dose Regimen - Part 2 (Safety Set) 
  
 
  
 
 
  
 
14.2.5.1  
Plasma Concentrations of Lanadelumab by Visit and Treatment Group (PK Set) 
14.2.5.2  
Plasma Kallikrein Activity (%cHMWK), 
 and 
 by Visit and Treatment Group (PD Set) 
14.3.1.1.1  
Overall Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by Treatment Group 
(Safety Set) 
14.3.1.1.2  
Overall Treatment-Emergent HAE Attack Reported Adverse Events by Treatment Group (Safety Set) 
14.3.1.1.3  
Overall Treatment-Emergent Adverse Events of Investigator-Reported AESI (Excluding HAE Attack 
Reported Events) by Treatment Group (Safety Set) 
14.3.1.1.4  
Overall Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by Age Group and 
Treatment Group (Safety Set) 
14.3.1.1.5 
Overall Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by Sex and 
Treatment Group (Safety Set) 
14.3.1.1.6 
Overall Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by Race Group and 
Treatment Group (Safety Set) 
14.3.1.1.7 
Overall Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by Geographic 
Region and Treatment Group (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 82 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.3.1.1.8 
Overall Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by Weight Percentile 
Group and Treatment Group (Safety Set) 
14.3.1.1.9 
Overall Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by BMI Percentile 
Group and Treatment Group (Safety Set) 
14.3.1.1.10 
Overall Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by Baseline HAE 
Attack Rate Group and Treatment Group (Safety Set) 
14.3.1.1.11 
Overall Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by Type of LTP 
Therapy and Treatment Group (Safety Set) 
14.3.1.1.12 
Overall Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by HAE Type and 
Treatment Group (Safety Set) 
14.3.1.1.13 
Overall Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by History of 
Laryngeal HAE Attack and Treatment Group (Safety Set) 
14.3.1.2.1  
Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by System Organ Class, 
Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.2  
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by System Organ 
Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.3  
Serious Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by System Organ 
Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.4  
Related Serious Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by System 
Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.5  
Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by System Organ 
Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.6  
Related Severe Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by System 
Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.7  
Treatment Emergent HAE Attack Reported Adverse Events by System Organ Class, Preferred Term and 
Treatment Group (Safety Set) 
14.3.1.2.8  
Related Treatment Emergent HAE Attack Reported Adverse Events by System Organ Class, Preferred Term 
and Treatment Group (Safety Set) 
14.3.1.2.9  
Serious Treatment Emergent HAE Attack Reported Adverse Events by System Organ Class, Preferred Term 
and Treatment Group (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 83 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.3.1.2.10  
Related Serious Treatment Emergent HAE Attack Reported Adverse Events by System Organ Class, 
Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.11  
Severe Treatment Emergent HAE Attack Reported Adverse Events by System Organ Class, Preferred Term 
and Treatment Group (Safety Set) 
14.3.1.2.12  
Related Severe Treatment Emergent HAE Attack Reported Adverse Events by System Organ Class, 
Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.13  
Treatment-Emergent Adverse Events of Investigator-Reported AESI by System Organ Class, Preferred Term 
and Treatment Group (Safety Set) 
14.3.1.2.14  
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Age Group, System 
Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.15  
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Age Group, 
System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.16  
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Age Group, 
System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.17 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Sex, System Organ Class, 
Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.18 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Sex, System 
Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.19 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Sex, System 
Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.20 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Race Group, System 
Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.21 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Race Group, 
System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.22 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Race Group, 
System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.23 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Geographic Region, 
System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.24 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Geographic 
Region, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 84 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.3.1.2.25 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Geographic 
Region, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.26 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Weight Percentile Group, 
System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.27 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Weight Percentile 
Group, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.28 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Weight Percentile 
Group, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.29 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by BMI Percentile Group, 
System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.30 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by BMI Percentile 
Group, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.31 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by BMI Percentile 
Group, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.32 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Baseline HAE Attack 
Rate Group, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.33 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Baseline HAE 
Attack Rate Group, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.34 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Baseline HAE 
Attack Rate Group, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.35 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Type of LTP Therapy, 
System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.36 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Type of LTP 
Therapy, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.37 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by Type of LTP 
Therapy, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.38 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by HAE Type, System 
Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.39 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by HAE Type, 
System Organ Class, Preferred Term and Treatment Group (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 85 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.3.1.2.40 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by HAE Type, 
System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.41 
Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by History of Laryngeal 
HAE Attack, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.42 
Related Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by History of 
Laryngeal HAE Attack, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.2.43 
Severe Treatment Emergent Adverse Events (Excluding HAE Attack Reported Events) by History of 
Laryngeal HAE Attack, System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.3.1  
Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity (Excluding HAE Attack Reported 
Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.3.2  
Related Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity (Excluding HAE Attack 
Reported Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.3.3  
Serious Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity (Excluding HAE Attack 
Reported Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.3.4  
Related Serious Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity (Excluding HAE 
Attack Reported Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.3.5  
Severe Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity (Excluding HAE Attack 
Reported Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.3.6  
Related Severe Treatment-Emergent Adverse Events of SMQ-Defined Hypersensitivity (Excluding HAE 
Attack Reported Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.4.1  
Treatment-Emergent Adverse Events of SMQ-Defined Bleeding (Excluding HAE Attack Reported Events) 
by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.4.2  
Related Treatment-Emergent Adverse Events of SMQ-Defined Bleeding (Excluding HAE Attack Reported 
Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.4.3  
Serious Treatment-Emergent Adverse Events of SMQ-Defined Bleeding (Excluding HAE Attack Reported 
Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.4.4   
Related Serious Treatment-Emergent Adverse Events of SMQ-Defined Bleeding (Excluding HAE Attack 
Reported Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.4.5  
Severe Treatment-Emergent Adverse Events of SMQ-Defined Bleeding (Excluding HAE Attack Reported 
Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 86 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.3.1.4.6  
Related Severe Treatment-Emergent Adverse Events of SMQ-Defined Bleeding (Excluding HAE Attack 
Reported Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.5.1  
Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable (Excluding HAE Attack Reported 
Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.5.2  
Related Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable (Excluding HAE Attack 
Reported Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.5.3  
Serious Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable (Excluding HAE Attack 
Reported Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.5.4  
Related Serious Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable (Excluding HAE 
Attack Reported Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.5.5  
Severe Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable (Excluding HAE Attack 
Reported Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.5.6  
Related Severe Treatment-Emergent Adverse Events of SMQ-Defined Hypercoagulable (Excluding HAE 
Attack Reported Events) by System Organ Class, Preferred Term and Treatment Group (Safety Set) 
14.3.1.6.1  
Overall Treatment-Emergent Adverse Events of Injection Site Reaction by Treatment Group (Safety Set) 
14.3.1.6.2  
Treatment-Emergent Adverse Events of Injection Site Reaction by System Organ Class, Preferred Term and 
Treatment Group (Safety Set) 
14.3.1.6.3  
Treatment-Emergent Adverse Events of Injection Site Reaction by System Organ Class, Preferred Term, 
Maximum Severity and Treatment Group (Safety Set) 
14.3.1.6.4  
Summary of Number and Duration of Injection Site Reaction Treatment Emergent Adverse Events by 
Treatment Group (Safety Set) 
14.3.1.7.1  
Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by Preferred Term and 
Treatment Group (Safety Set) 
14.3.1.7.2  
Related Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by Preferred Term 
and Treatment Group (Safety Set) 
14.3.1.7.3  
Serious Treatment-Emergent Adverse Events (Excluding HAE Attack Reported Events) by Preferred Term 
and Treatment Group (Safety Set) 
14.3.2.1  
Listing of Serious Treatment-Emergent Adverse Events (Safety Set) 
14.3.2.2  
Listing of Treatment-Emergent Adverse Events Leading to Death (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 87 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.3.2.3  
Listing of Treatment-Emergent Adverse Events Leading to Discontinuation from the Study or Study Drug 
(Safety Set) 
14.3.2.4  
Listing of Follow-up Period Adverse Events (Safety Set) 
14.3.4.1.1  
Quantitative Clinical Laboratory Results by Visit and Treatment Group: Chemistry (Safety Set) 
14.3.4.1.2  
Categorical Clinical Laboratory Results by Visit and Treatment Group: Chemistry (Safety Set) 
14.3.4.1.3  
Highest Chemistry Results by Study Period and Treatment Group (Safety Set) 
14.3.4.1.4  
Shift Table of Highest Chemistry Results by Treatment Group (Safety Set) 
14.3.4.2.1  
Quantitative Clinical Laboratory Results by Visit and Treatment Group: Hematology (Safety Set) 
14.3.4.2.2  
Categorical Clinical Laboratory Results by Visit and Treatment Group: Hematology (Safety Set) 
14.3.4.2.3 
Highest Hematology Results by Study Period and Treatment Group (Safety Set) 
14.3.4.2.4 
Shift Table of Highest Hematology Results by Treatment Group (Safety Set) 
14.3.4.3.1  
Quantitative Clinical Laboratory Results by Visit and Treatment Group: Coagulation (Safety Set) 
14.3.4.3.2  
Categorical Clinical Laboratory Results by Visit and Treatment Group: Coagulation (Safety Set) 
14.3.4.3.3 
Highest Coagulation Results by Study Period and Treatment Group (Safety Set) 
14.3.4.3.4 
Shift Table of Highest Coagulation Results by Treatment Group (Safety Set) 
14.3.4.4.1  
Highest Liver Function Tests by Study Period and Treatment Group (Safety Set) 
14.3.4.4.2  
Shift Table of Highest Liver Function Tests by Treatment Group (Safety Set) 
14.3.5.1  
Actual Values and Change from Baseline in Vital Signs by Visit and Treatment Group (Safety Set) 
14.3.6.1  
Immunogenicity by Visit and Treatment Group (Safety Set) 
14.3.7.1  
Treatment Compliance (Safety Set) 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 88 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table No. 
Title 
14.3.7.2  
Study Drug Exposure (Safety Set) 
14.3.7.3  
Study Drug Administration (Safety Set) 
14.3.7.4 
Treatment Compliance (PK Set) 
14.3.7.5 
Study Drug Exposure (PK Set) 
14.3.7.6 
Study Drug Administration (PK Set) 
14.3.7.7 
Treatment Compliance (PD Set) 
14.3.7.8 
Study Drug Exposure (PD Set) 
14.3.7.9 
Study Drug Administration (PD Set) 
 
 
 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 89 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table 19 List of Planned Figures 
Figure No. 
Title 
14.2.1.1.1 
Investigator-Confirmed HAE Attacks by Treatment Group During Treatment Period A (Safety Analysis Set) 
14.2.1.1.2 
Investigator-Confirmed HAE Attacks by Treatment Group During Presumed Steady State Period for Treatment 
Period A (Safety Analysis Set) 
14.2.1.1.3 
Investigator-Confirmed HAE Attacks by Treatment Group During Treatment Period B (Safety Analysis Set) 
14.2.1.1.4 
Investigator-Confirmed HAE Attacks by Treatment Group During Overall Treatment Period (Safety Analysis 
Set) 
14.2.1.1.5 
Investigator-Confirmed HAE Attacks by Treatment Group During Overall Presumed Steady State Period 
(Safety Analysis Set) 
14.2.1.2.1 
Kaplan-Meier Plot for Time to First Investigator-confirmed HAE Attack During Treatment Period A (Safety 
Analysis Set) 
14.2.1.2.2 
Kaplan-Meier Plot for Time to First Investigator-confirmed HAE Attack During Presumed steady state period 
for Treatment Period A (Safety Analysis Set) 
14.2.1.2.3 
Kaplan-Meier Plot for Time to First Investigator-confirmed HAE Attack During Treatment Period B (Safety 
Analysis Set) 
14.2.1.2.4 
Kaplan-Meier Plot for Time to First Investigator-confirmed HAE Attack During Overall Treatment Period 
(Safety Analysis Set) 
14.2.1.2.5 
Kaplan-Meier Plot for Time to First Investigator-confirmed HAE Attack During Overall Presumed Steady State 
Period (Safety Analysis Set) 
 
 
 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 90 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Table 20 List of Planned Listings 
Listing No.  
Title  
16.1.6 
Listing of Study Lot Numbers (Safety Set) 
16.2.1.1 
Subject Disposition (Safety Set) 
16.2.1.2.1 
Subjects Who Discontinued during Screening Phase (Screened Set) 
16.2.1.2.2 
Subjects Who Discontinued from Study (Safety Set) 
16.2.1.3 
Study Analysis Set Classification (Screened Set) 
16.2.2.1 
Listing of Protocol Deviations (Safety Set) 
16.2.2.2 
Listing of Protocol Deviations Related to COVID-19 (Safety Set) 
16.2.3 
Deviations from Inclusion/Exclusion Criteria (Screened Set) 
16.2.4.1.1 
Subject Demographics (Safety Set) 
16.2.4.1.2 
Subject Baseline Characteristics (Safety Set) 
16.2.4.2 
Subject Baseline HAE Attacks History (Safety Set) 
16.2.4.3 
Medical History (Safety Set) 
16.2.4.4 
Prior and Concomitant Medications (Safety Set) 
16.2.4.5 
Prior and Concomitant Therapy/Procedures (Safety Set) 
16.2.5.1 
Listing of Study Drug Administration (Safety Set) 
16.2.5.2 
Listing of Treatment Compliance and Exposure (Safety Set) 
16.2.5.3 
Listing of Plasma Concentration of Lanadelumab (PK Set) 
16.2.5.4 
Listing of Plasma Kallikrein Activity (%cHMWK), 
 and 
 (PD Set) 
16.2.6.1 
Listing of HAE Attacks (Safety Set) 
 
 
 
 
 
 
For non-commercial use only


Shire 
 
CONFIDENTIAL 
 
Page 91 
Lanadelumab  
Statistical Analysis Plan: SHP643-301 
 
 
v2.0 27 Sep 2021 
 
 
Listing No.  
Title  
16.2.7.1 
Adverse Events (Safety Set) 
16.2.7.2 
Listing of Treatment-Emergent Adverse Events Related to Investigational Product (Safety Set) 
16.2.7.3 
Listing of Severe Treatment-Emergent Adverse Events (Safety Set) 
16.2.7.4 
Listing of Investigator-reported AESI (Safety Set) 
16.2.7.5 
Listing of SMQ-Defined Hypersensitivity Adverse Events (Safety Set) 
16.2.7.6 
Listing of SMQ-Defined Bleeding Adverse Events (Safety Set) 
16.2.7.7 
Listing of SMQ-Defined Hypercoagulable Adverse Events (Safety Set) 
16.2.7.8 
Listing of Injection Site Reaction Adverse Events (Safety Set) 
16.2.8.1  
Clinical Laboratory Test Results: Chemistry (Safety Set) 
16.2.8.2 
Clinical Laboratory Test Results: Hematology (Safety Set) 
16.2.8.3 
Clinical Laboratory Test Results: Coagulation (Safety Set) 
16.2.8.4 
Listing of Clinically Significant Abnormal Results (Safety Set) 
16.2.8.5 
Vital Signs (Safety Set) 
16.2.8.6 
Immunogenicity (Safety Set) 
16.2.8.7 
Study Disruptions Related to COVID-19 Pandemic (Safety Set) 
 
For non-commercial use only

Prot_001.pdf: 
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


For non-commercial use only


Shire
CONFIDENTIAL
Page 4
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 5
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 6
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 7
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 8
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 9
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 10
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 11
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 12
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 13
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 14
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 15
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 16
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 17
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 18
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 19
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.  
For non-commercial use only


Shire
CONFIDENTIAL
Page 20
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 21
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 22
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 30
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 31
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 32
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019

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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 33
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 34
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 35
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 36
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 37
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 38
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 39
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 40
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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; 
For non-commercial use only


Shire
CONFIDENTIAL
Page 41
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 42
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 43
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 44
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 45
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 46
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 48
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 49
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019

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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 50
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 51
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 52
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 53
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 54
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 55
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 56
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 57
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 58
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 59
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
5.4.2
Male Contraception
The study population includes male children <12 years of age. Therefore, male contraception is 
not required in this study.
For non-commercial use only


Shire
CONFIDENTIAL
Page 60
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 61
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 62
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 63
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 64
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019

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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 65
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 66
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 67
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 68
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019

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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 69
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 70
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 71
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 77
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 78
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019

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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 79
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 80
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 81
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 83
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
For non-commercial use only


Shire
CONFIDENTIAL
Page 84
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
8.2.6.6
Healthcare Resource Utilization 
Not applicable.
For non-commercial use only


Shire
CONFIDENTIAL
Page 85
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 87
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 88
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 89
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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), 
For non-commercial use only


Shire
CONFIDENTIAL
Page 90
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 91
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019

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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 92
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.  
For non-commercial use only


Shire
CONFIDENTIAL
Page 93
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019

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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 94
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 95
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 96
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.  
For non-commercial use only


Shire
CONFIDENTIAL
Page 97
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 98
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
For non-commercial use only


Shire
CONFIDENTIAL
Page 99
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 100
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 101
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 102
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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).
For non-commercial use only


Shire
CONFIDENTIAL
Page 103
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 104
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 105
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 106
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 107
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 108
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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:
For non-commercial use only


Shire
CONFIDENTIAL
Page 109
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019

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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 110
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 111
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 112
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
For non-commercial use only


Shire
CONFIDENTIAL
Page 113
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019

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 
For non-commercial use only


Shire
CONFIDENTIAL
Page 114
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 115
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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.
For non-commercial use only


Shire
CONFIDENTIAL
Page 116
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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).
For non-commercial use only


Shire
CONFIDENTIAL
Page 117
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
For non-commercial use only


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.
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 118
For non-commercial use only


Shire
CONFIDENTIAL
 
 
 
 
 
Lanadelum
 
2019
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
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 119
For non-commercial use only


Shire
CONFIDENTIAL
 
 
 
 
 
Lanadelum
 
2019
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
3
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 120
For non-commercial use only


Shire
CONFIDENTIAL
 
 
 
 
 
Lanadelum
 
2019
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. 
4
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 121
For non-commercial use only


Shire
CONFIDENTIAL
 
 
 
 
 
Lanadelum
 
2019
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)
5
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 122
For non-commercial use only


Shire
CONFIDENTIAL
 
 
 
 
 
Lanadelum
 
2019

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 
6
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 123
For non-commercial use only


Shire
CONFIDENTIAL
 
 
 
 
 
Lanadelum
 
2019
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
7
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 124
For non-commercial use only


Shire
CONFIDENTIAL
 
 
 
 
 
Lanadelum
 
2019
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 
8
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 125
For non-commercial use only


Shire
CONFIDENTIAL
 
 
 
 
 
Lanadelum
 
2019
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. 
9
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 126
For non-commercial use only


Shire
CONFIDENTIAL
 
 
 
 
 
Lanadelum
 
2019
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.
10
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 127
For non-commercial use only


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. 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 128
For non-commercial use only


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. 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 129
For non-commercial use only


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 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 130
For non-commercial use only


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 
 
 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 131
For non-commercial use only


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 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 132
For non-commercial use only


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  
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 133
For non-commercial use only


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 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 134
For non-commercial use only


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 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 135
For non-commercial use only


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 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 136
For non-commercial use only


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
10 
cells/hpf 
cells/hpf 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 137
For non-commercial use only


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 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 138
For non-commercial use only


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 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 139
For non-commercial use only


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 
 
 
 
Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Page 140
For non-commercial use only


Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
Page 141
For non-commercial use only


Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
Page 142
For non-commercial use only


Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
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
Page 143
For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
11.
REFERENCES
Agostoni, A., Aygoren-Pursun, E., Binkley, K. E., Blanch, A., Bork, K., Bouillet, L., Bucher, C., 
Castaldo, A. J., Cicardi, M., Davis, A. E., De Carolis, C., Drouet, C., Duponchel, C., 
Farkas, H.and Fay, K. 2004. Hereditary and acquired angioedema: Problems and 
progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. 
Journal of Allergy and Clinical Immunology, The, 114, S51-S131.
Agostoni, A.and Cicardi, M. 1992. Hereditary and acquired C1-inhibitor deficiency: Biological 
and clinical characteristics in 235 patients. Medicine, 71, 206-215.
Baldrick, P. 2010. Juvenile animal testing in drug development - Is it useful? Regulatory 
Toxicology and Pharmacology, 57, 291-299.
Banerji, A. 2013. The burden of illness in patients with hereditary angioedema. Ann Allergy 
Asthma Immunol, 111, 329-36.
Banerji, A., Busse, P., Shennak, M., Lumry, W., Davis-Lorton, M., Wedner, H. J., Jacobs, J., 
Baker, J., Bernstein, J. A., Lockey, R., Li, H. H., Craig, T., Cicardi, M., Riedl, M., Al-
Ghazawi, A., Soo, C., Iarrobino, R., Sexton, D. J., TenHoor, C., Kenniston, J. A., 
Faucette, R., Still, J. G., Kushner, H., Mensah, R., Stevens, C., Biedenkapp, J. C., 
Chyung, Y.and Adelman, B. 2017. Inhibiting Plasma Kallikrein for Hereditary 
Angioedema Prophylaxis. N Engl J Med, 376, 717-728.
Bennett, G.and Craig, T. 2015. Hereditary angioedema with a focus on the child. Allergy Asthma 
Proc, 36, 70-3.
Bork, K. 2013. Hereditary Angioedema with Normal C1 Inhibitor. Immunology and Allergy 
Clinics of North America, 33, 457-470.
Bork, K. 2014a. Current drugs in early development for hereditary angioedema: potential for 
effective treatment. Expert Opin Investig Drugs, 23, 887-91.
Bork, K. 2014b. An evidence based therapeutic approach to hereditary and acquired angioedema. 
Current Opinion in Allergy and Clinical Immunology, 14, 354-362.
Bork, K., Hardt, J., Schicketanz, K. H.and Ressel, N. 2003. Clinical studies of sudden upper 
airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor 
deficiency. Arch Intern Med, 163, 1229-35.
Bork, K., Hardt, J.and Witzke, G. 2012. Fatal laryngeal attacks and mortality in hereditary 
angioedema due to C1-INH deficiency. J Allergy Clin Immunol, 130, 692-7.
Bork, K., Meng, G., Staubach, P.and Hardt, J. 2006a. Hereditary angioedema: New findings 
concerning symptoms, affected organs, and course. American Journal of Medicine, 119, 
267-274.
Bork, K., Staubach, P., Eckardt, A. J.and Hardt, J. 2006b. Symptoms, course, and complications 
of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J 
Gastroenterol, 101, 619-27.
Page 145
For non-commercial use only


Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Bowen, T., Cicardi, M., Bork, K., Zuraw, B., Frank, M., Ritchie, B., Farkas, H., Varga, L., 
Zingale, L. C., Binkley, K., Wagner, E., Adomaitis, P., Brosz, K., Burnham, J., 
Warrington, R., Kalicinsky, C., Mace, S., McCusker, C., Schellenberg, R., Celeste, L., 
Hebert, J., Valentine, K., Poon, M. C., Serushago, B., Neurath, D., Yang, W., Lacuesta, 
G., Issekutz, A., Hamed, A., Kamra, P., Dean, J., Kanani, A., Stark, D., Rivard, G. E., 
Leith, E., Tsai, E., Waserman, S., Keith, P. K., Page, D., Marchesin, S., Longhurst, H. J., 
Kreuz, W., Rusicke, E., Martinez-Saguer, I., Aygoren-Pursun, E., Harmat, G., Fust, G., 
Li, H., Bouillet, L., Caballero, T., Moldovan, D., Spath, P. J., Smith-Foltz, S., Nagy, I., 
Nielsen, E. W., Bucher, C., Nordenfelt, P.and Xiang, Z. Y. 2008. Hereditary angiodema: 
a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus 
Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann 
Allergy Asthma Immunol, 100, S30-40.
Bygum, A. 2009. Hereditary angio-oedema in Denmark: a nationwide survey. The British 
journal of dermatology, 161, 1153-8.
Bygum, A., Fagerberg, C. R., Ponard, D., Monnier, N., Lunardi, J.and Drouet, C. 2011. 
Mutational spectrum and phenotypes in Danish families with hereditary angioedema 
because of C1 inhibitor deficiency. Allergy, 66, 76-84.
Caballero, T. 2013. Angio-oedema due to hereditary C1 inhibitor deficiency in children. Allergol 
Immunopathol (Madr), 41, 45-53.
Caballero, T., Aygoren-Pursun, E., Bygum, A., Beusterien, K., Hautamaki, E., Sisic, Z., Wait, 
S.and Boysen, H. B. 2014. The humanistic burden of hereditary angioedema: results from 
the Burden of Illness Study in Europe. Allergy Asthma Proc, 35, 47-53.
Cicardi, M., Bork, K., Caballero, T., Craig, T., Li, H. H., Longhurst, H., Reshef, A.and Zuraw, 
B. 2012. Evidence-based recommendations for the therapeutic management of 
angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an 
International Working Group. Allergy, 67, 147-57.
Craig, T., Aygoren-Pursun, E., Bork, K., Bowen, T., Boysen, H., Farkas, H., Grumach, A., 
Katelaris, C. H., Lockey, R., Longhurst, H., Lumry, W., Magerl, M., Martinez-Saguer, I., 
Ritchie, B., Nast, A., Pawankar, R., Zuraw, B.and Maurer, M. 2012a. WAO Guideline for 
the Management of Hereditary Angioedema. World Allergy Organ J, 5, 182-99.
Craig, T., Pursun, E. A., Bork, K., Bowen, T., Boysen, H., Farkas, H., Grumach, A., Katelaris, C. 
H., Lockey, R., Longhurst, H., Lumry, W., Magerl, M., Martinez-Saguer, I., Ritchie, B., 
Nast, A., Pawankar, R., Zuraw, B.and Maurer, M. 2012b. WAO Guideline for the 
Management of Hereditary Angioedema. World Allergy Organ J, 5, 182-199.
Craig, T. J., Levy, R. J., Wasserman, R. L., Bewtra, A. K., Hurewitz, D., Obtulowicz, K., Reshef, 
A., Ritchie, B., Moldovan, D., Shirov, T., Grivcheva-Panovska, V., Kiessling, P. C., 
Keinecke, H. O.and Bernst 2009. Efficacy of human C1 esterase inhibitor concentrate 
compared with placebo in acute hereditary angioedema attacks. Journal of Allergy and 
Clinical Immunology, The, 124, 801-808.
Davis, A. E. 2005. The pathophysiology of hereditary angioedema. Clinical Immunology, 114, 3-
9.
Davis, C. A., Vallota, E. H.and Forristal, J. 1979. Serum complement levels in infancy: age 
related changes. Pediatr Res, 13, 1043-6.
El-Hachem, C., Amiour, M., Guillot, M.and Laurent, J. 2005. Hereditary angioneurotic edema: a 
case report in a 3-year-old child. Archives de pédiatrie, 12, 1232-6.
Page 146
For non-commercial use only


Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Farkas, H. 2010. Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma 
Clin Immunol, 6, 18.
Farkas, H., Harmat, G., Fust, G., Varga, L.and Visy, B. 2002. Clinical management of hereditary 
angio-oedema in children. Pediatr Allergy Immunol, 13, 153-61.
Farkas, H., Varga, L., Szeplaki, G., Visy, B., Harmat, G.and Bowen, T. 2007. Management of 
hereditary angioedema in pediatric patients. Pediatrics, 120, e713-22.
Fouche, A. S., Saunders, E. F. H.and Craig, T. 2014a. Depression and anxiety in patients with 
hereditary angioedema. Annals of Allergy, Asthma & Immunology, 112, 371-375.
Fouche, C., Kenealy, T., Mace, J.and Shaw, J. 2014b. Practitioner perspectives from seven health 
professional groups on core competencies in the context of chronic care. J Interprof 
Care, 28, 534-40.
Frank, M. M., Gelfand, J. A.and Atkinson, J. P. 1976. Hereditary angioedema: the clinical 
syndrome and its management. Ann Intern Med, 84, 580-93.
Frank, M. M., Zuraw, B., Banerji, A., Bernstein, J. A., Craig, T., Busse, P., Christiansen, S., 
Davis-Lorton, M., Li, H. H., Lumry, W. R.and Riedl, M. 2016. Management of Children 
With Hereditary Angioedema Due to C1 Inhibitor Deficiency. Pediatrics, 138, 
e20160575-e20160575.
Gompels, M. M., Lock, R. J., Abinun, M., Bethune, C. A., Davies, G., Grattan, C., Fay, A. C., 
Longhurst, H. J., Morrison, L., Price, A., Price, M.and Watters, D. 2005a. C1 inhibitor 
deficiency: consensus document. Clin Exp Immunol, 139, 379-94.
Gompels, M. M., Lock, R. J., Abinun, M., Bethune, C. A., Davies, G., Grattan, C., Fay, A. C., 
Longhurst, H. J., Morrison, L., Price, A., Price, M.and Watters, D. 2005b. C1 inhibitor 
deficiency: consensus document. Clinical and Experimental Immunology, 139, 379-94.
Goring, H. D., Bork, K., Spath, P. J., Bauer, R., Ziemer, A., Hintner, H.and Wuthrich, B. 1998. 
Hereditary angioedema in the German-speaking region. Hautarzt, 49, 114-22.
Jolles, S., Williams, P., Carne, E., Mian, H., Huissoon, A., Wong, G., Hackett, S., Lortan, J., 
Platts, V., Longhurst, H., Grigoriadou, S., Dempster, J., Deacock, S., Khan, S., Darroch, 
J.and Simon, C. 2014. A UK national audit of hereditary and acquired angioedema. 
Clinical & Experimental Immunology, 175, 59-67.
Kenniston, J. A., Faucette, R. R., Martik, D., Comeau, S. R., Lindberg, A. P., Kopacz, K. J., 
Conley, G. P., Chen, J., Viswanathan, M., Kastrapeli, N., Cosic, J., Mason, S., DiLeo, M., 
Abendroth, J., Kuzmic, P., Ladner, R. C., Edwards, T. E., TenHoor, C., Adelman, B. A., 
Nixon, A. E.and Sexton, D. J. 2014. Inhibition of plasma kallikrein by a highly specific 
active site blocking antibody. J Biol Chem, 289, 23596-608.
Kuhlen, J. L., Jr.and Banerji, A. 2015. Hereditary angioedema: Special consideration in children, 
women of childbearing age, and the elderly. Allergy and Asthma Proceedings, 36, 425-
432.
Page 147
For non-commercial use only


Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Leeb-Lundberg, L. M. F., Marceau, F., Müller-Esterl, W., Pettibone, D. J.and Zuraw, B. L. 2005. 
International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: 
from Molecular Mechanisms to Pathophysiological Consequences. Pharmacological 
Reviews, 57, 27-77.
Lei, W. T., Shyur, S. D., Huang, L. H., Kao, Y. H.and Lo, C. Y. 2011. Type I hereditary 
angioedema in Taiwan -- clinical, biological features and genetic study. Asian Pac J 
Allergy Immunol, 29, 327-31.
Longhurst, H. J. 2017. Kallikrein Inhibition for Hereditary Angioedema. New England Journal 
of Medicine, The, 376, 788-789.
Lumry, W. R. 2013. Overview of epidemiology, pathophysiology, and disease progression in 
hereditary angioedema. American journal of managed care, The, 19, s103-10.
MacGinnitie, A. J. 2014. Pediatric hereditary angioedema. Pediatr Allergy Immunol, 25, 420-7.
Martin, P. L.and Weinbauer, G. F. 2010. Developmental Toxicity Testing of Biopharmaceuticals 
in Nonhuman Primates. International Journal of Toxicology, 29, 552-568.
Maurer, M., Magerl, M., Ansotegui, I., Aygoren Pursun, E., Betschel, S., Bork, K., Bowen, T., 
Balle Boysen, H., Farkas, H., Grumach, A., Hide, M., Katelaris, C., Lockey, R., 
Longhurst, H., Lumry, W., Martinez-Saguer, I., Moldovan, D., Nast, A., Pawankar, R., 
Potter, P., Riedl, M., Ritchie, B., Rosenwasser, L., Sanchez-Borges, M., Zhi, Y., Zuraw, 
B.and Craig, T. 2018. The international WAO/EAACI guideline for the management of 
hereditary angioedema - the 2017 revision and update. Allergy.
Morford, L. L., Bowman, C. J., Blanset, D. L., Bogh, I. B., Chellman, G. J., Halpern, W. G., 
Weinbauer, G. F.and Coogan, T. P. 2011. Preclinical safety evaluations supporting 
pediatric drug development with biopharmaceuticals: strategy, challenges, current 
practices. Birth Defects Res B Dev Reprod Toxicol, 92, 359-80.
Nanda, M. K., Elenburg, S., Bernstein, J. A.and Assa'ad, A. H. 2015. Clinical features of 
pediatric hereditary angioedema. J Allergy Clin Immunol Pract, 3, 392-5.
Nielsen, E. W., Johansen, H. T., Holt, J.and Mollnes, T. E. 1994. C1 inhibitor and diagnosis of 
hereditary angioedema in newborns. Pediatric Research, 35, 184-7.
Nordenfelt, P., Dawson, S., Wahlgren, C. F., Lindfors, A., Mallbris, L.and Bjorkander, J. 2014. 
Quantifying the burden of disease and perceived health state in patients with hereditary 
angioedema in Sweden. Allergy Asthma Proc, 35, 185-90.
Nzeako, U. C., Frigas, E.and Tremaine, W. J. 2001. Hereditary angioedema, a broad review for 
clinicians. Archives of Internal Medicine, 161, 2417-2429.
Pappalardo, E., Cicardi, M., Duponchel, C., Carugati, A., Choquet, S., Agostoni, A.and Tosi, M. 
2000. Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients 
with angioedema. Journal of Allergy and Clinical Immunology, The, 106, 1147-1154.
Read, N., Lim, E., Tarzi, M. D., Hildick-Smith, P., Burns, S.and Fidler, K. J. 2014. Paediatric 
hereditary angioedema: a survey of UK service provision and patient experience. Clin 
Exp Immunol, 178, 483-8.
Renne, T.and Gruber, A. 2012. Plasma kallikrein: novel functions for an old protease. Thromb 
Haemost, 107, 1012-3.
Roach, B., Kim, Y., Jerome, E.and Michael, A. F. 1981. Influence of age and sex on serum 
complement components in children. Am J Dis Child, 135, 918-20.
Page 148
For non-commercial use only


Shire
CONFIDENTIAL
SHP643-301 Protocol Amendment 1
Lanadelumab (SHP643)
12 Aug 2019
Roche, O., Blanch, A., Caballero, T., Sastre, N., Callejo, D.and Lopez-Trascasa, M. 2005. 
Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to 
the prevalence in Spain. Ann Allergy Asthma Immunol, 94, 498-503.
Sabharwal, G.and Craig, T. 2017. Pediatric hereditary angioedema: an update. F1000Research,
6.
Stray-Pedersen, A., Sorte, H. S., Samarakoon, P., Gambin, T., Chinn, I. K., Coban Akdemir, Z. 
H., Erichsen, H. C., Forbes, L. R., Gu, S., Yuan, B., Jhangiani, S. N., Muzny, D. M., 
Rodningen, O. K., Sheng, Y., Nicholas, S. K., Noroski, L. M., Seeborg, F. O., Davis, C. 
M., Canter, D. L., Mace, E. M., Vece, T. J., Allen, C. E., Abhyankar, H. A., Boone, P. 
M., Beck, C. R., Wiszniewski, W., Fevang, B., Aukrust, P., Tjonnfjord, G. E., Gedde-
Dahl, T., Hjorth-Hansen, H., Dybedal, I., Nordoy, I., Jorgensen, S. F., Abrahamsen, T. 
G., Overland, T., Bechensteen, A. G., Skogen, V., Osnes, L. T. N., Kulseth, M. A., 
Prescott, T. E., Rustad, C. F., Heimdal, K. R., Belmont, J. W., Rider, N. L., Chinen, J., 
Cao, T. N., Smith, E. A., Caldirola, M. S., Bezrodnik, L., Lugo Reyes, S. O., Espinosa 
Rosales, F. J., Guerrero-Cursaru, N. D., Pedroza, L. A., Poli, C. M., Franco, J. L., Trujillo 
Vargas, C. M., Aldave Becerra, J. C., Wright, N., Issekutz, T. B., Issekutz, A. C., Abbott, 
J., Caldwell, J. W., Bayer, D. K., Chan, A. Y., Aiuti, A., Cancrini, C., Holmberg, E., 
West, C., Burstedt, M., Karaca, E., Yesil, G., Artac, H., Bayram, Y., Atik, M. M., 
Eldomery, M. K., Ehlayel, M. S., Jolles, S., Flato, B., Bertuch, A. A., Hanson, I. C., 
Zhang, V. W., Wong, L. J., Hu, J., Walkiewicz, M., Yang, Y., Eng, C. M., Boerwinkle, 
E., Gibbs, R. A., Shearer, W. T., Lyle, R., Orange, J. S.and Lupski, J. R. 2017. Primary 
immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian 
disorders. J Allergy Clin Immunol, 139, 232-245.
Zuraw, B.and Christiansen, S. 2016. HAE Pathophysiology and Underlying Mechanisms. 
Clinical Reviews in Allergy & Immunology, 51, 216-229.
Zuraw, B. L. 2008. Clinical practice. Hereditary angioedema. N Engl J Med, 359, 1027-36.
Zuraw, B. L., Bernstein, J. A., Lang, D. M., Craig, T., Dreyfus, D., Hsieh, F., Khan, D., Sheikh, 
J., Weldon, D., Bernstein, D. I., Blessing-Moore, J., Cox, L., Nicklas, R. A., 
Oppenheimer, J., Portnoy, J. M., Randolph, C. R., Schuller, D. E., Spector, S. L., Tilles, 
S. A., Wallace, D., American Academy of Allergy, A., Immunology, American College 
of Allergy, A.and Immunology 2013. A focused parameter update: hereditary 
angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme 
inhibitor-associated angioedema. J Allergy Clin Immunol, 131, 1491-3.
Page 149
For non-commercial use only

Prot_000.pdf: 
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: 
Original Protocol: 
06 May 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
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


 
 
 
 
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE) or non-serious adverse event of special interest 
(AESI), the investigator must submit the report via the electronic data capture (EDC) system 
within 24 hours. The EDC system will then generate a report and send this to the Shire Global 
Drug Safety Department and the Shire Medical Monitor. 
In the event that the EDC system is unavailable, the investigator must fax or email the “Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol” within 24 hours. The fax number and e-mail address are provided on the 
form (sent under separate cover). A copy of this form must also be sent to the contract research 
organization (CRO)/Shire medical monitor using the details below. Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 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: 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 3 
 
06 May 2019
For non-commercial use only


 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 4 
 
06 May 2019
For non-commercial use only


 
 
 
 
TABLE OF CONTENTS
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
1.
PROTOCOL SUMMARY......................................................................................................11
1.1
Synopsis ...................................................................................................................11
1.2
Schema .....................................................................................................................18
1.3
Schedule of Activities ..............................................................................................19
2.
INTRODUCTION..................................................................................................................28
2.1
Disease Etiology and Pathophysiology....................................................................28
2.2
Disease Diagnosis in the Pediatric Population.........................................................29
2.3
Epidemiology in the Pediatric Population................................................................30
2.4
Indication and Current Treatment Options...............................................................31
2.5
Product Background and Clinical Information ........................................................32
2.5.1
Drug Information..........................................................................................32
2.5.2
Nonclinical Studies with Lanadelumab........................................................34
2.5.3
Clinical Studies with Lanadelumab..............................................................34
2.5.4
Adolescent Clinical Trial Experience ..........................................................37
2.6
Study Rationale ........................................................................................................38
2.7
Benefit/Risk Assessment..........................................................................................39
2.8
Compliance Statement..............................................................................................42
3.
OBJECTIVES AND ENDPOINTS........................................................................................43
3.1
Study Objectives ......................................................................................................43
3.1.1
Primary Objective ........................................................................................43
3.1.2
Secondary Objectives...................................................................................43
.43
3.2
Study Endpoints .......................................................................................................43
4.
STUDY DESIGN ...................................................................................................................46
4.1
Overall Design..........................................................................................................46
4.2
Scientific Rationale for Study Design......................................................................47
4.3
Justification for Dose ...............................................................................................49
4.4
Duration of Subject Participation and Study Completion Definition ......................52
4.5
Sites and Regions .....................................................................................................53
5.
STUDY POPULATION.........................................................................................................54
5.1
Inclusion Criteria......................................................................................................54
5.2
Exclusion Criteria.....................................................................................................55
5.3
Restrictions...............................................................................................................55
5.3.1
Medical Interventions...................................................................................55
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 5 
 
06 May 2019
For non-commercial use only


 
 
 
 
5.3.2
Fluid and Food Intake ..................................................................................55
5.3.3
Activity.........................................................................................................55
5.4
Reproductive Potential .............................................................................................56
5.4.1
Female Contraception ..................................................................................56
5.4.2
Male Contraception......................................................................................57
6.
STUDY INTERVENTION ....................................................................................................58
6.1
Investigational Product.............................................................................................58
6.1.1
Identity of Investigational Product...............................................................58
6.1.2
Blinding the Treatment Assignment ............................................................58
6.2
Administration of Investigational Product ...............................................................58
6.2.1
Interactive Response Technology for Investigational Product 
Management.................................................................................................58
6.2.2
Allocation of Subjects to Treatment.............................................................58
6.2.3
Dosing ..........................................................................................................58
6.2.4
Unblinding the Treatment Assignment ........................................................61
6.2.5
Dose Modification........................................................................................61
6.3
Labeling, Packaging, Storage, and Handling of Investigational Product.................61
6.3.1
Packaging and Labeling ...............................................................................61
6.3.2
Storage and Handling...................................................................................62
6.4
Drug Accountability.................................................................................................63
6.5
Subject Compliance..................................................................................................64
6.6
Prior and Concomitant Therapy...............................................................................64
6.6.1
Prior Treatment ............................................................................................65
6.6.2
Concomitant Treatment................................................................................65
6.6.3
Permitted Treatment.....................................................................................65
6.6.4
Prohibited Treatment....................................................................................65
7.
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL..........................................................................67
7.1
Discontinuation of Study Treatment ........................................................................67
7.2
Reasons for Discontinuation ....................................................................................67
7.3
Withdrawal from the Study......................................................................................67
7.4
Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit..............................68
7.5
Stopping Rules .........................................................................................................68
7.5.1
Study Level Stopping Rules.........................................................................68
7.5.2
Individual Stopping Rules............................................................................68
7.5.3
Follow-Up for Subjects Meeting Stopping Criteria .....................................68
8.
STUDY ASSESSMENTS AND PROCEDURES..................................................................69
8.1
Study Periods............................................................................................................69
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 6 
 
06 May 2019
For non-commercial use only


 
 
 
 
8.1.1
Screening Period (up to 4 weeks).................................................................69
8.1.2
Baseline Observation Period (up to 12 weeks) ............................................70
8.1.3
Treatment Period..........................................................................................70
8.1.3.1
Study Visit 1; Study Day 0................................................................70
8.1.3.2
Study Visit 2-Visit 52; Study Day 4- Study Day 364 .......................71
8.1.3.3
Final Treatment Visit (Study Visit 52; Study Day 364)....................72
8.1.4
Follow-up Period..........................................................................................73
8.1.5
Early Termination ........................................................................................74
8.1.6
Additional Care of Subjects after the Study.................................................74
8.2
Study Assessments ...................................................................................................74
8.2.1
Informed Consent.........................................................................................74
8.2.2
Eligibility Review ........................................................................................74
8.2.3
Demographic and Other Baseline Characteristics........................................74
8.2.3.1
Medical and Medication History.......................................................74
8.2.4
Clinical Outcomes........................................................................................74
8.2.4.1
Collection of Hereditary Angioedema Attacks .................................74
8.2.4.2
Management of Acute Hereditary Angioedema Attacks...................75
8.2.5
Safety............................................................................................................75
8.2.5.1
Physical Examination........................................................................75
8.2.5.2
Vital Signs .........................................................................................76
8.2.5.3
Pregnancy Test ..................................................................................76
8.2.5.4
Clinical Laboratory Tests for Safety Assessments............................76
8.2.5.5
Adverse Events..................................................................................77
8.2.5.6
Adverse Events of Special Interest (AESI) .......................................79
8.2.6
Other.............................................................................................................79
8.2.6.1
Clinical Pharmacology ......................................................................79
8.2.6.2
Pharmacodynamics............................................................................79
8.2.6.3
Immunogenicity (Anti-drug Antibody Testing) ................................80
8.2.6.4
Biomarkers ........................................................................................80
81
8.2.6.6
Healthcare Resource Utilization........................................................82
8.2.6.7
Self-administration of Lanadelumab .................................................83
8.2.6.8
Injection Report and Subcutaneous Administration Survey .............84
8.2.7
Volume of Blood to Be Drawn from Each Subject|.....................................84
8.2.8
Blood Sample Collection, Storage, and Shipping........................................85
9.
STATISTICAL CONSIDERATIONS ...................................................................................86
9.1
Statistical Analysis Process......................................................................................86
9.2
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......86
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 7 
 
06 May 2019
For non-commercial use only


 
 
 
 
9.3
Sample Size and Power Considerations...................................................................86
9.4
Statistical Analysis Set(s).........................................................................................87
9.5
Analysis Set Description and Exposure ...................................................................87
9.5.1
Subject Disposition ......................................................................................87
9.5.2
Demographics and Other Baseline Characteristics ......................................87
9.5.3
Medical History............................................................................................87
9.5.4
Treatment Exposure and Compliance ..........................................................87
9.5.5
Prior and Concomitant Medications.............................................................87
9.6
Clinical Outcome Analyses......................................................................................87
9.6.1
Primary Clinical Outcome Endpoint............................................................88
9.6.2
Secondary Clinical Outcome Endpoints ......................................................88
9.6.2.1
Normalized Number of Investigator-confirmed Hereditary 
Angioedema Attacks .........................................................................89
9.6.2.2
Time to First Attack...........................................................................90
9.6.2.3
Characteristics of Investigator-confirmed Hereditary Angioedema 
Attacks...............................................................................................90
9.6.2.4
Achievement of Attack-free Status ...................................................91
.91
9.7
Safety Analyses........................................................................................................91
9.7.1
Adverse Events.............................................................................................91
9.7.2
Laboratory Test Results ...............................................................................92
9.7.3
Vital Signs....................................................................................................93
9.8
Other Analyses .........................................................................................................93
.93
9.8.2
Pharmacokinetic/Pharmacodynamic Analyses.............................................94
9.8.3
Immunogenicity Analyses............................................................................94
9.9
Statistical/Analytic Considerations ..........................................................................94
9.9.1
Multiplicity Adjustment ...............................................................................94
9.9.2
Handling of Missing Data ............................................................................94
9.9.3
Multicenter Studies ......................................................................................94
9.9.4
Subgroup Analyses.......................................................................................94
9.10
Sensitivity Analyses .................................................................................................94
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .........96
Appendix 1 Regulatory, Ethical, and Study Oversight Considerations...........................96
Appendix 1.1
Regulatory and Ethical Considerations .............................................96
Appendix 1.2
Sponsor’s Responsibilities.................................................................96
Appendix 1.3
Investigator’s Responsibilities...........................................................97
Appendix 1.4
Data Management Considerations...................................................100
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 8 
 
06 May 2019
For non-commercial use only


 
 
 
 
Appendix 1.5
Ethical Considerations.....................................................................100
Appendix 2 Clinical Laboratory Tests...........................................................................104
Appendix 3 Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ......................................................105
Appendix 3.1
Adverse Event Definitions ..............................................................105
Appendix 3.2
Collection of Adverse Events..........................................................108
Appendix 3.3
Assessment of Adverse Events........................................................108
Appendix 3.4
Safety Reporting..............................................................................110
Appendix 3.5
Serious Adverse Event Collection Time Frame ..............................111
Appendix 3.6
Serious Adverse Event Onset and Resolution Dates.......................111
Appendix 3.7
Fatal Outcome .................................................................................112
Appendix 3.8
Pregnancy ........................................................................................112
Appendix 3.9
Abuse, Misuse, Overdose and Medication Error.............................113
Appendix 3.10 Urgent Safety Measures ..................................................................113
Appendix 3.11 Regulatory Agency, Institutional Review Board, Ethics 
Committee and Site Reporting ........................................................114
115
Appendix 5 Hereditary Angioedema Attack Assessment and Reporting Procedures 
(HAARP)....................................................................................................116
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) ..............................................................................117
Appendix 7 Abbreviations .............................................................................................118
Appendix 8 Protocol History .........................................................................................121
11. REFERENCES .....................................................................................................................122
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 9 
 
06 May 2019
For non-commercial use only


 
 
 
 
LIST OF TABLES
Table 1:
Schedule of Activities- Screening and Baseline Observation Period............19
Table 2:
Schedule of Activities- Treatment Period A (Day 0 [Week 1] to Day 
182 [Week 26])..............................................................................................21
Table 3:
Schedule of Activities- Treatment Period B (Day 183 [Week 27] 
through Day 364 [Week 52]) and Follow-up Period.....................................24
Table 4:
Objectives and Endpoints..............................................................................44
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) ...........................................................................................................51
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) ...........................................................................................................52
Table 7:
Treatment Period Dosing Schedule...............................................................60
Table 8:
Volume of Blood to Be Drawn from Each Subject.......................................85
LIST OF FIGURES
Figure 1:
Study Design .................................................................................................18
Figure 2:
Lanadelumab Specifically Inhibits Plasma Kallikrein (pKal).......................33
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 10 
 
06 May 2019
For non-commercial use only


 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 11 
 
06 May 2019
For non-commercial use only


 
 
 
 
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 parent/caregiver (hereafter referred to as self-administration) is 
allowed after the parent/caregiver has received appropriate training by the investigator or designee and their 
understanding is confirmed. 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.
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. 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 12 
 
06 May 2019
For non-commercial use only


 
 
 
 
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 
available data and confirm the proposed dose regimens 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 all of the following:

Documented clinical history consistent with HAE (SC or mucosal, nonpruritic swelling episodes without 
accompanying urticaria);

A family history consistent with HAE Type I or II, or C1q within normal range;

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. 
4.
Have initiated androgen treatment (eg, stanozolol, danazol, oxandrolone, methyltestosterone, and testosterone) 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 13 
 
06 May 2019
For non-commercial use only


 
 
 
 
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).
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 
and reported separately:
o
Cmax,ss: Maximum observed concentration at steady state
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 14 
 
06 May 2019
For non-commercial use only


 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 15 
 
06 May 2019
For non-commercial use only


 
 
 
 
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 
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. 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 16 
 
06 May 2019
For non-commercial use only



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.  
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 17 
 
06 May 2019
For non-commercial use only


Page 18
 
 
06 May 2019
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 18 
 
06 May 2019
For non-commercial use only


Page 19
 
 
06 May 2019
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 19 
 
06 May 2019
For non-commercial use only


Page 20
 
 
06 May 2019
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 (single assay antibody/Western Blot) 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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 20 
 
06 May 2019
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


 
 
 
 
 
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). 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 28 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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). 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 29 
 
06 May 2019
For non-commercial use only


 
 
 
 
 

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 
States. Similarly, if we examine the pediatric population ≤12 years of age in the United States, 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 30 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
inhibitor [human]) for acute attacks and pre-procedure prevention for patients under 12 years of 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 31 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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. 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 32 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 33 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 34 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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. 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 35 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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. 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 36 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 37 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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; 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 38 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 39 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 40 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 41 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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. C1 esterase inhibitor
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 42 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 43 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 44 
 
06 May 2019
For non-commercial use only


For non-commercial use only


 
 
 
 
 
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 46 
 
06 May 2019
For non-commercial use only


 
 
 
 
 

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 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 available data and confirm the proposed dose regimens 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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 47 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 48 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 49 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
 
for patients and would be considered if the subjects are well controlled (eg., attack 
free for 26 weeks) on the recommended dose.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 50 
 
06 May 2019
For non-commercial use only


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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 51 
 
06 May 2019
For non-commercial use only


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. 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 52 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 53 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 all of the following:

Documented clinical history consistent with HAE (SC or mucosal, nonpruritic swelling 
episodes without accompanying urticaria);

A family history consistent with HAE Type I or II, or C1q within normal range;

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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 54 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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).
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.
5.3.3
Activity
There are no activity restrictions. Subjects may continue their usual activity regimens.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 55 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 56 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
5.4.2
Male Contraception
The study population includes male children <12 years of age. Therefore, male contraception is 
not required in this study.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 57 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 58 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 59 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 60 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 all available data and confirm the dose regimens. 
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.
Parents/caregivers who elect to self-administer investigational product to the subject, where 
permitted per protocol (see Section 8.2.6.7), will be provided the following supplies as 
applicable:

1 dose supply of investigational product
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 61 
 
06 May 2019
For non-commercial use only


 
 
 
 
 

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 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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 62 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 63 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 64 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 65 
 
06 May 2019
For non-commercial use only


 
 
 
 
 

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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 66 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 67 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 68 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 69 
 
06 May 2019
For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


For non-commercial use only


 
 
 
 
 
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 75 
 
06 May 2019
For non-commercial use only


 
 
 
 
 

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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 76 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 77 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 78 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 79 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
Day 182, when the samples may be collected at any time of the scheduled day. 
 
8.2.6.3
Immunogenicity (Anti-drug Antibody Testing)
Immunogenicity will be measured based on the presence or absence of neutralizing or 
non-neutralizing ADA in plasma. Blood samples will be collected at the study days specified in 
Table 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. 
 
8.2.6.4
Biomarkers
Diagnostic Biomarkers (C1-INH, C1q, and C4)
One blood sample will be obtained at the screening visit for evaluation of C1-INH, C4, and C1q 
to confirm a diagnosis of HAE. Results of a C1-INH functional assay are required for eligibility 
assessment in all subjects. Results of the C4 assay are required for eligibility in subjects with a 
C1-INH level of 40-50%, and results of C1q assay are required for eligibility in subjects without 
a documented family history consistent with HAE Type I or II. With prior sponsor approval, 
subjects may be retested for C1-INH or C4 if results are incongruent with clinical history or 
believed by the investigator to be confounded by recent LTP use. Note: Because C1-INH therapy 
may alter the laboratory results of C1-INH functional assay, the investigator's discretion in 
collaboration with medical monitor is advised for proper documentation of eligibility.
During the treatment period, additional blood samples will be collected for evaluation of C1-INH 
and C4 as exploratory PD endpoints (see Section 8.2.6.2).
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 80 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 81 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
8.2.6.6
Healthcare Resource Utilization 
Not applicable.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 82 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
8.2.6.7
Self-administration of Lanadelumab
Self-administration of lanadelumab is defined as administration by a subject’s parent/caregiver, 
either at the clinic or in an offsite location. Self-administration of lanadelumab is only permitted 
by a parent/caregiver; self-administration of lanadelumab by the subject is not permitted in this 
study.
Self-administration by the parent/caregiver is allowed after the parent/caregiver has received 
appropriate training by the investigator or designee and their understanding is confirmed. The
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 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 parents/caregivers who elect to self-administer 
lanadelumab to the subject 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 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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 83 
 
06 May 2019
For non-commercial use only


For non-commercial use only


 
 
 
 
 
Table 8:
Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samplesa
5
15
75
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
5
10
50
Safety
Clinical Chemistry
2.5
13
32.5
Coagulation
2.7
13
35.1
Hematology
2
13
26
Total
30.9
94b
305.2
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 1 mL will be discarded if a catheter is used, after which, withdraw 4 mL and dispense into the appropriate tube for PK 
sampling. A total of 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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 85 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 available data and confirm the proposed dose regimens 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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 86 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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), 
median, minimum, and maximum. Whenever appropriate, clinical outcome endpoints 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 87 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.

Normalized number of high morbidity investigator-confirmed HAE attacks for each 
efficacy evaluation period.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 88 
 
06 May 2019
For non-commercial use only


 
 
 
 
 

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.
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 89 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.  

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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 90 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 91 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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. 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 92 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 93 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.  
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 94 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 95 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 96 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 97 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 98 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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).
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 99 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 100 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 101 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 102 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 103 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 104 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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:
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 105 
 
06 May 2019
For non-commercial use only


 
 
 
 
 

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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 106 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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).
Otherwise, symptoms of the disease under study should not be classed as AEs as long as they are
within the normal day-to-day fluctuation or expected disease progression and are part of the 
clinical outcomes or effectiveness data collected in the study. Significant worsening of 
symptoms should be recorded as an AE.
Preexisting conditions prior to randomization or initiation of study medication are described in 
the medical history, and those that manifest with the same severity, frequency, or duration after 
drug exposure, are not be recorded as AEs. However, when there is an increase in the severity, 
duration or frequency of a preexisting condition, the event must be described on the AE CRF.
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 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 107 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 108 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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
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,
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 109 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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

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/Shire medical monitor within 24 hours of becoming aware 
of the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors (see Appendix 3.9) unless they result in an SAE. 
In addition, occurrence of AESIs and cancer should be reported expeditiously by the investigator 
or qualified designee to the sponsor’s Global Drug Safety Department. 
The investigator must submit all initial and follow-up SAE reports and non-serious AESI reports 
via the electronic data capture (EDC) system, verifying the accuracy of the information recorded 
in EDC with the corresponding source documents (Note: Source documents are not to be sent 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 110 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
unless requested), The EDC system will then generate a report and send this to the Shire Global 
Drug Safety Department and the Shire Medical Monitor.
In the event that the EDC system is unavailable, 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. Once the EDC system is available, the investigator must 
enter and submit all information via the EDC system.
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 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 111 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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 Shire Investigational and Marketed Products 
Pregnancy Report Form. 
A copy of the Shire Investigational and Marketed Products Pregnancy Report Form (and any 
applicable follow-up reports) must also be sent to the CRO/Shire medical monitor using the 
details specified in the emergency contact information section of the protocol. The pregnant 
female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days and 1 year 
post-partum.
Pregnancy complications such as spontaneous abortion/miscarriage, elective abortion or 
congenital abnormality are considered SAEs and must be reported using the Shire Clinical Study 
Serious Adverse Event and Non-serious AEs Required by the Protocol Form. 
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine -hCG 
test or ultrasound result will determine the pregnancy onset date.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 112 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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.
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 113 
 
06 May 2019
For non-commercial use only


 
 
 
 
 

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).
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 114 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 115 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
APPENDIX 5
HEREDITARY ANGIOEDEMA ATTACK ASSESSMENT AND 
REPORTING PROCEDURES (HAARP)
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 116 
 
06 May 2019
For non-commercial use only


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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 117 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
 
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 118 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
 
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 119 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
 
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. 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 120 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
 
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)
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 121 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
 

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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 122 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
 
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 123 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
 
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 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 124 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
 
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. 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 125 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
 
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.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 126 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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)
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 127 
 
06 May 2019
For non-commercial use only


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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 128 
 
06 May 2019
For non-commercial use only


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. 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 129 
 
06 May 2019
For non-commercial use only


',9,6,212)0,&52%,2/2*<$1',1)(&7,286
',6($6(6'0,'3(',$75,&72;,&,7<7$%/(6
129(0%(5
'5$)7

6HOHFWHG9DOXHVIRUFKLOGUHQOHVVWKDQRUHTXDO
WRPRQWKVRIDJH±GRHVQRWDSSO\IRUSUHWHUPLQIDQWV
)RUDOOSDUDPHWHUVQRWOLVWHGRQWKLVWDEOHSOHDVHUHIHU
WRWKH'0,'7R[LFLW\7DEOHIRUFKLOGUHQ!PRQWKVRIDJH
+(0$72/2*<
*5$'(
*5$'(
*5$'(
*5$'(
+HPRJORELQ
GD\VROG
JPG/
JPG/
JPG/
&DUGLDF)DLOXUH
VHFRQGDU\WR$QHPLD
GD\VROG
JPG/
JPG/
JPG/
&DUGLDF)DLOXUH
VHFRQGDU\WR$QHPLD
GD\VROG
 JPG/
JPG/
JPG/
&DUGLDF)DLOXUH
VHFRQGDU\WR $QHPLD
GD\VROG
JPG/
JPG/
JPG/
&DUGLDF)DLOXUH
VHFRQGDU\WR$QHPLD
GD\VROG
JPG/
JPG/
JPG/
&DUGLDF)DLOXUH
VHFRQGDU\WR$QHPLD
$EV1HXWURSKLO&W
GD\ROG
PP
PP
PP
PP
GD\VROG
PP
PP
PP
PP
GD\VROG
PP
PP
PP
PP
GD\VROG
PP
PP
PP
PP
%LOLUXELQ )UDFWLRQDWHGELOLUXELQWHVWPXVWEHSUHIRUPHGZKHQWRWDOELOLUXELQLVHOHYDWHG
GD\VROG

PJG/
PJG/
!PJG/
GD\VROG
[1
;Q
[1
![1
GD\VROG
[1
[1
[1
![1
6KLUH
6+33URWRFRO
/DQDGHOXPDE6+3
&21),'(17,$/
3DJH
0D\
)RUQRQFRPPHUFLDOXVHRQO\
Q \
VH
VH
VH RQ
VH
VH
XV
FLD
V
FLD
P
FR
FR
FR
P
FR
FR
FR
FR
QR
FR
FR
FR
QR
RU
)RU
)

PG/
PG/
JPG
JP


PG/
G/





',9,6,212)0,&52%,2/2*<$1',1)(&7,286
',6($6(6'0,'3(',$75,&72;,&,7<7$%/(6
129(0%(5
'5$)7

6HOHFWHG9DOXHVIRUFKLOGUHQOHVVWKDQRUHTXDO
WRPRQWKVRIDJH
+(0$72/2*<FRQWLQXHG
*5$'(
*5$'(
*5$'(
*5$'(
&UHDWLQLQH
GD\VROG
 PJG/
PJG/
PJG/
!PJG/
GD\VROG
PJG/
PJG/
PJG/
!PJG/
GD\VROG
PJG/
PJG/
PJG/
!PJG/
&U&OHDUDQFH
GD\VROG
POPLQ
POPLQ
POPLQ
POPLQ
GD\VROG
POPLQ
POPLQ
POPLQ
POPLQ
GD\VROG
POPLQ
POPLQ
POPLQ
POPLQ
+\SRFDOFHPLD
GD\VROG
± P(T/
 P(T/
 P(T/
 P(T/
GD\VROG
 P(T/
 P(T/
 P(T/
 P(T/
GD\VROG
 P(T/
 P(T/
 P(T/
 P(T/
+\SHUFDOFHPLD
GD\VROG
 P(T/
 P(T/
 P(T/
! P(T/
GD\VROG
 P(T/
 P(T/
 P(T/
! P(T/
GD\VROG
 P(T/
 P(T/
 P(T/
! P(T/
6KLUH
6+33URWRFRO
/DQDGHOXPDE6+3
&21),'(17,$/
3DJH
0D\
)RUQRQFRPPHUFLDOXVHRQO\O\
PJ
PJ
O\
RQ

R
VH
DO XVH
X
DO
UF
POPLQ
OPLQ
UF
PH
POP
PO
PH
P


RP
F
F
R
P(T/
(T/
QR
RU
R

 P(T/
P(T
RU
)


',9,6,212)0,&52%,2/2*<$1',1)(&7,286
',6($6(6'0,'3(',$75,&72;,&,7<7$%/(6
129(0%(5
'5$)7

*UHDWHUWKDQPRQWKVRIDJH
/2&$/5($&7,216
*5$'(
*5$'(
*5$'(
*5$'(
,QGXUDWLRQ
PP
PP
PP
!PP
(U\WKHPD
PP
PP
PP
!PP
(GHPD
PP
PP
PP
!PP
5DVKDW,QMHFWLRQ6LWH
PP
PP
PP
!PP
3UXULWXV
6OLJKWLWFKLQJDW
LQMHFWLRQVLWH
0RGHUDWHLWFKLQJDW
LQMHFWLRQH[WUHPLW\
,WFKLQJDWLQMHFWLRQ
H[WUHPLW\DQGRWKHU
VLWHV
,WFKLQJRYHUHQWLUH
ERG\
+(0$72/2*<
*5$'(
*5$'(
*5$'(
*5$'(
+HPRJORELQIRU
FKLOGUHQJUHDWHUWKDQ
PRQWKVDQGOHVVWKDQ
\HDUVRIDJH
JPG/
JPG/
JPG/
&DUGLDF )DLOXUH
VHFRQGDU\WRDQHPLD
+HPRJORELQIRU
FKLOGUHQJUHDWHUWKDW
\HDUVRIDJH
JPG/
JPG/
JPG/
&DUGLDF)DLOXUH
VHFRQGDU\WRDQHPLD
$EVROXWH1HXWURSKLO
&RXQW
PP
PP
PP
PP
3ODWHOHWV

PP
PP
PP
3URWKURPELQ7LPH
37
[8/1
[8/1
[8/1
![8/1
3DUWLDO
7KURPERSODVWLQ7LPH
377
[8/1
[8/1
[8/1
![8/1
6KLUH
6+33URWRFRO
/DQDGHOXPDE6+3
&21),'(17,$/
3DJH
0D\
)RUQRQFR
QR
FR
FRP


PPHUFLDOXVHRQO\


O\

P
P
O\
R
,WFKLQJ
,WFK
H[WUH
H[W
VL
DO XV
DO
R
VH
FLD
FLD
H
*5$'
*5$
PH
PP
P
FR
JPG/
JP
QR


',9,6,212)0,&52%,2/2*<$1',1)(&7,286
',6($6(6'0,'3(',$75,&72;,&,7<7$%/(6
129(0%(5
'5$)7

*UHDWHUWKDQPRQWKVRIDJH
*$6752,17(67,1$/
*5$'(
*5$'(
*5$'(
*5$'(
%LOLUXELQZKHQ
DFFRPSDQLHGE\DQ\
LQFUHDVHLQRWKHUOLYHU
IXQFWLRQWHVW
[8/1
[8/1
±[8/1
![8/1
%LOLUXELQZKHQRWKHU
OLYHUIXQFWLRQDUHLQ
WKHQRUPDOUDQJH
[8/1
[8/1
±[8/1
![8/1
$676*27
[8/1
±[8/1
±[8/1
![8/1
$/76*37
[8/1
±[8/1
±[8/1
![8/1
**7
[8/1
±[8/1
±[8/1
![8/1
3DQFUHDWLF$P\ODVH
[8/1
[8/1
[8/1
![8/1
8ULF$FLG
PJG/
PJG/
PJG/
!PJG/
&3.
6HH1HXURPXVFXODU7R[LFLW\
$SSHWLWH

'HFUHDVHGDSSHWLWH
$SSHWLWHYHU\
GHFUHDVHGQRVROLG
IRRGWDNHQ
1RVROLGRUOLTXLGWDNHQ
$EGRPLQDO3DLQ
0LOG
0RGHUDWH
1R7UHDWPHQW1HHGHG
0RGHUDWH
7UHDWPHQW1HHGHG
6HYHUH
+RVSLWDOL]HGIRUWUHDWPHQW
'LDUUKHD
6OLJKWFKDQJHLQ
FRQVLVWHQF\DQGRU
IUHTXHQF\RIVWRROV
/LTXLGVWRROV
/LTXLGVWRROVJUHDWHU
WKDW[WKHDPRXQWRU
QXPEHUQRUPDOIRU
WKLVFKLOG
/LTXLGVWRROVJUHDWHUWKDQ[
WKHDPRXQWRUQXPEHU
QRUPDOIRUWKLVFKLOG
6KLUH
6+33URWRFRO
/DQDGHOXPDE6+3
&21),'(17,$/
3DJH
0D\
)RUQRQFRPPHUFLDOXVHRQO\
[8
RQ

± 
X
RQ
XV
X
/1
X
FLDO XV
X
[8/1
[8
FLD
PH
[8
[
P
RP


RP
F
LW\
F
R

QR
)


',9,6,212)0,&52%,2/2*<$1',1)(&7,286
',6($6(6'0,'3(',$75,&72;,&,7<7$%/(6
129(0%(5
'5$)7

*UHDWHUWKDQPRQWKVRIDJH
*$6752,17(67,1$/FRQWLQXHG
*5$'(
*5$'(
*5$'(
*5$'(
&RQVWLSDWLRQ
6OLJKWFKDQJHLQWKH
FRQVLVWHQF\IUHTXHQF\
RIVWRRO
+DUGGU\VWRROVZLWK
DFKDQJHLQIUHTXHQF\
$EGRPLQDOSDLQ
'LVWHQWLRQDQG
9RPLWLQJ
1DXVHD
0LOG
0RGHUDWH
'HFUHDVHGRUDOLQWDNH
6HYHUH/LWWOH
RUDOLQWDNH
8QDEOHWRLQJHVWIRRG
RUIOXLGIRUPRUHWKDQ
KRXUV
9RPLWLQJ
HSLVRGHGD\
HSLVRGHV
SHUGD\
HSLVRGHVSHUGD\
*UHDWHUWKDQHSLVRGHV
SHUGD\RU,QWUDFWDEOH
9RPLWLQJ
6KLUH
6+33URWRFRO
/DQDGHOXPDE6+3
&21),'(17,$/
3DJH
0D\
)RUQRQFRPPHUFLDOXVHRQO\
QO\
HSLVRGHV
SLVRGH
X
QO\
XV
XV


',9,6,212)0,&52%,2/2*<$1',1)(&7,286
',6($6(6'0,'3(',$75,&72;,&,7<7$%/(6
129(0%(5
'5$)7

*UHDWHUWKDQPRQWKVRIDJH
(/(&752/<7(6
*5$'(
*5$'(
*5$'(
*5$'(
&5($7,1,1(
0RQWKV<HDUVRI
DJH
[8/1
[8/1
[8/1
! [8/1
<HDUV <HDUVRI
DJH
[8/1
[8/1
[8/1
![8/1
*UHDWHUWKDQ
<HDUVRIDJH
[8/1
[8/1
[8/1
! [8/1
6KLUH
6+33URWRFRO
/DQDGHOXPDE6+3
&21),'(17,$/
3DJH
0D\
)RUQRQFRPPHUFLDOXVH
VHRQO\
QO\
[8
[
QO\
VH
VH


',9,6,212)0,&52%,2/2*<$1',1)(&7,286
',6($6(6'0,'3(',$75,&72;,&,7<7$%/(6
129(0%(5
'5$)7

*UHDWHUWKDQPRQWKVRIDJH
(/(&752/<7(6
*5$'(
*5$'(
*5$'(
*5$'(
+\SHUQDWUHPLD
P(T/
 P(T/
!P(T/RU
DEQRUPDOVRGLXP
$1'PHQWDOVWDWXV
FKDQJHV
+\SRQDWUHPLD
P(T/
 P(T/
P(T/ RU
DEQRUPDOVRGLXP
$1'PHQWDOVWDWXV
FKDQJHV
+\SHUNDOHPLD
P(T/
P(T/
 P(T/
! P(T/ RU
DEQRUPDOSRWDVVLXP
$1'FDUGLDF
DUUK\WKDPLD
+\SRNDOHPLD
P(T/
 P(T/
 P(T/
 P(T/ RU
DEQRUPDOSRWDVVLXP
$1'FDUGLDF
DUUK\WKPLD
+\SHUFDOFHPLD
PJG/
 PJG/
 PJG/
! PJG/
+\SRFDOFHPLD
PJG/
 PJG/
 PJG/
 PJG/
+\SRPDJQHVHPLD
P(T/
 P(T/
 P(T/
 P(T/ RU
DEQRUPDOPDJQHVLXP
$1'FDUGLDF
DUUK\WKPLD
+\SRJO\FHPLD
PJG/
 PJG/
 PJG/
 PJG/ RU
DEQRUPDOJOXFRVH
$1'PHQWDOVWDWXV
FKDQJHV
+\SHUJO\FHPLD
PJG/
 PJG/
 PJG/
!PJG/ RU
NHWRDFLGRVLV
3URWHLQXULD
7U
RU
PJGD\

RU
PJGD\

RU
PJGD\

RU
1HSKURWLFV\QGURPH
!PJGD\
+HPDWXULD
0LFURVFRSLF
0LFURVFRSLF!
*URVVKHPDWXULD
6KLUH
6+33URWRFRO
/DQDGHOXPDE6+3
&21),'(17,$/
3DJH
0D\
)RU
P(T
P(
U QRQFRPPHUFLDOXVHRQO\
 P(T
P(
H

HUF
XVH
X

 P(T
P(
F
HUF
FR
F
G/
F
RQF
PJG/
JG/
RQ
U


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
10 
cells/hpf 
cells/hpf 
 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 137 
 
06 May 2019
For non-commercial use only


',9,6,212)0,&52%,2/2*<$1',1)(&7,286
',6($6(6'0,'3(',$75,&72;,&,7<7$%/(6
129(0%(5
'5$)7

*UHDWHUWKDQPRQWKVRIDJH
&(175$/1(592866<67(0&16
*5$'(
*5$'(
*5$'(
*5$'(
*HQHUDOL]HG&16
6\PSWRPV
'L]]LQHVV
+\SRWRQLF
K\SRUHVSRQVLYH
HSLVRGHV
6HL]XUHV
$SQHD%UDG\FDUGLD
,QFRQVRODEOHFU\LQJ!
KUV
+HDGDFKH
0LOG
0RGHUDWH5HVSRQGV
WRQRQQDUFRWLF
DQDOJHVLD
0RGHUDWHWR6HYHUH
5HVSRQGVWRQDUFRWLF
DQDOJHVLD
,QWUDFWDEOH
/HYHORI$FWLYLW\
6OLJKWO\LUULWDEOH25
VOLJKWO\VXEGXHG
9HU\LUULWDEOH25
/HWKDUJLF
,QFRQVRODEOH25
2EWXQGHG
9LVXDO
%OXUULQHVVGLSORSLD
RUKRUL]RQWDO
Q\VWDJPXVRI
KRXUGXUDWLRQZLWK
VSRQWDQHRXV
UHVROXWLRQ
0RUHWKDQHSLVRGH
RI*UDGH
V\PSWRPVSHUZHHN
RUDQHSLVRGHRI
*UDGHV\PSWRPV
ODVWLQJPRUHWKDQ
KRXUZLWK
VSRQWDQHRXV
UHVROXWLRQE\
KRXUVRUYHUWLFDO
Q\VWDJPXV
'HFUHDVHLQYLVXDO
DFXLW\YLVXDOILHOG
GHILFLWRURFXORJ\ULF
FULVLV
0\HORSDWK\
1RQH
1RQH
0\HORSDWKLFVSLQDO
FRUGV\PSWRPVVXFK
DVS\UDPLGDOWUDFW
ZHDNQHVVDQG
GLVLQKLELWLRQVHQVRU\
OHYHOORVVRI
SURSULRFHSWLRQ
EODGGHUERZHO
G\VIXQFWLRQ
6KLUH
6+33URWRFRO
/DQDGHOXPDE6+3
&21),'(17,$/
3DJH
0D\
)RUQRQF
)
Q
QFRPPHUF
VVGLSORSLD
VGLSOR
UL]RQWDO
RQWDO
VWDJPXVRI
DJPXV
KRXUGXUDW
RXUGX
VSRQWDQ
VSRQW
UFLDOXVHRQO\
QO\
GHUDWHWR6H
DWHWR
5HVSRQGVWR
SRQ
DQDOJHVLD
DQDOJHV
QO\
XV
25
25
XHG
9HU
/
UF DO X
O
UHVR
UHV
UF
QF


',9,6,212)0,&52%,2/2*<$1',1)(&7,286
',6($6(6'0,'3(',$75,&72;,&,7<7$%/(6
129(0%(5
'5$)7

*UHDWHUWKDQPRQWKVRIDJH
3(5,3+(5$/1(592866<67(0
3$5$0(7(5
*5$'(
*5$'(
*5$'(
*5$'(
1HXURSDWK\
/RZHU0RWRU
1HXURSDWK\
0LOGWUDQVLHQW
3DUHVWKHVLDRQO\
3HUVLVWHQWRU
SURJUHVVLYH
SDUHVWKHVLDVEXUQLQJ
VHQVDWLRQLQIHHWRU
PLOGG\VHVWKHVLDQR
ZHDNQHVVPLOGWR
PRGHUDWHGHHS
WHQGRQUHIOH[
FKDQJHVQRVHQVRU\
ORVV
2QVHWRIVLJQLILFDQW
ZHDNQHVVGHFUHDVHRU
ORVVRI'75VVHQVRU\
ORVVLQVWRFNLQJ
JORYHGLVWULEXWLRQ
UDGLFXODU VHQVRU\ORVV
PXOWLSOHFUDQLDOQHUYH
LQYROYHPHQWEODGGHU
RUERZHOG\VIXQFWLRQ
IDVFLFXODWLRQV
UHVSLUDWRU\
HPEDUUDVVPHQWIURP
FKHVWZDOOZHDNQHVV
0\RSDWK\RU
1HXURPXVFXODU
-XQFWLRQ,PSDLUPHQW
1RUPDORUPLOG
[8/1&3.
HOHYDWLRQ
0LOGSUR[LPDO
ZHDNQHVVDQGRU
DWURSK\QRWDIIHFWLQJ
JURVVPRWRUIXQFWLRQ
0LOGP\DOJLDV
PLOG&3.HOHYDWLRQ
[8/1
3UR[LPDOPXVFOH
ZHDNQHVVDQGRU
DWURSK\DIIHFWLQJ
PRWRUIXQFWLRQ
&3.HOHYDWLRQRU
VHYHUHP\DOJLDVZLWK
&3.![8/1
2QVHWRIP\DVWKHQLD
OLNHV\PSWRPV
IDWLJDEOHZHDNQHVV
ZLWKH[WHUQDOYDULDEOH
RSKWKDOPRSOHJLD
DQGRUSWRVLVRU
QHXURPXVFXODU
MXQFWLRQEORFNDGH
DFXWHSDUDO\VLV
V\PSWRPV
6KLUH
6+33URWRFRO
/DQDGHOXPDE6+3
&21),'(17,$/
3DJH
0D\
)RUQRQF
RU
QF
)RU
FRPPHUFLD
LPDODO
VVDQGRU
DQGR
SK\QRWDIIH
\QRWDI
URVVPRWRU
VVPRWR
0LOGP\D
0LOGP
PLOG&
PLOG


FLDOXVHRQO\
PLO
GHHS
GHHS
QUHIOH[
HIOH[
DQJHVQRVH
HVQR
RVV
LDO X
FLD
F


',9,6,212)0,&52%,2/2*<$1',1)(&7,286
',6($6(6'0,'3(',$75,&72;,&,7<7$%/(6
129(0%(5
'5$)7

*UHDWHUWKDQPRQWKVRIDJH
27+(5
*5$'(
*5$'(
*5$'(
*5$'(
$OOHUJ\
3UXULWXVZLWKRXW5DVK
3UXULWLF5DVK
0LOG8UWLFDULD
6HYHUH8UWLFDULD
$QDSK\OD[LV
$QJLRHGHPD
'UXJ)HYHU5HFWDO

&
±)
*UHDWHUWKDQ&
*UHDWHUWKDQ)
6XVWDLQHG)HYHU
(TXDORUJUHDWHUWKDQ
&)IRU
ORQJHUWKDQGD\V
&XWDQHRXV
/RFDOL]HGUDVK
'LIIXVH
PDFXORSDSXODU
5DVK
*HQHUDOL]HGXUWLFDULD
6WHYHQV-RKQVRQ
6\QGURPHRU(U\WKHPD
PXOWLIRUPH
6WRPDWLWLV
0LOGGLVFRPIRUW
3DLQIXOGLIILFXOW\
VZDOORZLQJEXWDEOH
WRHDWDQGGULQN
3DLQIXOXQDEOHWR
VZDOORZVROLGV
3DLQIXOXQDEOHWR
VZDOORZOLTXLGV
UHTXLUHV,9IOXLGV
&OLQLFDOV\PSWRPV
QRWRWKHUZLVH
VSHFLILHG LQWKLVWDEOH
1RWKHUDS\PRQLWRU
FRQGLWLRQ
0D\UHTXLUHPLQLPDO
LQWHUYHQWLRQDQG
PRQLWRULQJ
5HTXLUHVPHGLFDOFDUH
DQGSRVVLEOH
KRVSLWDOL]DWLRQ
5HTXLUHVDFWLYH
PHGLFDOLQWHUYHQWLRQ
KRVSLWDOL]DWLRQRU
KRVSLFHFDUH
/DERUDWRU\YDOXHVQRW
RWKHUZLVHVSHFLILHG LQ
WKLVWDEOH
$EQRUPDOEXW
UHTXLULQJQR
LPPHGLDWH
LQWHUYHQWLRQIROORZ
6XIILFLHQWO\DEQRUPDO
WRUHTXLUHHYDOXDWLRQ
DVWRFDXVDOLW\DQG
SHUKDSVPLOG
WKHUDSHXWLF
LQWHUYHQWLRQEXWQRW
RIVXIILFLHQWVHYHULW\
WRZDUUDQWLPPHGLDWH
FKDQJHVLQVWXG\GUXJ
6XIILFLHQWO\VHYHUHWR
UHTXLUHHYDOXDWLRQ
DQGWUHDWPHQW
LQFOXGLQJDWOHDVW
WHPSRUDU\VXVSHQVLRQ
RIVWXG\GUXJ
/LIHWKUHDWHQLQJ
VHYHULW\5HTXLUHV
LPPHGLDWHHYDOXDWLRQ
WUHDWPHQWDQGXVXDOO\
KRVSLWDOL]DWLRQ6WXG\
GUXJPXVWEHVWRSSHG
LPPHGLDWHO\DQG
VKRXOGQRWEHUHVWDUWHG
XQWLOWKHDEQRUPDOLW\LV
FOHDUO\IHOWWREH
FDXVHGE\VRPHRWKHU
PHFKDQLVPWKDWVWXG\
GUXJ
6KLUH
6+33URWRFRO
/DQDGHOXPDE6+3
&21),'(17,$/
3DJH
0D\
)RUQRQFRPPHUFLDOXVHRQO\
KD
RQ
*HQHUDOL]
*HQHUDO
O XV
RQ
XV
LFXOW\
XOW\
QJEXWDEOH
JEXWD
DQGGULQN
GGULQ
DO
PH
0D\UHTXLUH
D\UHTX
LQWHUYHQW
QWHUYH
PRQLWR
PRQ
Q F
PH
FR
EXW
XW
QR
QR
GLDWH
DWH
UYHQWLRQI
UYHQWLRQ
RQ


 
 
 
 
 
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 141 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 142 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
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
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 143 
 
06 May 2019
For non-commercial use only


For non-commercial use only


 
 
 
 
 
11.
REFERENCES
Agostoni, A., Aygoren-Pursun, E., Binkley, K. E., Blanch, A., Bork, K., Bouillet, L., Bucher, C., 
Castaldo, A. J., Cicardi, M., Davis, A. E., De Carolis, C., Drouet, C., Duponchel, C., 
Farkas, H.and Fay, K. 2004. Hereditary and acquired angioedema: Problems and 
progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. 
Journal of Allergy and Clinical Immunology, The, 114, S51-S131.
Agostoni, A.and Cicardi, M. 1992. Hereditary and acquired C1-inhibitor deficiency: Biological 
and clinical characteristics in 235 patients. Medicine, 71, 206-215.
Baldrick, P. 2010. Juvenile animal testing in drug development - Is it useful? Regulatory 
Toxicology and Pharmacology, 57, 291-299.
Banerji, A. 2013. The burden of illness in patients with hereditary angioedema. Ann Allergy 
Asthma Immunol, 111, 329-36.
Banerji, A., Busse, P., Shennak, M., Lumry, W., Davis-Lorton, M., Wedner, H. J., Jacobs, J., 
Baker, J., Bernstein, J. A., Lockey, R., Li, H. H., Craig, T., Cicardi, M., Riedl, M., Al-
Ghazawi, A., Soo, C., Iarrobino, R., Sexton, D. J., TenHoor, C., Kenniston, J. A., 
Faucette, R., Still, J. G., Kushner, H., Mensah, R., Stevens, C., Biedenkapp, J. C., 
Chyung, Y.and Adelman, B. 2017. Inhibiting Plasma Kallikrein for Hereditary 
Angioedema Prophylaxis. N Engl J Med, 376, 717-728.
Bennett, G.and Craig, T. 2015. Hereditary angioedema with a focus on the child. Allergy Asthma 
Proc, 36, 70-3.
Bork, K. 2013. Hereditary Angioedema with Normal C1 Inhibitor. Immunology and Allergy 
Clinics of North America, 33, 457-470.
Bork, K. 2014a. Current drugs in early development for hereditary angioedema: potential for 
effective treatment. Expert Opin Investig Drugs, 23, 887-91.
Bork, K. 2014b. An evidence based therapeutic approach to hereditary and acquired angioedema.
Current Opinion in Allergy and Clinical Immunology, 14, 354-362.
Bork, K., Hardt, J., Schicketanz, K. H.and Ressel, N. 2003. Clinical studies of sudden upper 
airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor 
deficiency. Arch Intern Med, 163, 1229-35.
Bork, K., Hardt, J.and Witzke, G. 2012. Fatal laryngeal attacks and mortality in hereditary 
angioedema due to C1-INH deficiency. J Allergy Clin Immunol, 130, 692-7.
Bork, K., Meng, G., Staubach, P.and Hardt, J. 2006a. Hereditary angioedema: New findings 
concerning symptoms, affected organs, and course. American Journal of Medicine, 119, 
267-274.
Bork, K., Staubach, P., Eckardt, A. J.and Hardt, J. 2006b. Symptoms, course, and complications 
of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J 
Gastroenterol, 101, 619-27.
Bowen, T., Cicardi, M., Bork, K., Zuraw, B., Frank, M., Ritchie, B., Farkas, H., Varga, L., 
Zingale, L. C., Binkley, K., Wagner, E., Adomaitis, P., Brosz, K., Burnham, J., 
Warrington, R., Kalicinsky, C., Mace, S., McCusker, C., Schellenberg, R., Celeste, L., 
Hebert, J., Valentine, K., Poon, M. C., Serushago, B., Neurath, D., Yang, W., Lacuesta, 
G., Issekutz, A., Hamed, A., Kamra, P., Dean, J., Kanani, A., Stark, D., Rivard, G. E., 
Leith, E., Tsai, E., Waserman, S., Keith, P. K., Page, D., Marchesin, S., Longhurst, H. J., 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 145 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
Kreuz, W., Rusicke, E., Martinez-Saguer, I., Aygoren-Pursun, E., Harmat, G., Fust, G., 
Li, H., Bouillet, L., Caballero, T., Moldovan, D., Spath, P. J., Smith-Foltz, S., Nagy, I., 
Nielsen, E. W., Bucher, C., Nordenfelt, P.and Xiang, Z. Y. 2008. Hereditary angiodema: 
a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus 
Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann 
Allergy Asthma Immunol, 100, S30-40.
Bygum, A. 2009. Hereditary angio-oedema in Denmark: a nationwide survey. The British 
journal of dermatology, 161, 1153-8.
Bygum, A., Fagerberg, C. R., Ponard, D., Monnier, N., Lunardi, J.and Drouet, C. 2011. 
Mutational spectrum and phenotypes in Danish families with hereditary angioedema 
because of C1 inhibitor deficiency. Allergy, 66, 76-84.
Caballero, T. 2013. Angio-oedema due to hereditary C1 inhibitor deficiency in children. Allergol 
Immunopathol (Madr), 41, 45-53.
Caballero, T., Aygoren-Pursun, E., Bygum, A., Beusterien, K., Hautamaki, E., Sisic, Z., Wait, 
S.and Boysen, H. B. 2014. The humanistic burden of hereditary angioedema: results from 
the Burden of Illness Study in Europe. Allergy Asthma Proc, 35, 47-53.
Cicardi, M., Bork, K., Caballero, T., Craig, T., Li, H. H., Longhurst, H., Reshef, A.and Zuraw, 
B. 2012. Evidence-based recommendations for the therapeutic management of 
angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an 
International Working Group. Allergy, 67, 147-57.
Craig, T., Aygoren-Pursun, E., Bork, K., Bowen, T., Boysen, H., Farkas, H., Grumach, A., 
Katelaris, C. H., Lockey, R., Longhurst, H., Lumry, W., Magerl, M., Martinez-Saguer, I., 
Ritchie, B., Nast, A., Pawankar, R., Zuraw, B.and Maurer, M. 2012a. WAO Guideline for 
the Management of Hereditary Angioedema. World Allergy Organ J, 5, 182-99.
Craig, T., Pursun, E. A., Bork, K., Bowen, T., Boysen, H., Farkas, H., Grumach, A., Katelaris, C. 
H., Lockey, R., Longhurst, H., Lumry, W., Magerl, M., Martinez-Saguer, I., Ritchie, B., 
Nast, A., Pawankar, R., Zuraw, B.and Maurer, M. 2012b. WAO Guideline for the 
Management of Hereditary Angioedema. World Allergy Organ J, 5, 182-199.
Craig, T. J., Levy, R. J., Wasserman, R. L., Bewtra, A. K., Hurewitz, D., Obtulowicz, K., Reshef, 
A., Ritchie, B., Moldovan, D., Shirov, T., Grivcheva-Panovska, V., Kiessling, P. C., 
Keinecke, H. O.and Bernst 2009. Efficacy of human C1 esterase inhibitor concentrate 
compared with placebo in acute hereditary angioedema attacks. Journal of Allergy and 
Clinical Immunology, The, 124, 801-808.
Davis, A. E. 2005. The pathophysiology of hereditary angioedema. Clinical Immunology, 114, 3-
9.
Davis, C. A., Vallota, E. H.and Forristal, J. 1979. Serum complement levels in infancy: age 
related changes. Pediatr Res, 13, 1043-6.
El-Hachem, C., Amiour, M., Guillot, M.and Laurent, J. 2005. Hereditary angioneurotic edema: a 
case report in a 3-year-old child. Archives de pédiatrie, 12, 1232-6.
Farkas, H., Harmat, G., Fust, G., Varga, L.and Visy, B. 2002. Clinical management of hereditary 
angio-oedema in children. Pediatr Allergy Immunol, 13, 153-61.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 146 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
Farkas, H., Varga, L., Szeplaki, G., Visy, B., Harmat, G.and Bowen, T. 2007. Management of 
hereditary angioedema in pediatric patients. Pediatrics, 120, e713-22.
Fouche, A. S., Saunders, E. F. H.and Craig, T. 2014a. Depression and anxiety in patients with 
hereditary angioedema. Annals of Allergy, Asthma & Immunology, 112, 371-375.
Fouche, C., Kenealy, T., Mace, J.and Shaw, J. 2014b. Practitioner perspectives from seven health 
professional groups on core competencies in the context of chronic care. J Interprof 
Care, 28, 534-40.
Frank, M. M., Gelfand, J. A.and Atkinson, J. P. 1976. Hereditary angioedema: the clinical 
syndrome and its management. Ann Intern Med, 84, 580-93.
Frank, M. M., Zuraw, B., Banerji, A., Bernstein, J. A., Craig, T., Busse, P., Christiansen, S., 
Davis-Lorton, M., Li, H. H., Lumry, W. R.and Riedl, M. 2016. Management of Children 
With Hereditary Angioedema Due to C1 Inhibitor Deficiency. Pediatrics, 138, 
e20160575-e20160575.
Gompels, M. M., Lock, R. J., Abinun, M., Bethune, C. A., Davies, G., Grattan, C., Fay, A. C., 
Longhurst, H. J., Morrison, L., Price, A., Price, M.and Watters, D. 2005a. C1 inhibitor 
deficiency: consensus document. Clin Exp Immunol, 139, 379-94.
Gompels, M. M., Lock, R. J., Abinun, M., Bethune, C. A., Davies, G., Grattan, C., Fay, A. C., 
Longhurst, H. J., Morrison, L., Price, A., Price, M.and Watters, D. 2005b. C1 inhibitor 
deficiency: consensus document. Clinical and Experimental Immunology, 139, 379-94.
Goring, H. D., Bork, K., Spath, P. J., Bauer, R., Ziemer, A., Hintner, H.and Wuthrich, B. 1998. 
Hereditary angioedema in the German-speaking region. Hautarzt, 49, 114-22.
Jolles, S., Williams, P., Carne, E., Mian, H., Huissoon, A., Wong, G., Hackett, S., Lortan, J., 
Platts, V., Longhurst, H., Grigoriadou, S., Dempster, J., Deacock, S., Khan, S., Darroch, 
J.and Simon, C. 2014. A UK national audit of hereditary and acquired angioedema. 
Clinical & Experimental Immunology, 175, 59-67.
Kenniston, J. A., Faucette, R. R., Martik, D., Comeau, S. R., Lindberg, A. P., Kopacz, K. J., 
Conley, G. P., Chen, J., Viswanathan, M., Kastrapeli, N., Cosic, J., Mason, S., DiLeo, M., 
Abendroth, J., Kuzmic, P., Ladner, R. C., Edwards, T. E., TenHoor, C., Adelman, B. A., 
Nixon, A. E.and Sexton, D. J. 2014. Inhibition of plasma kallikrein by a highly specific 
active site blocking antibody  J Biol Chem 289  23596-608
Kuhlen, J. L., Jr.and Banerji, A. 2015. Hereditary angioedema: Special consideration in children, 
women of childbearing age, and the elderly. Allergy and Asthma Proceedings, 36, 425-
432.
Leeb-Lundberg, L. M. F., Marceau, F., Müller-Esterl, W., Pettibone, D. J.and Zuraw, B. L. 2005. 
International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: 
from Molecular Mechanisms to Pathophysiological Consequences. Pharmacological 
Reviews, 57, 27-77.
Lei, W. T., Shyur, S. D., Huang, L. H., Kao, Y. H.and Lo, C. Y. 2011. Type I hereditary 
angioedema in Taiwan -- clinical, biological features and genetic study. Asian Pac J 
Allergy Immunol, 29, 327-31.
Longhurst, H. J. 2017. Kallikrein Inhibition for Hereditary Angioedema. New England Journal 
of Medicine, The, 376, 788-789.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 147 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
Lumry, W. R. 2013. Overview of epidemiology, pathophysiology, and disease progression in 
hereditary angioedema  American journal of managed care  The 19  s103-10
MacGinnitie, A. J. 2014. Pediatric hereditary angioedema. Pediatr Allergy Immunol, 25, 420-7.
Martin, P. L.and Weinbauer, G. F. 2010. Developmental Toxicity Testing of Biopharmaceuticals 
in Nonhuman Primates. International Journal of Toxicology, 29, 552-568.
Maurer, M., Magerl, M., Ansotegui, I., Aygoren Pursun, E., Betschel, S., Bork, K., Bowen, T., 
Balle Boysen, H., Farkas, H., Grumach, A., Hide, M., Katelaris, C., Lockey, R., 
Longhurst, H., Lumry, W., Martinez-Saguer, I., Moldovan, D., Nast, A., Pawankar, R., 
Potter, P., Riedl, M., Ritchie, B., Rosenwasser, L., Sanchez-Borges, M., Zhi, Y., Zuraw, 
B.and Craig, T. 2018. The international WAO/EAACI guideline for the management of 
hereditary angioedema - the 2017 revision and update. Allergy.
Morford, L. L., Bowman, C. J., Blanset, D. L., Bogh, I. B., Chellman, G. J., Halpern, W. G., 
Weinbauer, G. F.and Coogan, T. P. 2011. Preclinical safety evaluations supporting 
pediatric drug development with biopharmaceuticals: strategy, challenges, current 
practices. Birth Defects Res B Dev Reprod Toxicol, 92, 359-80.
Nanda, M. K., Elenburg, S., Bernstein, J. A.and Assa'ad, A. H. 2015. Clinical features of 
pediatric hereditary angioedema. J Allergy Clin Immunol Pract, 3, 392-5.
Nielsen, E. W., Johansen, H. T., Holt, J.and Mollnes, T. E. 1994. C1 inhibitor and diagnosis of 
hereditary angioedema in newborns. Pediatric Research, 35, 184-7.
Nordenfelt, P., Dawson, S., Wahlgren, C. F., Lindfors, A., Mallbris, L.and Bjorkander, J. 2014. 
Quantifying the burden of disease and perceived health state in patients with hereditary 
angioedema in Sweden. Allergy Asthma Proc, 35, 185-90.
Nzeako, U. C., Frigas, E.and Tremaine, W. J. 2001. Hereditary angioedema, a broad review for 
clinicians. Archives of Internal Medicine, 161, 2417-2429.
Pappalardo, E., Cicardi, M., Duponchel, C., Carugati, A., Choquet, S., Agostoni, A.and Tosi, M. 
2000. Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients 
with angioedema. Journal of Allergy and Clinical Immunology, The, 106, 1147-1154.
Read, N., Lim, E., Tarzi, M. D., Hildick-Smith, P., Burns, S.and Fidler, K. J. 2014. Paediatric 
hereditary angioedema: a survey of UK service provision and patient experience. Clin 
Exp Immunol, 178, 483-8.
Renne, T.and Gruber, A. 2012. Plasma kallikrein: novel functions for an old protease. Thromb 
Haemost, 107, 1012-3.
Roach, B., Kim, Y., Jerome, E.and Michael, A. F. 1981. Influence of age and sex on serum 
complement components in children. Am J Dis Child, 135, 918-20.
Roche, O., Blanch, A., Caballero, T., Sastre, N., Callejo, D.and Lopez-Trascasa, M. 2005. 
Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to 
the prevalence in Spain. Ann Allergy Asthma Immunol, 94, 498-503.
Sabharwal, G.and Craig, T. 2017. Pediatric hereditary angioedema: an update. F1000Research,
6.
Stray-Pedersen, Sorte, Samarakoon, Gambin, Chinn, Coban Akdemir, Erichsen, Forbes, Gu, 
Yuan, Jhangiani, Muzny, Rødningen, Sheng, Nicholas, Noroski, Seeborg, Davis, Canter, 
Mace, Vece, Allen, Abhyankar, Boone, Beck, Wiszniewski, Fevang, Aukrust, 
Tjønnfjord, Gedde-Dahl, Hjorth-Hansen, Dybedal, Nordøy, Jørgensen, Abrahamsen, 
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 148 
 
06 May 2019
For non-commercial use only


 
 
 
 
 
Øverland, Bechensteen, Skogen, Osnes, Kulseth, Prescott, Rustad, Heimdal, Belmont, 
Rider, Chinen, Cao, Smith, Caldirola, Bezrodnik, Lugo Reyes, Espinosa Rosales, 
Guerrero-Cursaru, Pedroza, Poli, Franco, Trujillo Vargasand Aldave Becerr 2017. 
Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous 
Mendelian disorders. Journal of Allergy and Clinical Immunology, The, 139, 232-245.
Tosi, M. 1998. Molecular genetics of C1 inhibitor. Immunobiology, 199, 358-65.
Zuraw, B.and Christiansen, S. 2016. HAE Pathophysiology and Underlying Mechanisms. 
Clinical Reviews in Allergy & Immunology, 51, 216-229.
Zuraw, B. L. 2008. Clinical practice. Hereditary angioedema. N Engl J Med, 359, 1027-36.
Zuraw, B. L., Bernstein, J. A., Lang, D. M., Craig, T., Dreyfus, D., Hsieh, F., Khan, D., Sheikh, 
J., Weldon, D., Bernstein, D. I., Blessing-Moore, J., Cox, L., Nicklas, R. A., 
Oppenheimer, J., Portnoy, J. M., Randolph, C. R., Schuller, D. E., Spector, S. L., Tilles, 
S. A., Wallace, D., American Academy of Allergy, A., Immunology, American College 
of Allergy, A.and Immunology 2013. A focused parameter update: hereditary 
angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme 
inhibitor-associated angioedema. J Allergy Clin Immunol, 131, 1491-3.
Shire 
SHP643-301 Protocol 
Lanadelumab (SHP643)
CONFIDENTIAL 
 
Page 149 
 
06 May 2019
For non-commercial use only