Conditions: Angioedema
Keywords: Drug Therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 77
Healthy volunteers: no

Brief summary:
The main aim of this study is to check if repeated subcutaneous (SC) injections of lanadelumab can prevent angioedema attacks in teenagers and adults with non-histaminergic angioedema with normal C1-INH. Another aim is to check if they tolerate the repeated SC injections.

Participants will receive a SC injection of lanadelumab every two weeks for 26 weeks. The first two doses of lanadelumab will be given at the study clinic. Once a participant (and/or parent/caregiver) has been appropriately trained, lanadelumab can be self-injected. Visits to the study clinic are planned for the first, third and fourth week and then every 4 weeks.

Detailed description:
This study consists of non-histaminergic normal C1-INH angioedema population with 12 years of age and above. Participants will be randomized 2:1 to receive repeated SC administrations of lanadelumab or placebo in a double-blind fashion. Randomization will be stratified based on baseline angioedema attack rate (1 to less than (\<) 2 attacks/4 weeks, and greater than (\>=) 2 attacks/4 weeks), as well as subtype (known mutations, family history and unknown mutation, idiopathic).

Arms:
arm 1: Participants received placebo-matching lanadelumab subcutaneous (SC) injection once every 2 weeks (q2w) for up to 7 months. arm 2: Participants received 300 mg of lanadelumab solution in a prefilled syringe (PFS) as SC injection once (q2w) for up to 6 months.

Interventions: intervention 1: Placebo intervention 2: Lanadelumab
Intervention descriptions: intervention 1: Placebo-matching lanadelumab SC injection. intervention 2: Lanadelumab solution in a PFS for injection.

Protocol document:
Prot_000.pdf: 


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19 Apr 2021
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the “Takeda 
Safety Report Form” within 24 hours to the Takeda Global Patient Safety Evaluation (GPSE) 
Group. 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)/Takeda 
medical monitor using the details below.
Fax number: +1-484-595-8155
E-mail: drugsafety@shire.com
For protocol- or safety-related questions or concerns during or outside of normal business 
hours the investigator must contact the IQVIA medical monitor. Contact details are 
available via the study specific contact list. 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
A summary of the changes incorporated into Amendment 3 is provided in the table below.
Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected by Change
Sponsor has been revised from Shire to Takeda 
Development Centers Americas, Inc. (TDCA) / Takeda 
Cover Page
Protocol Signature Page
Product Quality Complaints
Section 6.4
Appendix 1.5
Appendix 3.5
Removed IQVIA medical monitor contact information 
and added reference to the study specific contact list. The 
contact list contains the most accurate and up-to-date
contact information. 
Emergency Contact Information
The email address for reporting product quality 
complaints was updated to: ctmcomplaint@takeda.com
Product Quality Complaints
Revised to include appropriate Takeda forms for 
reporting adverse events (AEs) and pregnancy.
Emergency Contact Information
Appendix 3.4
Appendix 3.8
Revised footnote to clarify that subjects <18 years of age 
will only be enrolled if allowed based on local site and / 
or country regulations. 
Section 1.1
Section 4.1
Revised inclusion criterion #3 to clarify that subjects with
C4 level not below the normal range should be enrolled. 
Section 1.1
Section 5.1
Revised footnote f for Table 1 (Table 1 Schedule of 
Activities - Screening and Observation Period) to clarify
that an additional confirmatory test may be performed 
during the observation period if C1-INH therapy washout 
was not completed during the screening period.
Section 1.3
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Revised footnote g for Table 1 (Table 1 Schedule of 
Activities - Screening and Observation Period) to clarify
that the 2-week washout period will be completed in the 
screening period only for subjects where it is deemed 
safe to complete.
Section 1.3
An “X” for site check-in call that was inadvertently 
missing at Visit 2 (Table 2 Schedule of Activities –
Treatment Period) was added to align with 
Section 8.2.2.2 of the protocol. 
Section 1.3
Revised Study DX-2930-04 from “ongoing” to 
“completed.”
Section 2.6
Timeframe for male contraception was revised to align 
with female contraception (for the duration of the study 
and 70 days after the last dose of investigational product). 
Section 5.4.2
Specific quantitative stopping criteria, particularly in 
regard to liver values was added.
Section 7.5.2
Added language to clarify that sample collection for 
genotype testing during the screening period is required; 
an additional sample for exploratory genetic analyses is 
optional. 
Section 8.3.6.5
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Takeda 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 Takeda 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:
ctmcomplaint@takeda.com
Telephone number (provided for reference if needed):
Takeda, Lexington, MA (USA)
1-800-828-2088
For instructions on reporting AEs related to product complaints, see Appendix 3.4.
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................6
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
1
PROTOCOL SUMMARY......................................................................................................12
1.1
Synopsis ...................................................................................................................12
1.2
Schema .....................................................................................................................20
1.3
Schedule of Activities ..............................................................................................21
2
INTRODUCTION..................................................................................................................25
2.1
Disease Etiology and Pathophysiology....................................................................25
2.2
Epidemiology ...........................................................................................................26
2.3
Indication and Current Treatment Options...............................................................27
2.4
Product Background and Clinical Information ........................................................28
2.4.1
Drug Information ...................................................................................................28
2.4.2
Nonclinical Studies with Lanadelumab .................................................................30
2.4.3
Clinical Studies with Lanadelumab .......................................................................30
2.4.4
Adolescent Clinical Trial Experience....................................................................33
2.5
Study Rationale ........................................................................................................34
2.6
Benefit/Risk Assessment..........................................................................................35
2.7
Compliance Statement..............................................................................................38
3
OBJECTIVES AND ENDPOINTS........................................................................................39
3.1
Study Objectives ......................................................................................................39
3.1.1
Primary Objective..................................................................................................39
3.1.2
Secondary Objectives.............................................................................................39
3.1.3
Exploratory Objectives ..........................................................................................39
3.2
Study Endpoints .......................................................................................................39
4
STUDY DESIGN ...................................................................................................................42
4.1
Overall Design..........................................................................................................42
4.2
Scientific Rationale for Study Design......................................................................43
4.3
Justification for Dose ...............................................................................................44
4.4
Duration of Subject Participation and Study Completion Definition ......................45
4.5
Sites and Regions .....................................................................................................45
5
STUDY POPULATION.........................................................................................................46
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5.1
Inclusion Criteria......................................................................................................46
5.2
Exclusion Criteria.....................................................................................................47
5.3
Restrictions...............................................................................................................48
5.3.1
Medical Interventions ............................................................................................48
5.3.2
Fluid and Food Intake............................................................................................48
5.3.3
Activity ..................................................................................................................48
5.4
Reproductive Potential .............................................................................................49
5.4.1
Female Contraception............................................................................................49
5.4.2
Male Contraception................................................................................................50
6
STUDY INTERVENTION ....................................................................................................51
6.1
Investigational Product.............................................................................................51
6.1.1
Identity of Investigational Product.........................................................................51
6.1.2
Blinding the Treatment Assignment......................................................................51
6.2
Administration of Investigational Product ...............................................................51
6.2.1
Interactive Response Technology for Investigational Product Management ........51
6.2.2
Allocation of Subjects to Treatment ......................................................................52
6.2.3
Dosing....................................................................................................................52
6.2.4
Unblinding the Treatment Assignment..................................................................52
6.2.5
Dose Modification .................................................................................................53
6.3
Labeling, Packaging, Storage, and Handling of Investigational Product.................53
6.3.1
Labeling .................................................................................................................53
6.3.2
Packaging...............................................................................................................53
6.3.3
Storage and Handling.............................................................................................54
6.4
Drug Accountability.................................................................................................55
6.5
Subject Compliance..................................................................................................56
6.6
Prior and Concomitant Therapy...............................................................................56
6.6.1
Prior Treatment ......................................................................................................57
6.6.2
Concomitant Treatment .........................................................................................57
6.6.3
Permitted Treatment...............................................................................................57
6.6.4
Prohibited Treatment .............................................................................................58
7
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL..........................................................................59
7.1
Discontinuation of Study Treatment ........................................................................59
7.2
Reasons for Discontinuation ....................................................................................59
7.3
Withdrawal from the Study......................................................................................60
7.4
Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit..............................60
7.5
Stopping Rules .........................................................................................................60
7.5.1
Study Level Stopping Rules...................................................................................60
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7.5.2
Individual Stopping Rules......................................................................................60
7.5.3
Follow-up for Subjects Meeting Stopping Criteria................................................61
8
STUDY ASSESSMENTS AND PROCEDURES..................................................................62
8.1
Changes to Study Procedures Due to the COVID-19 Pandemic..............................62
8.2
Study Periods............................................................................................................63
8.2.1
Screening and Observation Period.........................................................................63
8.2.1.1
Screening Period (up to 8 weeks, including 2-week LTP washout if 
applicable) ..............................................................................................63
8.2.1.2
Start of Observation Period....................................................................64
8.2.1.3
Observation Period (minimum of 4 weeks and up to 8 weeks) .............64
8.2.2
Treatment Period....................................................................................................65
8.2.2.1
Study Visit 1; Study Day 0.....................................................................65
8.2.2.2
Study Visit 2 (Study Day 4) to Study Visit 25 (Study Day 175) ...........66
8.2.2.3
Final Visit of Treatment Period (Study Visit 26; Study Day 182).........67
8.2.3
Follow-up Period ...................................................................................................68
8.2.4
Early Termination..................................................................................................68
8.2.5
Additional Care of Subjects after the Study ..........................................................68
8.3
Study Assessments ...................................................................................................68
8.3.1
Informed Consent...................................................................................................68
8.3.2
Eligibility Review..................................................................................................68
8.3.3
Demographic and Other Baseline Characteristics .................................................68
8.3.3.1
Medical and Medication History............................................................68
8.3.4
Efficacy..................................................................................................................69
8.3.4.1
Collection of Angioedema Attack Data .................................................69
8.3.4.2
Management of Acute Angioedema Attacks..........................................69
8.3.5
Safety .....................................................................................................................69
8.3.5.1
Physical Examination.............................................................................69
8.3.5.2
Adverse Events.......................................................................................70
8.3.5.3
Adverse Events of Special Interest (AESIs) ..........................................71
8.3.5.4
Vital Signs..............................................................................................72
8.3.5.5
Clinical Laboratory Tests.......................................................................72
8.3.5.6
Pregnancy Test .......................................................................................72
8.3.5.7
Electrocardiogram ..................................................................................72
8.3.6
Other Study Assessments.......................................................................................73
8.3.6.1
Clinical Pharmacology...........................................................................73
8.3.6.2
Pharmacodynamics.................................................................................73
8.3.6.3
Immunogenicity (Antidrug Antibody Testing) ......................................73
8.3.6.4
Biomarkers .............................................................................................73
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8.3.6.5
Genetics..................................................................................................74
8.3.6.6
Health-related Quality of Life................................................................74
8.3.6.7
Healthcare Resource Utilization.............................................................75
8.3.6.8
Self-administration of Investigational Product ......................................75
8.3.6.9
Injection Report......................................................................................76
8.3.7
Volume of Blood to Be Drawn from Each Subject ...............................................76
8.3.8
Blood Sample Collection, Storage, and Shipping..................................................77
9
STATISTICAL CONSIDERATIONS ...................................................................................78
9.1
Statistical Analysis Process......................................................................................78
9.2
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......78
9.3
Sample Size and Power Considerations...................................................................78
9.4
Statistical Analysis Set(s).........................................................................................79
9.5
Disposition, Demographics and Baseline Characteristics, and Exposure................79
9.5.1
Subject Disposition................................................................................................79
9.5.2
Demographics and Other Baseline Characteristics................................................79
9.5.3
Exposure and Treatment Compliance....................................................................79
9.5.4
Prior and Concomitant Medications ......................................................................80
9.6
Efficacy Analyses.....................................................................................................80
9.6.1
Primary Efficacy Endpoint ....................................................................................80
9.6.2
Secondary Efficacy Endpoints...............................................................................80
9.6.3
Exploratory Efficacy Endpoints.............................................................................82
9.7
Safety Analyses........................................................................................................82
9.8
Other Analyses .........................................................................................................82
9.8.1
Health-related Quality of Life Analyses................................................................82
9.8.2
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses ...........................83
9.8.3
Immunogenicity Analyses .....................................................................................83
9.9
Statistical/Analytic Considerations ..........................................................................83
9.9.1
Control of Type I Error..........................................................................................83
9.9.2
Multiplicity Adjustment.........................................................................................83
9.9.3
Handling of Missing Data......................................................................................83
9.9.4
Multicenter Studies................................................................................................84
9.9.5
Subgroup Analyses ................................................................................................84
9.9.6
Sensitivity Analyses...............................................................................................84
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .........85
11 REFERENCES .....................................................................................................................114
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LIST OF TABLES
Table 1
Schedule of Activities - Screening and Observation Period .........................21
Table 2
Schedule of Activities - Treatment Period (Day 0 [Week 1] to Day 182 
[Week 26]) and Follow-up Period (through Day 196 [Week 28])................23
Table 3
Objectives and Endpoints..............................................................................40
Table 4
Volume of Blood to Be Drawn from Each Subject.......................................77
LIST OF FIGURES
Figure 1
Study Schematic Diagram .............................................................................20
Figure 2
Multiple Therapeutic Strategies to Treat HAE Target the Kallikrein–
Kinin Pathway ...............................................................................................25
Figure 3
Lanadelumab Specifically Inhibits Plasma Kallikrein (pKal).......................29
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol number: SHP643-303
Drug: Lanadelumab
Title of the study: A Phase 3, Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the 
Efficacy and Safety of Lanadelumab for Prevention Against Acute Attacks of Non-histaminergic Angioedema with 
Normal C1-Inhibitor (C1-INH) 
Short title: Efficacy and Safety of Lanadelumab for Prevention Against Acute Attacks of Non-histaminergic 
Angioedema with Normal C1-Inhibitor (C1-INH) 
Study phase: Phase 3
Number of subjects (total and per treatment arm):
Approximately 75 subjects (male or female) aged 12 years1 and above with non-histaminergic normal C1-INH 
angioedema will be randomized 2:1 to receive lanadelumab or placebo. 
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 60 sites in North America (United States, Canada), Europe and Japan will participate. 
Study period (planned):
Nov 2019 to Aug 2022
Clinical phase:
3
Objectives:
Primary: To evaluate the efficacy of repeated subcutaneous (SC) administrations of lanadelumab in preventing 
angioedema attacks in adolescents (12 to <18 years of age) and adults with non-histaminergic angioedema with 
normal C1-INH.
Secondary: 

To evaluate the safety of repeated SC administrations of lanadelumab in preventing angioedema attacks in
adolescents and adults with normal C1-INH angioedema.

To evaluate the pharmacokinetics (PK) of repeated SC administrations of lanadelumab in preventing angioedema 
attacks in adolescents and adults with normal C1-INH angioedema.

To evaluate the pharmacodynamics (PD) of repeated SC administrations of lanadelumab in preventing 
angioedema attacks in adolescents and adults with normal C1-INH. 

To evaluate the immunogenicity of repeated SC administrations of lanadelumab in preventing angioedema 
attacks in adolescents and adults with normal C1-INH angioedema. 

To evaluate the effect of lanadelumab on health-related quality of life (HR-QoL) assessments in adolescents and 
adults with normal C1-INH angioedema.
Exploratory:

To evaluate the effect of lanadelumab on exploratory biomarker(s) of angioedema disease-state bioactivity in 
adolescents and adults with normal C1-INH angioedema.
Rationale:
Based on the mechanism of action and past case studies with icatibant (FIRAZYR®) (Bouillet et al., 2009; Wirth et 
al., 1991; Boccon-Gibod and Bouillet, 2012; Bouillet et al., 2017; Zanichelli et al., 2017; Cicardi and Zanichelli, 
2010; Zanichelli et al., 2012; Regoli et al., 1998) and ecallantide (KALBITOR®) (Bhoola et al., 1992; Markland et
                                                
1 Enrollment of non-histaminergic normal C1-INH patients <18 years of age will be allowed based on
local site and / or country regulations. 
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al., 1996; Cicardi and Zanichelli, 2010), there are strong scientific rationale and high unmet medical need to expand 
the use of lanadelumab as a prophylactic therapy for patients with likely bradykinin-mediated angioedema other than 
Type I/II HAE. The study aims to evaluate the efficacy and safety of lanadelumab for the prevention of angioedema 
attacks in subjects with non-histaminergic angioedema with normal C1-INH. 
Investigational product, dose, and mode of administration:
Subjects who enter the blinded treatment period will receive SC administration lanadelumab 300 mg or placebo 
every 2 weeks (q2wks) for 26 weeks.
The drug product is a sterile, preservative-free, ready-to-use solution of lanadelumab at a concentration of 
150 mg/mL. Drug product will be provided in a prefilled syringe (PFS) at a dosage strength of 300 mg 
(300 mg/2 mL). Each PFS is filled to deliver a nominal volume of 2.0 mL of drug product subcutaneously.
The placebo product consists of the inactive formulation of the drug product. Placebo will be provided in a PFS and
is filled to deliver a nominal volume of 2.0 mL subcutaneously. 
Investigational product will be administered by SC injection in the abdominal area (preferred), thigh, or upper arm. 
Self-administration of investigational product will be permitted after a subject and/or parent/caregiver has received 
appropriate training by the investigator or designee and has demonstrated their understanding of self-administration. 
Methodology:
This study targets to enroll approximately 75 subjects (12 years of age and above) with normal C1-INH angioedema. 
All enrolled subjects (who have signed informed consent form) must have an investigator-confirmed diagnosis of 
non-histaminergic angioedema with normal C1-INH at screening. Screened subjects who have been on any long-
term prophylaxis (LTP) (eg, C1-INH, androgens, or anti-fibrinolytics), are required to undergo a minimum 2-week 
washout period prior to the observation period. This LTP washout period is permitted as long as the investigator 
determines that doing so would not place the subject at any undue safety risk, and that the subject is at least 18 years 
of age. During the observation period, all subjects must discontinue LTP. The attack rate in the observation period 
will serve as the baseline for this study. Subjects with any exposure to prophylactic plasma kallikrein (pKal) 
inhibitors prior to screening will be excluded from the study.
Enrolled subjects meeting all eligibility criteria at screening will enter an observation period of up to 8 weeks to 
determine the baseline angioedema attack rate and confirm their eligibility. Subjects meeting a minimum baseline 
angioedema attack rate of at least 1 investigator-confirmed angioedema attack per 4 weeks during the observation 
period may be allowed to exit the observation period at 4 weeks for randomization and will enter the treatment 
period. In addition, during the observation period, subjects (≥18 years of age) need to be treated with icatibant for at 
least 2 angioedema attacks or at least 1 moderate or severe attack. In the opinion of the investigator, subjects with no 
response to icatibant for acute angioedema attacks in the past medical history/screening, or no improvement or 
worsened attack severity 2 hours after icatibant treatment during the observation period (based on totality of 
assessments), will not be eligible. Subjects without at least 1 investigator-confirmed attack in the first 4 weeks may 
have their observation period extended for another 4 weeks. Subjects who have their observation period extended 
must complete the full 8-week observation period and must have at least 2 investigator-confirmed attacks during this 
time to be eligible to enter treatment period. 
Subjects who do not meet the minimum attack rate during the observation period will be considered screen failures; 
subjects who screen fail will not be allowed to rescreen for the study.
After verification of eligibility in the observation period, subjects will be randomized 2:1 to receive repeated SC 
administrations of lanadelumab or placebo in a double-blind fashion.
Randomization will be stratified by baseline angioedema attack rate (1 to <2 attacks/4 weeks, and ≥2 attacks/4
weeks) and by subtype: 1) with known mutations (coagulation factor 12 [FXII], plasminogen [PLG], angiopoietin-1 
[ANGPT1], or kininogen 1 [KNG1], genes associated with normal C1-INH angioedema); 2) with family history (a 
first-degree relative) and unknown mutations; and 3) with idiopathic non-histaminergic angioedema (INHA). 
Acute angioedema attacks during the observation period and the treatment period will be managed with icatibant. 
Therefore, subjects ≥18 years of age need to be willing to be tested for their response to icatibant treatment for 
angioedema attacks that occur during the observation period. For subjects 12 to <18 years of age, standard of care 
therapy per local protocols should be provided. 
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Subjects may roll over into a 26-week long open-label extension (OLE) study (Study TAK-743-3001) upon 
completion of all assessments scheduled on Day 182. Those subjects who choose to roll over will provide consent 
no later than the last day of blinded treatment period (Day 182) and will be discharged from Study SHP643-303 
after completion of all assessments on Day 182. Subjects who choose not to roll over to the OLE will continue to the 
planned 2 weeks of safety follow-up at the completion of all study assessments scheduled on Day 182.
Inclusion and Exclusion Criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the applicable population criteria 
listed below.
1. Males and females, 12 years of age and older for subjects with non-histaminergic normal C1-INH angioedema at 
the time of signing of the informed consent form (ICF).
2. Documented clinical history of recurrent attacks of angioedema in the absence of wheals/urticaria.
3. Investigator-confirmed diagnosis of non-histaminergic bradykinin-mediated angioedema with normal C1-INH as 
documented by a history of angioedema attack(s) at screening and occurrence of attacks during the observation 
period:

History of recurrent angioedema with at least an average of 1 angioedema attack per 4 weeks prior to 
screening and this attack rate must be confirmed during the observation period while treated with chronic 
high-dose antihistamine (cetirizine 40 mg/day or equivalent high-dose second-generation antihistamine 
medication). 

Diagnostic testing results obtained during screening from a sponsor-approved central laboratory that confirm 
C1-INH function ≥50% of normal and C4 level not below the normal range. With prior sponsor approval, 
subjects may be retested during the observation period if results are incongruent with clinical history.

Clinical history of not responding to high-dose antihistamine treatment (cetirizine 40 mg/day or equivalent 
high-dose second-generation antihistamine medication), which must be confirmed during the observation 
period with at least 1 angioedema attack per 4 weeks with chronic high-dose antihistamine treatment and no 
significant difference (as assessed by the investigator and in consultation with the sponsor’s medical monitor, 
as necessary) from the historic attack rate without high-dose antihistamine treatment.
4. Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
5. Subjects ≥18 years of age must be willing to use icatibant as the rescue medication during the observation and 
treatment period. During the observation period, subjects need to be treated with icatibant for at least 
2 angioedema attacks or at least 1 moderate or severe attack. In the opinion of the investigator, subjects with no 
response to icatibant for acute angioedema attacks in the past medical history/screening, or no improvement or 
worsened attack severity 2 hours after icatibant treatment during the observation period (based on totality of 
assessments), will not be included. Note: For subjects 12 to <18 years of age, standard of care therapy per local 
protocols should be provided. 
6. Males, or non-pregnant, non-lactating females who are of child-bearing potential and who agree to be abstinent2
or agree to comply with the applicable contraceptive requirements of this protocol for the duration of the study. 
Female subjects of childbearing potential must have a negative serum pregnancy test at screening and must be 
willing to undergo pregnancy tests throughout the study. Females of non-childbearing potential are defined as 
surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or 
                                                
2 Abstinence will be accepted as a highly effective method only if sexual abstinence is the preferred and 
usual lifestyle of the subject. Periodic abstinence (eg, calendar, symptothermal or post-ovulation), 
declaration of abstinence for the duration of exposure to IMP, or withdrawal (coitus interruptus) are not 
acceptable methods of contraception.
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post-menopausal for at least 12 months.
7. The subject (or the subject’s parent/legal guardian, if applicable) has provided written informed consent 
approved by the institutional review board/research ethics board/ethics committee (IRB/REB/EC). 
If the subject is an adult, be informed of the nature of the study and provide written informed consent 
before any study-specific procedures are performed.
OR
If the subject is a minor (ie, <18 years of age), have a parent/legal guardian who is informed of the nature 
of the study provide written informed consent (ie, permission) for the minor to participate in the study 
before any study-specific procedures are performed. Assent will be obtained from minor subjects. 
Exclusion Criteria:
The subject will be excluded from the study if any of the following exclusion criteria are met. 
1. Concomitant diagnosis of Type I or Type II HAE, or recurrent angioedema associated with urticaria.
2. Dosing with any investigational drug or exposure to an investigational device within 4 weeks prior to screening.
3. Exposure to angiotensin-converting enzyme (ACE) inhibitors or rituximab within 6 months prior to screening.
4. Use of any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal 
replacement therapy) within 4 weeks prior to screening. 
5. Response to omalizumab (prophylactic) or corticosteroid (acute/prophylactic) or epinephrine (acute) or 
anti-leukotrienes (prophylactic) treatments in the past. 
6. Use of long-term prophylactic therapy for HAE, eg, C1-INH, attenuated androgens (eg, danazol, 
methyltestosterone, testosterone), or anti-fibrinolytics within 2 weeks prior to entering the observation period as 
long as the investigator determines that doing so would not place the subject at any undue safety risk, and that 
the subject is at least 18 years of age.
7. Any exposure to prophylactic plasma kallikrein inhibitors prior to screening. 
8. Use of short-term prophylaxis for HAE within 7 days prior to entering the observation period. Short-term 
prophylaxis is defined as C1-INH, attenuated androgens, or anti-fibrinolytics used to avoid angioedema 
complications from medically indicated procedures. 
9. 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 the treatment period. 
10. 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).
11. Pregnancy or breast feeding.
12 Subject has a known hypersensitivity to the investigational product or its components.
13. Have any uncontrolled underlying medical condition which would require treatment adjustment during the study 
treatment period that, in the opinion of the investigator or sponsor, may confound the results of the safety 
assessments or may place the subject at risk. Subjects with stable treatment for at least 3 months prior to 
screening and NOT expecting any change to their treatment regimen for 6 months during the study treatment 
period, will not be excluded.
14. Have any condition (surgical or medical) 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 comorbidities that the investigator considers may 
confound the interpretation of study results).
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Maximum duration of subject participation in the study:

Planned duration of screening period: up to 8 weeks (including a 2-week LTP washout period, if applicable)

Planned duration of baseline observation period: at least 4 weeks up to 8 weeks. 

Planned duration of treatment period: 26 weeks 

Planned duration of safety follow-up period: 2 weeks
Pharmacogenomic Sampling:
Blood samples will be collected (per local regulations and subject's consent) during the screening period and at 
predose on Day 0 for the purpose of 1) identifying genetic mutations to aid in subject stratification prior to 
randomization and 2) for future exploratory evaluation of genes or gene categories that may be associated with 
non-histaminergic angioedema with normal C1-INH disease susceptibility and drug action.
Statistical analysis:
The analysis sets are defined as:

Treatment Period Full Analysis Set (FAS) will include all randomized subjects who receive any exposure to the 
investigational product during the treatment period. Subjects will be analyzed according to their randomized 
treatment assignment regardless of the treatment actually received.

Steady State Period FAS will include all randomized subjects who receive any exposure to the investigational 
product during the steady state period. Subjects will be analyzed according to their randomized treatment 
assignment regardless of the treatment actually received.

Safety Analysis Set (SAS) will include all subjects who receive any exposure to the investigational product. 
Subjects will be analyzed according to the treatment actually received regardless of randomized treatment 
assignment. 

Pharmacokinetic Set (PK Set) will include all subjects in the SAS who have at least 1 evaluable postdose PK 
concentration value. 

Pharmacodynamic Set (PD Set) will include all subjects in the SAS who have at least 1 evaluable postdose PD 
concentration value.
Efficacy Endpoints
Primary efficacy endpoint:

Number of investigator-confirmed angioedema attacks during the treatment period (Day 0 through Day 182) 
Rank-ordered Secondary Efficacy Endpoints: 
1. Subjects that are attack-free during the treatment period (Day 0 through Day 182) 
2. Number of investigator-confirmed moderate or severe angioedema attacks during the treatment period (Day 0 
through Day 182)
3. Number of investigator-confirmed angioedema attacks during the presumed steady state period (Day 70 through 
Day 182)
4. Subjects that are attack-free during the presumed steady state period (Day 70 through Day 182)
5. Number of investigator-confirmed moderate or severe angioedema attacks during the presumed steady state 
period (Day 70 through Day 182)
Additional Secondary Efficacy Endpoints:

Maximum attack severity during presumed steady state period (Day 70 through Day 182) and treatment period 
(Day 0 through Day 182)

Time to first angioedema attack after Day 0

Time to first angioedema attack after Day 70

Achievement of at least a 50%, 70%, 90% and 100% reduction in the investigator-confirmed normalized number 
of attacks (NNA) per 4 weeks during each of the efficacy evaluation periods relative to the observation period 
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NNA

Achievement of an efficacy evaluation period NNA <1.0 per 4 weeks during each of the efficacy evaluation 
periods 
Subjects will use a diary to record the symptoms and occurrences of angioedema attacks according to the BAARP 
(non-histaminergic bradykinin-mediated angioedema attack assessment and recording procedures) criteria. An 
angioedema attack will be further reviewed and confirmed by the investigator. Any subject-reported or 
parent/caregiver-reported attack not confirmed by the investigator must have an alternate adverse event (AE) 
diagnosis reported.
There must be a full symptom-free calendar day or at least 24 hours preceding the onset of symptoms for an attack 
to be considered a new attack. Therefore,

Attacks that progress from one site to another will be considered a single attack,

Attacks that begin to regress and then worsen before complete resolution will be considered one attack, and

Attacks that begin to appear to resolve, and then reappear without a symptom-free calendar day reported after the 
appearance of resolution will also be considered one attack.
NOTE: An angioedema attack does NOT include swelling due to trauma or symmetrical non-painful swelling of the 
lower extremities.
The overall severity of the subject's attack will be determined by the site using the following definitions: 

Mild: Transient or mild discomfort

Moderate: Mild to moderate limitation in activity with some assistance needed

Severe: Marked limitation in activity, assistance required
Safety Endpoints

Treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs) and adverse events of 
special interest (AESIs)

Clinical laboratory testing (hematology, clinical chemistry, coagulation, and urinalysis)

Vital signs including blood pressure, heart rate, body temperature, and respiratory rate 
Pharmacokinetic Endpoint

Plasma concentrations of lanadelumab
Pharmacodynamic Endpoint

Plasma cleaved high molecular weight kininogen (cHMWK) and pKal activity
Immunogenicity Endpoint

Presence or absence of neutralizing or non-neutralizing antidrug antibodies (ADA) in plasma
Health Economics and Outcomes Research Endpoints

Health-related quality of life will be measured using the angioedema quality of life (AE-QoL) questionnaire 
Exploratory Endpoints

Exploratory biomarker(s) of angioedema disease-state bioactivity 
Statistical Methodology for Efficacy Endpoints
The primary efficacy endpoint, number of investigator-confirmed angioedema attacks during the treatment period 
(Day 0 through Day 182), will be compared between treatment group (lanadelumab versus placebo) using the 
Treatment Period FAS.
The primary efficacy endpoint will be analyzed using a generalized linear model for count data assuming a Poisson 
distribution with a log link function and Pearson chi-square scaling of standard errors to account for potential 
overdispersion. The model will include fixed effects for treatment group (categorical), normalized baseline attack 
rate (continuous), and stratification factor of subtype (categorical). The logarithm of time in days each subject was 
observed during the treatment period will be used as an offset variable in the model. From this model, the least 
squares mean rate and standard error for each treatment group as well as the mean rate ratios relative to the placebo 
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group and corresponding 95% confidence intervals will be estimated. These estimates will be reported as mean 
event rates per 4 weeks by transforming the estimates using the exponential function and scaling by the unit of time.
The primary endpoint will be tested by the following hypothesis:
H0: λlanadelumab / λplacebo = 1 versus H1: λlanadelumab / λplacebo ≠1
Where λlanadelumab refers to the mean investigator-confirmed angioedema attack rate in the lanadelumab group and 
λplacebo refers to the mean investigator-confirmed angioedema attack rate in the placebo group. The null hypothesis 
is that the mean investigator-confirmed angioedema attack rate ratio is 1 (no difference between treatment groups), 
versus the alternative hypothesis that the angioedema attack rate ratio is not 1. Estimated attack rate ratios less than 
1 would indicate that subjects treated with lanadelumab, on average, have a lower incidence of investigator-
confirmed angioedema attacks during the presumed steady-state treatment period. The hypothesis will be tested 
using the model-based least squares means estimate of the treatment difference (expressed as rate ratio relative to 
placebo) using a Wald-based chi-square test with Type I error set at 5%. 
The rank-ordered secondary endpoints based on count data (ie, number of angioedema attacks during a specified 
period) will be analyzed using the same method as described for the primary efficacy endpoint with adjustments 
made to the offset term and analysis set based on the defined analysis period. 
The rank-ordered secondary endpoints based on binary endpoints (ie, subjects that are attack-free during a specified 
analysis period) will be compared between treatment groups using the FAS specific to the analysis period of 
interests. 
The number and percentage of subjects who are attack-free for the specified analysis period, as well as the 
difference between treatment arms and corresponding 95% confidence interval (CI) will be summarized. For 
subjects who discontinue the study prior to completion of the analysis period of interest, subjects will be classified 
as attack-free or not based on the observed contribution to the analysis period. 
The rank-ordered binary endpoints will be tested by the following hypothesis:
H0: planadelumab = pplacebo versus H1: planadelumab ≠ pplacebo
Where planadelumab refers to the proportion of subjects that are attack-free during the specified analysis period in 
the lanadelumab group and pplacebo refers to the proportion of subjects that are attack-free during the specified 
analysis period in the placebo group. The null hypothesis is that the proportion of attack-free subjects in the 
lanadelumab treatment group is equal to that in the placebo group, versus the alternative hypothesis that the 
proportions are not equal. A Cochran-Mantel-Haenszel (CMH) test, adjusting for baseline stratification factor(s) 
(categorical), will be used to test the null hypothesis, with Type I error set at 5%. A Mantel-Haenszel estimate for 
the common risk difference and corresponding stratified Newcombe confidence limits will be presented. 
To adjust for the potential of inflated overall Type I error rate, the rank ordered secondary endpoints will be tested in 
a fixed sequence using a general gatekeeping approach consistent with the logical restrictions of the rank ordering of 
the endpoints. Secondary endpoints will not be declared statistically significant unless the primary endpoint is found 
to be statistically significant. Lower ranked secondary endpoints will not be declared statistically significant unless 
the primary and all of the higher ranked secondary endpoints are found to be statistically significant.
Statistical Methodology for Safety Endpoints
All safety analyses will be based on the SAS. Analyses will be summarized by treatment group. 
Treatment-emergent AEs are defined as AEs with onset at the time of or following the start of treatment with study 
medication, or medical conditions present prior to the start of treatment but increasing in severity or relationship at 
the time of or following the start of treatment. The number and percentage of subjects with TEAEs will be displayed 
for each treatment group by system organ class (SOC) and preferred term (PT) using the Medical Dictionary for 
Regulatory Activities (MedDRA®). Summaries in terms of severity and relationship to study medication will also be 
provided. Related, serious, related serious AEs, and AESIs will be summarized separately in a similar fashion. 
Patient listings of AEs causing discontinuation of study medication, AEs leading to death, SAEs, and AESIs will be 
produced.
Actual values and change from baseline in vital signs and clinical laboratory tests will be summarized by treatment 
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group with descriptive statistics at each assessment obtained.
Statistical Methodology for PK/PD Endpoints
No formal statistical hypothesis will be tested. Individual PK concentrations and PD levels will be provided in 
subject data listing(s) and tabularly summarized using descriptive statistics (number of subjects, arithmetic mean, 
standard deviation [SD], coefficient of variation, median, minimum, maximum, geometric mean, and coefficient of 
variation of geometric mean). Figures of individual and mean (±SD) concentration-time profiles of plasma 
lanadelumab and time-course of PD will be generated. 
A population PK/PD modeling and simulation will be performed using data from this study and data from other 
studies and reported separately.
Sample Size Justification
Approximately 75 subjects with non-histaminergic normal C1-INH angioedema will be randomized.
Power analyses were based on 10,000 simulations from a negative binomial distribution with dispersion 
parameter of 2 and 0.5 for lanadelumab and placebo-treated subjects, respectively, a 10% dropout with exponential 
loss-to-follow-up, and analyzed using a general linear model for count data assuming a Poisson distribution with 
Pearson chi-square scaling of standard errors to account for potential overdispersion. The randomization ratio was 
set at 2:1 for lanadelumab:placebo. The effect size of 60% reduction compared to placebo was based on the results 
observed in the pivotal study in subjects with HAE (Study DX-2930-03). In Study DX-2930-03, the lower 95% 
confidence limit for attack rate reduction (lanadelumab 300 mg q2wks group versus placebo) was 76.2%. Due to 
higher disease variability, a more conservative effect size assumption of 60% was assumed for subjects with 
non-histaminergic angioedema with normal C1-INH. 
Assuming a treatment effect of at least a 60% reduction in the investigator-confirmed attack rate as compared with 
placebo and a placebo attack rate of 1 attack/4 weeks during the analysis period, a sample size of 75 subjects would 
provide at least 85% power (at =0.025, 1-sided). 
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1.2
Schema
Figure 1
Study Schematic Diagram
C1-INH=C1-esterase inhibitor; LTP=long-term prophylaxis; OLE=open-label study; q2wks=every 2 weeks 
* Confirmation of negative response to high-dose antihistamine treatment (cetirizine 40 mg/day or equivalent 
high-dose second-generation antihistamine medication) during the observation period. For subjects ≥18 years of age, 
investigator confirmation of response to icatibant rescue medication for at least 2 angioedema attacks or at least 
1 moderate or severe attack is a requisite; subjects with no improvement or worsened attack severity 2 hours after 
icatibant treatment during the observation period (based on totality of assessments), will be excluded. 
** The 3 subtypes are: 1) with known mutations; 2) with family history (a first-degree relative) and unknown 
mutations; 3) idiopathic nonhistaminergic angioedema [INHA].
Note: Subjects may roll over into an open-label extension study upon completion of all assessments scheduled on 
Day 182.
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1.3
Schedule of Activities
Table 1
Schedule of Activities - Screening and Observation Period
Procedures
Screeninga
(up to 8 weeks)
OBSERVATION PERIOD (BY STUDY WEEK)m
See protocol 
section below 
for details
Start of 
Observation 
Period
1
2
3
4 
5 
6 
7
8
Informed consent 
(written permission 
and assent)
X
8.3.1
Eligibility review
X
X
8.3.2
Demographics and 
medical/angioedema
history
X
8.3.3 and
8.3.4.1
Prior/current 
medications, 
therapies, and 
proceduresb
X
X-------------------------------------------------------------------------------------------------------------------X
6.6
Telephone contactc
X
X
X
X
8.2.1.3
Angioedema attack 
monitoringb
X
X-------------------------------------------------------------------------------------------------------------------------------------X
8.2.1
Antihistamine 
treatmentd
X-------------------------------------------------------------------------------------------------------------------X
8.2.1.3
Distribute icatibant 
and antihistamine 
treatment
X
8.2.1.2
Genotype testinge
X
8.3.6.5
C1-INH, C4, and 
C1q testingf
X
8.2.1.1
LTP washoutg
X
8.2.1.1
Vital signsh
X
8.3.5.4
Physical exami
X
8.3.5.1
12-lead ECG
X
8.3.5.7
Pregnancy testj
X
8.3.5.6
Clinical laboratory 
testingk
X
8.3.5.5
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Virology testing: 
HBsAg, HCV, and 
HIV (serologies)l
X
8.3.5.5
Adverse events
X
X-------------------------------------------------------------------------------------------------------------------------------------X
8.3.5.2
C1-INH=C1 esterase inhibitor; ECG=electrocardiogram; HbsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; LTP=long-term 
prophylactic therapy
a Subjects are allowed up to 8 weeks to complete all screening procedures. When all screening results are available, an eligibility review will be conducted by the site to determine 
if the subject meets all study eligibility criteria. As indicated in Table 2, a final eligibility review will be conducted prior to dosing on Day 0.
b All angioedema attacks will be reported after signing the ICF and assessed in accordance with BAARP (Appendix 5). From the start of the observation period, all subjects or 
parents/caregivers will use a diary to record symptoms and occurrences of angioedema attacks and any medications taken by the subject for the management of attacks. 
Angioedema attacks will be monitored daily and recorded as they occur. Subjects or parents/caregivers are instructed to notify and report details of an attack to the study site 
within 72 hours of the onset of an angioedema attack, in accordance with BAARP (Appendix 5).
c Study personnel will contact the subject or parent/caregiver by telephone on Weeks 2, 4, 6, and 8 to discuss study compliance (completion of the diary) and to evaluate the 
subject’s attack frequency and other adverse events that may have occurred since the last contact. Telephone contacts will be documented in the source notes at the clinical site.
d Subjects will receive daily treatment with chronic high-dose antihistamine treatment (cetirizine 40 mg/day or equivalent high-dose second-generation antihistamine medication) 
throughout the observation period. 
e A blood sample will be collected (per local regulations and subject's consent) at a single time point during screening for the purpose of identifying genetic mutations to aid in 
subject stratification prior to randomization. Confirmation of genetic mutations in the FXII, PLG, ANGPT1, or KNG1 genes, or other mutations associated with angioedema with 
normal C1-INH, must be obtained from the sponsor-approved central laboratory.
f C1-INH, C4, and C1q testing is required at screening from the sponsor-approved central laboratory. If C1-INH LTP is used, an additional confirmatory test may be performed 
after the C1-INH has washed out for at least 5 half-lives.
g Subjects who are receiving LTP for their angioedema will be required to undergo a minimum 2-week washout period prior to the start of the observation period. This LTP 
washout is permitted as long as the investigator determines that doing so will not place the subject at any undue safety risk and the subject is at least 18 years of age. The 
investigator will confirm that the subject has successfully completed the 2-week washout period, if safe to do so, before they may enter the observation period.
h Vital signs, including sitting or supine blood pressure, heart rate, body temperature, and respiratory rate.
i Physical examinations include measurement of height and weight.
j Pregnancy testing is required for all female subjects of childbearing potential; the test will be serum-based at the screening visit and may be serum- or urine-based at other visits.
k Clinical laboratory testing including hematology, serum chemistry, coagulation, and urinalysis. 
l HIV (single assay antibody/Western Blot) and hepatitis (hepatitis B surface antigen, hepatitis C antibody) will be tested only at the screening visit.
m Subjects who do not complete the observation period due to COVID-19 related factors may be allowed to re-start the observation period if deemed eligible by the investigator 
and Sponsor’s medical monitor.
Note: Subjects must stay in the observation period for minimum of 4 weeks and up to 8 weeks. Subjects meeting a minimum baseline angioedema attack rate of at least 
1 investigator-confirmed angioedema attack per 4 weeks may be allowed to exit the observation period at 4 weeks for randomization. Subjects without at least 1 Investigator-
confirmed attack in the first 4 weeks may have their observation period extended for another 4 weeks. Subjects who have their observation period extended must complete the full 
8-week observation period and must have at least 2 investigator-confirmed attacks during this time to be eligible for randomization.
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a Subjects meeting a minimum baseline angioedema attack rate of at least 1 investigator-confirmed angioedema attack per 4 weeks during the observation period may be allowed to 
exit the observation period at 4 weeks for randomization and will enter the treatment period. In addition, during the observation period, subjects (≥ 18 years of age) need to be treated 
with icatibant for at least 2 angioedema attacks or at least 1 moderate or severe attack. In the opinion of the investigator, subjects with no response to icatibant for acute angioedema 
attacks in the past medical history/screening, or no improvement or worsened attack severity 2 hours after icatibant treatment during the observation period (based on totality of 
assessments), will not be eligible. Subjects without at least 1 investigator-confirmed attack in the first 4 weeks may have their observation period extended for another 4 weeks. 
Subjects who have their observation period extended must complete the full 8-week observation period and must have at least 2 investigator-confirmed attacks during this time to be 
eligible to enter treatment period.
b Vital signs, including sitting or supine blood pressure, heart rate, body temperature, and respiratory rate, 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 investigational product and 30 minutes (±15 minutes) after completion of the injection of investigational 
product. 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 Pregnancy testing may be urine- or serum-based and will be performed for females of childbearing potential.
e Clinical laboratory testing including hematology, serum chemistry, coagulation, and urinalysis.
f Blood samples for measurements of lanadelumab concentrations in plasma will be obtained predose (except on the Day 182/ET visit). Blood samples to measure cleaved high 
molecular weight kininogen (cHMWK) level and plasma kallikrein (pKal) activity will be obtained predose (except on the Day 182/ET visit). 
g Blood samples for testing formation of ADA will be obtained predose (except on the Day 182/ET visit). 
h A blood sample will be collected (per local regulations and subject's consent) at a single time point (predose) for future exploratory evaluation of genes or gene categories that may 
be associated with non-histaminergic angioedema with normal C1-INH and drug action.
i During the treatment and follow-up period, subjects or parents/caregivers will use a diary to record symptoms and occurrences of angioedema attacks and any medications taken by 
the subject for the management of attacks. Angioedema attacks will be monitored daily and recorded as they occur. Subjects or parents/caregivers are instructed to notify and report 
details of an attack to the study site within 72 hours of the onset of an angioedema attack, in accordance with BAARP (Appendix 5). Any subject-reported or parent/caregiver-
reported attack not confirmed by the investigator must have an alternate AE diagnosis recorded in the source documents and electronic case report form.
j Health-related quality of life (HR-QoL) data will be obtained predose at the scheduled time points.
k Site personnel will call subjects within approximately 3 days after the planned self-administration of investigational product to ensure the administration occurred, to collect AEs and 
concomitant medications and to ensure all attacks have been appropriately documented. 
l Collect the injection reports assessing the subject’s or parent/caregiver’s experience with SC injection of investigational product.
m On dosing days, collected predose and postdose.
n Subjects who elect to roll over into a 26-week long open-label extension (OLE) study, must provide consent no later than the last day of blinded treatment period on Day 182 
(Visit 26). After the completion of all scheduled assessments on Day 182 (Visit 26), subjects will be discharged from this study and will enter the OLE study and receive their first 
dose of open-label lanadelumab. All other subjects will be discharged from the study after the completion of the end of study (EOS) assessments scheduled on Day 196 (Visit 27).
o Subjects who terminate from the study early will undergo (if possible) all of the assessments and procedures as Day 182 (Visit 26) at their final study visit.
p Subjects who choose not to roll over to the OLE, will continue to the planned 2-week safety follow-up period at the completion all assessments scheduled on Day 182 (Visit 26).
q Study personnel will contact the subject or parent/caregiver by telephone on Day 196 (Visit 27) to complete the EOS assessments. Telephone contacts will be documented in the 
source notes at the clinical site.
r Subjects should begin the treatment period (Visit 1) within 7 days after completion of the observation period. Any delayed start to the treatment period (i.e., >7 days from the 
observation period) due to unexpected event(s) should be discussed with the Sponsor
s To extend flexibility to patients during the COVID-19 public health emergency, an in-person visit may be substituted with a remote visit. The type of remote visit (e.g., telehealth 
visit or home health care visit) will be documented in the study records and eCRF. See Section 8.1 of the protocol for additional details. 
* Last dose in blinded study medication at Visit 24 or Day 168 (±4 days).
Note: Permissible assessment window during treatment period and follow-up period: Study Visit Day ±4 days
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2
INTRODUCTION
2.1
Disease Etiology and Pathophysiology
Hereditary angioedema (HAE) is a long-term, debilitating, and life-threatening disease caused by 
mutations in the C1 esterase inhibitor (C1-INH) SERPING1 gene (Tosi, 1998), resulting in 
heterozygous deficiency (Type I HAE) or dysfunction (Type II HAE) of C1-INH plasma protein 
(Sosada et al., 2013). HAE manifests clinically as unpredictable, intermittent attacks of
subcutaneous or submucosal edema of the face, larynx, gastrointestinal tract, limbs, and/or 
genitalia (Zuraw, 2008). Despite lacking a precise understanding of the triggering events that
initiate an HAE attack, identification of the key components of the kallikrein-kinin pathway has
facilitated the development of multiple therapeutic strategies to treat HAE (Figure 2).
Unregulated plasma kallikrein (pKal) is recognized as the key pathophysiologic defect
responsible for the development of HAE attacks (Schneider et al., 2007). Blocking bradykinin 
production with pKal inhibitors or blocking bradykinin B2 receptors are rational therapeutic
strategies to treat or prevent HAE attacks. The importance of kallikrein-kinin pathway
components as drug targets in HAE have been described in the literature and demonstrated by
the approval of ecallantide and icatibant to treat acute attacks and approval of lanadelumab for
attack prevention (Kaplan and Joseph, 2014; Busse et al., 2019; Duffey and Firszt, 2015).
Figure 2
Multiple Therapeutic Strategies to Treat HAE Target the Kallikrein–Kinin 
Pathway 
B2R=bradykinin type 2 receptor; C1-INH=C1 esterase inhibitor; GPCR=G protein-couple receptor; HMWK=high 
molecular weight kininogen; pKal=plasma kallikrein.
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In addition to Type I or Type II HAE, bradykinin is also an important mediator for other types of 
non-histaminergic angioedema, such as non-histaminergic angioedema with normal C1-INH.
Unlike HAE Type I/II, which are well-characterized forms readily diagnosed by low levels of 
functional C1-INH along with a positive family history in most cases and that have several 
approved treatments, for the other forms of non-histaminergic angioedema an unclear 
pathophysiology and lack of consistent diagnostic criteria have limited the opportunity for the 
clinical investigation and new treatment development (Craig et al., 2014). Consequently, there 
are still no approved treatments for non-histaminergic angioedema patients 
(Bygum and Vestergaard, 2013), who are unresponsive to conventional 
antihistamine/glucocorticoid treatment (Craig et al., 2014). The clinical research for 
non-histaminergic angioedema has made significant progress recently. Similar to what is 
observed with Type I or II HAE, kallikrein-kinin pathway potentially plays a critical role in the 
underlying pathophysiology of non-histaminergic angioedema, including non-histaminergic
normal C1-INH angioedema (Castelli et al., 2013; Zuraw, 2018). For example, pKal from 
patients with non-histaminergic normal C1-INH angioedema exhibits a similar enhanced 
propensity for activation as was observed for C1-INH deficient patients, which was higher than 
that of healthy controls or patients with histaminergic angioedema (Lara-Marquez et al., 2018). 
In addition, bradykinin has been shown to be elevated in plasma from non-histaminergic 
angioedema patients during acute attacks (Cugno et al., 2017). Cleaved high molecular weight 
kininogen (cHMWK), which is generated by pKal concomitant with bradykinin, was also 
elevated in the plasma from patients with non-histaminergic angioedema with normal C1-INH 
(Cugno et al., 1995; Baroso et al., 2016). Furthermore, mutations identified to date in HAE with 
normal C1-INH have been associated with dysregulation of the plasma kallikrein-kinin system. 
For example, patients with HAE with normal C1-INH and a mutation in coagulation factor XII 
(FXII) that substitutes a threonine at position 309 to either a lysine or an arginine have a form of 
FXII that is more prone to activation by plasmin and leads to a truncated enzyme that has 15-fold 
higher catalytic efficiency towards prekallikrein activation (de Maat et al., 2016; 
Ivanov et al., 2019). A mutation in the gene encoding plasminogen (PLG) in HAE patients with 
normal C1-INH substitutes a lysine at position 330 with a glutamate and has been hypothesized 
to be associated with increased activation of the plasma kallikrein-kinin system by plasmin 
(Bork et al., 2018). The reported missense mutation in the angiopoietin-1 gene (ANGPT1) from 
HAE patients with normal C1-INH is hypothesized to increase bradykinin B2 receptor activation 
(Bafunno et al., 2018). Recently, a mutation in the kininogen gene (KNG1) to substitute a 
methionine to a lysine at position 379 was reported and the effect of this mutation on bradykinin 
metabolism is under investigation (Bork et al., 2019). Therefore, it is hypothesized that 
lanadelumab has the potential to be an effective therapy and address an unmet medical need for 
these patients with likely bradykinin-mediated angioedema (BMA).
2.2
Epidemiology
The exact prevalence of HAE is unknown; however, current estimates range from 1 per 
10,000 to 1 per 150,000 persons, with many authors agreeing that 1 per 50,000 is likely the 
closest estimate (Bygum, 2009; Goring et al., 1998; Lei et al., 2011; 
Nordenfelt et al., 2014; Roche et al., 2005). The prevalence for non-histaminergic normal
C1-INH angioedema are even much lower (Busse and Buckland, 2012; Agostoni et al., 2004; 
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Aygören-Pürsün et al., 2018; Maurer et al., 2018) compared to Type I or Type II HAE. 
Non-histaminergic angioedema with normal C1-INH is a very rare disease, with clinical features 
similar to those of HAE with C1-INH deficit (Maurer et al., 2018). Until recently it was assumed 
that HAE is a disease that results exclusively from a genetic deficiency of the C1-INH. In the 
year 2000, families with HAE and normal levels of C1-INH were described (Bork et al., 2000). 
Since then several patients and families with that condition have been reported. Most of the 
patients by far were women. In part of the affected women, oral contraceptives, hormone 
replacement therapy containing estrogens, and pregnancies were more prone to trigger the 
clinical symptoms (Bork, 2010). According to the latest classification (Zuraw et al., 2012; 
Zuraw, 2018), within the non-histaminergic normal C1-INH angioedema, the following subtypes 
are defined:
1) normal C1-INH angioedema with demonstrated genetic mutations associated with the disease; 
eg, mutations in the coagulation factor F12 gene (HAE-FXII), plasminogen gene (HAE-PLG),
angiopoietin-1 gene (HAE-ANGPT1), or kininogen 1 gene [HAE-KNG1], or other mutations 
associated with non-histaminergic normal C1-INH angioedema (de Maat et al., 2016; 
Ivanov et al., 2018; Bork et al., 2018; Bork et al., 2019);
2) normal C1-INH angioedema with unknown genetic mutations, but with family history of 
recurrent angioedema in a first-degree relative; 
3) idiopathic non-histaminergic angioedema (INHA) (Cicardi et al., 1999) with similar features 
to normal C1-INH angioedema with unknown genetic mutations, but with no clear family
history.
The frequency of non-histaminergic angioedema with normal C1-INH is not clearly known; the 
information available from the current literature indicate that in 1 case, in a cohort of 
138 Brazilian patients with HAE, the preponderance of HAE with C1-INH deficiency was 
77.5% (n=107) followed by HAE with normal C1-INH at 22.5% (n=31) (Alonso et al., 2017). 
Similarly, in a cohort of Italian patients in 2016, the minimum prevalence of normal C1-INH 
with the FXII mutation was 37:59,394,000 inhabitants and normal C1-INH without this mutation 
was 60:59,394,000, which was equivalent to 1:1,605,243 for FXII-HAE and 1:989,900 for 
without this mutation (Bova et al., 2017). 
2.3
Indication and Current Treatment Options
Management of HAE has evolved over the last 10 years from underdiagnosed disability and 
higher risk of death from asphyxiation if undiagnosed, towards self-administration and 
independence from inpatient treatment. Effective management of HAE, including optimization 
of therapy, may reduce the clinical burden and have an overall favorable impact on the quality of 
life for individual HAE patients and their families (Banerji, 2013; Caballero et al., 2014).
Unlike HAE Types I and II, there are no approved treatments for the other forms of 
non-histaminergic angioedema (Bygum and Vestergaard, 2013), which are unresponsive to 
conventional antihistamine/glucocorticoid treatment (Craig et al., 2014). 
Lanadelumab is expected to fulfill an unmet medical need for patients with non-histaminergic 
angioedema with normal C1-INH by providing a long-term safe, effective and convenient 
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intervention to prevent angioedema attacks. Lanadelumab may provide significant benefit to 
these patients with other forms of BMA, given the similarity in the pathophysiology and the 
demonstrated efficacy in preventing angioedema attacks in patients with Types I and II HAE. In
the HAE population, lanadelumab has a convenient dosing schedule with a recommended 
starting dose of 300 mg every 2 weeks (q2wks) and a dosing interval of every 4 weeks (q4wks) 
can be considered if the patient is well controlled (eg, stably attack-free for more than 6 months) 
in adolescent and adults. A similar convenient dosing interval of q2wks is being proposed for 
patient populations in this study. In addition, lanadelumab has a convenient route of 
administration (subcutaneous; SC), with the flexibility to allow self-administration.
The targeted indication for lanadelumab (TAK-743/SHP643) currently under study is 
prophylaxis to prevent attacks of non-histaminergic angioedema with normal C1-INH in patients 
12 years and older. 
2.4
Product Background and Clinical Information
2.4.1
Drug Information
Mechanism of Action
Lanadelumab is a fully human, immunoglobulin G1 kappa light chain monoclonal antibody 
expressed in Chinese hamster ovary cells. It is a potent (inhibition constant=125 pM) and 
specific inhibitor of active pKal activity that binds both soluble and membrane-bound forms of 
the enzyme (Kenniston et al., 2014). Lanadelumab was designed to specifically bind active pKal 
as opposed to prekallikrein, the zymogen form of the enzyme mainly present in plasma. This 
specificity of lanadelumab for active pKal indicates that the main form of the antibody in the 
circulation is free to inhibit the excess amount of pKal generated during an attack enabling near 
normal levels of enzyme activity prior to reversible inhibition by the antibody. Nonclinical data 
demonstrates that the specific inhibition of pKal by lanadelumab prevents the release of 
bradykinin from high molecular weight kininogen (HMWK). 
Inhibition of bradykinin generation prevents the vascular leak and swelling during an
angioedema attack initiated when bradykinin binds to the B2 receptor (Figure 3). The 
pharmacokinetic (PK) properties of lanadelumab offer the potential for a long-acting and 
sustained therapeutic effect (administration q2wks or q4wks) through the control of pKal 
activity, limiting both contact system activation as well as the generation of bradykinin in 
patients with HAE.
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Figure 3
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 of lanadelumab at a
concentration of 150 mg/mL. Drug product will be provided in a single-use prefilled syringe 
(PFS) at a dosage strength of 300 mg (300 mg/2mL). Each PFS is filled to deliver a nominal 
volume of 2.0 mL of drug product subcutaneously.
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Route of Administration
Lanadelumab is formulated as a liquid for injection and is intended for SC administration in the 
abdomen (preferred), thigh, or upper arm. The upper arm location is not recommended for 
self-administration but rather as an additional injection site when administered by a 
parent/caregiver or healthcare provider.
2.4.2
Nonclinical Studies with Lanadelumab
The nonclinical program conducted to date indicated no safety signal or toxicity with SC 
administered lanadelumab at doses of up to and including the highest tested dose (50 mg/kg, 
once weekly) for 6 months in cynomolgus monkeys. At the no-observed-adverse-effect-level in 
the 6-month cynomolgus monkey study, exposure margins based on maximum observed 
concentration (Cmax) occurring at time to reach maximum observed plasma concentration (tmax) 
and area under the drug concentration-time curve (AUC) were approximately 22- and 23-fold 
higher, respectively, than those observed at the clinical dosage of 300 mg q2wks 
(Study DX-2930-03).
The battery of genotoxicity studies routinely conducted for pharmaceuticals is not applicable to 
biotechnology-derived pharmaceuticals and therefore was not conducted. Carcinogenicity studies 
were not conducted. A weight-of-evidence approach indicates a low risk for carcinogenicity in 
humans as lanadelumab is a fully human immunoglobulin molecule that does not target any 
hormonal or cell proliferation pathways; the pharmacologic mechanism of action does not pose 
an increased risk for carcinogenicity, nor is there evidence from any of the preclinical studies for 
an increased risk of hyperplasia, preneoplasia, or neoplastic lesions.
Nonclinical juvenile toxicology studies were not performed. However, the range of ages of 
cynomolgus monkeys used in the completed repeat-dose toxicity studies correspond to
juvenile/adolescents to adults in human (Baldrick, 2010; Morford et al., 2011). Furthermore, no 
effects on development parameters were noted in an enhanced pre-and post-natal development 
(ePPND) study conducted in cynomolgus monkeys. In the ePPND study in pregnant cynomolgus 
monkeys administered once weekly SC doses, there were no lanadelumab-related effects on 
pregnancy and parturition or embryo-fetal development. In the infants maintained for 3 months 
post-partum, exposure to lanadelumab was dose-proportional to maternal dose and no 
lanadelumab-related defects on survival, growth, and/or postnatal development were noted. It is 
expected that the exposure of infants to lanadelumab during the fetal period and during the first 
3 to 6 months of postnatal life covers many critical periods relevant to human development 
(Martin and Weinbauer, 2010).
Collectively, the nonclinical studies demonstrate that lanadelumab did not have adverse effects 
on vital functions or produce adverse target organ pathologies in rats or cynomolgus monkeys 
and support the safe use in patients with HAE as a prophylactic treatment by SC injection.
2.4.3
Clinical Studies with Lanadelumab
To date, the worldwide applications for marketing authorization of lanadelumab have been 
supported by 4 clinical studies. The proposed indication of lanadelumab for routine prophylaxis 
to prevent attacks of HAE in patients 12 years and older is primarily supported by the efficacy 
results from a double-blind, placebo-controlled Phase 3 study (DX-2930-03). 
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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 of lanadelumab in healthy adult subjects (DX-2930-01). 
Refer to the latest version of the lanadelumab investigator’s brochure (IB) for details.
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 patients 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 antidrug 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 patients. 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 
long-term prophylaxis (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. 
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Evaluation of the lanadelumab plasma concentrations at the time of attacks reported by 
lanadelumab-treated subjects in DX-2930-02 suggested that the 3 planned dosing regimens 
would provide a meaningful range of clinical response. 
The primary objective of the study was to evaluate the efficacy of lanadelumab in preventing 
HAE attacks. The secondary objective was evaluation of the safety of repeated SC administration 
of lanadelumab. Each subject underwent a treatment period consisting of 13 doses of blinded 
investigational medicinal product (IMP) for a period of 26 weeks from the date of the first dose 
on Day 0 through 2 weeks after the final dose (for the 150 mg q4wks and 300 mg q4wks 
regimens, every second dose was placebo). Over the 26-week treatment period, all 
3 lanadelumab dose regimens, 150 mg q4wks, 300 mg q4wks, and 300 mg q2wks, resulted in a 
highly statistically significant percentage reduction in the least squares mean 
investigator-confirmed HAE attack rate compared with placebo of 76%, 73%, and 87% (adjusted 
p<0.001), respectively, for the primary endpoint. During the estimated steady-state 16-week 
period (Day 70 through Day 182), the percentage reduction in the mean monthly HAE attack
rates for lanadelumab-treated subjects compared with placebo was 78% in the 150 mg q4wks 
arm, 81% in the 300 mg q4wks arm, and 91% in the 300 mg q2wks arm. Furthermore, all 
3 lanadelumab regimens demonstrated highly statistically significant attack rate reductions 
compared with placebo for all secondary efficacy analyses (adjusted p<.001 for all comparisons): 
attacks requiring acute treatment (74% 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 (HR-QoL) based on angioedema quality of life (AE-QoL) 
scores. Lower 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 
adverse event (TEAE). Two subjects (1 lanadelumab treated and 1 placebo) discontinued the 
study due to a TEAE. The overall incidence of ADAs 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.
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Study DX-2930-04 (HELP Study Extension™) is an open-label, long-term safety and efficacy 
extension study of DX-2930-03 to evaluate the IMP, lanadelumab, in preventing acute 
angioedema attacks in patients with Type I or Type II HAE. 
The open-label extension study DX-2930-04 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 Aug 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 HR-QoL 
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. 
2.4.4
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 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 (standard deviation 
[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 subjects <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 
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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 
clinical study in patients with HAE, including adolescents (Study DX-2930-04 Interim Analysis 
2 data cutoff on 31 Aug 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 Aug 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 Aug 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).
Population PK analyses for adolescents and adults in Phase 3 studies, indicate no apparent 
influence of age 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 IB.
2.5
Study Rationale
Based on the mechanism of action (Figure 2) and past case studies with icatibant 
(Bouillet et al., 2009; Wirth et al., 1991; Boccon-Gibod and Bouillet, 2012; Bouillet et al., 2017; 
Zanichelli et al., 2017; Cicardi and Zanichelli, 2010; Zanichelli et al., 2012; Regoli et al., 1998) 
and ecallantide (Bhoola et al., 1992; Markland et al., 1996; Cicardi and Zanichelli, 2010) there is 
strong scientific rationale to expand the use of lanadelumab as a prophylactic therapy for BMA 
patients other than those with Type I/II HAE. Prophylactic treatment with lanadelumab may be 
beneficial for other forms of BMA such as non-histaminergic angioedema with normal C1-INH 
based on the benefit/risk assessment of lanadelumab established in adolescents and adults with 
Type I or Type II HAE in the clinical development program, along with the convenience of a low 
volume, infrequent, SC administration for patients.
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2.6
Benefit/Risk Assessment 
Clinical studies with lanadelumab demonstrated the improved efficacy and safety for routine 
prophylaxis to prevent and control symptoms of HAE in patients 12 years and older 
(Section 2.4.3 and Section 2.4.4; 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 analysis 2 data cutoff for 
Study DX-2930-04 on 31 Aug 2018). 
In the pivotal study (DX-2930-03), lanadelumab was generally well tolerated over the 26-week 
treatment period. No treatment-related SAEs or deaths were reported. No discernible 
dose-response pattern or dose-dependent or limiting toxicity was observed for any related 
TEAEs. Hypersensitivity reactions occurred in few patients and were generally mild, transient, 
did not lead to discontinuation and did not need further treatment. The most frequent TEAE was 
injection site reaction, a majority of which were generally mild, lasted <0.5 hours in duration, 
and did not lead to study discontinuation. The safety profile in the completed Phase 3 open-label 
study (DX-2930-04) was consistent with that of the pivotal study. 
As of the data cutoff on 31 Aug 2018, the most frequently reported AEs in the 
lanadelumab-treated population across Study DX-2930-03 and Study DX-2930-04 were injection 
site pain (49.5%), viral upper respiratory tract infection (35.9%), headache (25.5%), upper 
respiratory tract infection (21.4%), injection site erythema (15.9%), and injection site bruising 
(12.3%).
Overall, 60% (132/220) of lanadelumab-treated subjects reported a total of 1834 related TEAEs 
across Study DX-2930-03 and Study DX-2930-04. The vast majority of related TEAEs were 
injection site reactions (ISRs), eg: injection site pain (45.9%, 101/220), injection site erythema 
(15%, 33/147), injection site bruising (9.1%, 20/220), injection site swelling (5.5%, 12/220), and 
injection site pruritus (5.0%, 11/220) in ≥5.0% of lanadelumab-treated population. The most 
frequently occurring non-ISR related AE was headache, reported by 5.0% (11/220) of 
lanadelumab-treated population. Other related non-ISR AEs reported by ≥2 subjects included 
hypersensitivity (2.3%, 5/220), alanine aminotransferase (ALT) increased (1.4%, 3/220), 
aspartate aminotransferase (AST) increased (1.4%, 3/220), dizziness, (1.4%, 3/220), dysgeusia 
(0.9%, 2/220), and nausea (0.9%, 2/220) as a non-ISR TEAE reported by ≥2 subjects (0.9%, 
2/220).
Across both Phase 3 studies, 8.6% (19/220) of lanadelumab-treated subjects reported SAEs, and
none of them were related to lanadelumab treatment. There was no discernible pattern or 
commonality to the events reported as SAEs.
Across both Phase 3 studies, changes in hematology, coagulation, and chemistry laboratory 
parameters over time were small and no clinically relevant trends were observed, especially in 
adolescent subjects. Overall, there were no clinically meaningful changes in vital signs and 
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physical findings. No subject receiving treatment with lanadelumab had an abnormal, clinically 
significant electrocardiogram (ECG) result.
Prespecified identified risks associated with the use of lanadelumab or other monoclonal 
antibodies include ISRs (identified risk) and hypersensitivity (important identified risk).
In the pivotal Study DX-2930-03, 84 lanadelumab-treated subjects received 2118 injections of 
investigational product. Approximately half (52.4%) of the lanadelumab treated subjects 
experienced 398 ISRs, most of which were considered related to investigational product (98.2%) 
and were mild in intensity (97%), and none of which were serious or severe. No subject 
discontinued due to an ISR. The majority of ISRs were ≤0.5 hours duration, with over 90% of all 
ISRs resolving within 1 day of onset.
As of the data cutoff date on 31 Aug 2018 for Study DX-2930-04, 109 (51.4%) subjects had a 
total of 1567 ISR TEAEs during the treatment period. These ISRs occurred across a collective 
8013 doses, equivalent to a mean of 37.8 doses per subject. Most of the ISRs were related to 
lanadelumab (1382 of 1567 ISR TEAEs). None of the ISRs were serious or severe. Most ISRs 
were mild in severity (98.7% [1547 of 1567 ISR TEAEs]) and reports of moderate ISRs were 
infrequent; the most frequent single event, injection site pain, had a maximum severity of mild in 
89 subjects and moderate in 2 subjects. The majority of ISRs (91.2%) resolved within a day, 
while 76.3% resolved within an hour. Similar frequencies of ISRs were reported by subjects 
regardless of administration type (self-administered at home, self-administered in-clinic, and 
study staff administration in-clinic).
An important identified risk was hypersensitivity. Hypersensitivity reactions were prespecified 
AESIs due to the theoretical risk associated with monoclonal antibodies, including anaphylactoid 
events or anaphylaxis. At the time of the global marketing and authorization application, the 
incidence of hypersensitivity was low (1.8%) in the lanadelumab-treated population and there 
were no events of anaphylaxis observed in either Phase 3 study. Few investigator-defined AESIs
were reported in the pivotal Study DX-2930-03: 1 subject in the 300 mg q2wks arm had 2 related 
events reported as hypersensitivity reactions (1 mild and 1 moderate in severity), which included 
symptoms of tingling, itchiness, and discomfort of the tongue, dry cough, and mild headache and 
3 lanadelumab-treated subjects from 1 clinical site (1 in each dosing arm) had a total of 5 related 
events (all mild in severity) that were investigator-defined AESIs, 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 AESIs of hypersensitivity were reported in the
placebo group. 
As of the data cutoff on 31 Aug 2018, in Study DX-2930-04, there were 9 investigator-reported 
hypersensitivity AESIs: 4 events in rollover subjects and 5 events in nonrollover subjects. 
Four of the AESIs were hypersensitivity reactions (all occurring in nonrollover subjects); there 
were also 5 ISRs that were classified as hypersensitivity. All of the hypersensitivity AESIs were 
classified as related to lanadelumab. None of the events were serious. Three of the subjects 
discontinued due to the hypersensitivity AESIs. One of these AESIs of hypersensitivity was 
classified as related and severe because it coincided with an HAE attack and ongoing disease 
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under study. However, no anaphylaxis and no anaphylactoid reactions were observed and none 
of the subjects with these AESIs developed ADA. 
Besides hypersensitivity, disordered coagulation (bleeding events or hypercoagulable events 
potentially associated with the mechanism of action of lanadelumab, an active pKal inhibitor) 
was a prespecified AESI. One adult subject in Study DX-2930-03 diagnosed with 
gastroesophageal reflux had an investigator-reported AESI, 1 mild event of microcytic anemia, 
although screening hemoglobin and hematocrit were below the normal range and there was no 
actual event of “bleeding” reported. Two subjects had 4 investigator-reported AESIs of vaginal 
bleeding in Study DX-2930-04 (1 subject had uncontrolled hypothyroidism and the other subject 
had comorbidity of uterine adenomyosis). None of these 4 events were related to lanadelumab 
treatments or required dosing interruption. While coagulopathy is a theoretical risk with drugs 
affecting the plasma kallikrein-kinin system and lanadelumab may cause activated partial 
thromboplastin time (aPTT) prolongation (Appendix 3.1), there does not seem to be a clinical 
association with abnormal bleeding events based on the lack of effect on hemostasis in 
Studies DX-2930-03 and DX-2930-04. Therefore, disordered coagulation (bleeding events or 
hypercoagulable events) is no longer considered an AESI for lanadelumab in this protocol.
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. As of the data cutoff for the second interim 
analysis, the overall prevalence of ADAs in treated subjects in Study DX-2930-04 was 9.9% 
(21/212 subjects), which included 13 rollover and 8 nonrollover subjects. A total of 6 subjects on 
the study developed ADAs classified as neutralizing; therefore, the prevalence of neutralizing 
antibody was 2.8% (6/212). Except for 1 subject at one time point, all other ADA-positive 
samples were consistent with the low titer range (20-1280) observed in the prior interim analysis 
data and in Study DX-2930-03. 
Overall, the formation of ADAs or neutralizing antibodies had no observable effect on the PK, 
PD, efficacy or safety profiles. 
In summary, safety signals have not emerged from all available clinical and nonclinical data to 
date for systemically administered lanadelumab. The proposed study in patients with 
non-histaminergic angioedema with normal C1-INH is being initiated after establishing the 
efficacy and safety profile of lanadelumab in adolescent and adult HAE patients. Additionally, 
the type and frequency of safety assessments in this study will be similar to the pivotal Phase 3 
study in HAE patients (see Schedule of Activities, Table 1 and Table 2).
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.
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2.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for
Harmonisation Guideline for Good Clinical Practice E6 (Integrated Addendum to ICH E6[R1]: 
Guideline for Good Clinical Practice E6[R2] Current Step 4 version, 9 November 2016), Title 21 
of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 2005/28/EC), 
and applicable national and local regulatory requirements.
The responsibilities of the study sponsor and investigator(s) are described fully in Appendix 1.
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3
OBJECTIVES AND ENDPOINTS
3.1
Study Objectives
3.1.1
Primary Objective
To evaluate the efficacy of repeated SC administrations of lanadelumab in preventing 
angioedema attacks in adolescents (12 to <18 years of age) and adults with non-histaminergic 
angioedema with normal C1-INH.
3.1.2
Secondary Objectives
The secondary objectives of the study are:

To evaluate the safety of repeated SC administrations of lanadelumab in preventing 
angioedema attacks in adolescents and adults with normal C1-INH.

To evaluate the PK of repeated SC administrations of lanadelumab in preventing angioedema 
attacks in adolescents and adults with normal C1-INH angioedema.

To evaluate the PD of repeated SC administrations of lanadelumab in preventing angioedema 
attacks in adolescents and adults with normal C1-INH angioedema.

To evaluate the immunogenicity of repeated SC administrations of lanadelumab in 
preventing angioedema attacks in adolescents and adults with normal C1-INH angioedema.

To evaluate the effect of lanadelumab on health-related quality of life (HR-QoL) assessments 
in adolescents and adults with normal C1-INH angioedema.
3.1.3
Exploratory Objectives
To evaluate the effect of lanadelumab on exploratory biomarker(s) of angioedema disease-state 
bioactivity in adolescents and adults with normal C1-INH angioedema.
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 analyses are provided in Section 9.
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Table 3
Objectives and Endpoints
Objective
Endpoint(s)
Primary

To evaluate the efficacy of 
repeated SC administrations of 
lanadelumab in preventing 
angioedema attacks in 
adolescents (12 to <18 years of 
age) and adults with 
non-histaminergic angioedema 
with normal C1-INH.
Primary Efficacy Endpoint

Number of investigator-confirmed angioedema attacks during the 
treatment period (Day 0 through Day 182) 
Rank-ordered Secondary Efficacy Endpoints
1. Subjects that are attack-free during the treatment period (Day 0 through 
Day 182)
2. Number of investigator-confirmed moderate or severe angioedema 
attacks during the treatment period (Day 0 through Day 182)
3. Number of investigator-confirmed angioedema attacks during the 
presumed steady state period (Day 70 through Day 182)
4. Subjects that are attack-free during the presumed steady state period 
(Day 70 through Day 182)
5. Number of investigator-confirmed moderate or severe angioedema 
attacks during the presumed steady state period (Day 70 through Day 
182)
Additional Secondary Efficacy Endpoints:

Maximum attack severity during presumed steady state period (Day 70 
through Day 182) and treatment period (Day 0 through Day 182)

Time to first angioedema attack after Day 0

Time to first angioedema attack after Day 70

Achievement of at least a 50%, 70%, 90% and 100% reduction in the 
investigator-confirmed NNA per 4 weeks during each of the efficacy 
evaluation periods relative to the observation period NNA

Achievement of an efficacy evaluation period NNA <1.0 per 4 weeks 
during each of the efficacy evaluation periods 
Secondary

To evaluate the safety of 
repeated SC administrations of
lanadelumab in preventing 
angioedema attacks in 
adolescents and adults with 
normal C1-INH angioedema.

TEAEs, including AESIs and SAEs

Clinical laboratory testing (hematology, clinical chemistry, coagulation, 
and urinalysis)

Vital signs including blood pressure, heart rate, body temperature, and 
respiratory rate 

To evaluate the PK of repeated 
SC administrations of 
lanadelumab in preventing 
angioedema attacks in
adolescents and adults with 
normal C1-INH angioedema.

Plasma concentrations of lanadelumab
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Table 3
Objectives and Endpoints
Objective
Endpoint(s)

To evaluate the PD of repeated 
SC administrations of 
lanadelumab in preventing 
angioedema attacks in 
adolescents and adults with 
normal C1-INH angioedema.

Plasma cHMWK and pKal activity

To evaluate the immunogenicity
of repeated SC administrations of 
lanadelumab in preventing 
angioedema attacks in 
adolescents and adults with 
normal C1-INH angioedema.

Presence or absence of neutralizing or non-neutralizing ADA in plasma

To evaluate the effect of 
lanadelumab on HR-QoL
assessments in adolescents and 
adults with normal C1-INH 
angioedema.

Measured by the AE-QoL questionnaire, which consists of 
17 disease-specific quality-of-life items, to produce a total AE-QoL 
score and 4 domain scores (functioning, fatigue/mood, fear/shame, and 
nutrition). Change in total AE-QoL score during the treatment period 
(Day 0 through Day 182) will be assessed
Exploratory

To evaluate the effect of 
lanadelumab on exploratory 
biomarker(s) of angioedema
disease-state bioactivity in 
adolescents and adults with 
normal C1-INH angioedema.

Exploratory biomarker(s) of angioedema-disease state bioactivity (eg, 
pKal) in blood and plasma
ADA=antidrug antibodies; AE-QoL=angioedema quality of life; AESI=adverse event of special interest; C1-INH=C1 esterase 
inhibitor; cHMWK=cleaved high molecular weight kininogen; HR-QoL=health-related quality of life; NNA=normalized number 
of attacks; PD=pharmacodynamic; PK=pharmacokinetic; pKal=plasma kallikrein; SAE=serious adverse event; 
SC=subcutaneous; TEAE=treatment-emergent adverse event
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4
STUDY DESIGN
4.1
Overall Design 
Study SHP643-303 targets to enroll approximately 75 subjects (12 years of age and above3) with 
normal C1-INH angioedema. All enrolled subjects (who have signed informed consent form) 
must have an investigator-confirmed diagnosis of non-histaminergic angioedema with normal 
C1-INH at screening. Screened subjects who have been on any LTP (eg, C1-INH, androgens, or 
anti-fibrinolytics), are required to undergo a minimum 2-week washout period prior to the 
observation period. This LTP washout period is permitted as long as the investigator determines 
that doing so would not place the subject at any undue safety risk, and that the subject is at least 
18 years of age. During the observation period, all subjects must discontinue LTP. The attack 
rate in the observation period will serve as the baseline for this study. Subjects with any exposure 
to prophylactic pKal inhibitors prior to screening will be excluded from the study.
Enrolled subjects meeting all eligibility criteria at screening will enter an observation period of 
up to 8 weeks to determine the baseline angioedema attack rate and confirm their eligibility. 
Subjects meeting a minimum baseline angioedema attack rate of at least 1 investigator-confirmed 
angioedema attack per 4 weeks during the observation period may be allowed to exit the 
observation period at 4 weeks for randomization and will enter the treatment period. In addition, 
during the observation period, subjects (≥18 years of age) need to be treated with icatibant for at 
least 2 angioedema attacks or at least 1 moderate or severe attack. In the opinion of the 
investigator, subjects with no response to icatibant for acute angioedema attacks in the past 
medical history/screening, or no improvement or worsened attack severity 2 hours after icatibant 
treatment during the observation period (based on totality of assessments), will not be eligible. 
Subjects without at least 1 investigator-confirmed attack in the first 4 weeks may have their 
observation period extended for another 4 weeks. Subjects who have their observation period 
extended must complete the full 8-week observation period and must have at least 
2 investigator-confirmed attacks during this time to be eligible to enter treatment period. 
Subjects who do not meet the minimum attack rate during the observation period will be 
considered screen failures; subjects who screen fail will not be allowed to rescreen for the study.
After verification of eligibility in the observation period, subjects will be randomized 2:1 to 
receive repeated SC administrations of lanadelumab or placebo in a double-blind fashion.
Randomization will be stratified by baseline angioedema attack rate (1 to <2 attacks/4 weeks, 
and ≥2 attacks/4 weeks) and by subtype: 1) with known mutations (FXII, PLG, ANGPT1, or 
KNG1 genes associated with normal C1-INH angioedema); 2) with family history (a first-degree 
relative) and unknown mutations; and 3) with idiopathic non-histaminergic angioedema (INHA). 
                                                
3 Enrollment of non-histaminergic normal C1-INH patients <18 years of age will be allowed based on 
local site and /or country regulations.
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Acute angioedema attacks during the observation period and the treatment period will be 
managed with icatibant. Therefore, subjects ≥18 years of age need to be willing to be tested for 
their response to icatibant treatment for angioedema attacks that occur during the observation 
period. For subjects 12 to <18 years of age, standard of care therapy per local protocols should 
be provided. Further details on icatibant and the management of acute angioedema attacks during 
the study are provided in Section 6.6.3.
During the 26-week treatment period all subjects will receive SC administration of 
investigational product q2wks. Section 4.3 provides justification for the dosing regimen 
proposed for this study. Further details on dosing and self-administration of lanadelumab are 
provided in Section 6.2.3 and Section 8.3.6.8. 
Subjects with non-histaminergic angioedema with normal C1-INH may roll over into a 26-week 
long open-label extension (OLE) study (Study TAK-743-3001) upon completion of all 
assessments scheduled on Day 182. Those subjects who choose to roll over will provide consent 
no later than the last day of blinded treatment period (Day 182) and will be discharged from 
Study SHP643-303 after completion of all assessments on Day 182. Subjects who choose not to 
roll over to the OLE will continue to the planned 2 weeks of safety follow-up at the completion 
of all study assessments scheduled on Day 182.
Individual subject participation from screening through the completion of safety follow-up visit 
will be approximately 44 weeks (up to 8-week screening period [including a 2-week washout of 
LTP if applicable], up to 8-week baseline observation period, 26-week treatment period, and 
2-week safety follow-up period). An overview of the study design scheme is provided in 
Figure 1. All study procedures are detailed in the schedule of assessments (Table 1 and Table 2). 
Details of procedures for collection of angioedema attack information are provided in 
Appendix 5.
4.2
Scientific Rationale for Study Design
This Phase 3, double-blinded, placebo-controlled study aims to evaluate the efficacy and safety 
of lanadelumab for the prevention of angioedema attacks in approximately 75 subjects with 
non-histaminergic angioedema with normal C1-INH for a 26-week treatment period. Subjects 
must experience at least 1 attack per 4 weeks in the observation period (investigator-confirmed 
baseline attack rate) for inclusion in the study (see Section 5 for inclusion/exclusion criteria).
The number of investigator-confirmed angioedema attacks during the treatment period is the 
direct way to evaluate the primary efficacy endpoint (see Section 9.6.1 for planned statistical 
analyses). 
The non-histaminergic bradykinin-mediated angioedema attack assessment and reporting 
procedures (BAARP; see Appendix 5) will provide the standardized definition of an angioedema 
attack and define a standard set of procedures for the reporting and assessment of events reported 
by subjects to determine whether those events were true attacks. The secondary efficacy 
endpoints are also based on investigator-confirmed angioedema attacks (reporting, collection, 
and assessment in accordance with the BAARP). The secondary objectives of the study include 
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evaluation of safety endpoints, PD effects of lanadelumab, PK, immunogenicity, and effect on 
HR-QoL of chronically administered lanadelumab (Table 3).
The clinical pharmacology properties and proposed therapeutic target of lanadelumab in this 
study population with BMA support the same dose regimen demonstrated to be efficacious in 
subjects with Type I and Type II HAE, 300 mg q2wks.
Currently, there are no approved treatments for the BMA disease populations included in this 
study; therefore, use of an active comparator is not applicable. A placebo comparator has been 
chosen to evaluate and interpret the efficacy of lanadelumab. Per the protocol, for subjects 
≥18 years of age, icatibant will be used as rescue medication during the observation and 
treatment period for the management of acute angioedema attacks. For subjects 12 to <18 years 
of age, standard of care therapy per local protocols will be provided. Since subjects on placebo 
are permitted to treat acute angioedema attacks either with icatibant or in accord with the 
investigator’s usual care of their patients, the use of placebo arm as the comparator is justified.
4.3
Justification for Dose
Reports in the literature suggest that, similar to Type I or II HAE, the pathophysiology of 
non-histaminergic angioedema with normal C1-INH is potentially attributed to the dysregulation 
of pKal activity and elevated bradykinin. For example, pKal from patients with 
non-histaminergic normal C1-INH angioedema had a comparable enhanced propensity for 
activation as was observed for C1-INH deficient patients, which was higher than that of healthy 
controls or patients with histaminergic angioedema (Lara-Marquez et al., 2018). In addition, 
bradykinin has been shown to be elevated in plasma from patients during an attack 
(Cugno et al., 2017). Cleaved high molecular weight kininogen, which is generated by pKal 
concomitant with bradykinin, was elevated in the plasma from patients with HAE with normal 
C1-INH (Cugno et al., 1994; Baroso et al., 2016). Furthermore, mutations identified to date in 
HAE with normal C1-INH have been associated with dysregulation of the plasma kallikrein-
kinin system. For example, patients with HAE with normal C1-INH and a substitution mutation 
in coagulation factor XII (FXII) at position threonine 309 to either a lysine or an arginine yields 
a form of FXII that is more prone to activation by plasmin and leads to a truncated enzyme that 
has 15-fold higher catalytic efficiency towards prekallikrein activation (de Maat et al., 2016; 
Ivanov et al., 2019). A mutation in the gene encoding plasminogen (PLG) in HAE patients with 
normal C1-INH substitutes a lysine at position 330 with a glutamate and has been hypothesized 
to be associated with increased activation of the plasma kallikrein-kinin system by plasmin 
(Bork et al., 2018). The reported missense mutation in the angiopoietin-1 gene (ANGPT1) from 
HAE patients with normal C1-INH is hypothesized to increase bradykinin B2 receptor activation 
(Bafunno et al., 2018).
Further support for the role of the plasma kallikrein-kinin system in non-histaminergic 
angioedema with normal C1-INH is supported by case studies with doses of icatibant 
(Boccon-Gibod and Bouillet, 2012; Bouillet et al., 2017; Zanichelli et al., 2017; 
Cicardi and Zanichelli, 2010) or ecallantide (Cicardi and Zanichelli, 2010) approved for HAE 
with C1-INH deficiency. Several reports indicate that icatibant or ecallantide reduces attack 
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duration in angioedema patients with normal C1-INH (Boccon-Gibod and Bouillet, 2012; 
Bouillet et al., 2017; Cronin and Maples, 2012). 
Meanwhile, target-mediated drug disposition for therapeutic monoclonal antibodies, which is 
linked to the high affinity and high specificity of antibody molecules for their targets 
(Grimm, 2009), have been frequently reported. However, it has recently been recognized that 
2 elimination pathways are involved in the disposition of therapeutic monoclonal antibodies: (1) 
‘nonspecific’ elimination via phagocytic and endothelial cells of the reticuloendothelial system 
clearing both antigen-bound and free monoclonal antibodies – this usually is not saturable and 
thus follows linear kinetics; and (2) antigen specific target-mediated disposition that is dependent 
on binding to target antigen to be eliminated – this usually is a saturable process and therefore 
may follow nonlinear kinetics (Ryman and Meibohm, 2017). The lanadelumab clinical 
development program in subjects with Types I and II HAE characterized the clinical PK and PD 
properties of lanadelumab and established the optimal benefit risk profile of lanadelumab dose 
regimen. The clinical pharmacology package of lanadelumab suggests the elimination of 
lanadelumab may not be involved in target-mediated drug disposition, following linear kinetics. 
Thus, the clinical pharmacology properties and proposed therapeutic target of lanadelumab in the 
new indications support the same dose regimen demonstrated to be efficacious in subjects with 
Type I and Type II HAE.
Therefore, the lanadelumab 300 mg q2wk dose regimen is the appropriate dose for this pivotal 
study in subjects with BMA other than Type I and Type II HAE.
4.4
Duration of Subject Participation and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 44 weeks. 
Individual subject participation from screening through the completion of safety follow-up visit 
will include: up to 8-week screening period (including a 2-week washout of LTP, if applicable), 
up to 8-week baseline observation period, 26-week treatment period, and 2-week safety 
follow-up period. The study will be completed in approximately 34 months.
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 8.2.3 for the defined follow-up period for this protocol).
4.5
Sites and Regions
This is a multicenter study. Approximately 60 sites in North America (United States, Canada), 
Europe and Japan will participate.
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5
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
5.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the applicable 
population criteria below.
1. Males and females, 12 years of age and older for subjects with non-histaminergic normal 
C1-INH angioedema at the time of signing of the informed consent form (ICF).
2. Documented clinical history of recurrent attacks of angioedema in the absence of 
wheals/urticaria.
3. Investigator-confirmed diagnosis of non-histaminergic bradykinin-mediated angioedema 
with normal C1-INH as documented by a history of angioedema attack(s) at screening and 
occurrence of attacks during the observation period:

History of recurrent angioedema with at least an average of 1 angioedema attack per 
4 weeks prior to screening and this attack rate must be confirmed during the observation 
period while treated with chronic high-dose antihistamine (cetirizine 40 mg/day or 
equivalent high-dose second-generation antihistamine medication). 

Diagnostic testing results obtained during screening from a sponsor-approved central 
laboratory that confirm C1-INH function ≥50% of normal and C4 level not below the 
normal range. With prior sponsor approval, subjects may be retested during the 
observation period if results are incongruent with clinical history.

Clinical history of not responding to high-dose antihistamine treatment (cetirizine 
40 mg/day or equivalent high-dose second-generation antihistamine medication), which 
must be confirmed during the observation period with at least 1 angioedema attack per 
4 weeks with chronic high-dose antihistamine treatment and no significant difference (as 
assessed by the investigator and in consultation with the sponsor’s medical monitor, as 
necessary) from the historic attack rate without high-dose antihistamine treatment. 
4. Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
5. Subjects ≥18 years of age must be willing to use icatibant as the rescue medication during the 
observation and treatment period. During the observation period, subjects need to be treated 
with icatibant for at least 2 angioedema attacks or at least 1 moderate or severe attack. In the 
opinion of the investigator, subjects with no response to icatibant for acute angioedema 
attacks in the past medical history/screening, or no improvement or worsened attack severity 
2 hours after icatibant treatment during the observation period (based on totality of 
assessments), will not be included. Note: For subjects 12 to <18 years of age, standard of 
care therapy per local protocols should be provided. 
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6. Males, or non-pregnant, non-lactating females who are of child-bearing potential and who 
agree to be abstinent4 or agree to comply with the applicable contraceptive requirements of 
this protocol for the duration of the study. Female subjects of childbearing potential must 
have a negative serum pregnancy test at screening and must be willing to undergo pregnancy 
tests throughout the study. Females of non-childbearing potential are defined as surgically 
sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or
post-menopausal for at least 12 months.
7. The subject (or the subject’s parent/legal guardian, if applicable) has provided written 
informed consent approved by the institutional review board/research ethics board/ethics 
committee (IRB/REB/EC).
If the subject is an adult, be informed of the nature of the study and provide written 
informed consent before any study-specific procedures are performed.
OR
If the subject is a minor (ie, <18 years of age), have a parent/legal guardian who is 
informed of the nature of the study provide written informed consent (ie, permission) for 
the minor to participate in the study before any study-specific procedures are performed. 
Assent will be obtained from minor subjects.
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 Type I or Type II HAE, or recurrent angioedema associated with 
urticaria.
2. Dosing with any investigational drug or exposure to an investigational device within 4 weeks 
prior to screening.
3. Exposure to angiotensin-converting enzyme (ACE) inhibitors or rituximab within 6 months 
prior to screening.
4. Use of any estrogen-containing medications with systemic absorption (such as oral 
contraceptives or hormonal replacement therapy) within 4 weeks prior to screening. 
5. Response to omalizumab (prophylactic) or corticosteroid (acute/prophylactic) or epinephrine 
(acute) or anti-leukotrienes (prophylactic) treatments in the past. 
6. Use of long-term prophylactic therapy for HAE, eg, C1-INH, attenuated androgens (eg, 
danazol, methyltestosterone, testosterone), or anti-fibrinolytics within 2 weeks prior to 
                                                
4 Abstinence will be accepted as a highly effective method only if sexual abstinence is the preferred and 
usual lifestyle of the subject. Periodic abstinence (eg, calendar, symptothermal or post-ovulation), 
declaration of abstinence for the duration of exposure to IMP, or withdrawal (coitus interruptus) are not 
acceptable methods of contraception.
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entering the observation period as long as the investigator determines that doing so would not 
place the subject at any undue safety risk, and that the subject is at least 18 years of age. 
7. Any exposure to prophylactic plasma kallikrein inhibitors prior to screening. 
8. Use of short-term prophylaxis for HAE within 7 days prior to entering the observation 
period. Short-term prophylaxis is defined as C1-INH, attenuated androgens, or 
anti-fibrinolytics used to avoid angioedema complications from medically indicated 
procedures. 
9. 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 the treatment period. 
10. Any of the following liver function test abnormalities: ALT >3x upper limit of normal, or 
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).
11. Pregnancy or breast feeding.
12. Subject has a known hypersensitivity to the investigational product or its components.
13. Have any uncontrolled underlying medical condition which would require treatment 
adjustment during the study treatment period that, in the opinion of the investigator or 
sponsor, may confound the results of the safety assessments or may place the subject at risk. 
Subjects with stable treatment for at least 3 months prior to screening and NOT expecting 
any change to their treatment regimen for 6 months during the study treatment period, will 
not be excluded.
14. Have any condition (surgical or medical) 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 
comorbidities 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.
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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 was observed (see the latest version of 
lanadelumab IB).
5.4.1
Female Contraception
Sexually active females of childbearing potential should use an 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.
Female subjects should be one of the following:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and age 51 years).

Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization.

Of childbearing potential with a negative urine or serum beta-human chorionic 
gonadotropin (β-hCG) pregnancy test at predose on Study Day 0 (Visit 1). Females of 
childbearing potential must agree to abstain from sexual activity5 that could result in 
pregnancy or agree to use acceptable methods of contraception.

Premenarchal with a negative urine or serum -hCG pregnancy test at predose on Study 
Day 0 (Visit 1).
                                                
5 Abstinence will be accepted as a highly effective method only if sexual abstinence is the preferred and 
usual lifestyle of the subject. Periodic abstinence (eg, calendar, symptothermal or post-ovulation), 
declaration of abstinence for the duration of exposure to IMP, or withdrawal (coitus interruptus) are not 
acceptable methods of contraception.
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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 the subject becomes sexually active during the study, she should use 
one of the other acceptable methods noted above in addition to the hormonal 
contraceptive until it has been stabilized for 30 days.
5.4.2
Male Contraception
Males, including males who are surgically sterile (post-vasectomy), with female partners of 
childbearing potential must agree to be abstinent5 or else use a medically acceptable form of 
contraception throughout the study period and for 70 days following the last dose of 
investigational product.
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6
STUDY INTERVENTION
6.1
Investigational Product
6.1.1
Identity of Investigational Product
The investigational product is lanadelumab, which will be provided in a PFS at a dosage strength 
of 300 mg (300 mg/2 mL). Each PFS is filled to deliver a nominal volume of 2.0 mL of drug 
product subcutaneously. Additional information regarding the dosage forms is provided in the 
latest version of lanadelumab IB or the medication guide.
The reference/comparator product is placebo, which will be provided in in a PFS and is filled to 
deliver a nominal volume of 2.0 mL subcutaneously. 
Commercial icatibant labeled for clinical trial use will be supplied as rescue medication for the 
treatment of acute angioedema attacks during the study for subjects ≥18 years of age 
(Section 6.6.3). The product will be supplied in a single-dose glass PFS delivering 3 mL of 
solution containing 30 mg icatibant and should be stored at or below 25°C (must not be frozen).
6.1.2
Blinding the Treatment Assignment
This study will be double-blinded. All study site personnel, subjects, healthcare providers, and 
the sponsor will be blinded to treatment.
To maintain the blind, lanadelumab and placebo will have an identical presentation, including its 
packaging and labeling, such that the contents of the PFS within the prepackaged study kits will 
be indistinguishable from each other. As described in Section 6.3.2, investigational product will 
be identified only by a unique study drug kit number. Each prepackaged study kit will contain 
1 PFS of investigational product (nominal volume of 2 mL).
Knowledge of the PK/PD and ADA data would compromise the study blind. As such, the 
independent external laboratory performing the PK/PD analyses will keep the results in strict 
confidence until the study is unblinded.
Additionally, a limited number of representatives of the sponsor responsible for the interactive 
response technology (IRT) and product labeling will be unblinded to treatment assignment in 
order to review drug accountability on an ongoing basis throughout the study.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
An IRT vendor will be used for this study to manage packaged IMP supply, IMP shipments, 
receipt of IMP at clinical sites, randomization of IMP to subjects, expiry tracking, IMP returns, 
and IMP accountability.
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6.2.2
Allocation of Subjects to Treatment 
This is a randomized, double-blind, placebo-controlled study. The actual treatment given to 
individual subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. Subjects will be randomized 2:1 to 
receive administrations of lanadelumab or placebo. Randomization will be stratified by baseline 
angioedema attack rate (1 to <2 attacks/4 weeks, and ≥2 attacks/4 weeks) and by subtype: 1) 
with known mutations (FXII, or PLG, or ANGPT1, or KNG1 genes, or other predefined 
mutations); 2) with family history (a first-degree relative) and unknown mutations; and 3) with 
INHA. 
Individual subject treatment is automatically assigned by the IRT.
Once a randomization number/unique identifier has been assigned, that number must not be used 
again if, for example, a subject is withdrawn from the study. If a randomization number/unique 
identifier is allocated incorrectly, the clinical research associate (CRA)/study monitor must be 
notified as soon as the error is discovered. 
Investigational product packaging identification numbers, separate from randomization 
numbers/unique identifiers, may also be assigned to subjects for specific treatment assignment as 
dictated by the study. In these cases, the same investigational product packing identification 
number may not be assigned to more than 1 subject.
6.2.3
Dosing
Investigational product will be administered by SC injection in the abdominal area (preferred), 
thigh, or upper arm. Self-administration of investigational product will be permitted after a 
subject (and/or parent/caregiver) has received appropriate training by the investigator or designee 
and has demonstrated their understanding of self-administration; refer to Section 8.3.6.8 for 
details.
All subjects will receive investigational product every 2 weeks from Visit 1 (Day 0) to Visit 24 
(Day 168), for a total of 13 doses during the treatment period. 
The presentation of investigational product is a PFS filled to deliver a nominal volume of 2.0 mL 
of drug product SC.
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be unblinded during the study except in emergency situations 
where the identification of the investigational product is required for medical management of the 
subject. The investigator should contact the medical monitor as soon as possible after the 
treatment code has been broken and the investigator is unblinded. 
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In the event that the treatment assignment code is broken, the date and the signature of the person 
who broke the code are recorded on the IRT and the source documents, as applicable. The reason 
for breaking the code will be recorded in source documents, as appropriate, based on safety or 
deviation reporting. Upon breaking the blind, the subject is withdrawn from the study, but should 
be followed up for safety purposes. Any code-breaks that occur must be reported to the sponsor. 
The data monitoring committee (DMC; see Section 9.2), in consultation with sponsor, may also 
request unblinding of an individual’s treatment assignment for reasons of subject safety.
6.2.5
Dose Modification
No dose modifications (including dosing frequency) are allowed in this study.
6.3
Labeling, Packaging, Storage, and Handling of Investigational Product
6.3.1
Labeling
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, and 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 a site number, subject 
number, and investigator name. 
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product will be supplied by the sponsor and pre-packaged in a study kit for the 
study. Each study kit will contain 1 PFS. Both the PFS and carton (kit) will be appropriately 
labeled according to local regulations and bear the unique study drug kit number. The 
investigative site will provide ancillary supplies including, syringes (as applicable), needles, and 
alcohol wipes to subjects. The site has the option of using needles of a different gauge to aid 
subject comfort with each SC injection.
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Detailed instructions on preparation and administration of investigational product will be 
provided to the clinical sites in a Pharmacy Manual.
Subjects and parents/caregivers who elect to self-administer investigational product to the 
subject (see Section 8.3.6.8), 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 PFS should be returned to the study kit cartons/boxes and transported to the 
site for drug accountability. Written instructions on investigational product handling and 
self-administration procedures will be provided to the trained subjects and parent/caregiver prior 
to initiating self-administration. Refer to the Pharmacy Manual for additional details on 
investigational product and its administration.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier on the investigational product 
syringe/carton labels as they are distributed.
Investigational product should be stored in a refrigerator at 2-8°C. Prefilled syringes should be 
removed from refrigeration and allowed to get to room temperature before administration. Do 
not freeze. The PFS should be protected from light in the original carton. Refer to the latest 
version of the IB for current stability data.
Before use, each PFS of study drug should be inspected for appearance. Any PFS 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 PFS. 
Any unused contents of the PFS of study medication should be discarded in accordance with 
local requirements for investigational materials. Intact PFS of study medication that are not used 
during the course of the clinical study should be returned according to direction from the 
sponsor.
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 
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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/dispensing investigational product 
(for dosing by site personnel and self-administration, respectively). Where permissible, tasks 
may be delegated to a qualified designee (eg, a pharmacist) who is adequately trained in the 
protocol and who works under the direct supervision of the investigator. This delegation must be 
documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable 
study delegation of authority form) will administer/dispense the investigational product 
only to subjects included in this study following the procedures set out in the study 
protocol. Each subject will be given only the investigational product carrying his/her 
treatment assignment. All administered/dispensed medication will be documented in the 
subject’s source and/or other investigational product record. The investigator is responsible for 
ensuring the retrieval of all study supplies from subjects. Due to the health/safety concerns with 
returning the investigational product container, the investigator must request that subjects keep 
the empty investigational product packaging after use and return it to the site for drug 
accountability purposes.
No investigational product stock or returned inventory from a Takeda-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.
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The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised. 
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 products 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 (eg, bottles, trays, 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 
pharmacokinetic equivalent of 5 half-lives, whichever is longer) and through the final study 
contact (including protocol-defined follow-up period) must be recorded in the subject’s source 
document.
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6.6.1
Prior Treatment
Prior treatment includes all non-study treatments received with 28 days (4 weeks) prior to the 
screening visit (or PK equivalent of 5 half-lives, whichever is longer) up to the date of first dose 
of investigational product. Prior treatment information must be recorded in the subject’s source 
document.
6.6.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded in the subject’s source document.
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 angioedema 
attacks (see below), are permitted if not excluded during the study (see Section 6.6.4). 

The use of periprocedural prophylactic treatment for angioedema will be permitted if 
medically indicated. 

Therapies to treat any AEs the subject experiences during the study will be permitted.

If a subject (≥18 years of age) experiences an acute angioedema attack at any time during 
the study (including the observation and treatment period), icatibant should be 
administered as the rescue medication to treat the attack. Icatibant treatment is 
recommended within 6 hours and no later than 12 hours after the onset of the attack. 
Icatibant is to be administered by the SC route in the abdominal area. The entire volume 
in the syringe should be administered and the injection should occur over at least 
30 seconds. If response is inadequate or symptoms recur, additional injections of 30 mg 
may be administered at intervals of at least 6 hours. Do not administer more than 
3 injections in 24 hours. The subject will be allowed to self-administer icatibant if already 
trained by a healthcare provider or after receiving instructions on the use and appropriate 
training by study site personnel or healthcare provider. If a laryngeal attack occurs (ie, 
swelling of the airways), the subject should inject icatibant and proceed immediately to 
the nearest medical care facility. If it is the opinion of the investigator that the subject still 
needs medication for his/her acute angioedema attack after icatibant administration, then 
other standard of care therapy may be provided per locally approved product information. 
For subjects ≥12 to <18 years of age standard of care therapy per locally approved 
product information should be provided. 
Administration of investigational product and study procedures will continue without alteration 
to the protocol-specified study schedule, even if the subject has symptoms of an angioedema 
attack the day of investigational product administration and/or receives treatment for an 
angioedema attack. The administration of investigational product can also be re-scheduled as 
long as the minimum and maximum timeframe between doses are met based on subject 
preference or physician discretion.
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6.6.4
Prohibited Treatment
Use of the following treatments will not be permitted during the study:

Long-term prophylaxis for angioedema attacks (eg, use of C1-INH for LTP, attenuated 
androgens, or anti-fibrinolytics) within 2 weeks prior to entering the observation period 
and during the study.

Angiotensin-converting enzyme inhibitors or rituximab within 6 months 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-angioedema related medical conditions or for angioedema, within 
2 weeks prior to entering the observation period and during the study.

Any other investigational drug or device.
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7
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Treatment
Subjects who prematurely discontinue investigational product, regardless of the reason, should 
undergo the final visit of the treatment period procedures specified for Study Day 182 (Visit 26) 
as completely as possible (see Section 8.2.2.3). Comments (spontaneous or elicited) or 
complaints made by the subject must be recorded in the source documents. The reason for 
discontinuation, date of discontinuation of the investigational product, and the total amount of 
investigational product administered must be recorded in the source documents.
Subjects who are discontinued from the study because they do not meet the minimum 
angioedema attack rate during the observation period, or who are otherwise determined to be 
ineligible based on screening assessments will be considered to be screen failures. 
Subjects who prematurely discontinue investigational product will not be replaced.
7.2
Reasons for Discontinuation 
The reason for discontinuation (from treatment and/or study) must be determined by the 
investigator and recorded in the subject’s source document. If a subject is discontinued for more 
than 1 reason, each reason should be documented in the source and the primary reason should be 
indicated. 
Reasons for discontinuation include, but are not limited to:

Withdrawal of consent (by a parent or both parents/legal authorized representative for 
adolescent subjects)

Adverse Event

Protocol deviation (eg, lack of compliance, use of experimental drug) 

Pregnancy

Sponsor decision 

Investigator decision 

Death

Lost to follow-up

Lack of efficacy

Other (must specify on the electronic case report form [eCRF])
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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.
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 telephone contact). 
At least 1 of these documented attempts must include a written communication sent to the 
subject’s last known address via courier or mail (with an acknowledgement of receipt request) 
asking that 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 AESIs (as defined in Section 8.3.5.3), will be monitored 
regularly throughout the duration of the study. If any potential safety signal is identified as a 
result of monitoring in this study, the sponsor may take actions as deemed appropriate, including 
suspending dosing in the study, while the potential risk is evaluated and a course of action is 
determined.
7.5.2
Individual Stopping Rules
Dosing for any individual subject will be discontinued if the subject experiences an 
investigational product-related SAE (or an investigational product-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. 
Dosing for any individual subject will be discontinued if the following criteria are met with 
confirmed results in liver functional test: 
1. Alanine aminotransferase (ALT) >3x ULN OR
2. Aspartate aminotransferase (AST) >3x ULN, AND
3. Total Bilirubin >2x ULN
If a subject meets the above criteria with confirmed test results, no other reason can be found to 
explain the combination of increased ALT or AST and total bilirubin, and both the investigator 
and sponsor deem this causality as related to study drug, the study may be suspended for further 
investigation, or possibly terminated. 
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Subjects who prematurely discontinue investigational product should undergo final visit of the 
treatment period procedures specified for Study Day 182 (Visit 26) as completely as possible 
(see Section 8.2.2.3).
7.5.3
Follow-up for Subjects Meeting Stopping Criteria
Subjects who develop either an SAE or other toxicity considered clinically relevant (AE, 
laboratory, physical examination, or vital sign finding) will be carefully monitored until 
resolution, which may include the following:

Additional clinical laboratory tests and/or other clinical investigations

Additional visits or extended duration of follow-up

Obtaining a specialist consultation
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8
STUDY ASSESSMENTS AND PROCEDURES
8.1
Changes to Study Procedures Due to the COVID-19 Pandemic
Given the public health emergency associated with the COVID-19 pandemic, in-person visits 
may be substituted with a remote visit (eg, telehealth visit or home health care visit). However,
all attempts should be made to perform study assessments at the study site if feasible per 
COVID-19 regulations in your region. As the COVID-19 pandemic may peak in different 
regions at different times and restrictions implemented by local laws and recommendations may 
vary, any decision on procedural changes should be made on a case-by-case basis by the 
principal investigator in consultation with the study team and the medical team as needed, while 
maintaining patient safety and confidentiality as the priority.
Procedural changes due to COVID-19 may include the following:

Observation period: Subjects who do not complete the observation period due to 
COVID-19 related factors may be allowed to restart the observation period if deemed 
eligible by the investigator and Sponsor’s medical monitor.

Treatment period (Visit 1): As indicated in Section 8.2.2.1, subjects should begin the 
treatment period (Visit 1) within 7 days after completion of the observation period. Any 
delayed start to the treatment period (ie, >7 days from the observation period) due to 
unexpected events, such as COVID-19, should be discussed with the Sponsor. 

On-site Visits: To extend flexibility to patients during the COVID-19 public health 
emergency, an in-person visit may be substituted with a remote visit. The type of remote 
visit (eg, telehealth visit or home health care visit) will be documented in the study 
records and eCRF. At a minimum, the following should be collected to assess subject 
safety and overall clinical status: 
o
Adverse events 
o
Concomitant medications
o
Angioedema attacks
o
Blinded treatment q2wk administration
o
Any additional assessment(s) deemed necessary by the investigator for patient safety
Deviations from the protocol-specific procedures (eg, not collecting a protocol-specified 
specimen, such as bloodwork) will be recorded as related to COVID-19. 
Missed clinical visits due to COVID-19 must be recorded on the eCRF. 
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
Direct-to-patient (DTP) delivery of study drug: Alternative study drug deliveries may 
include dispensing additional study drug at clinic visits or DTP delivery of the study drug 
from the investigational site to subjects in compliance with national laws or temporary 
national emergency measures. 
8.2
Study Periods
Refer to Table 1 and Table 2 for the schedule of study activities. Study assessments are detailed 
in Section 8.3.
8.2.1
Screening and Observation Period
8.2.1.1
Screening Period (up to 8 weeks, including 2-week LTP washout if 
applicable) 
Informed consent must be obtained before any study specific procedures are performed.
As indicated in Table 1, the following procedures and assessments are to be performed during 
Screening:

Informed consent 

Demographics, medical history, and angioedema history

Prior/current medications, therapies and procedures

Angioedema attack monitoring 

Genotype sample collection (sample will be used to identify genetic mutations to aid in 
subject stratification prior to randomization)

C1-INH function, C4, and C1q testing. If C1-INH therapy is used, the drug needs to be 
washed out for at least 5 half-lives before the testing sample is collected.

LTP washout, if applicable

Vital signs including blood pressure (BP), heart rate (HR), body temperature, and 
respiratory rate (RR) 

Complete physical examination, including documentation of height and weight.

12-lead ECG

Pregnancy test (serum-based; for female subjects of childbearing-potential)

Clinical laboratory testing including hematology, serum chemistry, coagulation, and 
urinalysis

Virology testing for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), and 
human immunodeficiency virus (HIV)

Adverse events collection
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Subjects are allowed up to 8 weeks to complete all screening procedures. When all screening 
results are available, an eligibility review will be conducted by the site to determine if the subject 
meets all study eligibility criteria. (Note: As indicated in Section 8.2.2.1, a final eligibility 
review will be conducted prior to dosing on Day 0.)
Eligible subjects who are on LTP therapy are required to undergo a minimum 2-week washout 
period prior to the start of the observation period. This LTP washout is permitted as long as the 
investigator determines that doing so would not place the subject at any undue safety risk and the 
subject is at least 18 years of age. The investigator must confirm that the subject has successfully 
completed the 2-week washout period before they can enter the observation period.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or meets at least 1 of the exclusion criteria and has not been randomized and administered 
investigational product(s). Subjects cannot be rescreened once they have been designated as a 
screen failure. 
8.2.1.2
Start of Observation Period 
As indicated in Table 1, the following procedures and assessments are to be performed at the 
start of the observation period: 

Eligibility review 

Angioedema attack monitoring 

Adverse events collection

Distribution of icatibant and antihistamine treatment 
8.2.1.3
Observation Period (minimum of 4 weeks and up to 8 weeks)
Eligible subjects will enter an observation period to determine their baseline attack rate. LTP 
therapy is not allowed in this period. The observation period will be at least 4 weeks and may be 
extended up to 8 weeks, as described below. 
Subjects will receive daily treatment with chronic high-dose antihistamine treatment (cetirizine 
40 mg/day or equivalent high-dose second-generation antihistamine medication) throughout the 
observation period.
As indicated in Table 1, during the observation period, the following information will be 
collected on an ongoing basis: 

Angioedema attack data (Note: Subjects must report details of an angioedema attack to the 
study site within 72 hours of onset of the attack, in accordance with BAARP) [Appendix 5]). 
Subjects will also use the diary for recording of antihistamine treatment compliance and 
response to icatibant treatment for acute angioedema attacks.

Prior/current medications, therapies, and procedures.

Adverse events collection, including SAEs and AESIs.
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Site check-in calls will occur at Weeks 2, 4, 6, and 8 of the observation period (Table 1) to
discuss study compliance (completion of the diary) and to evaluate the subject’s attack frequency 
and other AEs that may have occurred since the last contact. The preferred method of site 
check-in is a telephone call; however, an alternate method of contact may be considered as site 
policies permit. Telephone contact will be documented in the source notes at the clinical site.
Subjects meeting a minimum baseline angioedema attack rate of at least 1 investigator confirmed 
angioedema attack per 4 weeks during the observation period may be allowed to exit the 
observation period at 4 weeks for randomization and will enter the treatment period. In addition, 
during the observation period, subjects (≥18 years of age) need to be treated with icatibant for at 
least 2 angioedema attacks or at least 1 moderate or severe attack. In the opinion of the 
investigator, subjects with no response to icatibant for acute angioedema attacks in the past 
medical history/screening, or no improvement or worsened attack severity 2 hours after icatibant 
treatment during the observation period (based on totality of assessments), will not be eligible. 
Subjects without at least 1 investigator-confirmed attack in the first 4 weeks may have their 
observation period extended for another 4 weeks. Subjects who have their observation period 
extended must complete the full 8-week observation period and must have at least 
2 investigator-confirmed attacks during this time to be eligible to enter treatment period.
8.2.2
Treatment Period
8.2.2.1
Study Visit 1; Study Day 0
Visit 1 on Day 0 will be a scheduled on-site visit. After completion of the observation period, if 
eligible, subjects should begin the treatment period (Visit 1) within 7 days. Any delayed start to 
the treatment period (ie, >7 days from observation period) due to unexpected event(s) should be 
discussed with the Sponsor. The following procedures and assessments are to be performed on 
Day 0 prior to the first dose of investigational product administration. Any angioedema attack 
must be resolved prior to the first dose in the treatment period.

Confirmation of study eligibility

Randomization to blinded study treatment

Vital signs, including body temperature, HR, BP, and RR

Complete physical examination (including documentation of body weight)

12-lead ECG

Pregnancy test (for female subjects of childbearing-potential)

Clinical laboratory testing including hematology, serum chemistry, coagulation, and 
urinalysis

Pharmacokinetic sample collection 

Pharmacodynamic sample collection 

Plasma ADA sample collection 
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
Genotype sample collection (for future exploratory genetic analyses)

Health-related quality of life assessment (using the AE-QoL questionnaire)

Prior therapies, medications, and procedures

Angioedema attack data

Adverse events collection, including SAEs and AESIs 
As specified in Table 2, after the first dose of investigational product administration, the 
following post-treatment procedures and assessments will be performed:

Investigational product injection report

Vital signs including body temperature, HR, BP, and RR at 30 minutes postdose

Concomitant therapies, medications, and procedures

Adverse events collection, including SAEs and AESIs 
8.2.2.2
Study Visit 2 (Study Day 4) to Study Visit 25 (Study Day 175)
As indicated in Table 2, the following procedures and assessments are to be performed prior to 
the dose administration, as specified for a visit/study day during the treatment period:

Vital signs including body temperature, HR, BP, and RR 

Physical examination (including documentation of body weight)

Clinical laboratory testing, including hematology, serum chemistry, coagulation, and 
urinalysis

Pharmacokinetic predose sample collection 

Pharmacodynamic predose sample collection 

Plasma ADA predose sample collection 

Angioedema attack data

Health-related quality of life assessment (using the AE-QoL questionnaire)

Concomitant therapies, medications, and procedures

Adverse events collection, including SAEs and AESIs 

Pregnancy test (for females of childbearing potential) - Visit 16 (Study Day 112) ONLY
As specified in Table 2, after investigational product administration (q2wks; Section 6.2.3), the 
following post-treatment procedures and assessments will be performed:

Investigational product injection report

Vital signs including body temperature, HR, BP, and RR at 30 minutes postdose
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
Concomitant therapies, medications, and procedures

Adverse events collection, including SAEs and AESIs 
On-site visits will be scheduled at Visits 1, 3, 4, 8, 12, 16, 20, and 24 (shaded columns in 
Table 2). 
Site check-in calls will occur throughout the treatment period. If a subject does not have a 
scheduled on-site visit on study days specified in Table 2 (Visits 2, 5-7, 9-11, 13-15, 17-19, 
21-23, and 25), site personnel will perform a site check-in (within 3 days of the study day) to 
collect AEs and concomitant medications and to ensure all angioedema attacks have been 
appropriately documented and, if applicable, ensure that self-administration of investigational 
product (by subject 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.
8.2.2.3
Final Visit of Treatment Period (Study Visit 26; Study Day 182)
As indicated in Table 2, Visit 26 will be an on-site visit. The following procedures and 
assessments are to be performed:

Vital signs including body temperature, HR, BP, and RR 

Physical examination (including documentation of body weight)

12-lead ECG

Pregnancy test (for female subjects of childbearing-potential)

Clinical laboratory testing, including hematology, serum chemistry, coagulation, and
urinalysis

Pharmacokinetic sample collection 

Pharmacodynamic sample collection 

Plasma ADA sample collection 

Health-related quality of life assessment (using the AE-QoL questionnaire)

Angioedema attack data

Concomitant therapies, medications, and procedures

Adverse events collection, including SAEs and AESIs 
Subjects who elect to roll over into a 26-week long OLE study, must provide consent no later 
than the last day of blinded treatment period on Day 182 (Visit 26). After the completion of all 
scheduled assessments on Day 182 (Visit 26), subjects will be discharged from this study and 
will enter the OLE study and receive their first dose of open-label lanadelumab.
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8.2.3
Follow-up Period
The follow-up period for this study is 14 days (2 weeks). The final end of study (EOS) visit 
(Day 196, Visit 27) will be by telephone call from the site to collect information on angioedema 
attacks, concomitant therapies, medications, and procedures, and AEs. All AEs and SAEs that 
are not resolved at the time of this contact will be followed to closure (see Appendix 3.2). 
Subjects will be discharged from the study after the completion of the EOS assessments.
8.2.4
Early Termination
All procedures and assessments scheduled for final visit of the treatment period (Day 182, 
Visit 26) will be followed for the early termination (ET) visit (see Table 2).
8.2.5
Additional Care of Subjects after the Study
No aftercare is planned for this study.
8.3
Study Assessments 
Refer to the Study Schedule of Activities in Table 1 and Table 2.
8.3.1
Informed Consent
Informed consent and assent forms must be approved for use by the reviewing IRB, REB or EC. 
Informed consent must be obtained for all subjects participating in the study (or their 
parent/caregiver, as applicable) prior to performing any study-related activities. Assent will also 
be obtained from each subject, where required in accordance with IRB/REB/EC and local 
regulations, prior to performing any study-related activities. Subjects and their 
parent(s)/caregiver(s) may withdraw consent at any time. Participation in the study may be 
terminated at any time without the consent/assent of the subject (or their parent/caregiver, as 
applicable) as determined by the investigator.
8.3.2
Eligibility Review
The investigator or qualified site personnel will confirm that all inclusion criteria have been met 
(Section 5.1) and none of the exclusion criteria have been met (Section 5.2).
8.3.3
Demographic and Other Baseline Characteristics
Subject demographic information including sex, age, and race will be collected prior to the 
subject receiving the first dose of investigational product. 
8.3.3.1
Medical and Medication History
Medical and medication history will be collected during screening and recorded in the subject’s 
source documents. 
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8.3.4
Efficacy
8.3.4.1
Collection of Angioedema Attack Data 
Historical angioedema attack information will be collected at screening. Throughout the study 
(ie, from screening through follow-up), angioedema attack information will be solicited by site 
personnel during scheduled study visits and site check-ins, as shown Table 1 and Table 2. In 
addition, study subjects (or parent/caregivers, in the event the subject is <18 years old or is 
incapacitated) will be instructed to report details of the angioedema attack to the study site within 
72 hours of the onset of the attack.
The collection, reporting and assessment of angioedema attacks in this study will be done in 
accordance with the BAARP provided in Appendix 5 of this protocol. Site personnel will be 
trained on BAARP prior to screening subjects at their site.
8.3.4.2
Management of Acute Angioedema Attacks
As mentioned in Section 6.6.3, acute angioedema attacks during the study are to be managed 
with icatibant for subjects (≥18 years of age) and according to the local standard of care for 
subjects ≥12 to <18 years. 
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 angioedema attack.
8.3.5
Safety
8.3.5.1
Physical Examination
A complete physical examination will be performed by the investigator or his/her qualified 
designee according to the Study Schedule of Activities (Table 1 and Table 2). The date and time 
of each examination will be recorded on the source documents and 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:

General appearance

Ears, nose, and throat

Head and Neck

Ophthalmological

Respiratory

Cardiovascular

Abdomen

Neurological

Extremities
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
Dermatological

Lymphatic

Body weight
In addition, height will be measured at screening visit only.
8.3.5.2
Adverse Events
Each subject will be monitored for the occurrence of AEs, including SAEs and AESIs, from 
signing of the informed consent form through the final follow-up visit:

Subjects will be questioned and/or examined by the investigator or a qualified designee 
for evidence of AEs. The questioning of subjects with regard to the possible occurrence 
of AEs will be generalized such as, “How have you been feeling since your last visit?” 
The presence or absence of specific AEs should not be elicited from subjects.

The efficacy endpoint, angioedema attacks, will also be captured as AEs in this study (see 
details below).

Subjects having TEAEs will be monitored until resolution with relevant clinical 
assessments and laboratory tests, as determined by the investigator. Adverse events, 
actions taken as a result of AEs, and follow-up results must be recorded in the eCRF as 
well as in the subject's source documentation. Follow-up laboratory results should be 
filed with the subject's source documentation.

For any SAEs or AEs that require the subject to be discontinued from dosing, relevant 
clinical assessments and laboratory tests will be repeated as clinically appropriate, until 
final resolution or stabilization of the event(s). Subjects who discontinue treatment will 
complete the procedures specified for the final visit of the treatment period (Day 182, 
Visit 26) 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 angioedema attack AEs). Any AE meeting 
criteria for an SAE, as defined in Appendix 3.1, 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 8.3.5.3, must also be reported to the sponsor using the same timelines as 
described for SAE reporting. 
Further information on AE definitions, collection time frame, assessment of causality and 
severity, and safety reporting is provided in Appendix 3.1, Appendix 3.2, Appendix 3.3, and
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 efficacy endpoint, angioedema 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 
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based on whether the AE is (or is not) identified in the eCRF as a subject- or caregiver-reported 
angioedema attack: 

Non-angioedema attack AEs will include the subset of AEs that are not identified in the 
eCRF as a subject-reported angioedema attack. Essentially, this will be AEs excluding 
the subject-reported angioedema attack events. These non-angioedema attack AEs will 
be reported on the AE page of the eCRF. The severity of these AEs will be assessed 
according to the Division of Microbiology and Infectious Diseases (DMID) Adult 
Toxicity Table (Appendix 6) and the DMID Pediatric Toxicity Table (Appendix 7). 

Angioedema attack AEs will include the subset of AEs identified in the eCRF as a 
subject-reported angioedema attack. This will include, but will not be limited to, 
investigator-confirmed angioedema attacks. These angioedema attack AEs will be 
reported on the designated angioedema attack page of the eCRF. Severity of the 
angioedema attack will be assessed in accordance with BAARP (Appendix 5), which 
includes an assessment using BAARP criteria and an assessment using DMID criteria.
For all SAEs that are reported as angioedema attacks, the investigator will review the event 
within 24 hours of initial notification and, in accordance with BAARP, evaluate if it represented 
a confirmed angioedema attack. For all non-serious AEs that are reported as angioedema attacks, 
the investigator will review the event within 3 days of initial notification and, in accordance with 
BAARP, evaluate if it represented a confirmed angioedema 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 angioedema attacks will be recorded 
in the eCRF. Note: Non-histaminergic angioedema with normal C1-INH is the indication for 
treatment and should be considered subject to expedited reporting.
Emergency department visits for angioedema attacks and angioedema attacks resulting in 
hospital admissions will be captured in the eCRF and reported to the Takeda Global Patient 
Safety Evaluation (GPSE) Group.
8.3.5.3
Adverse Events of Special Interest (AESIs) 
Adverse events of special interest (AESIs) will be captured and monitored during this study. 
Investigators will report all AESIs to the sponsor, regardless of causality, using the same 
timelines as described for SAE reporting. The following describe the AESIs and the criteria 
for reporting AESIs.
Hypersensitivity Reactions
As hypersensitivity reactions have been observed for monoclonal antibodies as a class, these 
events are considered AESIs 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.
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8.3.5.4
Vital Signs
Vital signs will be assessed by the investigator or his/her qualified designee according to the 
Study Schedule of Activities in Table 1 and Table 2. Routine vital sign assessments will be taken 
with the subject in the sitting or supine position after 5 minutes at rest and will include body 
temperature, HR, BP, and RR. Blood pressure should be determined using the same arm and the 
same equipment, and the same position for each assessment throughout the study.
Vital signs assessment on dosing days will be obtained prior (within 60 minutes) to the injection 
of investigational product and 30 minutes (± 15 minutes) after completion of the injection of 
investigational product. Every effort should be made to measure and record vital signs prior to 
any blood sample collection.
During the study, additional vital sign measurements will be performed if clinically indicated. 
The investigator will assess whether a change from baseline (ie, the predose measurement at 
Visit 1/Day 0) in vital signs may be deemed clinically significant and whether the change should 
be considered and recorded as an AE. 
8.3.5.5
Clinical Laboratory Tests
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. 
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.
8.3.5.6
Pregnancy Test
For all females of childbearing potential, pregnancy testing (β-hCG) will be performed at the 
time points specified in the Schedule of Activities in Table 1 and Table 2; if pregnancy is 
suspected or on withdrawal (early termination visit) of the subject from the study. Pregnancy 
testing at the screening visit will be serum-based. All other pregnancy testing in this study may 
be urine- or serum-based. 
8.3.5.7
Electrocardiogram
A standard 12-lead ECG (single recording) will be performed at the time points specified in 
Schedule of Activities in Table 1 and Table 2. The date and time of each ECG and its results will 
be documented in the source documents and eCRF.
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8.3.6
Other Study Assessments
8.3.6.1
Clinical Pharmacology 
Blood samples for the measurement of plasma lanadelumab concentration will be obtained at the 
study days specified in Table 2. Samples should be obtained prior to dosing (ie, within 2 hours 
prior to dosing), with the exception of the Day 182/ET visit. Residual sample may be used for 
exploratory biomarker analysis (see Section 8.3.6.4).
8.3.6.2
Pharmacodynamics 
Blood samples for the measurement of cHMWK and pKal activity will be obtained at the study 
days specified in Table 2. Samples should be obtained prior to dosing (ie, within 2 hours prior to 
dosing), with the exception of the Day 182/ET visit. Residual sample may be used for 
exploratory biomarker analysis (see Section 8.3.6.4).
8.3.6.3
Immunogenicity (Antidrug 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. Samples should be obtained prior to dosing (ie, within 2 hours prior to dosing), with the 
exception of the Day 182/ET visit. Residual sample may be used for exploratory biomarker 
analysis (see Section 8.3.6.4).
8.3.6.4
Biomarkers
Diagnostic Biomarkers
A blood sample will be obtained at the screening visit for evaluation of C1-INH function, C4, 
and C1q to confirm a diagnosis of non-histaminergic angioedema with normal C1-INH. 
Diagnostic testing will be performed by a sponsor-approved central laboratory. Subjects may be 
retested if results are incongruent with clinical history or believed by the investigator to be 
confounded by recent C1-INH use.
Exploratory Biomarkers
During the treatment period, residual aliquots of blood samples for PK, PD, and ADA 
assessments, which will be collected at the time points indicated in Table 2, may also be tested 
for exploratory biomarkers of angioedema disease-state bioactivity (eg, pKal activity). The intent 
of this exploratory research is to aid in biomarker development, design and interpretation of 
clinical studies, exploration of guided treatment strategies, and to increase disease understanding.
Samples will be stored in biorepositories for up to 15 years. Any results of this exploratory 
research will be reported separately from the main clinical study report. Results may be used 
internally to help support the design of additional clinical studies, form part of scientific 
publication, or be made known to the regulatory authorities as part of a new drug application. 
The sponsor has no obligation to perform this additional exploratory research.
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8.3.6.5
Genetics
The sponsor intends to apply genomic research across the TAK-743 development program. The 
intent of this exploratory research is to aid in biomarker development, design and interpretation 
of clinical studies, exploration of guided treatment strategies, and to increase disease 
understanding.
To support these aims, a 5.0 mL sample will be collected at screening for the purpose of 
identifying genetic mutations to aid in subject stratification prior to randomization (one time 
only) and an additional 5.0 mL sample will be collected at predose on Day 0 (baseline, one time 
only) for exploratory genetic analyses. The additional sample collection is optional, has no 
impact on participation in the main study, and requires a separate informed consent. To ensure 
subject confidentiality, samples will be stored and analyzed in a de-identified format. Samples 
will be stored in biorepositories for up to 15 years.
The scope of any present and/or future research will be restricted to candidate 
gene/proteins/markers related to responses to TAK-743 and BMA such as non-histaminergic 
angioedema with normal C1-INH. 
The intent of this research is not to return results to subjects, unless required to do so by law. 
Subjects can request return of individual results, but it will not be possible to interpret these. No 
record of participation in any pharmacogenomic research, or any results derived from it should 
be recorded in a subject’s personal medical records.
Any results of this exploratory research will be reported separately from the main clinical study 
report. Results may be used internally to help support the design of additional clinical studies, 
form part of scientific publication, or be made known to the regulatory authorities as part of a 
new drug application. The sponsor has no obligation to perform this additional exploratory 
research.
For additional information and details, see Appendix 4.
8.3.6.6
Health-related Quality of Life 
Health-related quality of life will be assessed using the AE-QoL questionnaire, with the 
assessments to occur at predose on the study visits specified in Table 2.
The AE-QoL questionnaire is a self-administered validated instrument to assess HR-QoL among 
patients with recurrent angioedema (Weller et al., 2012). The AE-QoL consists of 
17 disease-specific quality-of-life items, each of the 17 items has a five-point response scale 
ranging from 1 (Never) to 5 (Very Often). Per the developers’ guidelines (Weller et al., 2012), 
the questionnaire is scored to produce a total score and four domain scores (functioning, 
fatigue/mood, fear/shame, and nutrition). Raw domain scores (mean of the item scores within 
each scale) and the raw total score (mean of all item scores) are rescaled using linear 
transformations into final percentage scores ranging 0 to 100, based on the maximum possible 
score, where the lower the score the lower the impairment. The minimal clinically important 
difference for the total score is 6 (Weller et al., 2012).
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The AE-QoL has good psychometric properties, including reliability (test-retest and internal 
consistency), construct validity (convergent/divergent and known groups), ability to detect 
change and responder definition (Weller et al., 2012). The AE-QoL has been shown to be a 
content valid, reliable, construct valid, sensitive and interpretable measure of HR-QoL for 
patients with HAE.
Further information concerning AE-QoL assessment included in the study is provided in 
Appendix 8.
8.3.6.7
Healthcare Resource Utilization 
Not applicable.
8.3.6.8
Self-administration of Investigational Product
Self-administration of investigational product is allowed and is defined as administration by the 
subject or their parent/caregiver at the investigational site or in an offsite location.
Self-administration will be permitted after a subject (and/or their parent/caregiver) has received 
appropriate training by the investigator or designee and has demonstrated their understanding of 
self-administration. Subjects may initiate self-administration after receiving the first 2 doses of 
investigational product administered by study staff at the study site. The subject is required to 
return to the site for visits as outlined in the Study Schedule of Activities (Table 2). At these 
on-site visits, the subject (or parent/caregiver) may continue to self-administer investigational 
product or may opt to have the product administered by study personnel or healthcare provider.
The investigator or designee will train subjects (and/or parents/caregivers) who elect to 
self-administer investigational product on the following:

The subject’s (or parent/caregiver’s) transportation of investigational product using a
sponsor-provided cooler, and the recommended storage conditions of investigational 
product when stored at an offsite location.

Maintenance of accurate records regarding each administration of investigational product 
including supply identification (ie, lot/kit number), date and time of injection, injection
site location, infusion time, and if applicable, any reason the self-administration could not 
be completed as instructed.

Retention of all used and unused PFS of investigational product for drug accountability 
purposes.

Additional information, as provided in the Pharmacy Manual.
If a subject (or parent/caregiver) is self-administering investigational product at home or another 
offsite location, site personnel will perform a site check-in (within 3 days after the study day) to 
ensure that self-administration of study treatment has occurred as scheduled. During this site 
check-in, the site will also solicit for any angioedema attacks not already reported by the subject 
and collect information on AEs and concomitant medications. The preferred method of site 
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contact is a telephone call; however, alternate methods of contact may be considered as site 
policies permit.
8.3.6.9
Injection Report
An injection report will be completed by the subject (or parent/caregiver) following each dose 
administration of investigational product, according to the assessment schedule in Table 2. The 
injection report will collect information on the subject’s (or parent/caregiver) experience with SC 
injection of investigational product. Study personnel will document the subject’s responses in the 
subjects’ medical record and eCRF.
8.3.7
Volume of Blood to Be Drawn from Each Subject
Laboratory testing will be performed according to the Study Activities Schedule (Table 1 and
Table 2).
Laboratory testing includes general safety parameters (hematology, serum chemistry, 
coagulation, and urinalysis), serology, pregnancy tests, C1-INH functional assay, C4 assay, 
C1q assay, PK, PD, plasma ADA testing, and pharmacogenomic/genotyping. All laboratory tests 
will be performed using established and validated methods.
When multiple sample collection types are performed at the same assessment time point, the 
samples will be drawn in the following order (depending on what sample types are to be 
collected at that time point): laboratory safety samples (hematology, coagulation, serum 
chemistry), C1-INH, C4, C1q, PK, ADA, PD. Subjects will be in a seated or supine position 
during blood collection.
As shown in Table 4, during this study it is expected that approximately 218 mL of blood will be 
drawn from all subjects (if they consent to provide blood samples for genetic testing as specified 
in Table 1 and Table 2), regardless of age or sex. Note: The amount of blood to be drawn for 
each assessment is an estimate. The amount of blood to be drawn may vary according to the 
instructions provided by the manufacturer or laboratory for an individual assessment; however, 
the total volume drawn over the course of the study should be approximately 218 mL. When 
more than one blood assessment is to be done at the time point/period, if they require the same
type of tube, the assessments may be combined. Please refer to the Laboratory Manual for more 
information.
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Table 4
Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic
5
9
45
Pharmacodynamic
2.7
9
24.3
Antidrug antibody
5
8
40
C1-INH, C4, C1q
5
1 
5
HBsAg, HIV, HCV
6
1
6
Safety
Clinical Chemistry
5
9
45
Hematology and Coagulation
4.7
9
42.3
Genotyping
5
2
10
Total mL
38.4
48a
217.6
C1-INH=C1 esterase inhibitor; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency 
virus
a This represents the total number of samples collected during the study. Up to 5 samples will be drawn at any given visit.
8.3.8
Blood Sample Collection, Storage, and Shipping
Blood samples for laboratory assessments will be collected at the site by a trained site staff 
designated and/or approved by the study investigator. Details for the collection, processing, 
storage and shipment of samples for all laboratory determinations will be provided in the 
Laboratory Manual. Biological material will be stored and secured in a manner that assures that 
unauthorized access is prohibited and the samples are not lost, allowed to deteriorate, or 
accidentally or illegally destroyed.
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9
STATISTICAL CONSIDERATIONS
9.1
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy 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.
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical analysis 
and study conclusions.
All statistical analyses will be performed using SASVersion 9.4 or higher (SAS Institute, Cary, 
NC 27513). 
9.2
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
No interim analysis or adaptive design is planned for this study. However, an independent DMC 
will be established to provide ongoing, independent review and assessment of the safety data, 
and to safeguard the interests and safety of the participating subjects in the study.
The DMC will adhere to a prospectively determined charter, which will be written by the 
sponsor and approved by the DMC. The charter will define the responsibilities of the DMC and 
sponsor, the number and timing of the DMC meetings, the conduct of the meetings, and the data 
sets to be reviewed by the DMC. Analysis of the data for DMC review will be conducted 
according to the DMC charter and DMC SAP. Because no formal hypothesis testing for safety 
assessments is planned, multiplicity concerns regarding repeated analyses are not an issue. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the first administration of investigational product. 
9.3
Sample Size and Power Considerations
Approximately 75 subjects with non-histaminergic normal C1-INH angioedema are planned to 
be randomized.
Power analyses were based on 10,000 simulations from a negative binomial distribution with 
dispersion parameter of 2 and 0.5 for lanadelumab and placebo-treated subjects, respectively, a 
10% dropout with exponential loss-to-follow-up, and will be analyzed using a general linear 
model for count data assuming a Poisson distribution with Pearson chi-square scaling of standard 
errors to account for potential overdispersion. The randomization ratio was set at 2:1 for 
lanadelumab:placebo. The effect size of 60% reduction compared to placebo was based on the 
results observed in the pivotal study in subjects with HAE (Study DX-2930-03). In 
Study DX-2930-03, the lower 95% confidence limit for attack rate reduction (lanadelumab 
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300 mg q2wks group versus placebo) was 76.2%. Due to higher disease variability, a more 
conservative effect size assumption of 60% was assumed for subjects with non-histaminergic 
angioedema with normal C1-INH. 
Assuming a treatment effect of at least a 60% reduction in the investigator-confirmed attack rate 
as compared with placebo and a placebo attack rate of 1 attack/4 weeks during the analysis 
period, a sample size of 75 subjects would provide at least 85% power (at =0.025, 1-sided). 
9.4
Statistical Analysis Set(s)
The analysis sets are defined as:

Treatment Period Full Analysis Set (FAS) will include all randomized subjects who receive 
any exposure to the investigational product during the treatment period. Subjects will be 
analyzed according to their randomized treatment assignment regardless of the treatment 
actually received.

Steady State Period FAS will include all randomized subjects who receive any exposure to 
the investigational product during the steady state period. Subjects will be analyzed 
according to their randomized treatment assignment regardless of the treatment actually 
received.

Safety Analysis Set (SAS) will include all subjects who receive any exposure to the 
investigational product. Subjects will be analyzed according to the treatment actually 
received regardless of randomized treatment assignment. 

Pharmacokinetic Set (PK Set) will include all subjects in the SAS who have at least 
1 evaluable postdose PK concentration value. 

Pharmacodynamic Set (PD Set) will include all subjects in the SAS who have at least 
1 evaluable postdose PD concentration value. 
9.5
Disposition, Demographics and Baseline Characteristics, and Exposure
9.5.1
Subject Disposition
The number of subjects randomized, treated with study drug, completing the study, and 
discontinuing prematurely by reason for withdrawal, will be summarized.
9.5.2
Demographics and Other Baseline Characteristics
Baseline disease characteristics and demographic variables will be summarized for each analysis 
population.
9.5.3
Exposure and Treatment Compliance
Treatment compliance and the extent of exposure to investigational product 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 who received at least 80% of planned doses, 
summarized for each analysis population.
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9.5.4
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 preferred term (PT) for each analysis population. A 
separate, similar table will be provided for the subset of concomitant medications classified as 
rescue medications.
9.6
Efficacy Analyses
9.6.1
Primary Efficacy Endpoint
The primary efficacy endpoint, number of investigator-confirmed angioedema attacks during the 
treatment period (Day 0 through Day 182), will be compared between treatment group 
(lanadelumab versus placebo) using the Treatment Period FAS.
The primary efficacy endpoint will be analyzed using a generalized linear model for count data 
assuming a Poisson distribution with a log link function and Pearson chi-square scaling of 
standard errors to account for potential overdispersion. The model will include fixed effects for 
treatment group (categorical), normalized baseline attack rate (continuous), and stratification 
factor of subtype (categorical). The logarithm of time in days each subject was observed during 
the treatment period will be used as an offset variable in the model. From this model, the least 
squares mean rate and standard error for each treatment group as well as the mean rate ratios 
relative to the placebo group and corresponding 95% confidence intervals will be estimated. 
These estimates will be reported as mean event rates per 4 weeks by transforming the estimates 
using the exponential function and scaling by the unit of time.
The primary endpoint will be tested by the following hypothesis:
H0: λlanadelumab / λplacebo = 1 versus H1: λlanadelumab / λplacebo ≠1
Where λlanadelumab refers to the mean investigator-confirmed angioedema attack rate in the 
lanadelumab group and λplacebo refers to the mean investigator-confirmed angioedema attack rate 
in the placebo group. The null hypothesis is that the mean investigator-confirmed angioedema 
attack rate ratio is 1 (no difference between treatment groups), versus the alternative hypothesis 
that the angioedema attack rate ratio is not 1. Estimated attack rate ratios less than 1 would 
indicate that subjects treated with lanadelumab, on average, have a lower incidence of 
investigator-confirmed angioedema attacks during the presumed steady-state treatment period. 
The hypothesis will be tested using the model-based least squares means estimate of the 
treatment difference (expressed as rate ratio relative to placebo) using a Wald-based chi-square 
test with Type I error set at 5%. 
9.6.2
Secondary Efficacy Endpoints
The rank-ordered secondary efficacy endpoints are as follows: 
1. Subjects that are attack-free during the treatment period (Day 0 through Day 182). 
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2. Number of investigator-confirmed moderate or severe angioedema attacks during the 
treatment period (Day 0 through Day 182).
3. Number of investigator-confirmed angioedema attacks during the presumed steady state 
period (Day 70 through Day 182).
4. Subjects that are attack-free during the presumed steady state period (Day 70 through 
Day 182).
5. Number of investigator-confirmed moderate or severe angioedema attacks during the
presumed steady state period (Day 70 through Day 182).
The rank-ordered secondary endpoints based on count data (ie, number of angioedema attacks 
during a specified period) will be analyzed using the same method as described for the primary 
efficacy endpoint with adjustments made to the offset term and analysis set based on the defined 
analysis period. 
The rank-ordered secondary endpoints based on binary endpoints (ie, subjects that are attack-free 
during a specified analysis period) will be compared between treatment groups using the FAS 
specific to the analysis period of interest. 
The number and percentage of subjects who are attack-free for the specified analysis period, as 
well as the difference between treatment arms and corresponding 95% confidence interval (CI) 
will be summarized. For subjects who discontinue the study prior to completion of the analysis 
period of interest, subjects will be classified as attack-free or not based on the observed 
contribution to the analysis period. 
The rank-ordered binary endpoints will be tested by the following hypothesis:
H0: planadelumab = pplacebo versus H1: planadelumab ≠ pplacebo
Where planadelumab refers to the proportion of subjects that are attack-free during the specified 
analysis period in the lanadelumab group and pplacebo refers to the proportion of subjects that are 
attack-free during the specified analysis period in the placebo group. The null hypothesis is that 
the proportion of attack-free subjects in the lanadelumab treatment group is equal to that in the 
placebo group, versus the alternative hypothesis that the proportions are not equal. A 
Cochran-Mantel-Haenszel (CMH) test, adjusting for baseline stratification factor(s) (categorical), 
will be used to test the null hypothesis, with Type I error set at 5%. A Mantel-Haenszel estimate 
for the common risk difference and corresponding stratified Newcombe confidence limits will be 
presented. 
To adjust for the potential of inflated overall Type I error rate, the rank ordered secondary 
endpoints will be tested in a fixed sequence using a general gatekeeping approach consistent with 
the logical restrictions of the rank ordering of the endpoints. Secondary endpoints will not be 
declared statistically significant unless the primary endpoint is found to be statistically 
significant. Lower ranked secondary endpoints will not be declared statistically significant unless 
the primary and all of the higher ranked secondary endpoints are found to be statistically 
significant. The multiple testing procedure is detailed in Section 9.9.2.
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Additional secondary efficacy endpoints are as follows:

Maximum attack severity during presumed steady state period (Day 70 through Day 182) and 
treatment period (Day 0 through Day 182)

Time to first angioedema attack after Day 0

Time to first angioedema attack after Day 70

Achievement of at least a 50%, 70%, 90% and 100% reduction in the investigator-confirmed 
normalized number of attacks (NNA) per 4 weeks during each of the efficacy evaluation 
periods relative to the observation period NNA

Achievement of an efficacy evaluation period NNA <1.0 per 4 weeks during each of the 
efficacy evaluation periods 
9.6.3
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints will be defined in the SAP.
9.7
Safety Analyses
All safety analyses will be based on the SAS. Analyses will be summarized by treatment. 
Treatment-emergent adverse events are defined as AEs with onset at the time of or following the 
start of treatment with study medication, or medical conditions present prior to the start of 
treatment but increasing in severity or relationship at the time of or following the start of 
treatment. The number and percentage of subjects with TEAEs will be displayed for each 
treatment group by system organ class (SOC) and PT using the Medical Dictionary for 
Regulatory Activities (MedDRA®). Summaries in terms of severity and relationship to study 
medication will also be provided. Related, serious, related serious AEs, and AESIs will be 
summarized separately in a similar fashion. Patient listings of AEs causing discontinuation of 
study medication, AEs leading to death, SAEs and AESIs will be produced.
Actual values and change from baseline in vital signs and clinical laboratory tests will be 
summarized for the treatment groups with descriptive statistics at each assessment obtained.
Usage of concomitant medications will be summarized descriptively for the treatment groups.
Abnormal physical examination findings will be listed.
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group 
and visit. Potentially clinically important findings will also be summarized or listed.
9.8
Other Analyses
9.8.1
Health-related Quality of Life Analyses
The AE-QoL total score and domain scores will be summarized using descriptive statistics by 
scheduled visit. A change in scores from baseline (Day 0) will be summarized.
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9.8.2
Pharmacokinetic, Pharmacodynamic, and Biomarker 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 and pKal levels, C1-INH, and 
C4, as appropriate, using nominal time points. 
The PK and PD properties of lanadelumab (including PK parameters, cHMWK, C1-INH, C4, 
and additional biomarkers 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 data will be summarized using descriptive statistics.
The effect on ADA and neutralizing antibodies on PK of lanadelumab, PD (cHMWK), and the 
number of investigator-confirmed angioedema attacks during the efficacy evaluation periods will 
be assessed and results will be provided in the population PK and PD analysis report.
9.9
Statistical/Analytic Considerations
9.9.1
Control of Type I Error
There will be 1 primary statistical comparison within this study with Type I error rate set at 5%.
9.9.2
Multiplicity Adjustment
The global family-wise Type I error rate (FWER) for the statistical tests of the primary and rank 
ordered secondary efficacy endpoints (rank specified in Section 9.6.2) will be controlled at 0.05. 
To strongly control the global FWER at this level, a general gatekeeping approach will be 
utilized in which the statistical tests will be conducted in a sequential manner. Testing will 
continue in sequence until the first test that the null hypothesis cannot be rejected; statistical 
significance cannot be declared for that test or for any of the remaining tests. 
To further illustrate this approach, the test for the primary endpoint will be conducted first at the 
5% significance level for the active treatment group compared with the placebo group and, if 
significant, the first secondary endpoint will be similarly tested at the 5% significance level. The 
testing sequence will continue in order through the remaining secondary endpoints for active
treatment group to placebo comparison as long as the null hypothesis is rejected at the 5% 
significance level. 
9.9.3
Handling of Missing Data
All available data will be included in the analysis. The length of time a subject was observed 
during the efficacy evaluation period will be included as an offset variable in the generalized 
linear model to adjust for differences in follow-up time.
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9.9.4
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.
9.9.5
Subgroup Analyses
Subgroup analyses are planned to be conducted for the primary efficacy endpoint and AEs 
(non-angioedema attack treatment period AEs, related AEs, and severe AEs). Any p-values that 
are presented will be descriptive.
The following subgroups will be used:

Age group

Sex

Race group

Weight group

Body mass index group

Observation period angioedema attack rate group

Subtype in angioedema 

Geographic region

History of laryngeal angioedema attack
The subgroups will be analyzed using the same method as described for the primary efficacy 
endpoint. Data summaries will parallel those described for the primary analysis of the primary 
efficacy endpoint and the adverse events.
9.9.6
Sensitivity Analyses
Sensitivity analyses will be performed on the primary efficacy endpoint and/or secondary 
endpoints to evaluate the robustness of the results. These analyses will be described in detail in 
the statistical analysis plan.
The following sensitivity analyses are planned: 
1. The primary analysis will be repeated using the SAS. 
2. The primary analysis will be repeated using all subject-reported angioedema attacks 
instead of limiting the analysis to those attacks that were investigator-confirmed.
3. The primary analysis will be repeated using a generalized linear model assuming a 
negative binomial distribution. 
4. The impact of missing data on the primary analysis will be explored using a tipping point 
analysis. 
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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.
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Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
The timing for study registration and results summary posting must be in accordance with 
applicable local and national requirements.
Submission of Summary of Clinical Study Report to Competent Authorities of Member 
States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance. 
The sponsor will provide the ECs with a copy of the same summary.
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
Appendix 1.3
Investigator’s Responsibilities
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP E6 R2 
(2016), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
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If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is 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 CRA/study monitor will verify the contents against the source data per the monitoring plan 
and the CRF completion guidelines. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
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The final, clean CRFs with subject data must be approved (signed-off in electronic data capture 
[EDC] system) by the investigator prior to database lock.
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file and original clinical laboratory reports.
All key data must be recorded in the subject’s source documents.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc).
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration [FDA], European Medicines Agency [EMA], UK Medicines and 
Healthcare products Regulatory Agency [MHRA]) 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 MHRA, other regulatory authorities, the 
sponsor or its representatives, and the IRB/EC for each site.
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
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Appendix 1.4
Data Management Considerations
Data Collection
The investigators’ authorized site personnel must enter the information required by the study 
CRF Completion Guidelines or similar for all data requiring transcription of the source. 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 or 
similar. 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 site personnel will make 
corrections to the clinical database, and all corrections are documented in an auditable manner.
Data Handling
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, antibodies to investigational product, treatment allocation, and investigational 
product preparation/accountability data) will be handled with special care during the data 
cleaning and review process. These data will be handled in such a way that, prior to unblinding, 
any data that may unblind study team personnel will be presented as blinded information or 
otherwise will not be made available. If applicable, unblinded data may be made available to 
quality assurance representatives for the purposes of conducting independent drug audits.
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. 
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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 
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 CRO 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.
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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 
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:
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If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment,
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
At least sixty (60) days prior to submitting an abstract, manuscript, or other document for 
publication, a copy of the proposed publication will be provided to the sponsor by the site for 
review. Upon the sponsor’s request, the site agrees to remove any and all confidential 
information (expressly excluding study results) identified in the publication and to delay such 
submission or presentation for an additional sixty (60) day period in order to allow the sponsor 
time to file any patent application(s). All publications of the study results shall appropriately 
reference the multi-site study publication, if any, or the fact that the study results are a subset of 
data resulting from a larger multi-site study.
Takeda is committed to transparent dissemination of all scientific, technical and medical 
manuscripts generated from Takeda-supported research. Therefore, after January 1, 2018, 
Takeda will require the submission of all Takeda-supported research manuscripts to journals that 
offer public availability via Open Access (including publisher platforms/repositories and 
self-archiving). Open Access refers to the free at point of entry, online availability of published 
research output with, where available, rights of re-use according to an End User License.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) Recommendation for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical journals. Participation as an investigator does not confer any rights to 
authorship of publications.
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Appendix 2
Clinical Laboratory Tests
The following clinical laboratory assessments will be performed as mentioned in Section 8.3.5.5.
See Section 8.3.7 for volume of blood to be drawn.
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)
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Urinalysis

Bilirubin

Glucose

Ketones

Blood 

Nitrite

pH

Protein

Specific gravity

Microscopy (if indicated by macroscopic findings)
Virology (at screening only)
Hepatitis B surface antigen (HBsAg); hepatitis C virus (HCV); human immunodeficiency virus 
(HIV)
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Appendix 3
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting
Appendix 3.1
Adverse Event Definitions
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this investigational product or medicinal product. An AE can therefore be any unfavorable 
and unintended sign (including a clinically significant laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
causality is suspected (ICH Guidance E2A 1995).
Treatment-emergent Adverse Event
A treatment-emergent adverse event (TEAE) is defined as any event emerging or manifesting at 
or after the initiation of treatment with an investigational product or medicinal product or any 
existing event that worsens in either intensity or frequency following exposure to the 
investigational product or medicinal product.
Serious Adverse Event
A serious adverse event (SAE) is any untoward clinical manifestation of signs, symptoms or 
outcomes (whether considered related to investigational product or not and at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of hospitalization. Note: 
Hospitalizations that are the result of elective or previously scheduled investigations 
procedures or surgery for pre-existing conditions and have not worsened after initiation 
of treatment should not be classified as SAEs. 

For example, an admission for a previously scheduled ventral hernia repair would not be
classified as an SAE; however, complication(s) resulting from a hospitalization for an 
elective or previously scheduled surgery that meet(s) serious criteria must be reported as 
SAE(s).

Results in persistent or significant disability/incapacity

Results in a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition. Examples of such medical events include:
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
Bronchospasm associated with anaphylaxis requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in 
inpatient hospitalization; or the development of drug dependency or drug abuse.

Reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), 
hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E 
virus (HEV), or parvovirus B19 (B19V)
Unexpected Adverse Event
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the 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 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 form the pharmacological properties of a product.
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is defined as any suspected adverse 
reaction to study treatment (ie, including active comparators) that is both serious and unexpected. 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
Symptoms of the Disease under Study
As discussed in Section 8.3.5.2 of this protocol, angioedema attacks will be captured as AEs in 
this study and will be evaluated in accordance with BAARP (Appendix 5).
Clinical Laboratory and Other Safety Assessment
A change in the value of a clinical laboratory parameter, vital sign measure, or ECG assessment 
can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. When evaluating such changes, the extent of deviation 
from the reference range, the duration until return to the reference range, either while continuing 
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.
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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 Adult Toxicity Table (Appendix 6) and DMID Pediatric 
Toxicity Table (Appendix 7).
Where discrepancies in the upper limit of normal and lower limit of normal 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 investigator’s brochure, aPTT 
prolongation due to pKal inhibition is an artifactual in vitro phenomenon. Although pKal 
drives fibrin formation in the aPTT assay, pKal-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 pKal) 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), vital sign, or ECG values which were not present at the 
pretreatment evaluation observed closest to the start of study treatment, further investigations 
should be performed until the values return to within the reference range or until a plausible 
explanation (eg, concomitant disease or expected disease evolution) is found for the abnormal 
values.
The investigator should assess, based on the above criteria and the clinical condition of the 
subject, whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
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Appendix 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 8.2.3. This includes events occurring during the 
screening phase of the study, regardless of whether or not investigational product is 
administered. 
All AEs/SAEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to baseline), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained.
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 Adult Toxicity 
Table (Appendix 6) and DMID Pediatric Toxicity Table (Appendix 7). Angioedema attacks are 
also captured as AEs in this study; angioedema attacks assessed as described in BAARP 
(Appendix 5), which includes an assessment using BAARP criteria and an assessment using 
DMID criteria.
For abnormalities not specifically found in the Toxicity Tables, the following general scale will 
be used to estimate grade of severity:

GRADE 1 (Mild): Transient or mild discomfort; no medical intervention/therapy required

GRADE 2 (Moderate): Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required

GRADE 3 (Severe): Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible 

GRADE 4 (Life-threatening): Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
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The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe nausea). This is not the same as “serious,” which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning.
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source.
The following additional guidance may be helpful:
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 investigational product); 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 investigational product); or

The AE is more likely explained by administration of investigational product than by 
another cause (ie, the AE shows a pattern consistent with previous knowledge of 
lanadelumab or the class of lanadelumab).
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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 latest version of the lanadelumab IB, 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 Takeda GPSE 
Group and the CRO/Takeda 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.
The investigator must complete, sign, and date the Takeda Safety Report Form, 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 
Takeda GPSE Group. A copy of the Takeda Safety Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Takeda 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 8.2.3 and 
must be reported to the Takeda GPSE Group and the CRO/Takeda medical monitor within 
24 hours of the first awareness of the event.
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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 Takeda GPSE 
Group 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.
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 8.2.3.
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Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Takeda GPSE Group using the Takeda
Pregnancy Report Form. 
A copy of the Takeda Pregnancy Report Form (and any applicable follow-up reports) must also 
be sent to the CRO/Takeda 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 
postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage, elective abortion or 
congenital abnormality are considered SAEs and must be reported using the Takeda Safety 
Report 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 Takeda Safety Report Form as well as the Takeda
Pregnancy Report Form. The test date of the first positive serum/urine -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 3.1. 
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.
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Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
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 is responsible for notifying the relevant regulatory authorities
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 TAK-743 program.
The investigator is responsible for notifying the local IRB/EC of SAEs or significant safety 
findings that occur at his or her site as required by IRB/EC procedures (see Appendix 1.5).
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Appendix 4
Genetics 
The sponsor intends to apply genetic research across the TAK-743 development program to 
explore how genomic variations may affect the clinical parameters associated with and response 
to TAK-743 (and any background products, comparators, and concomitant medications), and 
potentially the basis of the indication cohorts under study in the protocol, in this case BMA such 
as non-histaminergic angioedema with normal C1-INH. Collection of appropriate samples from 
populations with well described clinical characteristics may lead to improvements in the design 
and interpretation of clinical studies, genetically guided treatment strategies, and a better 
understanding of disease etiology, which may lead to new therapeutic approaches.
Candidate genes which may be studied include those potentially related to the mechanism of 
action of TAK-743, as well as those potentially responsible for absorption, disposition, 
metabolism, and excretion of TAK-743. Future research may suggest other genes, gene
categories, proteins, etc., as candidates for influencing not only response to TAK-743, but also 
susceptibility to BMA such as non-histaminergic angioedema with normal C1-INH for which
TAK-743 may be evaluated. Thus, this additional genomic research may involve the future study 
of additional unnamed genes or gene categories that may be associated with non-histaminergic 
angioedema with normal C1-INH disease susceptibility and drug action.
Samples will be drawn during screening and prior to the first administration of investigational 
product. A 5.0 mL sample will be collected at a single time point during screening for the 
purpose of identifying genetic mutations to aid in subject stratification prior to randomization 
and an additional 5.0 mL sample will be collected at predose on Day 0 (baseline, one time only) 
for the purpose of exploratory genetic analyses. Samples may only be collected from subjects 
who provide separate informed consent, as detailed in the laboratory manual. 
Samples will be labeled with the study protocol number, the subject’s study identification 
number, and information related to the sample (eg, sample type [DNA, RNA, protein], study 
day/period, sample time). No personal identifiers will be recorded on the sample labels.
Subjects terminating early from the study due to AE, tolerability, or drug-related issues should, 
where possible, be approached for their remaining protocol-defined samples at the earliest 
possible time. Unscheduled samples should be labeled with free text capturing study protocol 
number, subject’s study identification number, and information related to the sample (RNA or 
protein, sampling date, and time). Samples will be shipped to and stored at biorepositories as 
detailed in the laboratory manual. DNA, RNA, and protein will be extracted from the samples 
only when, and if, any separate exploratory research will be undertaken. 
No record of participation in this pharmacogenomics portion of the protocol, or any results 
derived from it, should be recorded in the subjects’ personal medical records. A record of 
participation in the pharmacogenomics portion of the protocol will, however, be captured in the 
study-specific source documentation records or CRF.
The sponsor, sponsor’s representatives, biorepositories, and any specialty laboratories will be 
blinded to the subject’s identity. The sample and/or extracted material will otherwise be stored 
for up to 15 years from the end of the study after which time it will be destroyed. Upon written 
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request, subjects will be permitted to withdraw their sample from the analysis and have their 
sample and/or extracted material destroyed. The link will also be destroyed at the same time as 
any remaining sample(s) are destroyed. Any results already generated from the samples will not 
be removed from any analyses that have already been performed. 
Participation in this portion of the study is optional and does not impact the subject’s eligibility 
for participation in the main clinical study. Subjects may continue to participate in the primary 
study if they refuse to provide a blood sample or if they withdraw their samples. 
Results of the genetic analyses may contribute to the global understanding of BMA such as 
non-histaminergic angioedema with normal C1-INH and its treatment and may be used internally 
to help support the design of additional clinical studies, form part of scientific publication, or be 
made known to the regulatory authorities as part of a new drug application. Any results 
generated will be for exploratory research purposes only and will not be made available unless 
required by law (ie, to regulatory authorities). Additionally, as any potential analysis does not 
form part of predefined analysis within the clinical study protocol, any results will be reported 
separately to the main clinical study report. Subjects may request the results of any analysis on 
their samples, although it will not be possible to interpret these.
For non-commercial use only


Title:
Non-histaminergic Bradykinin-mediated Angioedema Attack Assessment 
and Reporting Procedures (BAARP)
Product Name:
TAK743 / SHP643, lanadelumab (formerly DX-2930)
Sponsor:
Dyax Corp., a Takeda company
300 Shire Way, Lexington, MA 02421 USA
Original (v1.0):
14 September 2015
Version 2.0:
29 June 2017
Version 3.0:
06 May 2019
Version 4.0:
07 August 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.
APPENDIX 5
NON-HISTAMINERGIC BRADYKININ-MEDIATED ANGIOEDEMA 
ATTACK ASSESSMENT AND REPORTING PROCEDURES (BAARP), 
VERSION 4.0
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TABLE OF CONTENTS
NON-HISTAMINERGIC BRADYKININ-MEDIATED ANGIOEDEMA ATTACK
ASSESSMENT AND REPORTING PROCEDURES (BAARP)........................................1
TABLE OF CONTENTS..................................................................................................................2
LIST OF ABBREVIATIONS ..........................................................................................................3
1.
PURPOSE.................................................................................................................................4
2.
DEFINITION OF AN ANGIOEDEMA ATTACK ..................................................................4
3.
REPORTING AND ASSESSMENT OF ANGIOEDEMA ATTACK DATA .........................5
3.1
Subject (or Parent/Caregiver) Reported Symptoms...................................................5
3.1.1
Angioedema Attack Information .............................................................................5
3.1.2
Worsening Symptoms..............................................................................................6
3.1.3
Subject Training.......................................................................................................6
3.1.4
Reporting Multiple Angioedema Attacks................................................................6
3.1.5
Subject (or Parent/Caregiver) Contact with Sites....................................................6
3.2
Site Contact with the Subject .....................................................................................7
3.2.1
Review, Documenting, and Assessing a Reported Angioedema Attack .................7
3.2.2
Site Training.............................................................................................................8
3.3
Angioedema Attacks as Adverse Events....................................................................8
4.
INVESTIGATOR ATTACK ASSESSMENT........................................................................10
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LIST OF ABBREVIATIONS
AAE
acquired angioedema
AE
adverse event
BAARP
Non-histaminergic Bradykinin-mediation Angioedema Attack Assessment and 
Reporting Procedures
C1-INH
C1 inhibitor
eCRF
electronic case report form
HAE
hereditary angioedema
SAE
serious adverse event
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1.
PURPOSE
This document applies to clinical trials that involve investigator adjudication/assessment of non-
histaminergic bradykinin-mediated angioedema attacks that occur with hereditary angioedema (HAE) 
with C1 inhibitor (C1-INH) deficiency, normal C1-INH angioedema, and acquired angioedema (AAE) 
due to C1-INH deficiency. The purpose of this document is to provide a definition of non-histaminergic 
bradykinin-mediated angioedema attacks (subsequently simplified to “angioedema attacks”) 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 ANGIOEDEMA ATTACK
To be confirmed as an angioedema 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 angioedema 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-) reported use of an acute treatment for an attack by itself is not 
confirmation that the attack meets the protocol-defined criteria of an angioedema attack. 
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3.
REPORTING AND ASSESSMENT OF ANGIOEDEMA ATTACK DATA
At screening for applicable clinical trials, the subject’s angioedema 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 Angioedema 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 angioedema 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 Angioedema Attack Diary. 
On days a subject experiences an attack, additional information will be captured in the 
Angioedema 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 
Angioedema Attack Source Worksheet to document the reported attack. 
3.1.1
Angioedema Attack Information
The following information should be provided by the subject (or parent/caregiver) at the time 
they are reporting an angioedema attack to the site:

Date and time symptoms of an attack were first experienced

Description of symptoms experienced, including triggers and location(s)
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
Impact on activity and whether any assistance or medical intervention was required, 
including hospitalizations or emergency department visits

Name, date, and time of administration of any medications used to treat the attack, 
including both acute therapies and other medications. NOTE: During the observation 
period (as described in the study protocol), if icatibant is administered to treat the attack, 
the date and time of initial symptom improvement with icatibant treatment should be 
recorded.

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 Angioedema Attacks
If a subject experiences symptoms that he/she attributes to more than 1 unique angioedema 
attack, the subject (or parent/caregiver) may report this as multiple attacks to the site. Based on 
the definition of an angioedema 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 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.
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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 site needs to review the subject’s Daily Angioedema 
Attack Diary to ensure all required information has been filled out. The date and time for check-
ins can be modified based on when 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 Angioedema 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 angioedema attacks 
experienced by the subject, review the subject’s Daily Angioedema Attack Diary, and ensure 
information in the Diary is accurate.
The site will try to obtain all information necessary to document the attack completely. Missing 
information may impact the assessment of an angioedema attack and should be avoided 
whenever possible.
Complete and accurate documentation of each reported angioedema attack is important to 
making an investigator assessment of the attack. The site should document the following 
information about each angioedema 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 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.

Name, date, and time of administration of any medications used to treat the attack 
including acute therapy or other non-angioedema attack treatments. NOTE: During the 
observation period, if icatibant is administered to treat the attack, the date and time of 
initial symptom improvement with icatibant treatment should be recorded.

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
7
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
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 angioedema attack will be determined by the site using the 
following definitions (per BAARP):

Mild: Transient or mild discomfort

Moderate: Mild to moderate limitation in activity – some assistance may be needed

Severe: Marked limitation in activity, assistance required
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 angioedema attack. Any subject-reported (or parent/caregiver-reported) attack not 
confirmed by the investigator must have an alternate adverse event (AE) diagnosis reported.
All reported angioedema 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 the subject’s angioedema
attacks will need to pass a “collector” training assessment covering the following:

Review information reported in the Daily Angioedema Attack Diary

Definition of an angioedema 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 angioedema attacks as AEs

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 angioedema 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
Angioedema Attacks as Adverse Events
At the time of each contact, including scheduled study visits, site personnel will ask if the subject 
experienced any AEs or changes to the medications they are taking.
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Non-histaminergic Bradykinin-
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07 Aug 2019
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 angioedema attacks, the principal investigator 
or physician designee will review the event within 24 hours of initial notification and, in 
accordance with BAARP, evaluate if it represented a confirmed angioedema attack.
For all non-serious AEs that are reported as angioedema attacks, the principal investigator or 
physician designee will review the event within 3 days of initial notification and, in accordance 
with BAARP, evaluate if it represented a confirmed angioedema 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 in the source documents and eCRF. All subject-reported and investigator-confirmed 
angioedema attacks will also be recorded in the source documents and the study’s database.
Angioedema attacks will be captured as AEs; however, all angioedema attacks will be recorded 
on the designated angioedema attack page of the eCRF and not on the AE page of the eCRF. 
9
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Non-histaminergic Bradykinin-
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07 Aug 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 non-histaminergic bradykinin-mediated angioedema and 
familiar with the study subject’s disease history.
The assessor must review the relevant, subject-reported information and determine whether the 
event meets the criteria of an angioedema attack or not. If needed, the assessor can contact the 
subject (and/or parent/caregiver) to clarify information or ask for any additional detail. The 
determination will be documented in the source documents, along with the date and time the 
determination was made. Any angioedema event reported by the subject (and/or 
parent/caregiver) deemed not an angioedema acute attack by the investigator must be 
accompanied by an explanation and alternative diagnosis assigned by the assessor.
When reviewing subject information, the assessor will follow the definitions of an attack as 
outlined in these procedures and, taking all available information about the event into 
consideration, will determine if it is a confirmed attack. The assessment of the attack is the 
investigator or designee’s own, and not the opinion of the subject (or parent/caregiver) or any 
other site personnel. Assessors may consult with one another about a particular subject’s attack 
but only 1 assessor makes the documented determination. It is possible for both the principal 
investigator and physician designee to assess different attacks for the same subject.
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 APPENDIX 6       NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS                              
                                 DISEASES, DIVISION OF MICROBIOLOGY AND INFECTIOUS
                                 DISEASES (DMID) ADULT TOXICITY TABLES (US NATIONAL
                                   INSTITUTES OF HEALTH; NATIONAL INSTITUTE OF ALLERGY 
                                  AND INFECTION DISEASES
                                
 
....
DIVISION OF MICROBIOLOGY AND INFECTIOUS 
...
DISEASES (DMID) ADULT TOXICITY TABLE 
 
 NOVEMBER 2007 
 
DRAFT 
 
 
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, 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?  
  
Single site clinical trials evaluating healthy subjects should conform to the laboratory normal 
values at the single site. Multi-center clinical trials should reconcile among their laboratory normal 
values when evaluating a healthy volunteer population. 
  
Please confer with the DMID protocol team and DMID's Office of Clinical Research Affairs when 
selecting or developing a toxicity table for a DMID-sponsored trial. 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
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 
 
SERIOUS OR LIFE-THREATENING AEs 
 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event.  Clinical events considered to be serious or life-threatening 
include, but are not limited to:  seizures, coma, tetany, diabetic ketoacidosis, 
disseminated intravascular coagulation, diffuse petechiae, paralysis, acute psychosis, 
severe depression. 
 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s 
Common Toxicity Criteria (CTC), and World Health Organization (WHO)) have 
been adapted for use by the Division of Microbiology and Infectious Diseases 
(DMID) and modified to better meet the needs of participants in DMID trials. 
 
•  
For parameters not included in the following Toxicity Tables, sites should refer to 
the “Guide For Estimating Severity Grade”  located above. 
 
• 
Criteria are generally grouped by body system. 
 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supercede the use of these tables for specified criteria. 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
HEMATOLOGY 
 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hemoglobin 
 
9.5 - 10.5 gm/dL 
 
8.0  - 9.4gm/dL 
 
 6.5 - 7.9 gm/dL 
 
< 6.5 gm/dL 
 
Absolute Neutrophil Count 
 
1000-1500/mm3 
 
750-999/mm3 
 
500-749/mm3 
 
<500/mm3 
 
Platelets 
 
75,000-
99,999/mm3 
 
50,000-
74,999/mm3 
 
20,000-49,999/mm3 
 
<20,000/mm3 
WBCs  
11,000-13,000/ 
mm3 
13,000- 
15,000 /mm3 
15,000- 
30,000/mm3 
>30,000 or 
<1,000 /mm3 
% Polymorphonuclear 
Leucocytes + Band Cells 
 > 80% 
90 – 95% 
>95% 
---------- 
 
 
Abnormal 
Fibrinogen 
Low: 
100-200 mg/dL  
 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL  
 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
 
    ---------- 
Fibrinogen 
associated with 
gross bleeding or 
with 
disseminated 
coagulation 
 
Fibrin Split Product 
 
20-40 mcg/ml 
 
41-50 mcg/ml 
 
51-60 mcg/ml 
 
> 60 mcg/ml 
 
Prothrombin  
Time (PT) 
 
1.01 - 1.25 x ULN 
 
1.26-1.5 x ULN 
 
1.51 -3.0 x ULN 
 
>3 x ULN 
 
Activated Partial 
Thromboplastin (APPT) 
 
1.01 -1.66 x ULN 
 
1.67 - 2.33 x 
ULN 
 
2.34 - 3 x ULN 
 
> 3 x ULN 
 
Methemoglobin 
 
5.0 - 9.9 % 
 
10.0 - 14.9 % 
 
15.0 - 19.9% 
 
> 20.0 % 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CHEMISTRIES 
   
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hyponatremia 
 
130-135 mEq/L 
 
 123-129 
mEq/L 
 
116-122 mEq/L 
 
< 116 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
 
Hypernatremia 
 
146-150 mEq/L 
 
151-157 mEq/L 
 
158-165 mEq/L 
 
> 165 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
 
Hypokalemia 
 
3.0 - 3.4 mEq/L 
 
2.5 - 2.9 mEq/L 
 
2.0 - 2.4 mEq/L  
or intensive 
replacement 
therapy or 
hospitalization 
required 
 
< 2.0 mEq/L or 
abnormal 
potassium with 
 paresis, ileus or 
life-threatening 
arrhythmia 
 
Hyperkalemia 
 
5.6 - 6.0 mEq/L 
 
6.1 - 6.5 mEq/L 
 
6.6 - 7.0 mEq/l 
 
> 7.0 mEq/L 
or abnormal 
potassium  with 
life-threatening 
arrhythmia 
 
Hypoglycemia 
 
55-64 mg/dL 
 
40-54 mg/dL 
 
30-39 mg/dL 
 
<30 mg/dL or 
abnormal glucose 
with mental 
status changes or 
coma 
 
Hyperglycemia 
(nonfasting and no prior 
diabetes) 
 
116 - 160 mg/dL 
 
161- 250 
mg/dL 
 
251 - 500 mg/dL 
 
> 500 mg/dL or 
abnormal glucose 
with ketoacidosis 
 or seizures 
 
Hypocalcemia 
(corrected for albumin) 
 
8.4 - 7.8 mg/dL 
 
7.7 - 7.0 mg/dL 
 
6.9 - 6.1 mg/dL 
 
< 6.1 mg/dL 
or abnormal 
calcium with life 
threatening 
arrhythmia or 
tetany 
 
 
 
 
 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
CHEMISTRIES (continued) 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hypercalcemia 
(correct for albumin) 
 
10.6 - 11.5 mg/dL 
 
11.6 - 12.5 
mg/dL 
 
12.6 - 13.5 mg/dL 
 
> 13.5 mg/dL or 
abnormal calcium 
with life 
threatening 
arrhythmia 
 
Hypomagnesemia 
 
1.4 - 1.2 mEq/L 
 
1.1 - 0.9 mEq/L 
 
0.8 - 0.6 mEq/L 
 
< 0.6 mEq/L or 
abnormal 
magnesium with 
life-threatening 
arrhythmia 
 
Hypophosphatemia 
 
2.0 - 2.4 mg/dL 
 
1.5 -1.9 mg/dL 
or 
replacement Rx 
required 
 
1.0 -1.4 mg/dL  
intensive therapy  
or 
hospitalization 
required 
 
< 1.0 mg/dL or 
abnormal 
phosphate with 
life-threatening 
arrhythmia 
 
Hyperbilirubinemia (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 
 
Hyperbilirubinemia (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 
 
BUN 
 
1.25 - 2.5 x ULN 
 
2.6 - 5 x ULN 
 
5.1 - 10 x ULN 
 
> 10 x ULN 
Hyperuricemia (uric acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
 
 
 
Creatinine 
 
1.1 - 1.5 x ULN  
 
1.6 - 3.0 x ULN 
 
3.1 - 6 x ULN 
 
> 6 x ULN or 
dialysis required 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
ENZYMES 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
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 
 
Alkaline Phosphatase 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
Amylase 
 
1.1 - 1.5 x ULN 
 
1.6 - 2.0 x ULN 
 
2.1 - 5.0 x ULN 
 
> 5.1 x ULN 
Lipase  
 
1.1 - 1.5 x ULN 
 
1.6 - 2.0 x ULN 
 
2.1 - 5.0 x ULN 
 
> 5.1 x ULN 
 
 
URINALYSIS 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Proteinuria 
 
1+ 
 or  
200 mg - 1 gm 
loss/day 
 
2-3+  
or  
1- 2 gm 
loss/day 
 
4+ 
 or  
2-3.5 gm loss/day 
 
nephrotic 
syndrome  
or 
> 3.5 gm loss/day 
Hematuria 
 
microscopic only 
<10 rbc/hpf 
 
gross, no clots 
>10 rbc/hpf 
 
gross, with or 
without clots, OR 
red blood cell casts 
 
obstructive or 
required 
transfusion 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CARDIOVASCULAR 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cardiac Rhythm 
 
 
 
asymptomatic, 
transient signs, 
no 
Rx required 
 
recurrent/persistent; 
symptomatic Rx 
required 
 
unstable 
dysrythmia; 
hospitalization 
and treatment 
required 
 
Hypertension 
 
transient increase 
> 20 mm/Hg; no 
treatment 
 
recurrent, 
chronic 
increase 
 > 20mm/Hg. 
/treatment 
required 
 
acute treatment 
required; outpatient 
treatment or 
hospitalization 
possible 
 
end organ 
damage or 
hospitalization 
required 
 
Hypotension 
 
transient 
orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
 
symptoms due 
to orthostatic 
hypotension or 
BP decreased 
by <20 mm Hg 
systolic; 
correctable 
with oral fluid 
treatment 
 
requires IV fluids; 
no hospitalization 
required 
 
mean arterial 
pressure  
<60mm/ Hg or 
end organ 
damage or shock;   
requires 
hospitalization 
and vasopressor 
treatment 
 
Pericarditis 
 
minimal effusion 
 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
 
symptomatic 
effusion; pain; 
EKG changes 
 
tamponade; 
pericardiocentesis 
or surgery 
required 
 
Hemorrhage, Blood Loss 
 
microscopic/occult 
 
mild, no 
transfusion 
 
gross blood loss; 
1-2 units transfused 
 
massive blood 
loss; > 3 units 
transfused 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
RESPIRATORY 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cough  
 
transient- no 
treatment 
 
persistent 
cough; 
treatment 
responsive 
 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
 
Bronchospasm, Acute 
 
transient; no 
treatment; 
70% - 80% FEV1  
of peak flow 
 
requires 
treatment; 
normalizes with 
bronchodilator; 
FEV1 50% - 
70% 
(of peak flow) 
 
no normalization 
with 
bronchodilator; 
FEV1 25% - 50% 
of peak flow; or  
retractions present 
 
cyanosis: FEV1 
< 25% 
of peak flow or 
intubation 
necessary 
Dyspnea 
 
dyspnea on 
exertion 
dyspnea with 
normal activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
GASTROINTESTINAL 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Nausea 
 
mild or transient; 
maintains 
reasonable intake 
 
moderate 
discomfort; 
intake 
decreased 
significantly; 
some activity 
limited 
 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
 
Vomiting 
 
1 episode in 24 
hours 
2-5 episodes in 
24 hours 
>6 episodes in 24 
hours or needing 
IV fluids 
 
 
 
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral 
nutrition 
 
Constipation 
 
requiring stool 
softener or dietary 
modification 
requiring 
laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
 
obstruction or 
toxic megacolon 
 
Diarrhea 
 
mild or transient; 
3-4 loose 
stools/day or mild 
diarrhea last < 1 
week 
 
moderate or 
persistent; 5-7 
loose stools/day 
or diarrhea 
lasting >1 week 
>7 loose stools/day 
or bloody diarrhea; 
or orthostatic 
hypotension or 
electrolyte 
imbalance or >2L 
IV fluids required  
 
 
hypotensive 
shock or 
physiologic 
consequences 
requiring 
hospitalization   
 
Oral Discomfort/Dysphagia 
 
mild discomfort; 
no difficulty 
swallowing 
 
some limits on 
eating/drinking 
 
eating/talking very 
limited; unable to 
swallow solid 
foods 
 
unable to drink 
fluids; requires 
IV fluids 
 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
NEUROLOGICAL 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Neuro-Cerebellar 
 
slight 
incoordination 
dysdiadochokinesis 
 
intention 
tremor, 
dysmetria, 
slurred speech; 
nystagmus 
 
locomotor ataxia 
 
incapacitated 
 
Psychiatric 
 
mild anxiety or 
depression 
 
moderate 
anxiety or 
depression; 
therapy 
required; 
change in 
normal routine 
 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
 
acute psychosis 
requiring 
hospitalization;  
or suicidal 
gesture/attempt 
or hallucinations 
 
Muscle Strength 
 
subjective 
weakness 
no objective 
symptoms/ signs 
 
mild objective  
signs/symptoms 
no decrease in 
function 
 
objective weakness 
function limited 
 
paralysis 
Paresthesia (burning, tingling, 
etc.) 
mild discomfort; 
no treatment  
required 
moderate 
discomfort; 
non-narcotic 
analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision 
and/or hearing 
moderate 
impairment 
(mod decreased 
sensation, e.g., 
vibratory, 
pinprick, 
hot/cold to 
ankles) and/or 
joint position or 
mild 
impairment that 
is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or wrists) or 
loss of sensation of 
at least mod degree 
in multiple 
different body 
areas (i.e., upper 
and lower 
extremities) 
sensory loss 
involves limbs 
and trunk; 
paralysis;  or 
seizures 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
MUSCULOSKELATEL 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Arthralgia 
(joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics 
and/or pain 
interfering with 
function but not 
with activities 
of daily living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain 
with 
inflammation, 
erythema or 
joint swelling – 
interfering with 
function, but 
not with 
activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling –and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia with no 
limitation of  
activity 
muscle 
tenderness (at 
other than 
injection site) 
or with 
moderate 
impairment of 
activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
frank 
myonecrosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
SKIN 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, 
dry 
desquamation 
vesiculation or 
moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, 
mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected 
Stevens-Johnson 
or  necrosis 
requiring surgery 
Induration 
< 15mm  
15-30 mm 
>30mm 
 
Erythema 
< 15mm  
15-30 mm 
>30mm 
 
Edema 
< 15mm  
15-30 mm 
>30mm 
 
Rash at Injection Site 
< 15mm  
15-30 mm 
>30mm 
 
Pruritus 
slight itching at 
injection site 
moderate 
itching at 
injection 
extremity 
itching over entire 
body 
 
 
 
 
SYSTEMIC 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Allergic Reaction 
 
pruritus without 
rash 
 
localized 
urticaria 
 
generalized 
urticaria; 
angioedema 
 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, 
moderate; 
treatment 
required 
severe; responds to 
initial narcotic 
therapy 
intractable; 
requires repeated 
narcotic therapy 
 
Fever: oral 
 
37.7 - 38.5 C or  
100.0 - 101.5 F 
 
38.6 - 39.5 C or 
101.6 - 102.9 F 
 
39.6 - 40.5 C or 
103 - 105 F 
 
> 40 C or 
> 105 F 
 
Fatigue 
 
normal activity 
reduced < 48 hours 
 
 normal activity 
decreased 25- 
50% > 48 hours 
 
normal activity 
decreased > 50% 
can’t work 
 
unable to care for 
self 
 
 
 
 
 
 
 
 
 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT
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. 
 
 
 
APPENDIX 7
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) 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal     
 LLN = Lower Limit of Normal 
Rx  = Therapy        
Req = Required 
Mod = Moderate        
  IV  = Intravenous 
ADL = Activities of Daily Living 
 Dec = Decreased 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
GRADE 1 
Mild 
Transient or mild discomfort 
(< 48 hours); no medical intervention/therapy required 
GRADE 2 
Moderate 
Mild to moderate limitation in activity - 
some assistance may be needed; no or minimal medical 
intervention/therapy required 
GRADE 3 
Severe  
 
Marked 
limitation 
in 
activity, 
some 
assistance usually required; medical intervention/therapy required, 
hospitalizations possible 
GRADE 4 
Life-threatening 
Extreme limitation in activity, significant 
assistance required; significant 
medical 
intervention/therapy 
required, hospitalization or hospice care probable 
GRADE 5 
 Death 
SERIOUS OR LIFE-THREATENING AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event.  Clinical events considered to be serious or life-threatening include, 
but are not limited to:  seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
COMMENTS REGARDING THE USE OF THESE TABLES 
•
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common
Toxicity Criteria (CTC), and World Health Organization (WHO)) have been adapted for
use by the Division of Microbiology and Infectious Diseases (DMID) and modified to
better meet the needs of participants in DMID trials.
•
For parameters not included in the following Toxicity Tables, sites should refer to the
“Guide For Estimating Severity Grade”  located above.
•
Criteria are generally grouped by body system.
•
Some protocols may have additional protocol specific grading criteria, which will
supercede the use of these tables for specified criteria.
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
(Selected Values for children less than or equal  
to 3 months of age – does not apply for preterm infants)  
 
 
For all parameters not listed on this table, please refer 
 to the DMID Toxicity Table for children > 3 months of age. 
HEMATOLOGY  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hemoglobin 
1-7 days old 
13.0-14.0 gm/dL 
12.0-12.9 gm/dL 
<12 gm/dL 
Cardiac Failure  
secondary to Anemia 
8-21 days old 
12.0-13.0 gm/dL 
10.0-11.9 gm/dL 
<10.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
22-35 days old 
9.5-10.5 gm/dL 
8.0-9.4 gm/dL 
<8.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
36-60 days old 
8.5-9.4 gm/dL 
7.0-8.4 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
61-90 days old 
9.0-9.9 gm/dL 
7.0-8.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to Anemia 
Abs Neutrophil Ct 
1 day old 
5000-7000/mm3 
3000-4999/mm3 
1500-2999/mm3 
<1500/mm3 
2-6 days old 
1750-2500/mm3 
1250-1749/mm3 
750-1249/mm3 
<750/mm3 
7-60 days old 
1200-1800/mm3 
900-1199/mm3 
500-899/mm3 
<500/mm3 
61-90 days old 
750-1200/mm3 
400-749/mm3 
250-399/mm3 
<250/mm3 
Bilirubin (Fractionated bilirubin test must be preformed when total bilirubin is elevated) 
<7 days old 
. 
20-25mg/dL 
26-30 mg/dL 
>30 mg/dL 
7-60 days old 
1.1-1.9xN 
2.0-2.9Xn 
3.0-7.5xN 
>7.5xN 
61-90 days old 
1.1-1.9xN 
2.0-2.9xN 
3.0-7.5xN 
>7.5xN 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
(Selected Values for children less than or equal  
to 3 months of age)  
 
 
HEMATOLOGY (continued) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Creatinine 
<7 days old 
1.0-1.7 mg/dL 
1.8-2.4 mg/dL 
2.5-3.0 mg/dL 
>3.0 mg/dL 
7-60 days old 
0.5-0.9 mg/dL 
1.0-1.4 mg/dL 
1.5-2.0 mg/dL 
>2.0 mg/dL 
61-90 days old 
0.6-0.8 mg/dL 
0.9-1.1 mg/dL 
1.2-1.5 mg/dL 
>1.5 mg/dL 
Cr Clearance 
<7 days old 
35-40 ml/min 
30-34 ml/min 
25-29 ml/min 
<25 ml/min 
7-60 days old 
45-50 ml/min 
40-44 ml/min 
35-39 ml/min 
<35 ml/min 
61-90 days old 
60-75 ml/min 
50-59 ml/min 
35-49 ml/min 
<35 ml/min 
Hypocalcemia 
<7 days old 
6.5–6.9 mEq/L 
6.0-6.4 mEq/L 
5.5-5.9 mEq/L 
<5.5 mEq/L 
7-60 days old 
7.6-8.0 mEq/L 
7.0-7.5 mEq/L 
6.0-6.9 mEq/L 
<6.0 mEq/L 
61-90 days old 
7.8-8.4 mEq/L 
7.0-7.7 mEq/L 
6.0-6.9 mEq/L 
<6.0 mEq/L 
Hypercalcemia 
<7 days old 
12.0-12.4 mEq/L 
12.5-12.9 mEq/L 
13.0-13.5 mEq/L 
>13.5 mEq/L 
7-60 days old 
10.5-11.2 mEq/L 
11.3-11.9 mEq/L 
12.0-13.0 mEq/L 
>13.0 mEq/L 
61-90 days old 
10.5-11.2 mEq/L 
11.3-11.9 mEq/L 
12.0-13.0 mEq/L 
>13.0 mEq/L 
 
 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 
 (Greater than 3 months of age) 
 
LOCAL REACTIONS 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Induration 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Erythema 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Edema 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Rash at Injection Site 
< 10mm 
10-25 mm 
26-50mm 
>50mm 
Pruritus 
Slight itching at 
injection site 
Moderate itching at 
injection extremity 
Itching at injection 
extremity and other 
sites 
Itching over entire 
body 
 
HEMATOLOGY  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hemoglobin for 
children greater than 
months and less than 
2 years of age 
9.0-9.9 gm/dL 
7.0-8.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to anemia 
Hemoglobin for 
children greater that 2 
years of age 
10-10.9 gm/dL 
7.0-9.9 gm/dL 
<7.0 gm/dL 
Cardiac Failure  
secondary to anemia 
Absolute Neutrophil 
Count 
750-1200/mm3  
400-749/mm3 
250-399/mm3 
<250/mm3 
Platelets 
------- 
50,000-75,000/mm3 
25,000-49,999/mm3 
<25,000/mm3 
Prothrombin Time 
(PT) 
1.1-1.2 x ULN 
1.3 -1.5 x ULN 
1.6 -3.0 x ULN 
>3.0 x ULN 
Partial 
Thromboplastin Time 
(PTT) 
1.1-1.6 x ULN 
1.7-2.3 x ULN 
2.4 -3.0 x ULN 
>3.0 x ULN 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 (Greater than 3 months of age)  
 
GASTROINTESTINAL  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Bilirubin (when 
accompanied by any 
increase in other liver 
function test) 
 
1.1 - <1.25 x ULN 
 
1.25 - <1.5 x ULN 
 
1.5 – 1.75 x ULN 
 
> 1.75 x ULN 
Bilirubin (when other 
liver function are in 
the  normal range) 
 
1.1 - <1.5 x ULN 
 
1.5 - <2.0 x ULN 
 
2.0 – 3.0 x ULN 
 
> 3.0 x ULN 
AST (SGOT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
ALT (SGPT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
GGT 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
Pancreatic Amylase 
1.1-1.4 x ULN 
1.5-1.9 x ULN 
2.0-3.0 x ULN 
>3.0 x ULN 
Uric Acid 
7.5-9.9mg/dL 
10-12.4 mg/dL 
12.5-15.0 mg/dL 
>15.0 mg/dL 
CPK 
See Neuromuscular Toxicity 
Appetite 
----------------- 
Decreased appetite 
Appetite very 
decreased, no solid 
food taken 
No solid or liquid taken  
Abdominal Pain 
Mild 
Moderate-  
No Treatment Needed 
Moderate-  
Treatment Needed 
Severe-  
Hospitalized for treatment 
Diarrhea 
Slight change in 
consistency and/or 
frequency of stools 
Liquid stools 
Liquid stools greater 
that 4x the amount or 
number normal for 
this child 
Liquid stools greater than 8x 
the amount or number 
normal for this child  
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 (Greater than 3 months of age)  
 
GASTROINTESTINAL (continued) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Constipation 
Slight change in the 
consistency/frequency 
of stool 
Hard, dry stools with 
a change in frequency 
Abdominal pain 
Distention and 
Vomiting 
Nausea 
Mild 
Moderate-  
Decreased oral intake 
Severe-Little  
oral intake 
Unable to ingest food  
or fluid for more than 
24 hours 
Vomiting 
1 episode/day 
2-3 episodes  
per day 
4-6 episodes per day  
Greater than 6 episodes 
per day or Intractable 
Vomiting 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 (Greater than 3 months of age)  
 
ELECTROLYTES 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
CREATININE  
3 Months -2 Years of 
age  
0.6-0.8 x ULN 
0.9-1.1 x ULN 
1.2-1.5 x ULN 
>1.5 x ULN 
2 Years- 12 Years of 
age 
0.7-1.0 x ULN 
1.1-1.6 x ULN 
1.7-2.0 x ULN 
>2.0 x ULN 
Greater than  
12 Years of age 
1.0-1.7 x ULN 
1.8-2.4 x ULN 
2.5-3.5 x ULN 
>3.5 x ULN 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 (Greater than 3 months of age)  
 
ELECTROLYTES  
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Hypernatremia 
 
<145-149 mEq/L 
150-155 mEq/L 
>155 mEq/L or 
abnormal sodium 
AND mental status 
changes 
Hyponatremia 
 
130-135 mEq/L 
129-124 mEq/L 
<124 mEq/L or 
abnormal sodium 
AND mental status 
changes 
Hyperkalemia 
5.0-5.9 mEq/L 
6.0-6.4 mEq/L 
6.5-7.0 mEq/L 
>7.0 mEq/L or 
abnormal potassium 
AND cardiac 
arrhythamia 
Hypokalemia 
3.0-3-5 mEq/L 
2.5-2.9 mEq/L 
2.0-2.4 mEq/L 
<2.0 mEq/L or 
abnormal potassium 
AND cardiac 
arrhythmia 
Hypercalcemia 
10.5-11.2mg/dL 
11.3-11.9 mg/dL 
12.0-12.9 mg/dL 
>13.0 mg/dL 
Hypocalcemia 
7.8-8.4 mg/dL 
7.0-7.7 mg/dL 
6.0-6.9 mg/dL 
<6.0 mg/dL 
Hypomagnesemia 
1.2-1.4 mEq/L 
0.9-1.1 mEq/L 
0.6-0.8 mEq/L 
<0.6 mEq/L or 
abnormal magnesium 
AND cardiac 
arrhythmia 
Hypoglycemia 
55-65 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or 
abnormal glucose 
AND mental status 
changes 
Hyperglycemia 
116-159 mg/dL 
160-249 mg/dL 
250-400 mg/dL 
>400 mg/dL or 
ketoacidosis 
Proteinuria 
Tr-1+  
or 
 <150 mg/day 
2+  
or 
150-499 mg/day 
3+  
or  
500-1000 mg/day 
4+ 
 or 
 Nephrotic syndrome 
>1000 mg/day 
Hematuria 
Microscopic <25 
Microscopic >25 
 
Gross hematuria 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
cells/hpf 
cells/hpf 
 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 (Greater than 3 months of age) 
 
CENTRAL NERVOUS SYSTEM (CNS) 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
Generalized CNS 
Symptoms 
 
 
Dizziness 
Hypotonic, 
hyporesponsive 
episodes;   
Seizures; 
Apnea/Bradycardia; 
Inconsolable crying > 
3 hrs; 
Headache  
Mild 
Moderate, Responds 
to non-narcotic 
analgesia 
Moderate to Severe,  
Responds to narcotic 
analgesia 
Intractable 
Level of Activity 
 
Slightly irritable OR 
slightly subdued 
Very irritable OR 
Lethargic 
Inconsolable OR 
Obtunded 
Visual 
 
Blurriness, diplopia, 
or horizontal 
nystagmus of < 1 
hour duration, with 
spontaneous 
resolution 
More than 1 episode 
of Grade 2 
symptoms per week, 
or an episode of 
Grade 2 symptoms 
lasting more than  
1 hour with 
spontaneous 
resolution by 4 
hours or vertical 
nystagmus 
Decrease in visual 
acuity, visual field 
deficit, or oculogyric 
crisis  
Myelopathy 
 
None 
None 
Myelopathic/spinal 
cord symptoms, such 
as: pyramidal tract 
weakness and 
disinhibition, sensory 
level, loss of 
proprioception, 
bladder/bowel 
dysfunction 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
(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 
 
Page 139
Takeda Development Center Americas, Inc. CONFIDENTIAL
SHP643-303 Protocol Amendment 3
Lanadelumab (TAK-743/SHP643)
19 April 2021
For non-commercial use only


DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
 (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 
 
 
 
Page 140
Takeda Development Center Americas, Inc. CONFIDENTIAL
SHP643-303 Protocol Amendment 3
Lanadelumab (TAK-743/SHP643)
19 April 2021
For non-commercial use only


Takeda Development Center Americas, Inc. CONFIDENTIAL
SHP643-303 Protocol Amendment 3
Lanadelumab (TAK-743/SHP643)
19 April 2021
Appendix 8
Scales and Assessments
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Version Number
Date Issued
Angioedema quality of life (AE-QoL) questionnaire
Version 2010
2012
A separate master file containing each scale/assessment listed above will be provided to the site. 
Updates to scales/assessments during the study (if applicable) will be documented in the table 
above and a new master file containing the revised scale/assessment will be provided to the site. 
Page 141
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Takeda Development Center Americas, Inc. CONFIDENTIAL
SHP643-303 Protocol Amendment 3
Lanadelumab (TAK-743/SHP643)
19 April 2021
Appendix 9
Abbreviations 
Abbreviation
Definition
ACE
angiotensin-converting enzyme
ADA
antidrug antibodies
AE
adverse event
AESI
adverse event of special interest
AE-QoL
angioedema quality of life (questionnaire)
ALT
alanine aminotransferase (synonymous with SGPT)
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase (synonymous with SGOT)
AUC
area under the curve
AUC0-
area under the curve from time 0 to infinity
AUC0-last
area under the curve from time 0 to the time of last concentration 
measured
BAARP
Non-histaminergic Bradykinin-mediated Angioedema Attack 
Assessment and Reporting Procedures
-hCG
beta-human chorionic gonadotropin
BP
blood pressure
BMA
bradykinin-mediated angioedema
C1-INH
C1 inhibitor or C1 esterase inhibitor
CFR
Code of Federal Regulations
cHMWK
cleaved high molecular weight kininogen
Cmax
maximum concentration
CRF
case report form
CRA
clinical research associate
CRO
contract research organization
DMC
data monitoring committee
DMID
Division of Microbiology and Infectious Diseases
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
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Takeda Development Center Americas, Inc. CONFIDENTIAL
SHP643-303 Protocol Amendment 3
Lanadelumab (TAK-743/SHP643)
19 April 2021
Abbreviation
Definition
EOS
end of study
ET
early termination
EU
European Union
EUDRACT
European Union clinical trials database
FDA
Food and Drug Administration 
FWER
family-wise Type I error rate
GCP
Good Clinical Practice
HAE
hereditary angioedema
HIV
human immunodeficiency virus
HMWK
high molecular weight kininogen
HR
heart rate
HR-QoL
health-related quality of life
ICF
informed consent form
ICH
International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IRB
institutional review board
IRT
interactive response technology
ISR
injection site reaction
LTP
long-term prophylaxis
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
NNA
normalized number of attacks
OLE
open-label extension
PFS
prefilled syringe
PK
pharmacokinetic(s)
pKal
plasma kallikrein
PT
preferred term
q2wks
every 2 weeks
q4wks
every 4 weeks
Page 143
For non-commercial use only


Takeda Development Center Americas, Inc. CONFIDENTIAL
SHP643-303 Protocol Amendment 3
Lanadelumab (TAK-743/SHP643)
19 April 2021
Abbreviation
Definition
REB
research ethics board
RNA
ribonucleic acid
RR
respiratory rate
RSI
reference safety information
SAE
serious adverse event 
SAP
statistical analysis plan
SC
subcutaneous(ly)
SD
standard deviation
SOC
system organ class
TEAE
treatment-emergent adverse event
tmax
time to maximum concentration
UK
United Kingdom
US
United States
WHO
World Health Organization
Page 144
For non-commercial use only


For non-commercial use only


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Takeda Development Center Americas, Inc. CONFIDENTIAL
SHP643-303 Protocol Amendment 3
Lanadelumab (TAK-743/SHP643)
19 April 2021
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SHP643-303 Protocol Amendment 3
Lanadelumab (TAK-743/SHP643)
19 April 2021
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Lanadelumab (TAK-743/SHP643)
19 April 2021
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Shire
CONFIDENTIAL
Page 4
SHP643-303 Protocol Amendment 1
Lanadelumab (TAK-743/SHP643)
28 Apr 2020
SUMMARY OF CHANGES FROM PREVIOUS VERSION
A summary of changes incorporated into Amendment 1 is provided in the table below.
Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected 
by Change
Clarification that estrogen-containing medications are only excluded for 
patients with normal C1-INH angioedema; patients with AAE due to 
C1-INH deficiency are allowed to take estrogen-containing medications. 
Section 5.4.1
Section 6.6.4
Repeated footnotes (a-d) for Table 1 removed. 
Section 1.3
Table header formatting issues for Table 1 and Table 2. 
Section 1.3
Revision of inclusion criterion #8 to clarify that females of childbearing 
potential must have a negative serum pregnancy test at screening and be 
willing to undergo pregnancy tests throughout the study. 
Synopsis
Section 5.1
Definition of abstinence, as outlined in the CTFG guidance on 
contraceptions, was added. 
Synopsis
Section 5.1
Section 5.4.2
Patients <18 years of age will not be enrolled at study sites in Germany. 
Synopsis
Section 4.1
For non-commercial use only


Shire
CONFIDENTIAL
Page 4
SHP643-303 Protocol Amendment 1.1
Lanadelumab (TAK-743/SHP643)
14 May2020
SUMMARY OF CHANGES FROM PREVIOUS VERSION
A summary of the changes incorporated into Amendment 1 is provided in the table below. 
Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected 
by Change
Revised emergency contact information to reflect the most up-to-date 
and accurate information. 
Emergency Contact 
Information
Patients <18 years of age will not be enrolled at study sites in Germany. 
Section 1.1
Section 4.1
Revised the number of sites and included Asia-Pacific as an additional 
region that will have participating sites. 
Section 1.1
Definition of abstinence, as outlined in the CTFG guidance on 
contraceptions, was added. 
Section 1.1
Section 5.1
Section 5.4.2
Revision of inclusion criterion #8 to clarify that females of childbearing 
potential must have a negative serum pregnancy test at screening and be 
willing to undergo pregnancy tests throughout the study. 
Section 1.1
Section 5.1
Revised exclusion criterion #4 to exclude estrogen-containing 
medication within 4 weeks (versus 6 months) prior to screening. 
Section 1.1
Section 5.2
Section 6.6.4
Added the following language to exclusion criterion #6 “… as long as 
the investigator determines that doing so would not place the subject at 
any undue safety risk, and that the subject is at least 18 years of age.”
Section 1.1
Section 5.2
Removed the following language from exclusion criterion #9 and moved 
to description of Study Visit 1 (Study Day 0): “… any angioedema 
attack must be resolved prior to the first dose in the treatment period.”
Section 1.1
Section 5.2
Section 8.1.2.1
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Shire
CONFIDENTIAL
Page 5
SHP643-303 Protocol Amendment 1.1
Lanadelumab (TAK-743/SHP643)
14 May2020
Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected 
by Change
Extended the planned duration of the screening period to up to 8 weeks
and overall study duration to approximately 44 weeks. 
Section 1.1
Section 4.1
Section 4.4
Section 8.1.1.1
Revised the logarithm for the time in days for the primary efficacy 
endpoint to state “… during the treatment period…” (versus steady-state 
period)”.
Section 1.1
Section 9.6.1
Repeated footnotes (a-d) for Table 1 removed. 
Section 1.3
Table header formatting issues for Table 1 and Table 2. 
Section 1.3
Clarification that estrogen-containing medications are only excluded for 
patients with normal C1-INH angioedema; patients with AAE due to 
C1-INH deficiency are allowed to take estrogen-containing medications. 
Section 5.4.1
Section 6.6.4
Added pregnancy test at Visit 16 to align with Schedule of Activities. 
Section 8.1.2.2
Revised subgroup analysis to state “…non-angioedema attack treatment 
period.” (vs. non-HAE attack treatment period)
Section 9.9.5
Revised language on severity of AEs to be consistent across 
lanadelumab studies. 
Appendix 3.3
Removed language regarding double coding. 
Appendix 4
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Shire
CONFIDENTIAL
Page 4
SHP643-303 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
18 Aug 2020
SUMMARY OF CHANGES FROM PREVIOUS VERSION
A summary of the changes incorporated into Amendment 2 is provided in the table below. 
Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected by Change
Shire Global Drug Safety was updated to Takeda Global 
Patient Safety Evaluation (GPSE) Group. 
Emergency Contact Information
Section 8.3.5.2 Adverse Events
Appendix 3.4 Safety Reporting 
Appendix 3.5 Serious Adverse Event 
Collection Time Frame
Appendix 3.8 Pregnancy
, MD was added as contact for IQVIA 
medical monitor. 
Emergency Contact Information
The study population was revised to remove subjects 
with Acquired Angioedema (AAE) due to C1-INH 
deficiency. As a result of removing AAE subjects: 

Title of study revised to remove AAE subjects

Total subjects have been reduced to 
approximately 75

Study sites were reduced to approximately 60

The cap for each non-histaminergic C1-INH 
angioedema subtype was removed 

Objectives and endpoints were revised to remove 
AAE subjects.

Inclusion / Exclusion criteria were revised to 
remove AAE subjects.

Statistical analysis was revised to remove AAE 
subjects.

The Study Schema has been revised. 

Removed note that estrogen-containing 
medications are allowed for AAE subjects 
Section 1 Protocol Summary 
Section 2 Introduction 
Section 3 Objectives and Endpoints 
Section 4 Study Design 
Section 5.1 Inclusion Criteria 
Section 5.2 Exclusion Criteria
Section 5.4.1 Female Contraception
Section 6.2.2 Allocation of Subjects 
to Treatment
Section 6.6.4 Prohibited Treatment
Section 9 Statistical Considerations
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CONFIDENTIAL
Page 5
SHP643-303 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
18 Aug 2020
Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected by Change
For study site regions, removed specific countries in 
Europe and added Japan. 
Section 1.1 Synopsis 
Section 4.5 Sites and Regions 
Clarified that LTP must be discontinued during the 
observation period and that the observation period will 
serve as the baseline attack rate. 
Section 1.1 Synopsis 
Section 4 Study Design 
Section 8.2.1.3 Observation Period 
Clarified that observation period is up to 8 weeks and 
provided additional detail on subject eligibility. 
Section 1.1 Synopsis 
Section 1.3 Schedule of Activities 
Section 4 Study Design 
Section 8.2.1.3 Observation Period
The study number for the open-label extension study was 
added (Study TAK-743-3001). 
Section 1.1 Synopsis 
Section 4 Study Design 
“Antigen” in regards to C1-INH antigen was removed. 
Section 1.1 Synopsis 
Section 5.1 Inclusion Criteria
Section 8.3.6.4 Biomarkers
Section 8.3.7 Volume of Blood to be 
Drawn from Each Subject
Inclusion criteria #9 and #10 were combined into a single 
exclusion criterion (now #7). 
Section 1.1 Synopsis 
Section 5.1 Inclusion Criteria
“Concentration” in regards to plasma cHMWK and pKal 
levels was removed. 
Section 1.1 Synopsis
Table 3
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CONFIDENTIAL
Page 6
SHP643-303 Protocol Amendment 2
Lanadelumab (TAK-743/SHP643)
18 Aug 2020
Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected by Change
Clarified that the Screening period is up to 8 weeks. 
Section 1.2 Schema 
Section 1.3 Schedule of Activities 
Section 8.2.1.1 Screening Period 
An additional visit prior to the start of the observation 
period was added. This visit will allow for an eligibility 
review, angioedema attack and AE monitoring, and 
distribution of icatibant and antihistamine treatment. 
Section 1.3 Schedule of Activities 
Section 8.2.1.2 Start of Observation 
Period 
Clarified if C1-INH therapy has been used, the drug 
should be washed out for at least 5 half-lives before 
C1-INH, C4, and C1q testing. 
Section 1.3 Schedule of Activities 
Section 8.2.1.1 Screening Period
Added study procedure modifications due to COVID-19 
pandemic. 
Section 1.3 Schedule of Activities 
Section 8.1 Changes to Study 
Procedures Due to the COVID-19 
Pandemic 
Removed Plasma PK and PD Sample from Visit 2 to 
Visit 3. Visit 2 is now an off-site visit. Reference to 
collecting samples predose on Study Day 4 was removed. 
Section 1.3 Schedule of Activities 
Section 8.3.6.1 Clinical 
Pharmacology 
Section 8.3.6.2 Pharmacodynamics 
Provided clarification that subjects should being Visit 1 
in the treatment period within 7 days of the observation 
period. Any delay to the start of the treatment period 
should be discussed with the Sponsor. 
Section 1.3 Schedule of Activities 
Section 8.2.2.1 Study Visit 1; Study 
Day 0
Added angioedema attack monitoring. 
Section 8.2.1.1 Screening Period
Revised physical examinations to include body weight as 
part of all examinations. 
Section 8.3.5.1 Physical 
Examination 
Revised Exploratory Endpoints to Exploratory Efficacy 
Endpoints and added text indicating that exploratory 
efficacy endpoints will be defined in the SAP. 
Section 9.6.3 Exploratory Efficacy 
Endpoints
For non-commercial use only

SAP_001.pdf: 
NCT Number: NCT04206605
Title: A Phase 3, Multicenter, Randomized, Placebo-controlled, Double-blind 
Study to Evaluate the Efficacy and Safety of Lanadelumab for Prevention 
Against Acute Attacks of Non-histaminergic Angioedema with Normal C1-
Inhibitor (C1-INH)
Study Number: SHP643-303
Document Version and Date: Version 2.0 (10-November-2022)
Certain information within this document has been redacted (i.e., specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 
Statistical Analysis Plan


 
 
 
Statistical Analysis Plan 
Lanadelumab; TAK-743 (formerly SHP643, DX-2930) 
Phase 3 
A Phase 3, Multicenter, Randomized, Placebo-controlled, Double-blind Study to 
Evaluate the Efficacy and Safety of Lanadelumab for Prevention Against Acute 
Attacks of Non-histaminergic Angioedema with Normal C1-Inhibitor (C1-INH)  
Protocol Identifier: SHP643-303 
 
Study Sponsor(s): 
Takeda Development Center Americas, Inc. (TDCA)  
95 Hayden Avenue, Lexington, MA 02421 USA 
Author: 
 
 
Protocol: 
Amendment 3 
19 APR 2021 
SAP Version #: 
2.0 
SAP Date: 
10 NOV 2022 
Status: 
Final 
Confidentiality Statement 
This document contains confidential and proprietary information of Takeda 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 Takeda.  
 
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Page 2 of 89 
Lanadelumab 
Statistical Analysis Plan: SHP643-303 
Final 2.0 10Nov2022 
REVISION HISTORY 
Version  
Issue Date 
Summary of Changes 
2.0 
10 Nov 2022 
Added modified full analysis set and modified 
steady state full analysis set to include subjects 
who were eligible for the study and received 
study drug. 
 
The example of pKal is removed from the 
example as an exploratory endpoint. 
 
Added randomization listing that includes strata. 
 
Baseline attack rate strata removed from 
summary table but added to randomization 
listing. 
 
Added CMH analysis approach if CMH test with 
Newcombe CI does not produce estimates due to 
imbalance in stratification. 
 
Added duration category >1 -<5 days and 5 - <14 
days for injections site AE duration. 
 
Added analysis for all post-baseline results for lab 
values (hematology, coagulation, chemistry, 
urinalysis, vital signs). 
 
Added highest and shift tables for chemistry lab 
parameters. 
 
Included sensitivity analysis to exclude subjects 
who were enrolled and received study drug and 
they did not meet all eligibility criteria. 
 
Added tabulation of AE-QoL scores per visit per 
function and addition of patient reported 
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Page 3 of 89 
Lanadelumab 
Statistical Analysis Plan: SHP643-303 
Final 2.0 10Nov2022 
outcomes (PRO) SAP to address the AE-QoL 
endpoints. 
 
Protocol deviations section updated to detail the 
handling of the site level deviations and important 
protocol deviations. 
 
Included HAE attack rate responder threshold 
categories <0.75 attacks per month, <0.5 attacks 
per month, <0.25 attacks per month. 
 
1.0 
18 Nov 2020 
Not applicable. Final version of document. 
 
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Page 4 of 89 
Lanadelumab 
Statistical Analysis Plan: SHP643-303 
Final 2.0 10Nov2022 
TABLE OF CONTENTS 
REVISION HISTORY ......................................................................................................2 
TABLE OF CONTENTS ..................................................................................................4 
ABBREVIATIONS ............................................................................................................8 
1. 
INTRODUCTION................................................................................................10 
2. 
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS .......................................10 
2.1 
Objectives ..........................................................................................................10 
2.1.1 Primary Objective ......................................................................................10 
2.1.2 Secondary Objective(s) ..............................................................................10 
2.1.3 Exploratory Objective(s) ............................................................................11 
2.2 
Estimands ..........................................................................................................11 
2.3 
Endpoints ..........................................................................................................18 
2.3.1 Primary Efficacy Endpoint ........................................................................18 
2.3.2 Key Secondary Efficacy Endpoints ...........................................................18 
2.3.3 Other Secondary Efficacy Endpoints .........................................................18 
2.3.4 Exploratory Efficacy Endpoints .................................................................18 
2.3.5 Exploratory Endpoint .................................................................................19 
2.3.6 Safety Endpoints ........................................................................................19 
2.3.7 Pharmacokinetic Endpoint .........................................................................19 
2.3.8 Pharmacodynamics Endpoint.....................................................................19 
2.3.9 Health-related Quality of Life (QoL) Endpoint .........................................20 
2.3.10 Immunogenicity Endpoint .........................................................................20 
3. 
STUDY DESIGN ..................................................................................................20 
3.1 
General Description ..........................................................................................20 
3.2 
Randomization ..................................................................................................22 
3.3 
Blinding .............................................................................................................22 
3.4 
Sample Size and Power Considerations ............................................................23 
4. 
STATISTICAL ANALYSIS SETS .....................................................................23 
4.1 
Screened Set ......................................................................................................23 
4.2 
Enrolled Set .......................................................................................................24 
4.3 
Treatment Period Full Analysis Set (FAS) .......................................................24 
4.4 
Steady State Period Full Analysis Set (SS-FAS) ..............................................24 
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Lanadelumab 
Statistical Analysis Plan: SHP643-303 
Final 2.0 10Nov2022 
4.5 
Safety Analysis Set (SAS) ................................................................................24 
4.6 
Pharmacokinetic Set (PK Set) ...........................................................................25 
4.7 
Pharmacodynamic Set (PD Set) ........................................................................25 
5. 
STUDY SUBJECTS .............................................................................................25 
5.1 
Disposition of Subjects .....................................................................................25 
5.2 
Demographic and Other Baseline Characteristics.............................................26 
5.3 
Medical History .................................................................................................28 
5.4 
Prior Therapies, Procedures and Medication ....................................................28 
5.5 
Concomitant Therapies, Procedures and Medications ......................................28 
5.6 
Exposure to Investigational Product .................................................................29 
5.7 
Measurements of Treatment Compliance .........................................................30 
5.8 
Protocol Deviations ...........................................................................................30 
6. 
EFFICACY ANALYSES ....................................................................................33 
6.1 
Analyses of Primary Efficacy Endpoint ............................................................33 
6.1.1 Sensitivity Analyses of Primary Efficacy Endpoint ..................................35 
6.1.2 Supplementary Analyses of Primary Efficacy Endpoint ...........................36 
6.2 
Analyses of Key Secondary Efficacy Endpoints ..............................................36 
6.2.1 Sensitivity Analyses of Key Secondary Efficacy Endpoints .....................38 
6.2.2 Supplementary Analyses of Key Secondary Efficacy Endpoints ..............39 
6.3 
Analyses of Other Secondary Efficacy Endpoints ............................................39 
6.3.1 Sensitivity Analyses of Other Secondary Efficacy Endpoints ...................41 
6.3.2 Supplementary Analyses of Other Secondary Efficacy Endpoints ............41 
6.4 
Multiplicity Adjustment ....................................................................................41 
6.5 
Analyses of Exploratory Endpoints ..................................................................41 
6.6 
Subgroup Analyses ...........................................................................................46 
7. 
SAFETY ANALYSIS...........................................................................................46 
7.1 
Adverse Events (AE).........................................................................................46 
7.1.1 Adverse Events of Special Interest (AESI) ................................................49 
7.1.2 Injection Site Reaction AEs (ISR) .............................................................50 
7.1.3 AE Tabulations ..........................................................................................50 
7.2 
Clinical Laboratory Data ...................................................................................51 
7.3 
Vital Signs .........................................................................................................54 
7.4 
Electrocardiogram (ECG) .................................................................................54 
7.5 
Other Safety Data ..............................................................................................55 
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Lanadelumab 
Statistical Analysis Plan: SHP643-303 
Final 2.0 10Nov2022 
7.5.1 Biomarker Test...........................................................................................55 
7.5.2 Pregnancy Test ...........................................................................................55 
7.5.3 Physical Examination.................................................................................55 
8.
PHARMACOKINETIC ANALYSIS .................................................................55 
8.1 
Drug Concentration ...........................................................................................55 
8.2 
Handling Below Limit of Quantitation (BLQ) Values .....................................56 
8.3 
Statistical Analysis of Pharmacokinetic Data ...................................................56 
9.
PHARMACODYNAMIC ANALYSIS...............................................................56 
9.1 
Pharmacodynamic Data ....................................................................................56 
10.
OTHER ANALYSES ...........................................................................................56 
10.1 
Health-related Quality of Life Analyses ...........................................................56 
10.2 
Immunogenicity Analyses .................................................................................57 
11.
INTERIM ANALYSIS/ DATA MONITORING (REVIEW)
COMMITTEE ......................................................................................................57 
12.
DATA HANDLING CONVENTIONS ..............................................................57 
12.1 
General Data Reporting Conventions ...............................................................57 
12.2 
Definition of Baseline and EOS/ET ..................................................................58 
12.3 
Definition of Visit Windows .............................................................................58 
12.3.1 Analysis Periods.........................................................................................59 
12.4 
Derived Efficacy Endpoints ..............................................................................59 
12.4.1 Unique Angioedema Attacks .....................................................................59 
12.4.2 Angioedema Attack Duration ....................................................................60 
12.4.3 Investigator-Confirmed Angioedema Attacks ...........................................60 
12.4.4 Investigator-Confirmed Angioedema Attacks Requiring Acute 
Therapy ......................................................................................................60 
12.4.5 Moderate and Severe Investigator-Confirmed Angioedema Attacks ........60 
12.4.6 Angioedema Attack Severity .....................................................................60 
12.4.7 Angioedema Attack Rate ...........................................................................61 
12.4.7.1 Observation Period Angioedema Attack Rate .............................61 
12.4.7.2 Treatment Period Angioedema Attack Rate ................................61 
12.4.7.3 Presumed Steady State Period Angioedema Attack Rate ............61 
12.4.8 Time to First Angioedema Attack..............................................................61 
12.4.8.1 Time to First Angioedema Attack After Day 0 ...........................61 
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Lanadelumab 
Statistical Analysis Plan: SHP643-303 
Final 2.0 10Nov2022 
12.4.8.2 Time to First Angioedema Attack After Day 70 .........................62 
12.5 
Repeated or Unscheduled Assessments of Safety Parameters ..........................62 
12.6 
Handling of Missing, Unused, and Spurious Data ............................................62 
12.6.1 Missing Start or End Date and Time for Angioedema Attacks .................62 
12.6.2 Missing Date/Time Information for Prior or Concomitant 
Medications/Therapies/Procedures ............................................................63 
12.6.3 Missing Date Information for Adverse Events ..........................................64 
12.6.3.1 Incomplete Start Date/Time .........................................................64 
12.6.3.2 Incomplete Stop Date/Time .........................................................64 
12.6.3.3 Duration of Injection Site Reaction AEs .....................................64 
12.6.4 Missing Severity Assessment for Adverse Events.....................................64 
12.6.5 Missing Relationship to IP for Adverse Events .........................................65 
12.6.6 Clinical Significance Attributions for Laboratory Results ........................65 
12.6.7 Character Values of Clinical Laboratory Variables ...................................65 
13. 
ANALYSIS SOFTWARE ...................................................................................66 
14. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ............................66 
15. 
REFERENCES .....................................................................................................66 
16. 
APPENDICES ......................................................................................................67 
16.1 
Appendix 1 – Schedule of Activities ................................................................67 
16.2 
Appendix 2 – Details of Tipping Point Analysis ..............................................69 
16.3 
Appendix 3 – Sample SAS Code ......................................................................72 
16.3.1 GLM Model Sample SAS Code ................................................................72 
16.3.2 Tipping Point Analysis Sample SAS Code ................................................73 
16.3.3 Sample Code to Derive Relative Risk and Risk Difference ......................74 
16.3.4 Sample SAS Code for Time to Event Analysis .........................................74 
16.4 
Appendix 4 – List of Planned Outputs ..............................................................76 
 
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Lanadelumab 
Statistical Analysis Plan: SHP643-303 
Final 2.0 10Nov2022 
ABBREVIATIONS 
 
ADA 
Anti-drug Antibody 
AE 
Adverse Event 
AE-QoL 
Angioedema Quality of Life 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Transaminase 
aPTT 
Activated Partial Thromboplastin Time  
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
BAARP 
Non-histaminergic bradykinin-mediated angioedema attack assessment 
and reporting procedures 
BLQ 
Below Limit of Quantitation 
BMI 
Body Mass Index 
BP  
Blood Pressure 
BUN 
Blood Urea Nitrogen 
cHMWK 
Cleaved High-Molecular Weight Kininogen 
C1-INH 
C1 Esterase Inhibitor 
C1q 
Complement Component 1q 
C4 
Complement Component 4 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CO2 
Carbon Dioxide  
CPK 
Creatine Phosphokinase 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CS 
Clinically Significant 
CTMS 
Clinical Trial Management System 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOS 
End of Study 
ET 
Early Termination 
FAS 
Full Analysis Set 
FWER 
Family-wise type I error rate 
GLM 
Generalized linear model 
HAE 
Hereditary Angioedema 
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Lanadelumab 
Statistical Analysis Plan: SHP643-303 
Final 2.0 10Nov2022 
HR 
Heart Rate 
HRQoL 
Health-Related Quality of Life 
INR 
International Normalized Ratio 
IP 
Investigational Product 
ISR 
Injection Site Reaction 
IV 
Intravenous 
KM 
Kaplan-Meier 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantitation 
LTP 
Long-term Prophylaxis 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
msec 
Millisecond 
NCS 
Non Clinically Significant 
NNA 
Normalized Number of Attacks 
OLE 
Open-Label Extension 
PD 
Pharmacodynamic 
pH 
Potential Hydrogen 
PK 
Pharmacokinetic 
pKal 
Plasma Kallikrein 
PT 
Preferred Term (MedDRA®) 
QoL 
Quality of Life 
RBC 
Red Blood Cells 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard Deviation  
SMQ 
Standardized MedDRA® Query 
SOC 
System Organ Class 
SS-FAS 
Steady State Full Analysis Set 
TEAE   
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
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Page 10 of 89 
Lanadelumab 
Statistical Analysis Plan: SHP643-303 
Final 2.0 10Nov2022 
1. 
INTRODUCTION  
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy, safety, health-related quality of life, pharmacokinetic 
(PK)/pharmacodynamic (PD), biomarker and immunogenicity data as described in the 
protocol amendment 3 dated 19 April 2021. Specifications for tables, figures, and listings 
are contained in a separate document.  
The PK and PD properties of lanadelumab (including PK parameters, cHMWK, C1-INH, 
C4, and additional biomarkers 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 modeling and the analysis results will be 
reported separately. The effect on ADA and neutralizing antibodies on PK of 
lanadelumab, PD (cHMWK), and the number of investigator-confirmed angioedema 
attacks during the efficacy evaluation periods will be assessed and results will be 
provided in the separate PK/PD TLF and population PK and PD analysis reports. The 
effect of lanadelumab on health-related quality of life (HR-QoL) will be evaluated based 
on the AE-QoL questionnaire. A separate QoL SAP will describe the HR-QoL analysis, 
and the results will be reported separately.  
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock and unblinding of treatment assignment. If additional 
analyses are required to supplement the planned analysis described in this SAP after 
database lock, they may be completed and will be described in the clinical study report 
(CSR). 
2. 
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Primary Objective 
To evaluate the efficacy of repeated subcutaneous (SC) administrations of lanadelumab 
in preventing angioedema attacks in adolescents (12 to <18 years of age) and adults with 
non-histaminergic angioedema with normal C1-INH.  
2.1.2 Secondary Objective(s) 
The secondary objectives of the study are:  
• To evaluate the safety of repeated SC administrations of lanadelumab in 
preventing angioedema attacks.  
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Lanadelumab 
Statistical Analysis Plan: SHP643-303 
Final 2.0 10Nov2022 
• To evaluate the PK of repeated SC administrations of lanadelumab in preventing 
angioedema attacks. 
• To evaluate the PD of repeated SC administrations of lanadelumab in preventing 
angioedema attacks. 
• To evaluate the immunogenicity of repeated SC administrations of lanadelumab 
in preventing angioedema attacks. 
• To evaluate the effect of lanadelumab on health-related quality of life (HR-QoL) 
assessment.  
2.1.3 Exploratory Objective(s) 
The exploratory objective is to evaluate the effect of lanadelumab on exploratory 
biomarker(s) of angioedema disease-state bioactivity.  
2.2 
Estimands 
The primary and secondary estimands are described in Table 1. 
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Lanadelumab 
Statistical Analysis Plan: SHP643-303 
Final 2.0 10Nov2022 
Table 1. List of Select Estimands  
Estimand 
Definition 
Attributes 
A:  
Population 
B:  
Variable  
(or endpoint) 
C:  
Strategy for 
addressing 
intercurrent 
event 
D:  
Population-
level summary 
Primary  
The primary 
estimand is 
the effect of 
lanadeluma
b on the rate 
of 
angioedema 
attacks 
during the 
treatment 
period (Day 
0 through 
Day 182). 
Adolescents 
(12 to <18 
years of age) 
and adults with 
non-
histaminergic 
angioedema 
with normal 
C1-INH 
defined 
through 
inclusion and 
exclusion 
criteria as 
stated in the 
protocol and 
who received 
any exposure 
to the 
investigational 
product during 
the treatment 
period. 
Number of 
investigator-
confirmed 
angioedema 
attacks during 
the treatment 
period (Day 0 
through Day 
182). 
1/ Rescue 
medication: 
treatment policy 
(Regardless of 
whether or not 
rescue 
medication/supp
ortive treatment 
use had 
occurred.)   
2/ Premature 
study 
discontinuation 
before the end 
of the treatment 
period: while on 
treatment (The 
logarithm of 
time in days 
each subject 
was observed 
during the 
treatment period 
will be used as 
an offset 
variable in the 
model.) 
Least square 
mean of attack 
rate during the 
treatment 
period, 
adjusting for 
baseline attack 
rate. Mean rate 
ratio of 
lanadelumab 
relative to 
placebo and 
corresponding 
95% confidence 
interval (CI). 
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Table 1. List of Select Estimands  
Estimand 
Definition 
Attributes 
A:  
Population 
B:  
Variable  
(or endpoint) 
C:  
Strategy for 
addressing 
intercurrent 
event 
D:  
Population-
level summary 
Key 
Secondary 
(Rank 1)  
A 
supportive 
estimand is 
the effect of 
lanadeluma
b on 
achieving 
attack-free 
status 
during the 
treatment 
period (Day 
0 through 
Day 182). 
Adolescents 
(12 to <18 
years of age) 
and adults with 
non-
histaminergic 
angioedema 
with normal 
C1-INH 
defined 
through 
inclusion and 
exclusion 
criteria as 
stated in the 
protocol and 
who received 
any exposure 
to the 
investigational 
product during 
the treatment 
period. 
Achievement of 
attack-free 
status for the 
treatment period 
(Day 0 through 
Day 182). 
1/ Rescue 
medication: 
treatment policy 
(Regardless of 
whether or not 
rescue 
medication/supp
ortive treatment 
use had 
occurred.)   
2/ Premature 
study 
discontinuation 
before the end 
of the treatment 
period: while on 
treatment 
(Attack-free is 
evaluated up to 
study 
discontinuation.
) 
Proportion of 
subjects 
achieving 
attack-free 
status for the 
treatment period 
of Day 0 
through Day 
182 and 
corresponding 
exact 95% 
confidence 
interval (CI). 
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Table 1. List of Select Estimands  
Estimand 
Definition 
Attributes 
A:  
Population 
B:  
Variable  
(or endpoint) 
C:  
Strategy for 
addressing 
intercurrent 
event 
D:  
Population-
level summary 
Key 
Secondary 
(Rank 2) 
A 
supportive 
estimand is 
the effect of 
lanadeluma
b on the rate 
of moderate 
or severe 
angioedema 
attacks 
during the 
treatment 
period (Day 
0 through 
Day 182). 
Adolescents 
(12 to <18 
years of age) 
and adults with 
non-
histaminergic 
angioedema 
with normal 
C1-INH 
defined 
through 
inclusion and 
exclusion 
criteria as 
stated in the 
protocol and 
who received 
any exposure 
to the 
investigational 
product during 
the treatment 
period. 
Number of 
investigator-
confirmed 
moderate or 
severe 
angioedema 
attacks during 
the treatment 
period (Day 0 
through Day 
182). 
1/ Rescue 
medication: 
treatment policy 
(Regardless of 
whether or not 
rescue 
medication/supp
ortive treatment 
use had 
occurred.)   
2/ Premature 
study 
discontinuation 
before the end 
of the treatment 
period: while on 
treatment (The 
logarithm of 
time in days 
each subject 
was observed 
during the 
treatment period 
will be used as 
an offset 
variable in the 
model.) 
Least square 
mean of attack 
rate during the 
treatment 
period, 
adjusting for 
baseline attack 
rate. Mean rate 
ratio of 
lanadelumab 
relative to 
placebo and 
corresponding 
95% confidence 
interval (CI). 
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Table 1. List of Select Estimands  
Estimand 
Definition 
Attributes 
A:  
Population 
B:  
Variable  
(or endpoint) 
C:  
Strategy for 
addressing 
intercurrent 
event 
D:  
Population-
level summary 
Key 
Secondary 
(Rank 3)  
A 
supportive 
estimand is 
the effect of 
lanadeluma
b on the rate 
of 
angioedema 
attacks 
during the 
presumed 
steady state 
period (Day 
70 through 
Day 182). 
Adolescents 
(12 to <18 
years of age) 
and adults with 
non-
histaminergic 
angioedema 
with normal 
C1-INH 
defined 
through 
inclusion and 
exclusion 
criteria as 
stated in the 
protocol and 
who received 
any exposure 
to the 
investigational 
product during 
the presumed 
steady state 
period. 
Number of 
investigator-
confirmed 
angioedema 
attacks during 
the presumed 
steady state 
period (Day 70 
through Day 
182). 
1/ Rescue 
medication: 
treatment policy 
(Regardless of 
whether or not 
rescue 
medication/supp
ortive treatment 
use had 
occurred.)   
2/ Premature 
study 
discontinuation 
before the end 
of the treatment 
period: while on 
treatment (The 
logarithm of 
time in days 
each subject 
was observed 
during the 
presumed 
steady state 
period will be 
used as an 
offset variable 
in the model.) 
Least square 
mean of attack 
rate during the 
presumed 
steady state 
period, 
adjusting for 
baseline attack 
rate. Mean rate 
ratio of 
lanadelumab 
relative to 
placebo and 
corresponding 
95% confidence 
interval (CI). 
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Table 1. List of Select Estimands  
Estimand 
Definition 
Attributes 
A:  
Population 
B:  
Variable  
(or endpoint) 
C:  
Strategy for 
addressing 
intercurrent 
event 
D:  
Population-
level summary 
Key 
Secondary 
(Rank 4)  
A 
supportive 
estimand is 
the effect of 
lanadeluma
b on 
achieving 
attack-free 
status 
during the 
presumed 
steady state 
period (Day 
70 through 
Day 182). 
Adolescents 
(12 to <18 
years of age) 
and adults with 
non-
histaminergic 
angioedema 
with normal 
C1-INH 
defined 
through 
inclusion and 
exclusion 
criteria as 
stated in the 
protocol and 
who received 
any exposure 
to the 
investigational 
product during 
the presumed 
steady state 
period. 
Achievement of 
attack-free 
status for the 
presumed 
steady state 
period (Day 70 
through Day 
182). 
1/ Rescue 
medication: 
treatment policy 
(Regardless of 
whether or not 
rescue 
medication/supp
ortive treatment 
use had 
occurred.)   
2/ Premature 
study 
discontinuation 
before the end 
of the treatment 
period: while on 
treatment 
(Attack-free is 
evaluated up to 
study 
discontinuation.
) 
Proportion of 
subjects 
achieving 
attack-free 
status for the 
presumed 
steady state 
period of Day 
70 through Day 
182 and 
corresponding 
exact 95% 
confidence 
interval (CI). 
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Table 1. List of Select Estimands  
Estimand 
Definition 
Attributes 
A:  
Population 
B:  
Variable  
(or endpoint) 
C:  
Strategy for 
addressing 
intercurrent 
event 
D:  
Population-
level summary 
Key 
Secondary 
(Rank 5)  
A 
supportive 
estimand is 
the effect of 
lanadeluma
b on the rate 
of moderate 
or severe 
angioedema 
attacks 
during the 
presumed 
steady state 
period (Day 
70 through 
Day 182). 
Adolescents 
(12 to <18 
years of age) 
and adults with 
non-
histaminergic 
angioedema 
with normal 
C1-INH 
defined 
through 
inclusion and 
exclusion 
criteria as 
stated in the 
protocol and 
who received 
any exposure 
to the 
investigational 
product during 
the presumed 
steady state 
period. 
Number of 
investigator-
confirmed 
moderate or 
severe 
angioedema 
attacks during 
the presumed 
steady state 
period (Day 70 
through Day 
182). 
1/ Rescue 
medication: 
treatment policy 
Regardless of 
whether or not 
rescue 
medication/supp
ortive treatment 
use had 
occurred.   
2/ Premature 
study 
discontinuation 
before the end 
of the treatment 
period: while on 
treatment (The 
logarithm of 
time in days 
each subject 
was observed 
during the 
presumed 
steady state 
period will be 
used as an 
offset variable 
in the model.) 
Least square 
mean of attack 
rate during the 
presumed 
steady state 
period, 
adjusting for 
baseline attack 
rate. Mean rate 
ratio of 
lanadelumab 
relative to 
placebo and 
corresponding 
95% confidence 
interval (CI). 
 
 
 
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2.3 
Endpoints 
2.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the number of investigator-confirmed angioedema 
attacks during the treatment period (Day 0 through Day 182).  
2.3.2 Key Secondary Efficacy Endpoints  
The following are the rank-ordered secondary efficacy endpoints:  
1. Subjects that are attack-free during the treatment period (Day 0 through Day 182)  
2. Number of investigator-confirmed moderate or severe angioedema attacks during 
the treatment period (Day 0 through Day 182) 
3. Number of investigator-confirmed angioedema attacks during the presumed 
steady state period (Day 70 through Day 182) 
4. Subjects that are attack-free during the presumed steady state period (Day 70 
through Day 182) 
5. Number of investigator-confirmed moderate or severe angioedema attacks during 
the presumed steady state period (Day 70 through Day 182) 
2.3.3 Other Secondary Efficacy Endpoints 
Additional secondary efficacy endpoints include:  
• Maximum attack severity during presumed steady state period (Day 70 through 
Day 182) and treatment period (Day 0 through Day 182)  
• Time to first angioedema attack after Day 0 
• Time to first angioedema attack after Day 70 
• Achievement of at least a 50%, 70%, 90% and 100% reduction in the 
investigator-confirmed normalized number of attacks (NNA) per 4 weeks during 
each of the efficacy evaluation periods relative to the observation period NNA 
• Achievement of an efficacy evaluation period NNA <1.0 per 4 weeks during each 
of the efficacy evaluation periods 
2.3.4 Exploratory Efficacy Endpoints 
The following endpoints will also be analyzed: 
• Number of high-morbidity investigator-confirmed angioedema attacks during the 
treatment period (Day 0 through Day 182)  
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• Number of investigator-confirmed angioedema attacks resulting in an emergency 
department visit and/or admission to hospital during the treatment period (Day 0 
through Day 182)  
• Number of investigator-confirmed laryngeal angioedema attacks during the treatment 
period (Day 0 through Day 182)  
• Characteristics of investigator-confirmed angioedema attacks, including attack 
duration, severity, location, and medication use during the observation period, 
treatment period (Day 0 through Day 182), and presumed steady state period (Day 70 
through Day 182) 
• Percentage of attack free days during the treatment period (Day 0 through Day 182) 
and during the presumed steady state period (Day 70 through Day 182) 
• Achievement of investigator-confirmed angioedema attack-free interval of 1 month or 
3 months during the treatment period (Day 0 through Day 182)  
• Achievement of investigator-confirmed angioedema attack-free interval of 1 month or 
3 months during the presumed steady state period (Day 70 through Day 182)  
2.3.5 Exploratory Endpoint 
The exploratory endpoint include exploratory biomarker(s) of angioedema-disease state 
bioactivity () in blood and plasma. 
2.3.6 Safety Endpoints 
Safety endpoints are as follows: 
• TEAEs, including AESIs and SAEs 
• Clinical laboratory testing (hematology, clinical chemistry, coagulation, and 
urinalysis)  
• Vital signs including blood pressure, heart rate, body temperature, and respiratory 
rate 
2.3.7 Pharmacokinetic Endpoint 
The PK endpoint is plasma concentrations of lanadelumab. 
2.3.8 Pharmacodynamics Endpoint 
The PD endpoint is plasma cHMWK and pKal activity. 
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2.3.9 Health-related Quality of Life (QoL) Endpoint 
The health-related QoL endpoint will be measured by the AE-QoL questionnaire, which 
consists of 17 disease-specific quality-of-life items, to produce a total AE-QoL score and 
4 domain scores (functioning, fatigue/mood, fear/shame, and nutrition).  The responses to 
the AE-QoL for each item will be tabulated for each treatment group by study visit using 
the full analysis set.   
The health-related QoL endpoints are as follows and will be included in as separate 
patient reported outcomes (PRO) report: 
• Change in total AE-QoL scores from baseline (Day 0) to Day 182 
• Change in domain AE-QoL scores from baseline (Day 0) to Day 182 
2.3.10 Immunogenicity Endpoint  
The immunogenicity endpoint is the presence or absence of anti-drug antibody (ADA) in 
plasma (neutralizing or non-neutralizing antibody in plasma).  
3. 
STUDY DESIGN 
3.1 
General Description 
This randomized, placebo-controlled, double-blind, Phase 3 study will enroll 
approximately 75 subjects (12 years of age and above) with normal C1-INH angioedema. 
The study is composed of the following periods:  
• Screening Period and Washout Period 
All subjects will undergo screening assessments during a screening period of up to 8 
weeks.  
Screened subjects who have been on any long-term prophylaxis (LTP) (e.g., C1-INH, 
androgens, or antifibrinolytics) are required to undergo a minimum 2-week washout 
period prior to entering the observation period. The washout period is included in the 
screening period.  
• Observation Period 
Enrolled subjects meeting all eligibility criteria at screening will enter an observation 
period of 8 weeks to determine the baseline angioedema attack rate and confirm their 
eligibility.  
Only subjects meeting a minimum baseline attack rate of at least 1 investigator-confirmed 
attack per 4 weeks, along with being treated with icatibant for at least 2 angioedema 
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attacks or at least one moderate or severe attack, will be eligible for randomization and 
will enter the treatment period. Subjects who experience 3 or more investigator-
confirmed attacks within the first 4 weeks will be allowed to exit the observation period 
early at 4 weeks and proceed to randomization. Subjects who do not meet the minimum 
attack rate during the observation period will be considered screen failures; subjects who 
screen fail will not be allowed to rescreen for the study.  
• Double-blind Treatment Period  
Subjects who enter the double-blind treatment period will receive SC administration of 
investigational product q2wks for 26 weeks.  
• Open-Label Extension (OLE) Study  
Subjects may roll over into a 26-week long OLE study, TAK-743-3001, upon completion 
of all assessments scheduled on Day 182.  
• Safety Follow-up Period  
Subjects who choose not to roll over to the OLE study will continue to the planned 2 
weeks of safety follow-up at the completion of all study assessments scheduled on Day 
182.  
A schematic representation of the study design is displayed in Figure 1. The study 
schedule of events can be found in Appendix 1 Table 5 and Table 6 .  
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Figure 1 Study Design 
 
3.2 
Randomization 
After verification of eligibility in the observation period, subjects will be randomized 2:1 
via IRT to receive repeated SC administrations of lanadelumab or placebo in a double-
blind fashion.  
Randomization will be stratified by the baseline angioedema attack rate observed during 
the observation period and by subtype. The two levels of angioedema attack rate strata 
are 1-<2 attacks per 4 weeks and 2 or more attacks per 4 weeks. The three levels of 
subtype are 1) with known mutations (FXII, PLG, ANGPT1, or KNG1 genes, or other 
predefined mutations associated with normal C1-INH angioedema); 2) with family 
history (a first-degree relative) and unknown mutations; and 3) with idiopathic non-
histaminergic angioedema (INHA).  
3.3 
Blinding  
This is a double-blind study. Blinding was achieved by means of identical appearance for 
lanadelumab and placebo. To ensure the blind is maintained, data which is unblinding 
such as treatment, or potentially unblinding such as post-baseline attack data, and PK and 
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PD data, will be restricted as outlined in the Clinical Trial Integrity Document. 
Unblinding of the overall dataset will occur after the database has been locked.  
3.4 
Sample Size and Power Considerations 
Approximately 75 subjects with non-histaminergic normal C1-INH angioedema are 
planned to be randomized. Power analyses were based on 10,000 simulations from a 
negative binomial distribution with dispersion parameter of 2 and 0.5 for lanadelumab 
and placebo-treated subjects, respectively, a 10% dropout with exponential loss-to-
follow-up, and will be analyzed using a general linear model for count data assuming a 
Poisson distribution with Pearson chi-square scaling of standard errors to account for 
potential overdispersion. The randomization ratio was set at 2:1 for lanadelumab: 
placebo.  
The dispersion parameters chosen for the power analysis were estimated from the results 
observed in the pivotal lanadelumab study in subjects with HAE (Study DX2930-03). In 
Study DX2930-03, the dispersion parameter was estimated at 0.5 and 2.1, for the placebo 
arm and the lanadelumab 300 mg q2wks arm, respectively. Because the primary 
endpoint, number of angioedema attacks during the treatment period, is expected to 
behave in a similar fashion as was observed in pivotal study for HAE, Study DX2930-03, 
similar dispersion parameters were assumed for the sample size calculation. The effect 
size of 60% reduction compared to placebo were also based on the results observed in the 
pivotal study. In Study DX-2930-03, the lower 95% confidence limit for attack rate 
reduction (lanadelumab 300 mg q2wks group versus placebo) was 76.2%. Due to higher 
disease variability compared with HAE, a conservative effect size assumption of 60% 
was assumed for subjects with non-histaminergic angioedema with normal C1-INH. .  
Assuming a treatment effect of at least a 60% reduction in the investigator-confirmed 
attack rate as compared with placebo and a placebo attack rate of 1 attack/4 weeks during 
the analysis period, a sample size of 75 subjects would provide at least 85% power (at 
α=0.025, 1-sided).  
4. 
STATISTICAL ANALYSIS SETS 
The analysis sets are defined as:  
4.1 
Screened Set  
The Screened Set will consist of all subjects who have signed informed consent.  
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4.2 
Enrolled Set  
The Enrolled Set consists of all subjects who have signed informed consent and also 
passed inclusion/exclusion criteria. 
4.3 
Treatment Period Full Analysis Set (FAS) 
The Treatment Period Full Analysis Set (FAS) will include all randomized subjects who 
receive any exposure to the investigational product (IP) during the treatment period (Day 
0 through Day 182). Subjects will be analyzed according to their randomized treatment 
assignment regardless of the treatment actually received.  
4.3.1 
Treatment Period Modified Full Analysis Set (mFAS) 
The Treatment Period Modified Full Analysis Set (mFAS) will include all randomized 
subjects who receive any exposure to the investigational product (IP) during the treatment 
period (Day 0 through Day 182) and met all study eligibility criteria. Subjects will be 
analyzed according to their randomized treatment assignment regardless of the treatment 
actually received.  
 
4.4 
Steady State Period Full Analysis Set (SS-FAS) 
The Steady State Period FAS (SS-FAS) will include all randomized subjects who receive 
any exposure to the IP during the presumed steady state period (Day 70 through Day 
182). Subjects will be analyzed according to their randomized treatment assignment 
regardless of the treatment actually received.  
4.4.1 
Modified Steady State Full Analysis Set (mSS-FAS) 
The Steady State Period FAS (SS-FAS) will include all randomized subjects who receive 
any exposure to the IP during the presumed steady state period (Day 70 through Day 182) 
and met all study eligibility criteria. Subjects will be analyzed according to their 
randomized treatment assignment regardless of the treatment actually received.  
4.5 
Safety Analysis Set (SAS) 
The Safety Analysis Set (SAS) will include all subjects who receive any exposure to the 
IP. Subjects will be analyzed according to the treatment actually received regardless of 
randomized treatment assignment. In the event a subject receives both the correct and 
incorrect treatments during the study, the treatment used most often will be selected. 
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4.6 
Pharmacokinetic Set (PK Set) 
The Pharmacokinetic Set (PK Set) will include all subjects in the SAS who have at least 1 
evaluable postdose PK concentration value.  
4.7 
Pharmacodynamic Set (PD Set)  
The Pharmacodynamic Set (PD Set) will include all subjects in the SAS who have at least 
1 evaluable PD concentration value.  
5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
The number of subjects who were included in each defined analysis set (i.e., Screened, 
Enrolled, FAS, SS-FAS, SAS, PK and PD) will be summarized by randomized treatment 
assignment and overall for the Screened Set. The number of subjects included in each 
analysis population will be summarized by study site and country as well. 
The number and percentage of subjects who completed the treatment period (by either 
rolling over to the open-label long term extension study or continuing to the planned 2 
weeks of safety follow-up), completed the follow-up period, and prematurely 
discontinued, along with reasons for premature discontinuation, from the study will be 
summarized for the FAS population.  
The duration of enrollment, in days, will be summarized for each site, country and 
overall.  Duration of enrollment will be calculated as (last date of contact for any subject 
at that site – the first date of informed consent for any subject at that site + 1). 
Disposition of all subjects, including screen failures, will be presented in a listing for the 
Screened Set. Inclusion criteria not met and exclusion criteria met will be listed. A 
Kaplan-Meier (KM) plot showing the time to withdrawal will be presented by treatment 
group for the FAS population. Time to withdrawal will start with the date of 
randomization; subjects will be censored based on their completion date (either the end of 
the treatment period visit, Day 182, for subjects rolling over to the OLE study, or the end 
of the follow-up period for subjects not rolling over to the OLE study). 
A listing of subjects’ randomization assignments and stratification factors will be 
included. 
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5.2 
Demographic and Other Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group and overall for the SAS, FAS and SS-FAS populations.  
The following demographic and baseline characteristics will be summarized: 
• Age at informed consent date (years),  
• Age category (<18, 18 to <40, 40 to <65, ≥65 years),  
• Sex (Male, Female, Unknown, Intersex/Undifferentiated),  
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown), 
• Race (White, Black or African American, Native Hawaiian or Other Pacific Islander, 
Asian, American Indian or Alaska Native, Multiple, Other), 
• Race group (White, Other), 
• Geographical region (North America, Europe, and Other), 
• Weight (kg),  
• Weight group (<50, 50 to <75, 75 to <100, ≥100 kg),  
• Height (cm),  
• Body mass index (BMI) (kg/m2), calculated as 10000*weight (kg)/ height (cm)2,  
• BMI group for subjects ≥ 18 years of age (<18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2), 
and 
• BMI percentile group for subjects < 18 years of age based on growth charts from the 
Centers for Disease Control and Prevention (CDC) (Underweight: <5th percentile, 
Healthy or Overweight: 5th to <95th percentile, Obese: >=95th percentile),  
o Official and validated SAS programs created by CDC will be used to calculate 
the percentile of BMI. For more information on the CDC SAS programs, see 
http://www.cdc.gov/growthcharts/computer_programs.htm. 
The following baseline angioedema characteristics will be summarized in a separate 
table:  
• Age at onset of angioedema symptoms (years),  
• History of laryngeal attacks (yes, no),  
• Primary attack location (laryngeal, abdominal, peripheral, or a combination of these 
locations), 
• Number of attacks in the last 1, 3, and 12 months prior to screening,  
• Average attack duration (in days) in the last 12 months prior to screening,  
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• Average severity of angioedema attacks in the last 12 months prior to screening 
(mild, moderate, severe),  
• Number of attacks of different severity (mild, moderate, severe) in the last 3 months 
prior to screening,  
• Average attack duration category (less than 12 hours, 12-24 hours, 24-48 hours, 
greater than 48 hours, not applicable) in the last 3 months prior to screening,  
• Observation period angioedema attack rate (attacks/4 weeks),  
• Observation period angioedema attack rate categories (1-<2 attacks/4 weeks, ≥2 
attacks/4 weeks),  
• Observation period angioedema attack rate strata (1-<2 attacks/4 weeks, ≥2 attacks/4 
weeks), and 
• Type of LTP therapy before entering the observation period (C1-INH, Androgens, 
Anti-fibrinolytics, or not on LTP).  
The LTP (C1-INH, Androgens, or Anti-fibrinolytics) treatment a subject was on prior to 
the observation period will be determined by applying the algorithm below to prior 
medications (i.e., medications with start and stop date prior to the start date of 
observation period, imputing partial dates as described in Section 12.6.2) reported for that 
subject that lasted for ≥4 days:  
LTP 
Algorithm to Identify Medications 
C1-INH 
ATC level 4 in (‘B06AC’) and preferred drug name not in 
(‘icatibant’, ‘ecallantide’, ‘icatibant acetate’) 
Androgens 
ATC level 4 in (‘G03BA’, ‘G03BB’, ‘A14AA’) or 
preferred drug name in (‘danazol’, ‘oxandrolone’)  
Anti-fibrinolytics 
ATC level 4 in (‘B02AA’, ‘B02AB’) 
 
The three levels of subtype will be summarized 1) with known mutations (FXII, PLG, 
ANGPT1, or KNG1 genes, or other predefined mutations associated with normal C1-INH 
angioedema) – with summary to include the genotype categories; 2) with family history 
(a first-degree relative) and unknown mutations; and 3) with idiopathic non-histaminergic 
angioedema (INHA). See Section 12.4.7.1 for the calculation of the observation period 
angioedema attack rate.  
All baseline and demographic data will be presented in subject listings for the Screened 
Set. 
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5.3 
Medical History 
Medical history will be collected at the Screening Visit and will be coded using MedDRA 
Version 22.1 or newer.  
The medical history will be summarized by system organ class (SOC) and preferred term 
(PT) by treatment group and overall for the SAS population. Tabulations will be 
presented sorted by SOC in alphabetical order and by PT within each SOC by descending 
frequency in the lanadelumab group and then the placebo group.   
All medical history will be presented in subject listings for the Screened Set.  
5.4 
Prior Therapies, Procedures and Medication  
Prior medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) dated 01 Sep 2019. Prior therapies and procedures will be coded using 
MedDRA Version 22.1 or newer.  
Prior medication/therapy/procedure is defined as any medication/therapy/procedure with 
the start date and time prior to the date and time of the first dose of investigational 
product (IP).  
Partial date imputation for medications is described in Section 12.6.2.  
Prior medications will be summarized by the number and proportion of subjects within 
each Anatomical Therapeutic Chemical (ATC) Level 2 therapeutic class and PT for the 
SAS population. Tabulations will be presented sorted by therapeutic class in alphabetical 
order and by PT within each therapeutic class by descending frequency in the 
lanadelumab group and then the placebo group. Multiple medication usage by a subject in 
the same category (i.e., therapeutic class or preferred name) will be counted only once. 
All prior medications will be summarized, and a separate summary of prior medications 
taken during the observation period will be generated.  
All prior therapies, procedures and medication will be listed for the Screened Set. High-
dose antihistamines will be flagged in listings. 
5.5 
Concomitant Therapies, Procedures and Medications  
Concomitant medications will be coded using the WHO Drug Dictionary dated 01 Sep 
2019. Concomitant therapies and procedures will be coded using MedDRA Version 22.1 
or newer.  
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Concomitant medication/therapy is defined as any medication/therapy with a start date 
and time prior to the date and time of the first dose of IP and continuing after the first 
dose of IP or with a start date and time between the dates and times of the first dose of IP 
and end of the treatment period, inclusive. Concomitant procedure is defined as any 
procedure with a start date and time between the dates and times of the first dose of IP 
and end of the treatment period, inclusive.  
Any medication/therapy/procedure with a start date after the end of the treatment period 
will not be considered a concomitant medication/therapy/procedure. Partial date 
imputation for medications is described in Section 12.6.2.  
Concomitant medications will be summarized by the number and proportion of subjects 
within each ATC Level 2 therapeutic class and PT for the SAS population. Tabulations 
will be presented sorted by therapeutic class in alphabetical order and by PT within each 
therapeutic class by descending frequency in the lanadelumab group and then the placebo 
group. Multiple medication usage by a subject in the same category (i.e., therapeutic class 
or preferred name) will be counted only once.   
All concomitant therapies, procedures and medication will be listed for the Screened Set.  
5.6 
Exposure to Investigational Product 
Exposure to IP will be summarized by treatment group and overall in terms of treatment 
duration (month) and total dose received (mg) for the SAS and FAS populations.  
Treatment duration (month) will be calculated as (number of days from the date of the 
first dose to the earliest of the early discontinuation date or the date corresponding to the 
end of the treatment period, inclusively)/28.  
Total dose received (mg) will be calculated as the sum of subject’s dose (mg) received at 
each visit, i.e., 150 mg/mL*study drug volume (mL) administered at the visit.  
Descriptive statistics (n, mean, standard deviation [SD], minimum, median, and 
maximum) will be presented for treatment duration and total dose received. In addition, 
treatment duration will be summarized by category (<1 Month, 1 –< 3 Months, 3 –< 6 
Months, >= 6 Months).  
A listing of study drug administration and injection report data will be provided.  
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5.7 
Measurements of Treatment Compliance  
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 who received at least 80% of planned doses.  
The percentage of planned doses received will be calculated as the number of doses 
received / number of planned doses while on treatment * 100.  
The number of planned doses is the number of doses planned to be administered up to the 
date of study completion or early termination, based upon the q2wks dosing schedule.  
Descriptive statistics (n, mean, SD, minimum, median, and maximum) of total number of 
doses received by the subject, percentage of planned doses received, and the number and 
percentage of subjects that received at least 80% of planned doses will be presented by 
treatment group for the SAS and FAS populations.  
A listing of measurements of treatment compliance will be provided.  
5.8 
Protocol Deviations 
Protocol deviations as obtained from a clinical trial management system (CTMS) will be 
assessed throughout the study. All identified deviations will be reported in the CTMS. 
Protocol deviations from the CTMS will be coded to severity categories (“critical”, 
“major” and “minor”) and importance criteria (“yes”, “no”) and provided as part of the 
CTMS transfer to Biostatistics.   
 
Protocol deviations will be collected at both the site and subject level. Deviations at the 
site level will be programmatically applied to all subjects who were enrolled at that site at 
the time of the deviation for deviations recorded before 30Jun2022.  These deviations 
will be included in the tabular summary and protocol deviation listings.  Due to an update 
in the CRO system of collecting PDs, site-level protocol deviations recorded after 
30Jun2022 will be tracked as non-compliance in CTMS and a separate report will be 
transferred to Biostatistics which will be used to create a separate summary table and 
non-compliance listing. 
 
Important protocol deviations are a subset of protocol deviations that may significantly 
impact the completeness, accuracy and/or reliability of study data or that may 
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significantly affect a subject’s rights, safety, or well-being.  Due to an update in the CRO 
system of collecting PDs, deviations occurring after 14JUL2022 were classified as 
important or not.  These deviations will be identified with a flag in the listings, and a 
table with the summary of important protocol deviations will be summarized. 
 
Protocol deviations will be summarized by deviation type and severity by treatment 
group and overall for the FAS, and separately for protocol deviations specific to Covid-
19. Protocol deviations will be summarized according to the old protocol deviation 
categories as summarized prior to the update in the CRO system of collecting PDs and all 
new categories will be mapped to the old categories to facilitate output summaries 
(Please see Table 2: Old and New PD Categories)   . All protocol deviations will be 
included in a subject listing. 
 
Table 2: Old and New PD Categories 
Old PD Categories  
New PD Categories  
Categories presented in tables and 
listings (Old PD Categories) 
Informed Consent Criteria 
Informed Consent and Process 
Informed Consent Criteria 
Eligibility and Entry Criteria 
Inclusion Criteria 
Eligibility and Entry Criteria 
Eligibility and Entry Criteria 
Exclusion criteria 
Eligibility and Entry Criteria 
Concomitant Medication Criteria 
Concomitant Medication 
Concomitant Medication Criteria 
Laboratory Assessment Criteria 
Laboratory Assessment 
Laboratory Assessment Criteria 
Study Procedures Criteria 
Study Procedures  
Study Procedures Criteria 
Serious Adverse Event Criteria 
Safety 
Serious Adverse Event Criteria 
Randomization Criteria 
Randomization 
Randomization Criteria 
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Visit Schedule Criteria 
Visit Schedule 
Visit Schedule Criteria 
Investigational Product (IP) 
Compliance 
IP conditions  
Investigational Product (IP) 
Compliance 
 
Investigational Product (IP) 
Compliance 
 
IP preparation 
Investigational Product (IP) 
Compliance 
 
Investigational Product (IP) 
Compliance 
 
IP administration 
Investigational Product (IP) 
Compliance 
 
Investigational Product (IP) 
Compliance 
 
Subject IP compliance 
Investigational Product (IP) 
Compliance 
 
Efficacy Criteria 
Efficacy 
Efficacy Criteria 
Other Criteria  
Subject Discontinuation 
Other Criteria  
Administrative Criteria 
 
Administrative  
Administrative Criteria 
 
Other Criteria  
 
Blinding 
Other Criteria  
 
Other Criteria  
 
Patient Reported Outcomes 
Other Criteria  
 
Other Criteria  
 
PK/PD 
Other Criteria  
 
Other Criteria  
 
Other 
Other Criteria  
 
Source Documents Criteria 
 
Not applicable in the new 
categorisation as these are non-
compliances rather than PDs. 
Not applicable in the new 
categorisation as these are non-
compliances rather than PDs. 
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Regulatory or Ethics Approvals 
Criteria 
 
Not applicable in the new 
categorisation as these are non-
compliances rather than PDs. 
Not applicable in the new 
categorisation as these are non-
compliances rather than PDs. 
 
 
6. 
EFFICACY ANALYSES 
All efficacy analyses will be based on the FAS unless stated otherwise and will be 
conducted according to the treatment assigned.  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.  
For all efficacy analyses, unique angioedema attacks, as defined in Section 12.4.1, will be 
used. Handling of missing start or end date and time for angioedema attacks is described 
in Section 12.6.1. Additional details for deriving efficacy endpoints can be found in 
Section 12.  
All statistical tests will be 2-sided hypothesis tests performed at the 5% level of 
significance for main effects. All confidence intervals will be 2-sided 95% confidence 
intervals, unless stated otherwise. Control of Type I error is discussed in Section 6.4 in 
detail.  
Efficacy data, including derived efficacy parameters defined in the subsections below, 
will be presented in subject data listings.  
6.1 
Analyses of Primary Efficacy Endpoint 
The primary efficacy endpoint, number of investigator-confirmed angioedema attacks 
during the treatment period (Day 0 through Day 182), will be compared between 
treatment group (lanadelumab versus placebo) using the Treatment Period FAS.  
The primary efficacy endpoint will be analyzed using a generalized linear model (GLM) 
for count data assuming a Poisson distribution with a log link function and Pearson chi-
square scaling of standard errors to account for potential overdispersion. The model will 
include fixed effects for treatment group (categorical), normalized baseline attack rate 
(continuous), and the stratification factor of subtype (categorical). The logarithm of time 
in days each subject was observed during the treatment period will be used as an offset 
variable in the model. See Section 12.4.7.1 for the calculation of the normalized baseline 
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(observation period) attack rate. From this model, the least squares mean rate and 
standard error for each treatment group as well as the mean rate ratio relative to the 
placebo group and corresponding 95% confidence interval will be estimated. These 
estimates will be reported as mean event rates per 4 weeks by transforming the estimates 
using the exponential function and scaling by the unit of time.  
The primary endpoint will be tested by the following hypothesis:  
H0: λlanadelumab / λplacebo = 1 versus H1: λlanadelumab / λplacebo ≠ 1 
Where λlanadelumab refers to the mean investigator-confirmed angioedema attack rate in the 
lanadelumab group and λPlacebo refers to the mean investigator-confirmed angioedema 
attack rate in the placebo group. The null hypothesis is that the mean investigator-
confirmed angioedema attack rate ratio is 1 (no difference between treatment groups), 
versus the alternative hypothesis that the angioedema attack rate ratio is not 1. Estimated 
attack rate ratios less than 1 would indicate that subjects treated with lanadelumab, on 
average, have a lower incidence of investigator-confirmed angioedema attacks during the 
presumed treatment period. The hypothesis will be tested using the model-based least 
squares means estimate of the treatment difference (expressed as rate ratio relative to 
placebo) using a Wald-based chi-square test with Type I error set at 5%. See Section 
12.4.7.2 for the calculation of the treatment period attack rate. 
The percentage difference in mean investigator-confirmed angioedema attack rate of 
lanadelumab from the attack rate of placebo will be calculated as 100% * (mean rate ratio 
– 1). Similarly, the estimated upper and lower confidence limits for the mean rate ratio 
can be transformed by subtracting 1 and multiplying by 100% to calculate 95% 
confidence intervals for the percentage change.  The mean rate ratio and corresponding 
95% confidence interval will be estimated from the generalized linear model as described 
previously.  
Unadjusted monthly investigator-confirmed angioedema attack rates will be calculated 
for the observation and treatment periods.  See Section 12.4.7.1 and Section 12.4.7.2 for 
details.  The observation period, treatment period, and treatment period change from 
observation period in the monthly investigator-confirmed angioedema attack rate will be 
summarized by treatment group. This summary will include the total number of 
investigator-confirmed angioedema attacks reported and the subject-time in months 
subjects contributed to the observation and treatment periods. Figures by treatment group 
plotting the on-study investigator-confirmed angioedema attacks reported during the 
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treatment period with timing relative to randomization for each subject will be created 
(i.e., “birds on a wire” plots).   
In addition to the data summaries for the primary analysis of the primary efficacy 
endpoint described above, the number of investigator-confirmed angioedema attacks per 
month (defined as 28 days) will be summarized descriptively by month (per 28 day 
interval) and treatment group. The summary will include the monthly investigator-
confirmed angioedema attack rate, change from observation period, and percent change 
from observation period of investigator-confirmed angioedema attack rate. Investigator-
confirmed angioedema attacks will be grouped into 28-day intervals using the start date 
of the angioedema attack. The date of the first exposure to study drug 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 plus 28 days. Each successive interval will start the last day of the prior interval plus 
1 day and end 28 days later. See Section 12.3.1 for the definition of the observation 
period.  
6.1.1 
Sensitivity Analyses of Primary Efficacy Endpoint 
The following sensitivity analyses will be performed on the primary efficacy endpoint to 
evaluate the robustness of the results.  
1. The primary analysis will be repeated using the SAS population (subjects will be 
analyzed according to the treatment actually received regardless of randomized 
treatment assignment).  
2. The primary analysis will be repeated using all subject-reported angioedema attacks 
instead of limiting the analysis to those attacks that were investigator-confirmed. 
3. The primary analysis will be repeated using a generalized linear model assuming a 
negative binomial distribution. 
4. The impact of missing data on the primary analysis will be explored using a tipping 
point analysis. 
Subjects who do not complete the treatment period (Day 0 through Day 182) but who 
were dosed and have contributed any amount of time to the treatment period will be 
included in the primary analysis. These subjects will have some portion of the 
treatment period observed and the remainder of the treatment period, after study 
discontinuation, will be unobserved.  The model used for the primary analysis 
assumes that events occur at a constant rate within an individual, and uses only the 
number of events in the observed portion of the treatment period with an offset 
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parameter to account for the length of time in which those events were observed to 
derive the event rate for that individual.   
To better understand the impact of unobserved portion of the treatment period 
generated by subjects who discontinue early on the results of our primary analysis, a 
tipping point analysis will be conducted.  In this analysis, a range of progressively 
more conservative assumptions about the number of events occurring in the 
unobserved portion of the treatment period will be explored in order to find the 
assumption which will reverse the conclusion (i.e., yield a non-significant p-value) of 
the primary analysis.  The assumption that will reverse the conclusion is referred to as 
the tipping point.  Once the tipping point is identified, the clinical plausibility of the 
assumption can be assessed.   
The tipping point analysis will employ the same model as specified for the primary 
analysis including progressively conservative assumptions about the unobserved 
portion of time generated by subjects who discontinue early. The exact range of 
assumptions will be determined after treatment unblinding to ensure an appropriate 
range is explored based on the magnitude of treatment effect and pattern of missing 
data.  The results of the various assumptions will be summarized with attack rate 
ratios, corresponding 95% confidence intervals and p-values in both tabular and 
graphical presentations.  The details of this method are described in Appendix 2. 
The primary efficacy analysis will be repeated for  subjects in the modified full analysis 
set (mFAS) that were randomized and received study drug but did not meet study 
eligibility criteria. 
 
6.1.2 
Supplementary Analyses of Primary Efficacy Endpoint 
No supplementary analyses are planned for the primary efficacy endpoint.  
6.2 
Analyses of Key Secondary Efficacy Endpoints  
The rank ordered secondary efficacy endpoints are as follows: 
1. Subjects that are attack-free during the treatment period (Day 0 through Day 182). 
2. Number of investigator-confirmed moderate or severe angioedema attacks during the 
treatment period (Day 0 through Day 182). 
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3. Number of investigator-confirmed angioedema attacks during the presumed steady 
state period (Day 70 through Day 182). 
4. Subjects that are attack-free during the presumed steady state period (Day 70 through 
Day 182). 
5. Number of investigator-confirmed moderate or severe angioedema attacks during the 
presumed steady state period (Day 70 through Day 182).  
 
Detailed definition of these periods is given in Section 12.3.1. An angioedema attack will 
be counted for a specific efficacy evaluation period only if that angioedema attack started 
during that period. For example, if an angioedema attack starts before Day 70 and is 
ongoing after Day 70, it will not be counted for the efficacy period Day 70 through Day 
182. Moderate and severe angioedema attacks are defined in Section 12.4.5.  
The rank-ordered secondary endpoints based on count data (ie, number of angioedema 
attacks during a specified period) will be analyzed using the same method as described 
for the primary efficacy endpoint with adjustments made to the offset term and analysis 
set based on the defined analysis period (i.e., the SS-FAS population will be used for 
endpoints based on the presumed steady state period).  
The rank-ordered secondary endpoints based on binary endpoints (ie, subjects that are 
attack-free during a specified analysis period) will be compared between treatment 
groups using the FAS specific to the analysis period of interest.  
The number and percentage of subjects who are attack-free for the specified analysis 
period, as well as the difference between treatment groups and corresponding exact 95% 
Clopper-Pearson confidence interval (CI) will be summarized. A subject is considered as 
attack free during a time period if the subject has no investigator-confirmed angioedema 
attacks during that time period. For subjects who discontinue the study prior to 
completion of the analysis period of interest, subjects will be classified as attack-free or 
not based on the observed contribution to the analysis period.  
The rank-ordered binary endpoints will be tested by the following hypothesis:  
H0: planadelumab = pplacebo versus H1: planadelumab ≠pplacebo  
Where planadelumab refers to the proportion of subjects that are attack-free during the 
specified analysis period in the lanadelumab group and pplacebo refers to the proportion of 
subjects that are attack-free during the specified analysis period in the placebo group. The 
null hypothesis is that the proportion of attack-free subjects in the lanadelumab treatment 
group is equal to that in the placebo group, versus the alternative hypothesis that the 
proportions are not equal. A Cochran-Mantel-Haenszel (CMH) test, adjusting for baseline 
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stratification factor(s) (categorical), will be used to test the null hypothesis, with Type I 
error set at 5%. A Mantel-Haenszel estimate for the common risk difference and 
corresponding stratified Newcombe confidence limits will be presented.  If either the 
adjusted CMH test or common risk difference cannot be estimated because of an 
imbalance in the stratification factors, then the unadjusted CHM test or unadjusted risk 
difference and corresponding confidence limits will be presented. In this case, the 
potential bias in the unstratified analysis will be examined on an unblinded basis.  
To adjust for the potential of inflated overall Type I error rate, the rank ordered secondary 
endpoints will be tested in a fixed sequence using a general gatekeeping approach 
consistent with the logical restrictions of the rank ordering of the endpoints. Secondary 
endpoints will not be declared statistically significant unless the primary endpoint is 
found to be statistically significant. Lower ranked secondary endpoints will not be 
declared statistically significant unless the primary and all of the higher ranked secondary 
endpoints are found to be statistically significant. The multiple testing procedure is 
detailed in Section 6.4.   
6.2.1 
Sensitivity Analyses of Key Secondary Efficacy Endpoints 
The following sensitivity analyses will be performed on the key secondary endpoints to 
evaluate the robustness of the results. See Table 2 for details.  
1. The primary analysis of the endpoint will be repeated using the SAS population (only 
if the SAS population is different from the FAS population).  
2. The primary analysis of the endpoint will be repeated using all subject-reported 
angioedema attacks instead of limiting the analysis to those attacks that were 
investigator-confirmed.  
3.  The primary analysis of the endpoint will be repeated using an alternative approach 
for deriving attack-free status, where subjects who discontinue during a time period 
are considered as non-responders for that time period. 
Table 2: Sensitivity Analysis for Efficacy Endpoints 
Secondary Efficacy Endpoint 
Sensitivity Analysis Item 
1 
2 
 
3 
 
Rank 1: Subjects that are attack free during the treatment period 
x 
x 
x 
Rank 2: Number of moderate or severe angioedema attacks during the 
treatment period 
x 
x 
 
Rank 3: Number of angioedema attacks during the presumed steady state 
period 
x 
x 
 
Rank 4: Subjects that are attack free during the presumed steady state period 
x 
x 
x 
Rank 5: Number of moderate or severe angioedema attacks during the 
presumed steady state period 
x 
x 
 
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Note that for analysis of endpoints based on the presumed steady state period using the 
SAS population, only subjects who reach the visit of Day 70 will be included in the 
analysis and this number of subjects will be used as denominator for percentage 
calculation. 
Analyses for the key secondary endpoints will be repeated mFAS which excludes 
subjects that were randomized and received study drug but did not meet study entry 
criteria. 
 
6.2.2 
Supplementary Analyses of Key Secondary Efficacy Endpoints 
No supplementary analyses are planned for the key secondary efficacy endpoints.  
6.3 
Analyses of Other Secondary Efficacy Endpoints  
Additional secondary efficacy endpoints are as follows:  
• Maximum attack severity during presumed steady state period (Day 70 through 
Day 182) and treatment period (Day 0 through Day 182)  
• Time to first angioedema attack after Day 0 
• Time to first angioedema attack after Day 70 
• Achievement of at least a 50%, 70%, 90% and 100% reduction in the 
investigator-confirmed normalized number of attacks (NNA) per 4 weeks during 
each of the efficacy evaluation periods relative to the observation period NNA 
• Achievement of an efficacy evaluation period NNA <1.0 attacks per 4 weeks, 
<0.75 attacks per 4 weeks, <0.50 attacks per 4 weeks, and <0.25 attacks per 4 
weeks  during each of the efficacy evaluation periods 
Maximum attack severity during presumed steady state period and treatment period  
For each subject, the mean and maximum severity (based on BAARP) of all investigator-
confirmed angioedema attacks will be summarized for each efficacy evaluation period. 
See Section 12.4.6 for details on handling angioedema attack severity.  
The mean attack severity will be summarized for all subjects as well as only subjects with 
angioedema attacks. The number and percentage of subjects will be tabulated by 
maximum attack severity (no attacks, mild, moderate, and severe).   
Time to first angioedema attack after Day 0 
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The time to first angioedema attack (days) will be calculated from the date of Day 0 visit 
to the date of the first attack after Day 0 visit. Subjects who do not have an attack will be 
censored at the date of discontinuation (if prior to completion of the treatment period) or 
the date of the Day 182 visit. Time to the first angioedema attack after Day 0 will be 
summarized using Kaplan-Meier methods, stratified by baseline strata. A stratified log-
rank test comparing lanadelumab to placebo will be included.  
Time to first angioedema attack after Day 70 
The time to first angioedema attack (days) will be calculated from the date of Day 70 
visit to the date of the first attack after Day 70 visit. Subjects who do not have an attack 
will be censored at the date of discontinuation (if prior to completion of the treatment 
period) or the date of the Day 182 visit. Time to the first angioedema attack after Day 70 
will be summarized using Kaplan-Meier methods, stratified by baseline strata. A 
stratified log-rank test comparing lanadelumab to placebo will be included.  
Achievement of a pre-specified reduction in the investigator-confirmed normalized 
number of attacks (NNA) per 4 weeks during each of the efficacy evaluation periods 
relative to the observation period NNA 
The investigator-confirmed normalized number of attacks (NNA) per 4 weeks during 
observation period and each of the efficacy evaluation periods will be expressed as a 
monthly (4 weeks, i.e., 28 days) angioedema attack rate for each subject. In what follows, 
for conciseness, angioedema attack rate refers to NNA per 4 weeks.  
There will be four classes of responders based on pre-specified percentage reduction in 
the investigator-confirmed angioedema attack rate from the observation period attack 
rate: 50% or more reduction, 70% or more reduction, 90% or more reduction, and 100% 
reduction. For each subject, a treatment period angioedema attack rate and observation 
period angioedema attack rate will be calculated, as described in Section 12.4.7. The 
percentage reduction will be calculated as the observation period angioedema attack rate 
minus the treatment period angioedema attack rate divided by the observation period 
angioedema attack rate. Summary statistics will be presented for each of the five classes 
of responders by treatment. The five classes of responders are nested within each other 
and not mutually exclusive.  
Achievement of an efficacy evaluation period NNA <1.0 per 4 weeks during each of the 
efficacy evaluation periods 
There will be a class of responders based on achieving the pre-specified investigator-
confirmed NNA per 4 weeks of <1.0 for each of the efficacy evaluation periods. The 
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number and percentage of subjects achieving the predefined threshold will be 
summarized for each efficacy evaluation period.  
6.3.1 
Sensitivity Analyses of Other Secondary Efficacy Endpoints 
No sensitivity analyses are planned for other secondary efficacy endpoints.  
6.3.2 
Supplementary Analyses of Other Secondary Efficacy Endpoints 
No supplementary analyses are planned for other secondary efficacy endpoints.  
6.4 
Multiplicity Adjustment 
The global family-wise Type I error rate (FWER) for the statistical tests of the primary 
and rank ordered secondary efficacy endpoints (rank specified in Section 6.2) will be 
controlled at 0.05. To strongly control the global FWER at this level, a general 
gatekeeping approach will be utilized in which the statistical tests will be conducted in a 
sequential manner. Testing will continue in sequence until the first test that the null 
hypothesis cannot be rejected; statistical significance cannot be declared for that test or 
for any of the remaining tests. To further illustrate this approach, the test for the primary 
endpoint will be conducted first at the 5% significance level for the active treatment 
group compared with the placebo group and, if significant, the first secondary endpoint 
will be similarly tested at the 5% significance level. The testing sequence will continue in 
order through the remaining secondary endpoints for active treatment group to placebo 
comparison as long as the null hypothesis is rejected at the 5% significance level.  
6.5 
Analyses of Exploratory Endpoints 
Additional endpoints to be explored include those listed below. These endpoints are 
considered supportive and any statistical tests comparing treatments will be made without 
adjustment for multiplicity. The resulting p-values from these supportive analyses will be 
interpreted descriptively as summarizing the weight of evidence for a treatment effect. In 
the event of model non-convergence, descriptive results will be presented without p-
values. 
• Number of high-morbidity investigator-confirmed angioedema attacks during the 
treatment period (Day 0 through Day 182)  
• Number of investigator-confirmed angioedema attacks resulting in an emergency 
department visit and/or admission to hospital during the treatment period (Day 0 
through Day 182)  
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• Number of investigator-confirmed laryngeal angioedema attacks during the 
treatment period (Day 0 through Day 182)  
• Characteristics of investigator-confirmed angioedema attacks, including attack 
duration, severity, location, and medication use during the observation period, 
treatment period (Day 0 through Day 182), and steady state period (Day 70 
through Day 182) 
• Percentage of attack free days during the treatment period (Day 0 through Day 
182) and during the presumed steady state period (Day 70 through Day 182) 
• Achievement of investigator-confirmed angioedema attack-free interval of 1 
month or 3 months during the treatment period (Day 0 through Day 182)  
• Achievement of investigator-confirmed angioedema attack-free interval of 1 
month or 3 months during the presumed steady state period (Day 70 through Day 
182)   
Number of high-morbidity investigator-confirmed angioedema attacks during the 
treatment period 
A high-morbidity angioedema 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. If the 
length of hospitalization can’t be determined due to missing dates and times, then that 
hospitalization will be conservatively counted as being greater than 24 hours. The 
number of high-morbidity investigator-confirmed angioedema attacks during the 
treatment period (Day 0 through Day 182) will be analyzed using the same method as for 
the primary efficacy endpoint. Data summaries will parallel those described for the 
primary analysis of the primary efficacy endpoint.  
Number of investigator-confirmed angioedema attacks resulting in an emergency 
department visit or admission to the hospital during the treatment period 
For each angioedema attack, the site records if the attack resulted in a visit to the 
emergency department or admission to the hospital. The number of investigator-
confirmed angioedema attacks resulting in an emergency department visit or admission to 
the hospital during the treatment period (Day 0 through Day 182) will be analyzed using 
the same method as for the primary efficacy endpoint. Data summaries will parallel those 
described for the primary analysis of the primary efficacy endpoint.  
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Number of investigator-confirmed angioedema attacks resulting in an emergency 
department visit during the treatment period 
For each angioedema attack, the site records if the attack resulted in a visit to the 
emergency department. The number of investigator-confirmed angioedema attacks 
resulting in an emergency department visit during the treatment period (Day 0 through 
Day 182) will be analyzed using the same method as for the primary efficacy endpoint. 
Data summaries will parallel those described for the primary analysis of the primary 
efficacy endpoint.  
Number of investigator-confirmed angioedema attacks resulting in admission to the 
hospital during the treatment period 
For each angioedema attack, the site records if the attack resulted in hospitalization. The 
number of investigator-confirmed angioedema attacks resulting in admission to the 
hospital during the treatment period (Day 0 through Day 182) will be analyzed using the 
same method as for the primary efficacy endpoint. Data summaries will parallel those 
described for the primary analysis of the primary efficacy endpoint.  
Number of investigator-confirmed laryngeal angioedema attacks during the treatment 
period 
For each angioedema attack, the investigator records a primary location and up to 3 
secondary location(s). In this analysis, a laryngeal angioedema attack will be defined as 
an attack with either the primary or secondary location indicated as laryngeal.  
The number of investigator-confirmed laryngeal angioedema attacks during the treatment 
period (Day 0 through Day 182) will be analyzed using the same method as for the 
primary efficacy endpoint, with an addition of the history of laryngeal angioedema 
attacks (categorical) as a fixed effect in the model. Data summaries will parallel those 
described for the primary analysis of the primary efficacy endpoint.  
Characteristics of investigator-confirmed angioedema attacks, including attack duration, 
severity, location and medication use during the observation, treatment, and presumed 
steady state periods 
Attack characteristics at subject level and event level, as described below, will be 
summarized by treatment group for the observation period, the treatment period (Day 0 
through Day 182) and the presumed steady state period (Day 70 through Day 182).  
Subject level angioedema attack characteristics 
Angioedema Attack Duration 
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For each subject, the mean duration of all investigator-confirmed angioedema attacks will 
be calculated in hours and summarized. See Section 12.4 for details on handling 
angioedema attack data. 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).  
Angioedema Attack Severity 
For each subject, the mean and maximum severity of all investigator-confirmed 
angioedema attacks will be calculated using a numerical rating and summarized. See 
Section 12.4.6 for details. The number and percentage of subjects will be tabulated by 
maximum attack severity (no attacks, mild, moderate, and severe). 
Event level angioedema attack characteristics 
Angioedema Attack Location 
The number and percentage of subjects with attacks, as well as the number of events, 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 angioedema 
attack, as well as the number of events, will be tabulated by rescue medication type 
(ecallantide, icatibant, nano-filtered C1-INH, plasma-derived C1-INH, recombinant C1-
INH, fresh frozen plasma, standard of care, and other) as reported in the Angioedema 
Acute Attack CRF.  
Supportive Treatment Use 
The number and percentage of subjects with supportive treatment use for an angioedema 
attack, as well as the number of events, will be tabulated by supportive treatment by type 
(IV fluids, pain medication, oxygen, anti-emetic, and other) as reported in the 
Angioedema Acute Attack CRF.  
Percentage of angioedema attack free days during the treatment period 
The percentage of angioedema attack free days during the treatment period (Day 0 
through Day 182) will be calculated by counting the number of days in the treatment 
period without an angioedema attack and dividing by the number of days the subject was 
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in the treatment period. An attack-free day is defined as a calendar day with no 
investigator-confirmed angioedema attack.  
Descriptive statistics for the percentage of angioedema attack free days will be 
summarized by treatment group.  
Percentage of angioedema attack free days during the presumed steady state period 
The percentage of angioedema attack free days during the presumed steady state period 
(Day 70 through Day 182) will be calculated by counting the number of days in the 
presumed steady state period without an angioedema attack and dividing by the number 
of days the subject was in the treatment period. An attack-free day is defined as a 
calendar day with no investigator-confirmed angioedema attack.  
Descriptive statistics for the percentage of angioedema attack free days will be 
summarized by treatment group.  
Achievement of investigator-confirmed angioedema attack-free interval of 1 month or 3 
months during the treatment period 
A subject is considered as attack free during a time period if the subject has no 
investigator-confirmed angioedema attacks during that time period. For subjects who 
discontinue the study prior to completion of the analysis period of interest, subjects will 
be classified as attack-free or not based on the observed contribution to the analysis 
period.  
The number and percentage of subjects who achieve investigator-confirmed angioedema 
attack free intervals of 1 month (4 weeks; ‘Day 0 to one day before Day 28 visit’) or 3 
months (12 weeks; ‘Day 0 to one day before Day 84 visit’) during the treatment period 
will be tabulated by treatment group. Risk difference comparing lanadelumab to placebo, 
and corresponding exact 95% confidence interval (Santner, 1980) will be provided.  
Achievement of investigator-confirmed angioedema attack-free interval of 1 month, 3 
months, or until the Day 182 Visit during the presumed steady state period 
The number and percentage of subjects who achieve investigator-confirmed angioedema 
attack free intervals of 1 month (4 weeks; ‘Day 70 to one day before Day 98 visit’) or 3 
months (12 weeks; ‘Day 70 to one day before Day 154 visit’) during the presumed steady 
state period will be tabulated by treatment group. Risk difference comparing lanadelumab 
to placebo, and corresponding exact 95% confidence interval (Santner, 1980) will be 
provided.  
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6.6 
Subgroup Analyses 
Subgroup analyses are planned to be conducted for the primary efficacy endpoint. Any p-
values that are presented will be descriptive.  
The following subgroups will be used:  
• Age group (<18, 18 to <40, 40 to <65, ≥65 years) 
• Sex (Male, Female) 
• Race group (White, Other) 
• Weight group (<50, 50 to <75, 75 to <100, ≥100 kg)  
• BMI Group (<18.5, 18.5 to <25, 25 to <30, ≥30 kg/m2)  
• Observation period angioedema attack rate group (1 to <2, ≥2 attacks/4 weeks) 
• Subtype  
o with known mutations (FXII, PLG, ANGPT1, or KNG1 genes, or other 
predefined mutations associated with normal C1-INH angioedema) 
o with family history (a first-degree relative) and unknown mutations; and 
o with idiopathic non-histaminergic angioedema (INHA) 
• Geographical region (North America, Europe, and Other) 
• History of laryngeal angioedema attack (history laryngeal attack, no history of 
laryngeal attack) 
The subgroups will be analyzed using the same method as described for the primary 
efficacy endpoint. Data summaries will parallel those described for the primary analysis 
of the primary efficacy endpoint. For the subgroup analyses conducted for the primary 
efficacy endpoint, a forest plot depicting the rate ratio and corresponding 95% CI 
estimated from the Poisson generalized linear model will be provided for lanadelumab 
versus placebo within each subgroup.  
7. 
SAFETY ANALYSIS  
All safety analyses will be performed using the SAS population. Analyses will be 
summarized by treatment group.  
The definition of baseline is provided in Section 12.2.  
7.1 
Adverse Events (AE) 
AEs are reported on the Adverse Events (Drug Only) CRF and the Angioedema Acute 
Attack CRF and will be coded using MedDRA Version 22.1 or newer.  
Treatment-emergent AEs (TEAEs) 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 
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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. Partial date 
imputation for AE is described in Section 12.6.3.  
The analyses described in this section will be based on TEAEs only; plainly referred to as 
AEs in this section for brevity.  
Related AEs are AEs classified as related to study drug by the investigator. Missing 
relationship to study drug imputation is described in Section 12.6.5.  
Severe AEs are AEs classified as severe (grade 3) or life threatening (grade 4) by the 
investigator. Missing severity imputation is described in Section 12.6.4.  
In this study, the primary endpoint is based on an AE.  If lanadelumab is efficacious, it 
will result in a systematic difference in the incidence of AEs by treatment group which 
will complicate the interpretation of the safety.  Thus, the collection of tabulations 
described in this section (with the exception of the analyses of AEs of special interest 
(AESI) and injection site reaction (ISR)) will be produced for 2 mutually exclusive 
subgroups of AEs based on if the AE was reported as an angioedema attack or not, and 
defined as follows:  
• Non-Angioedema Attack Reported AEs will include the subset of AEs identified 
on the AE CRF page (events not reported as an angioedema attack).  Angioedema 
attack reported AEs are reported on a separate CRF page. 
• Angioedema Attack Reported AEs will include the subset of AEs identified on the 
Angioedema Acute Attack CRF page as a reported angioedema attack.  Note that 
this includes investigator-confirmed and non-confirmed angioedema attacks. 
For this analysis, AEs will be classified to one of three analysis periods:  
• Pretreatment Period AEs will include AEs starting at or after informed consent to 
those starting before the first exposure to study drug (AEs starting prior to 
treatment on Day 0).  
• Treatment Period AEs will include all AEs starting at or after the first exposure to 
study drug to those starting before or at the subject’s last visit date during the 
treatment period (AEs starting at or after treatment on Day 0 to the Day 182 visit). 
• Follow-up Period AEs will include all AEs starting at or after the subject’s last 
visit date of the treatment period (AEs starting after the Day 182 visit).  
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Detailed definition of these analysis periods is given in Section 12.3.1. For AEs with 
partial onset times, non-missing date parts will be used to determine if the AE falls within 
the period. If a determination cannot be made using the non-missing date parts as to if the 
AE falls within the period, the AE will be conservatively counted as a treatment-period 
AE.  
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 by treatment 
group. The number of deaths due to an AE, hospitalization due to an AE and study 
discontinuation due to an AE will be summarized by treatment group. This tabulation will 
be repeated for each of the analysis periods. For serious AEs and investigator-reported 
AESI during the treatment period, relative risks and risk differences, and their associated 
exact 95% CI (Santner, 1980) will be provided for the comparison between lanadelumab 
and placebo. If the relative risk cannot be calculated the risk difference will be provided.  
The number and percentage of subjects with an AE, as well as the total number of AEs, 
will be summarized for each treatment group 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 the treatment period and follow-up period 
AEs. This tabulation will be repeated for SAEs and severe AEs for pretreatment period. 
Tabulations will be presented sorted by SOC in alphabetical order and by PT within each 
SOC by descending frequency in the lanadelumab group and then the placebo group. For 
serious AEs during the treatment period and follow-up period, risk difference and 
corresponding exact 95% CI (Santner, 1980) will be provided for the comparison 
between lanadelumab and placebo by SOC and PT. If the relative risk cannot be 
calculated the risk difference will be provided.  
The number and percentage of subjects with an AE, as well as the total number of AEs, 
will be summarized for each treatment group by PT for treatment period AEs only. This 
tabulation will be repeated for related AEs and severe AEs, as well as for frequently 
occurring (≥5%) AEs for treatment period AEs. Tabulations will be presented sorted by 
PT by descending frequency in the lanadelumab group and then the placebo group.  
Subgroup analyses are planned to be conducted for non-angioedema attack treatment 
period AEs, related AEs, and severe AEs for the subgroups identified in Section 6.6. This 
will include an overall summary table for non-angioedema attack treatment period AEs, 
and summaries by SOC and PT for these subsets of AEs. 
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All AEs (TEAEs and non-TEAEs) will be provided in subject listings. In addition, 
subject listings of AEs causing discontinuation of study medication, AEs leading to 
death, and SAEs will be produced.  
7.1.1 
Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) for this study are hypersensitivity reactions. 
Investigators are required to document any potential AESI AEs on the AE CRF page, and 
to notify the sponsor within the timeline specified in the protocol. These AESI AEs are 
collectively referred to as investigator-reported AESI. In addition to investigator-reported 
AESI, the preferred terms from MedDRA 23.1 Standardized MedDRA Queries (SMQ) 
will be used to identify an SMQ-defined AESI. The SMQ ‘Hypersensitivity’ will be used 
to identify SMQ-defined AESI, and will include both narrow and broad search terms.  
Investigator-reported AESI and SMQ-defined AESI will be summarized separately, as 
shown below:  
• Summary of AESI: The number and percentage of subjects with any AESI AE, 
any related AESI AE, any severe AESI AE, any related severe AESI AE, any 
AESI SAE, and any related AESI SAE, as well as the total number of events for 
each category, will be summarized by treatment group. The number of deaths due 
to an AESI AE, hospitalization due to an AESI AE and study discontinuation due 
to an AESI AE will be summarized by treatment group for each analysis period. 
• AESI by SOC and PT: The number and percentage of subjects with an AESI, as 
well as the total number of AESIs, will be summarized for each treatment group 
by SOC and PT for each analysis period. Risk difference and corresponding exact 
95% CI (Santner, 1980) will be provided for the comparisons between 
lanadelumab and placebo. This tabulation will be repeated for related AESI for 
the treatment period and follow-up period AEs. Tabulations will be presented 
sorted by SOC in alphabetical order and by PT within each SOC by descending 
frequency in the lanadelumab group and then the placebo group. 
• Related AESI by SOC and PT: The number and percentage of subjects with a 
related AESI, as well as the total number of related AESIs, will be summarized 
for each treatment group by SOC and PT for the treatment period and follow-up 
period. Tabulations will be presented sorted by SOC in alphabetical order and by 
PT within each SOC by descending frequency in the lanadelumab group and then 
the placebo group. 
A listing of investigator-reported AESI will be provided.  
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7.1.2 
Injection Site Reaction AEs (ISR) 
Injection site reaction (ISR) AEs will be identified by adverse events with the preferred 
terms starting with ‘Injection site’, ‘Application site’, or ‘Administration site’, and will 
be analyzed for the treatment period only.  
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 by treatment group. 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 by treatment group.  
The number and percentage of subjects with an ISR AE, as well as the total number of 
ISR AEs, will be summarized for each treatment group by SOC and PT for the treatment 
period. The number and percentage of subjects with an ISR AE will be summarized for 
each treatment group by SOC, PT, and maximum severity for the treatment period.  
Tabulations will be presented sorted by SOC in alphabetical order and by PT within each 
SOC by descending frequency in the lanadelumab group and then the placebo group.  
The duration of ISR AEs overall and by PT will be summarized numerically (in hours, 
using summary statistics) and categorically (0 - 0.5 hour, >0.5 - 1 hour, >1- 12 hours, >12 
– 24 hours, ≤1 day - unclear, >1 – <5 days, 5- <14 days, and >14 days). The definition of 
the duration of ISR AEs is provided in Section 12.6.3.3. 
7.1.3 
AE Tabulations 
Table 3 provides a summary of the AE tabulations by analysis period as described in this 
section.  
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Table 3: Adverse Event Tabulations by Analysis Period 
 
Pretreatment 
Period 
Treatment 
Period 
Follow-up 
Period 
AE summary 
x 
x 
x 
AE by SOC and PT 
x 
x 
x 
AE by PT 
 
x 
 
Related AE by SOC and PT 
 
x 
x 
Related AE by PT 
 
x 
 
Severe AE by SOC and PT 
x 
x 
x 
Severe AE by PT 
 
x 
 
Related Severe AE by SOC and PT 
 
x 
x 
SAE by SOC and PT 
x 
x 
x 
Related SAE by SOC and PT  
 
x 
x 
Frequently Occurring AE 
 
x 
 
Summary of Investigator-reported AESI 
x 
x 
x 
Investigator-reported AESI by SOC and PT 
x 
x 
x 
Related Investigator-reported AESI by SOC and 
PT 
 
x 
x 
Summary of SMQ-defined AESI 
x 
xa 
x 
SMQ-defined AESI by SOC and PT 
x 
xa 
x 
Related SMQ-defined AESI by SOC and PT 
 
xa 
x 
Summary of ISR AEs 
 
x 
 
ISR AEs by SOC and PT 
 
x 
 
ISR AEs by SOC, PT, and Severity 
 
x 
 
Number and duration of ISR AEs 
 
x 
 
aFor SMQ-defined hypersensitivity AESI during the treatment period, two sets of summary tables will be provided for the AEs 
including or excluding injection site reactions  
7.2 
Clinical Laboratory Data 
Laboratory evaluations that are done at study site visits will be collected and processed 
via a central laboratory and presented in conventional units.  
Clinical laboratory parameters to be evaluated include the following: 
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Hematology 
Hemoglobin, hematocrit, red blood cells (RBC), white blood cells 
(WBC) count total and differential - neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), absolute platelet count. 
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. 
Coagulation 
Prothrombin time, activated partial thromboplastin time (aPTT), 
international normalized ratio (INR) 
Urinalysis 
Bilirubin, glucose, ketones, blood, nitrite, potential hydrogen (pH), 
protein, specific gravity, microscopy (if indicated by macroscopic 
findings). 
Virology 
Hepatitis B Surface Antigen (HbsAg); Hepatitis C Virus (HCV); 
Human Immunodeficiency Virus (HIV) 
Hematology, Chemistry, Coagulation, and Urinalysis results will be summarized as 
described below. Virology will be provided in SDTM datasets only. 
Continuous laboratory test results (hematology, chemistry, coagulation, and urine pH) 
will be summarized as described below.  
Actual values and change from baseline in clinical laboratory tests will be summarized 
for each treatment group by study visit.  Additionally, all post-baseline scheduled visits, 
unscheduled visits, and all post-baseline visit actual values and change from baseline will 
be summarized for each treatment group. 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. See Section 12.6.6 for details on handling 
clinical significance attribution for lab values.  The number of subjects with a non-
missing result, and the number and percentage of subjects with a clinically significant 
result less than the lower limit of normal (LLN), non-clinically significant result less than 
the LLN, within the normal range, non-clinically significant result more than the upper 
limit of normal (ULN), and clinically significant result more than the ULN will be 
summarized for each treatment group 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. Post-baseline analysis is summarized on non-missing post-
baseline most severe results per subject and per parameter. 
 
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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 
(e.g., “<X”), a coded value will be used in the analysis instead as specified in Section 
12.6.7. However, the actual values as reported in the database will be presented in data 
listings.  
Categorical laboratory test results (urinalysis excluding pH) will be summarized for each 
treatment group 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.  
All laboratory test results will be presented in subject listings. 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.  
 
Among chemistry parameters, additional analyses in Table 3 will be conducted on liver 
function tests for the Full Analysis Set using the highest pre-treatment and highest overall 
treatment period and follow-up period measurements. The number and percentage of 
subjects with highest results falling into the categories of normal (<=1 x ULN), >1 – <=3 
x ULN, >3 – <=5 x ULN, and greater than >5 x ULN on the liver function tests for ALT, 
AST will be summarized for all pre-treatment measurements and overall treatment period 
and follow-up period measurements. Total bilirubin (BILI) will be summarized by the 
number and percentage of subjects with highest results falling into the categories of <=2 
x ULN and >2 x ULN for all pre-treatment measurements and overall treatment period 
and follow-up period measurements. Additionally, for the Full Analysis Set, a shift table 
summarizing the shift in categories from highest pre-treatment measurements to the 
highest overall treatment period and follow-up period measurements will be created for 
the liver function tests including ALT, AST and BILI.  
Table 3. Lab Parameter Criteria Categories 
Parameter 
Criteria Categories 
Liver Function Tests 
Alanine transaminase (U/L) 
Normal (<=1 x 
ULN) 
>1 – <=3 x ULN 
>3 – <=5 x 
ULN 
>5 x ULN 
Aspartate transaminase 
(U/L) 
Normal (<=1 x 
ULN) 
>1 – <=3 x ULN 
>3 – <=5 x 
ULN 
>5 x ULN 
Bilirubin (umol/L) 
- 
<=2.0 x ULN 
>2 x ULN 
- 
 
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7.3 
Vital Signs 
The following vital signs will be measured:   
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• HR (beats per minute) 
• Body temperature (C) 
• RR (breaths per minute) 
Actual values and changes from baseline in vital signs will be summarized for each 
treatment group 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 last non-missing result 
will be selected for analysis.  
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 for each treatment group 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.  
All vital sign data will be presented in subject listings. 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.  
7.4 
Electrocardiogram (ECG) 
The following ECG variables will be measured: 
• HR (beats per minute) 
• RR duration (millisecond [msec]) 
• PR duration (msec) 
• QRS duration (msec) 
• QT duration (msec) 
Actual values and changes from baseline in ECG variables will be summarized for each 
treatment group by study visit. If more than one ECG result is reported per study visit and 
study time point per parameter, the last non-missing result will be selected for analysis. 
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ECG overall assessments will be classified according to clinical significance of ECG 
findings and abnormality as determined by the investigator. The number of subjects with 
a non-missing result, and the number and percentage of subjects with a normal overall 
assessment, subjects with an abnormal overall assessment and all ECG findings not 
clinically significant, and subjects with an abnormal overall assessment and at least one 
clinically significant ECG finding will be summarized for each treatment group by study 
visit. If more than one ECG result is reported per study visit per parameter, the result 
yielding the most severe classification will be selected for analysis.  
All ECG data will be presented in subject listings. Subjects with clinically significant 
abnormal ECG findings will be listed. This listing will include all ECG findings that were 
abnormal and determined to be clinically significant by the investigator for a subject 
across study time points to identify any trends.  
7.5 
Other Safety Data 
7.5.1 
Biomarker Test 
C1 esterase inhibitor (C1-INH), complement component 4 (C4), and complement 
component 1q (C1q) assays will be obtained at screening for eligibility assessment.  
A descriptive summary analysis (n, mean, standard deviation [SD], minimum, median, 
and maximum) will be performed for these results. Results will be listed for all subjects 
which will include the corresponding reference ranges.  
7.5.2 
Pregnancy Test 
Pregnancy test results will be listed by study visit.  
7.5.3 
Physical Examination  
Adverse events emerging from any physical examination will be recorded on eCRFs and 
reported with adverse events. Physical examination will be listed by study visit.  
8. 
PHARMACOKINETIC ANALYSIS  
All summaries and analyses of the pharmacokinetic data will be based on the PK Set 
defined in Section 4.6.  
8.1 
Drug Concentration 
The plasma concentrations of lanadelumab will be summarized using descriptive 
statistics (number of subjects, arithmetic mean, SD, coefficient of variation [CV%], 
median, minimum, maximum, geometric mean, and CV% of geometric mean) for each 
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treatment group by the protocol scheduled sampling visit, and provided in subject data 
listings.  
8.2 
Handling Below Limit of Quantitation (BLQ) Values 
Plasma concentrations below the lower limit of quantitation (LLOQ) will be set to zero in 
the calculation of summary statistics; they will not be imputed in the subject data listings.  
8.3 
Statistical Analysis of Pharmacokinetic Data  
No formal statistical hypothesis will be tested.  
9. 
PHARMACODYNAMIC ANALYSIS 
All summaries and analyses of the pharmacodynamic data will be based on the PD Set 
defined in Section 4.7.  
9.1 
Pharmacodynamic Data 
The plasma kallikrein activity will be measured by cHMWK and pKal levels. Results will 
be provided in subject data listings and summarized by treatment group using descriptive 
statistics (number of subjects, arithmetic mean, SD, CV%, median, minimum, maximum,, 
geometric mean, and CV% of geometric mean) for each sampling visit.  
  
10. 
OTHER ANALYSES 
Health-related quality of life analyses and immunogenicity analyses are planned for this 
study.  
10.1 
Health-related Quality of Life Analyses 
Health-related quality of life will be assessed using the angioedema quality of life (AE-
QoL) questionnaire (Weller et al., 2012), at the study visits specified in  Appendix 1 
Table 5 and Table 6  for the SAS population.  
The AE-QoL consists of 17 disease-specific quality-of-life items, each of the 17 items 
has a five-point response scale ranging from 0 (Never) to 4 (Very Often).  
The responses to the AE-QoL for each item will be tabulated for each treatment group by 
study visit. The AE-QoL questionnaire responses will be listed for each subject by study 
visit.  
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10.2 Immunogenicity Analyses 
Immunogenicity will be measured based on the presence or absence of neutralizing or 
non-neutralizing ADA in plasma.  
The ADA result (positive/negative/not evaluable) and neutralizing ADA result 
(reactive/non-reactive/not evaluable) will be summarized using descriptive statistics for 
each treatment group by study visit.  
The ADA result, ADA titer result (quantitative) and neutralizing ADA result will be 
listed for each subject by study visit.  
11. 
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE  
No interim analysis or adaptive design is planned for this study. However, an 
independent DMC will be established to provide ongoing, independent review and 
assessment of the safety data, and to safeguard the interests and safety of the participating 
subjects in the study. Analysis of the data for DMC review will be conducted according 
to the DMC Charter. Because no formal hypothesis testing for safety assessments is 
planned, multiplicity concerns regarding repeated analyses are not an issue.  
12. 
DATA HANDLING CONVENTIONS  
12.1 
General Data Reporting Conventions  
Outputs will be presented according to Shire TFLs Library V9.0.  
Unless otherwise specified, summary tabulations will be presented by treatment group 
(lanadelumab 300 mg every 2 weeks and Placebo).  
For categorical variables, the number and percentage of subjects within each category 
(with a category for missing data as needed) of the parameter will be presented. For 
continuous variables, the number of subjects, mean, median, SD, minimum, and 
maximum values will be presented. Where applicable, estimates from statistical model of 
least squares means, treatment differences, standard errors, p-values, and 95% confidence 
intervals (CI) for least squares mean treatment differences will be provided. Time-to-
event data will be summarized using Kaplan-Meier (KM) estimates of the 25th, 50th 
(median), and 75th percentiles with associated two-sided 95% CI, as well as percentage 
of censored observations. Plots of the KM curves and supporting data listings detailing 
each subject’s contribution to the analysis will be provided.  
For the summary statistics of all numerical variables, unless otherwise specified, 
minimum and maximum will be displayed to the same level of precision as reported. 
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Mean and median will be displayed to one level of precision greater than the data 
collected. Standard deviation will be displayed to two levels of precision greater than the 
data collected. P-values will be rounded to 3 decimal places, p-values <0.0005 will be 
displayed as <0.001.  
Percentages shall be reported to 1 decimal place, except when the percentage equals 
exactly 100 where it shall be displayed as an integer (100). For zero, only count and no 
percentage will be displayed. The denominator for all percentages will be the number of 
subjects within the population of interest, unless otherwise specified.  
BMI will be rounded to 1 decimal place and normalized number of angioedema attacks 
will be rounded to 2 decimal places for reporting.  
All data listings will be sorted by treatment group, site, subject number, visit (when 
available), assessment/event start date (when available), assessment/event end date (when 
available) and alphabetically by preferred term/name (when available), and will include 
the subject’s age, sex, and race.   
12.2 
Definition of Baseline and EOS/ET 
For safety analyses, baseline is defined as the last non-missing value prior to first 
exposure to study drug (based on date or date/time).   
For efficacy analyses, refer to observation period attack rate defined in Section 12.4.7.1. 
For safety analyses, EOS/ET will be defined as the last post-baseline assessment for 
generating descriptive statistics. 
12.3 
Definition of Visit Windows  
Although there is a visit window of ± 4 days around the expected visit date, nominal 
visits will be used for the per-visit analyses. Therefore, no windowing of visits by study 
day will be done for data obtained at the scheduled visits.  
For the analysis, 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 
Note that Day 0 will be equivalent to study day 1. 
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12.3.1 Analysis Periods 
The pretreatment period is defined as the interval of time:  
[date/time of informed consent, date/time prior of first exposure to study drug] 
The observation period is defined as the interval of time:   
o If the observation period end date < date of first dose of IP: 
[start date of observation period at 0:00, end date of observation period at 23:59] 
o If the observation period end date = date of first dose of IP: 
[start date of observation period at 0:00, date/time of first dose of IP – 1 minute]  
The treatment period of Day 0 through Day 182 is defined as the interval of time:     
[date/time of first exposure to study drug, date of Day 182 visit at 23:59] 
The presumed steady state period of Day 70 through Day 182 is defined as the interval of 
time:     
[date/time of first dose of IP + 70 days, date of Day 182 visit at 23:59] 
The follow-up period is defined as the interval of time: 
[date of Day 182 visit + 1 day at 0:00, date of last study contact at 23:59] 
12.4 
Derived Efficacy Endpoints  
The following rules apply to the handling of angioedema attack data for efficacy analyses 
only. Angioedema attacks starting prior to the observation period are not processed by 
these rules.  
12.4.1 Unique Angioedema 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.   
Specifically, there must be at least 24 hours between the stop 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 stop 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 
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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. If 
there are two attacks within 24 hours, but the start date of the later attack occurs after the 
end of the efficacy evaluation period, the attacks will be combined and counted as one 
attack that occurs within the efficacy evaluation period of the start time. 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.  
12.4.2 Angioedema Attack Duration  
The duration of an angioedema attack is calculated (in hours) as stop date/time – start 
date/time.  
12.4.3 Investigator-Confirmed Angioedema Attacks 
Investigator-confirmed angioedema attacks are those that the PI confirmed as meeting the 
BAARP criteria (as indicated on the Angioedema Acute Attack CRF) for an angioedema 
attack.  
12.4.4 Investigator-Confirmed Angioedema Attacks Requiring Acute Therapy 
Investigator-confirmed angioedema attacks requiring acute therapy are those attacks 
where it was indicated on the CRF that the subject received acute angioedema therapy 
treatment for the attack.  
12.4.5 Moderate and Severe Investigator-Confirmed Angioedema Attacks 
Moderate and severe investigator-confirmed angioedema attacks are those attacks that 
were classified as of moderate or severe according to the BAARP defined severity and 
reported as such on the Angioedema Acute Attack CRF.  
12.4.6 Angioedema 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 BAARP:  
• Mild: Transient or mild discomfort  
• Moderate: Mild to moderate limitation in activity - some assistance may be needed 
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• 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: 0=No attack, 1=Mild, 2=Moderate, and 3=Severe. Higher 
values will indicate more severe attacks, while lower values will indicate less severe 
attacks. 
12.4.7 Angioedema Attack Rate 
12.4.7.1 
Observation Period Angioedema Attack Rate 
The observation period angioedema attack rate will be presented as the normalized 
number of attacks per month (4 weeks) and calculated for each subject as number of 
angioedema attacks occurring during the observation period divided by the number of 
days the subject contributed to the observation period multiplied by 28 days.  
 
12.4.7.2 
Treatment Period Angioedema Attack Rate 
The treatment period angioedema attack rate will be presented as the normalized number 
of attacks per month and calculated for each subject as the number of angioedema attacks 
occurring during the treatment period divided by number of days the subject contributed 
to the treatment period multiplied by 28 days. No assessment of treatment compliance 
will be considered for this calculation. 
12.4.7.3 
Presumed Steady State Period Angioedema Attack Rate 
The presumed steady state period angioedema attack rate will be presented as the 
normalized number of attacks per month and calculated for each subject as the number of 
angioedema attacks occurring during the presumed steady state period divided by number 
of days the subject contributed to the presumed steady state period multiplied by 28 days. 
If the subject did not contribute to the presumed steady state period this rate will be 
missing. No assessment of treatment compliance will be considered for this calculation.  
12.4.8 
Time to First Angioedema Attack  
12.4.8.1 
Time to First Angioedema Attack After Day 0 
The time to first angioedema attack (days) after Day 0 will be calculated as the earliest of 
the date of the angioedema attack after Day 0, date of study discontinuation or 
completion, or date of Day 182 visit minus the date of Day 0 visit plus 1.   
Subjects with attacks occurring will be events. Subjects who discontinue/complete the 
study prior to having an angioedema attack will be censored.  
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12.4.8.2 
Time to First Angioedema Attack After Day 70 
The time to first angioedema attack (days) after Day 70 will be calculated as the earliest 
of the date of the angioedema attack after Day 70, date of study discontinuation or 
completion, or date of Day 182 visit minus the date of Day 70 visit plus 1.   
Subjects with attacks occurring will be events. Subjects who discontinue/complete the 
study prior to having an angioedema attack will be censored.  
12.5 
Repeated or Unscheduled Assessments of Safety Parameters  
Unscheduled measurements will not be included in by-visit summaries, however if a 
subject has repeated assessments before the start of IP, then the results from the final 
assessment made prior to the start of IP will be used as baseline. If EOS/ET assessments 
are repeated or unscheduled, the last post-baseline assessment will be used as the 
EOS/ET assessment for generating descriptive statistics. However, all assessments will 
be presented in the data listings.  
12.6 
Handling of Missing, Unused, and Spurious Data  
All subjects in the analysis sets defined in Section 4 will be included in the associated 
analyses.  
No imputation for missing data (e.g., last observation carried forward) will be applied 
except for the missing date/time for angioedema attacks, the partial dates for AEs and 
prior/concomitant medications, the missing severity for AEs and the missing relationship 
to IP for AEs. Imputation of missing date/time for angioedema attack data as described in 
Section 12.6.1 apply to efficacy analyses only. Angioedema attacks starting prior to the 
observation period are not processed by these rules. For safety analyses, angioedema 
attacks will be analyzed as reported, and missing date information will be handled as 
described for adverse events in Section 12.6.3. 
12.6.1 Missing Start or End Date and Time for Angioedema Attacks 
The following rules apply to the handling of angioedema attack data for efficacy analyses 
only.  
In general, missing start time will be imputed as described in Section 12.6.3. 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 angioedema 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 
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using the end time of the previous angioedema attack to ensure there are 24 hours in 
between the two attacks.  
• For angioedema 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 (see Section 12.4.1 for details on 
combining angioedema attacks)  
• For angioedema 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 angioedema attack to ensure there are 24 hours in between 
the two attacks.  
• For angioedema 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 (see Section 12.4.1 for details on 
combining angioedema attacks)  
For angioedema attacks with a non-missing start date and time and a missing stop date 
and time:  
• If the event is not indicated as ongoing, the stop 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 stop date and time will be imputed as the 
earliest of the following two date and time: 
➢ Start date and time + 48 hours or study completion date and the stop time 
of 23:59, whichever is later. 
➢ 24 hours before the start date and time of the next attack. 
12.6.2 Missing Date/Time 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/time will be used to determine 
if the medication/therapy/procedure is concomitant or prior. If a determination cannot be 
made using the non-missing date parts as to when the medication/therapy/procedure 
occurred relative to study drug administration, then the medication/therapy/procedure 
will be classified as concomitant.  
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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 IP, then the AE will be classified as treatment-emergent. 
 
To facilitate categorization of AEs as treatment emergent, imputation of start date/time 
will be used. Stop date/time will not be imputed. The handling of missing dates for ISRs 
is described in Section 12.6.3.3. 
12.6.3.1 Incomplete Start Date/Time  
Follow the same rules as in Section 12.6.2.1. 
12.6.3.2 Incomplete Stop Date/Time  
Not applicable.  
12.6.3.3 Duration of Injection Site Reaction AEs  
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. 
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 IP, 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 IP, then a severity of “Life threatening (grade 4)” will be 
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assigned.  The imputed values for severity assessment will be used for incidence 
summaries, while the actual values will be used in data listings. 
This rule applies also to BAARP severity for angioedema attacks for which the worst 
severity is “Severe”. 
12.6.5 Missing Relationship to IP for Adverse Events  
If the relationship to IP is missing for an AE starting on or after the date of the first dose 
of IP, a causality of “Related” will be assigned.  The imputed values for relationship to 
double-blind IP will be used for incidence summaries, while the actual values will be 
presented in data listings. 
12.6.6 Clinical Significance Attributions for Laboratory Results 
Lab results will be classified as Normal, CS Low, NCS Low, NCS High, or 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. 
12.6.7 Character Values of Clinical Laboratory Variables 
The non-standard laboratory results will be converted to numeric values using the rules 
shown in Table 4. 
 
 
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Table 4. Convention for Converting Non-Standard Laboratory Results 
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 
 *Note this logic should be applied to all other possible values recorded in the database. 
Gonzalez, Justo L. The Story of Christianity.: (The Early Church to the Reformation). Vol. 1. 
The Story of Christianity. HarperOne, 2014. 
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 pKal was removed as an example of an exploratory endpoint and only included as a 
secondary endpoint. 
15. 
REFERENCES 
 
Rubin, D. B. (1976). Inference and Missing Data. Biometrika; 63: 581–592. 
 
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John 
Wiley & Sons. 
 
Santner, T. S. (1980). Small-sample confidence intervals for p1 − p2 and p1/p2 in 2 × 2 
contingency tables. J. Amer. Statist. Assoc; 75: 386–394. 
 
Weller, K., Groffik, A., Magerl, M.,Tohme, N., Martus, P., Krause, K., Metz, M., 
Staubach, P. and Maurer, M. 2012. Development and construct validation of the 
angioedema quality of life questionnaire. Allergy; 67: 1289-98. 
 
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16. 
APPENDICES  
16.1 
Appendix 1 – Schedule of Activities 
Table 5: Schedule of Activities – Screening and Observation Period 
 
  
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Table 6: Schedule of Activities – Treatment Period and Follow-up Period 
 
 
 
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16.2 
Appendix 2 – Details of Tipping Point Analysis 
Figure 2 illustrates the missing data pattern generated from subjects who discontinue 
early from the treatment period of the SHP643-303 study.  Subject i receives first dose of 
the study drug at Day 0 and discontinues the study at Day ti prior to the end of the 
treatment period at Day 182.  The pre-withdrawal period for Subject i is defined as Day 0 
through Day ti and the post-withdrawal period is defined as Day ti + 1 through Day 182.  
In the pre-withdrawal period, we know both the length of the period (ni1) and the number 
of investigator-confirmed angioedema attacks during the period (yi1), and can calculate 
the observed attack rate (yi1/ni1) for the period.  In the post-withdrawal period, we know 
only the length of the period (ni2), however, both the number of investigator-confirmed 
angioedema attacks during the period (yi2) and the unobserved attack rate (yi2/ni2) for the 
period are unknown. 
Figure 2 Missing Data Pattern for Subjects who Discontinue Early from the 
Treatment Period of Study SHP643-303  
 
   
To assess the impact of the unobserved portion of the treatment period generated by 
subjects who discontinue the study prior to completing the treatment period on the results 
of our primary analysis, a tipping point analysis will be conducted.  In this analysis, a 
range of progressively more conservative assumptions about the number of events 
occurring in the post-withdrawal period will be explored in order to find the assumption 
which will reverse the conclusion (i.e., yield a non-significant p-value) of the primary 
analysis.  The assumption that will reverse the conclusion is referred to as the tipping 
point.  Once the tipping point is identified, the clinical plausibility of the assumption can 
be assessed.    
The tipping point analysis will employ the same model as specified for the primary 
analysis including progressively conservative assumptions about the unobserved attack 
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rate during the post-withdrawal period.  This is achieved by assuming that subjects in the 
active treatment arm who discontinue the study prior to completing the treatment period 
would have, on average, their unobserved attack rate worse by some amount (δ) 
compared with the observed attack rates of subjects that completed the study.  Subjects 
who discontinue the study prior to completing the treatment period from the placebo arm 
would have the same unobserved attack rate as those who completed the study. In 
contrast, the model used for the primary analysis assumes that events occur at a constant 
rate within an individual, and uses only the number of events in the observed portion of 
the treatment period with an offset parameter to account for the length of time in which 
those events were observed to derive the event rate for that individual (i.e., the observed 
attack rate).    
The tipping point analysis will be conducted as follows: 
Step 1: Multiple Imputation (MI)  
MI will be used to impute 1000 samples of the unobserved attack rate (yi2/ni2) for each 
subject who discontinued the study prior to completing the treatment period conditional 
on the observed data.  Multiple imputation is used to incorporate variance that accounts 
for the uncertainty associated with the imputed values (Rubin, 1976) (Rubin, 1987).  The 
imputed unobserved attack rate will be used to generate 1000 imputed values of the total 
number of attacks over the entire treatment period for each subject who discontinued the 
study prior to completing the treatment period.  
Steps 1a – 1c detail the multiple imputation approach to generate complete data for 
subjects who discontinued the study prior to completing the treatment period: 
Step 1a: 1000 independent samples are drawn from the posterior distribution of model 
parameters fit using a Bayesian analysis of the model defined for the primary 
analysis.  The sampled set of values of the model parameters are then used to generate 
a set of values for the expected unobserved attack rate (yi2/ni2) for each subject who 
discontinued the study prior to completing the treatment period using each subject’s 
covariate values.  This will result in 1000 imputed values for the unobserved attack 
rate for each discontinued subject. 
Step 1b: The expected unobserved attack rate (yi2/ni2) for each subject who 
discontinued the study prior to completing the treatment period is then multiplied by 
the length of the post-withdrawal period (ni2) for that subject to get the expected 
number of attacks for the post-withdrawal period (yi2).   
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Step 1c: The expected number of attacks for the post-withdrawal period (yi2) is added 
to the observed number of attacks in the pre-withdrawal period (yi1) to get the total 
number of attacks over the entire treatment period (yi1 + yi2) for subjects who 
discontinued the study prior to completing the treatment period.  
Step 2:  Analyze the MI Datasets with Primary Analysis Model 
The primary regression model will be run using each of the 1000 multiply imputed 
complete data sets.  The primary regression model is the Poisson regression generalized 
linear model with covariates for observation period attack rate, treatment group, and an 
offset variable for the log number of days observed.   
Step 3:  Combine Estimates using Rubin’s Rules 
From each of 1000 runs of the primary analysis model, the estimates will be combined 
using Rubin’s rules (Rubin, 1987) to get one estimate for each of the rate ratios 
comparing the active treatment groups to placebo and corresponding 95% confidence 
intervals and p-values.  These values will be summarized in both a tabular and graphical 
form. 
Step 4: Pattern Imputation with Delta Adjustment 
Steps 1 through 3 will be repeated with a slight modification at Step 1b to explore the 
impact of progressively worse assumptions (defined by δ) on the unobserved attack rate 
for subjects who discontinue early from the active treatment arm.  In this study, δ 
represents a rate ratio comparing the rate of investigator-confirmed angioedema attacks in 
the active treatment group to the rate of investigator-confirmed angioedema attacks in the 
placebo group. 
Modified Step 1b:  For subjects that discontinue the study prior to completing the 
treatment period from the active treatment arm, the expected unobserved attack rate 
(yi2/ni2) for each discontinued subject is first multiplied by a specific rate ratio δ, then 
multiplied by the length of post-withdrawal period (ni2) for that subject to get the 
expected number of attacks for the post-withdrawal period (yi2).  For subjects that 
discontinue the study prior to completing the treatment period from the placebo arm, 
Step 1b is followed without modification. 
Steps 1 through 4 are repeated for values of δ that represent progressively worse 
assumptions on the unobserved attack rate for subjects who discontinue the study prior to 
completing the treatment period from the active treatment arm until the tipping point is 
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identified (value of δ that yields a non-significant p-value). As the value of δ increases, 
the overall attack rate imputed for subjects in the active treatment arm increases.  Values 
of δ > 1 will be determined post-hoc in order to define reasonable increments for which 
to increase δ given the magnitude of treatment effect and the pattern of missing data.   
Note that the imputed results generated following Steps 1 through 3 without modification 
represent the case when δ=1, corresponding to missing at random (MAR) imputation. 
The estimates generated from the case when δ=1, should be very similar if not exactly the 
same as the estimates generated from the primary analysis model.  
If the value of δ which causes the study results to be reversed is plausible, then the 
missing data assumptions used are questionable.  However, if the value of δ is not 
plausible, then the missing data assumptions are reasonable.  
In the SHP643-303 study, the protocol specifies that there must be 24 hours in between 
each investigator-confirmed angioedema attack.  Therefore, the total number of attacks 
during the treatment period is restricted to about 1 attack per day.  If δ allows for more 
attacks than 1 per day, then the value of δ is not plausible under the study specifications 
and the missing data assumptions will be declared reasonable.  
16.3 
Appendix 3 – Sample SAS Code 
16.3.1 
GLM Model Sample SAS Code 
Sample code for the primary efficacy analysis of the primary endpoint. 
PROC GENMOD DATA=eff_data; 
CLASS trtgrp subtype; 
MODEL no_attks = trtgrp bl_rate subtype / DIST=poisson LINK=log 
OFFSET=logdays PSCALE; 
LSMEANS trt / DIFF CL EXP ILINK; 
ESTIMATE ‘300mg every 2 wk vs pbo’ trtgrp 1  -1 / EXP; 
RUN; 
Where: 
eff_data = efficacy analysis dataset 
trtgrp = treatment group (categorical) 
no_attks = number of angioedema attacks during the analysis period 
bl_rate = normalized pretreatment angioedema attack rate (continuous) 
subtype = genetic subtype of subject 
logdays = logarithm of time in days each subject was observed during the analysis 
period 
 
 
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For the sensitivity analysis using a generalized linear model assuming a negative 
binomial distribution, replace DIST=poisson with DIST=negbin. 
 
16.3.2 
Tipping Point Analysis Sample SAS Code 
Step 1: Use multiple imputation to impute the unobserved rate of attacks by completing 
the following process: 
1a. Sample code that draws 1000 independent samples from the posterior distribution of 
model parameters which are fit using a Bayesian analysis. 
proc genmod data = prim_eff_all order = data; 
   class trtpn; *treatment group; 
   model NUM_ATTKS = trtpn runbase /DIST= poisson LINK = log OFFSET 
= LNUMDAYS ;  
   bayes outpost=bayes_prim thin=1 nmc=1000 nbi=200; 
 run; 
Sample code for the sampled set of values being used to generate values for the 
unobserved attack rate for subjects who discontinued the study prior to completing the 
treatment period.  The values are generated using the model parameter estimates from 
Step 1a and each subject’s covariate values.  There should be 1000 imputed values for 
each discontinued subject.    
The variable miss_treat is an indicator for not completing the treatment period and 
attk_rate is the unobserved attack rate for the post-withdrawal period. 
%macro mi_data; 
%do i = 1 %to 1000; 
*estimate lambda for poisson distribution; 
data prim_eff_all&i; 
   set prim_eff_all; 
    
   *calculate the rate for each sample of coefficients from the 
model in Step 1a using each subject’s covariate values; 
   if TRTPN = 1 then lambda = exp(&&INTERCEPT&i + &&RUNBASE&i + 
&&TRTPN1&i); 
   if TRTPN = 2 then lambda = exp(&&INTERCEPT&i + &&RUNBASE&i + 
&&TRTPN2&i); 
    
*calculate the attack rate; 
 if miss_treat = 1 then attk_rate = RAND('POISSON', lambda); 
run; 
%end; 
%mend mi_data; 
1b. The expected unobserved attack rate (from step 1b) for each subject who discontinued 
early is then multiplied by the length of the post-withdrawal period for that subject to get 
the expected number of attacks for the post-withdrawal period. 
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1c. The expected number of attacks for the post-withdrawal period is added to the 
observed number of attacks in the pre-withdrawal period to get the total number of 
attacks over the entire treatment period. 
Step 2:  The sample code shows the for primary regression model being run using each of 
the 1000 multiply imputed complete data sets.  The imputation variable is the indicator 
for the which imputation dataset is being analyzed and prim_ efficacy is the dataset that 
includes the 1000 datasets that have been imputed using step 1. 
proc genmod data = prim_efficacy order = data; 
   by imputation; 
   class trtpn; *treatment group; 
   model num_attks_final = trtpn runbase /DIST= poisson LINK = log    
PSCALE; *model;  
  lsmeans trtpn/ diff cl exp ilink; 
run; 
Step 3: Combine the results from the multiply imputed datasets using Rubin’s rules (then 
exponentiate the estimate and the 95% confidence interval for the estimate of the rate 
ratios).  Below is the code used to combine the results across imputations (note: the 
estimates and the 95% CI of the estimates need to be exponentiated). 
proc mianalyze data = Diffs; 
   by trtpn; 
   where _trtpn = 1; 
   modeleffects estimate; 
   stderr stderr; 
run; 
16.3.3 
Sample Code to Derive Relative Risk and Risk Difference 
proc freq data=adae; 
   tables trt*SAE / riskdiff relrisk; 
   exact relrisk riskdiff; 
run; 
16.3.4 
Sample SAS Code for Time to Event Analysis 
The analysis of time to first angioedema attack after Day 0 (see Section 6.3) is based on 
the KM method. First angioedema attack is the event of interest. The following SAS code 
is proposed for analyses of time to first angioedema attack. 
Consider the subject level dataset ANEDATA which contains the variables ANETIME 
and STATUS. ANETIME is the time from first IP administration to the first investigator-
confirmed angioedema attack or censored time. STATUS=1 if the subject is censored and 
STATUS=0 if investigator-confirmed angioedema attack happens before the date and 
time of the end of the period. Details of censoring is provided in Section 6.3. 
PROC LIFETEST can be used as follows to obtain the KM plot. 
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ods graphics on; 
ods output Quartiles=Quarts CENSOREDSUMMARY=Summary; 
proc lifetest data=ANEDATA method=km plots=survival; 
   time ANETIME*STATUS(1); 
   strata trt01p/ diff = control('Placebo')  test = (logrank); 
run; 
 
Dataset QUARTS contains KM estimates of the 25th, 50th (median), and 75th percentiles 
with associated two-sided 95% CI.  
Dataset SUMMARY contains the number of events of interest, number and percentage of 
censored observations in Variable FAILED, CENSORED and PCTCENS, respectively. 
Similar code will apply to the analysis of time to first angioedema attack after Day 70. 
 
 
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16.4 
Appendix 4 – List of Planned Outputs 
Tables 
Table 14.1.1.1 
 Analysis Sets by Treatment Group (Screened Set) 
Table 14.1.1.2 
 Analysis Sets by Treatment Group and Site (Screened Set) 
Table 14.1.1.3 
 Disposition by Treatment Group (Full Analysis Set) 
Table 14.1.2.1 
 Protocol Deviations by Deviation Type, Severity and Treatment Group (Full Analysis Set) 
Table 14.1.2.2 
 Protocol Deviations by Deviation Type, Severity and Treatment Group (Covid-19 Specific 
Deviations) (Full Analysis Set) 
Table 14.1.2.3 
 Important Protocol Deviations (Full Analysis Set) 
Table 14.1.2.4 
 Protocol Non-compliance (Full Analysis Set) 
Table 14.1.3 
 Enrollment Duration by Country and Site (Enrolled Set) 
Table 14.1.4.1.1 
 Demographics and Baseline Characteristics by Treatment Group (Safety Analysis Set) 
Table 14.1.4.1.2 
 Demographics and Baseline Characteristics by Treatment Group (Full Analysis Set) 
Table 14.1.4.1.3 
 Demographics and Baseline Characteristics by Treatment Group (Steady State Full Analysis 
Set) 
Table 14.1.4.2.1 
 Baseline Angioedema Attack History by Treatment Group (Safety Analysis Set) 
Table 14.1.4.2.2 
 Baseline Angioedema Attack History by Treatment Group (Full Analysis Set) 
Table 14.1.4.2.3 
 Baseline Angioedema Attack History by Treatment Group (Steady State Full Analysis Set) 
Table 14.1.4.3 
 Medical History by System Organ Class, Preferred Term and Treatment Group (Safety 
Analysis Set) 
Table 14.1.4.4.1 
 Prior Medications by Treatment Group (Safety Analysis Set) 
Table 14.1.4.4.2 
 Prior Medications Taken During Observation Period by Treatment Group (Safety Analysis 
Set) 
Table 14.1.4.5 
 Concomitant Medications by Treatment Group (Safety Analysis Set) 
Table 14.1.5.1.1 
 Study Drug Exposure by Treatment Group (Safety Analysis Set) 
Table 14.1.5.1.2 
 Study Drug Exposure by Treatment Group (Full Analysis Set) 
Table 14.1.5.2.1 
 Treatment Compliance by Treatment Group (Safety Analysis Set) 
Table 14.1.5.2.2 
 Treatment Compliance by Treatment Group (Full Analysis Set) 
Table 14.2.1 
 Results of Primary and Secondary Endpoints by Treatment Group (Full Analysis Set) 
Table 14.2.1s 
Results of Primary and Secondary Endpoints by Treatment Group (modified Full Analysis 
Set) 
Table 14.2.2.1.1 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.1.1s 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by Treatment Group (modified Full Analysis Set) 
Table 14.2.2.1.2 
 Poisson Regression of Reported Angioedema Attacks during the Treatment Period (Day 0 to 
Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.2.1.3 
 Negative Binomial Regression of Investigator-Confirmed Angioedema Attacks during the 
Treatment Period (Day 0 to Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.2.1.4 
 Tipping Point Analysis: Poisson Regression of Investigator-Confirmed Angioedema Attacks 
during the Treatment Period (Day 0 to Day 182) after Missing Data Imputation by Treatment 
Group (Full Analysis Set) 
Table 14.2.2.1.5 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by Treatment Group (Safety Analysis Set) 
Table 14.2.2.2.1 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by Age Group and Treatment Group (Full Analysis Set) 
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Table 14.2.2.2.2 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by Sex and Treatment Group (Full Analysis Set) 
Table 14.2.2.2.3 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by Race Group and Treatment Group (Full Analysis Set) 
Table 14.2.2.2.4 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by Weight Group and Treatment Group (Full Analysis Set) 
Table 14.2.2.2.5 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by BMI Group and Treatment Group (Full Analysis Set) 
Table 14.2.2.2.6 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by Observation Period Angioedema Attack Rate Group and 
Treatment Group (Full Analysis Set) 
Table 14.2.2.2.7 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by Geographic Region and Treatment Group (Full Analysis Set) 
Table 14.2.2.2.8 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by Laryngeal Angioedema Attack History and Treatment Group 
(Full Analysis Set) 
Table 14.2.2.2.9 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by Normal C1-INH Subtype in Angioedema and Treatment Group 
(Full Analysis Set) 
Table 14.2.3.1.1 
 Achievement of Investigator-Confirmed Angioedema Attack Free Status during the 
Treatment Period (Day 0 to Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.3.1.1s 
 Achievement of Investigator-Confirmed Angioedema Attack Free Status during the 
Treatment Period (Day 0 to Day 182) by Treatment Group (modified Full Analysis Set) 
Table 14.2.3.1.2 
 Achievement of Reported Angioedema Attack Free Status during the Treatment Period (Day 
0 to Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.3.1.3 
 Achievement of Investigator-Confirmed Angioedema Attack Free Status (Alternative 
Approach to Imputation of Response Status) during the Treatment Period (Day 0 to Day 182) 
by Treatment Group (Full Analysis Set) 
Table 14.2.3.1.4 
 Achievement of Investigator-Confirmed Angioedema Attack Free Status during the 
Treatment Period (Day 0 to Day 182) by Treatment Group (Safety Analysis Set) 
Table 14.2.3.2.1 
 Poisson Regression of Investigator-Confirmed Moderate or Severe Angioedema Attacks 
during the Treatment Period (Day 0 to Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.3.2.1s 
 Poisson Regression of Investigator-Confirmed Moderate or Severe Angioedema Attacks 
during the Treatment Period (Day 0 to Day 182) by Treatment Group (modified Full Analysis 
Set) 
Table 14.2.3.2.2 
 Poisson Regression of Reported Moderate or Severe Angioedema Attacks during the 
Treatment Period (Day 0 to Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.3.2.3 
 Poisson Regression of Investigator-Confirmed Moderate or Severe Angioedema Attacks 
during the Treatment Period (Day 0 to Day 182) by Treatment Group (Safety Analysis Set) 
Table 14.2.3.3.1 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Presumed 
Steady State Period (Day 70 to Day 182) by Treatment Group (Steady State Full Analysis Set) 
Table 14.2.3.3.1s 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Presumed 
Steady State Period (Day 70 to Day 182) by Treatment Group (modified Steady State Full 
Analysis Set) 
Table 14.2.3.3.2 
 Poisson Regression of Reported Angioedema Attacks during the Presumed Steady State 
Period (Day 70 to Day 182) by Treatment Group (Steady State Full Analysis Set) 
Table 14.2.3.3.3 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks during the Presumed 
Steady State Period (Day 70 to Day 182) by Treatment Group (Safety Analysis Set) 
Table 14.2.3.4.1 
 Achievement of Investigator-Confirmed Angioedema Attack Free Status during the 
Presumed Steady State Period (Day 70 to Day 182) by Treatment Group (Steady State Full 
Analysis Set) 
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Table 14.2.3.4.1s 
 Achievement of Investigator-Confirmed Angioedema Attack Free Status during the 
Presumed Steady State Period (Day 70 to Day 182) by Treatment Group (modified Steady 
State Full Analysis Set) 
Table 14.2.3.4.2 
 Achievement of Reported Angioedema Attack Free Status during the Presumed Steady State 
Period (Day 70 to Day 182) by Treatment Group (Steady State Full Analysis Set) 
Table 14.2.3.4.3 
 Achievement of Investigator-Confirmed Angioedema Attack Free Status (Alternative 
Approach to Imputation of Response Status) during the Presumed Steady State Period (Day 
70 to Day 182) by Treatment Group (Steady State Full Analysis Set) 
Table 14.2.3.4.4 
 Achievement of Investigator-Confirmed Angioedema Attack Free Status during the 
Presumed Steady State Period (Day 70 to Day 182) by Treatment Group (Safety Analysis Set) 
Table 14.2.3.5.1 
 Poisson Regression of Investigator-Confirmed Moderate or Severe Angioedema Attacks 
during the Presumed Steady State Period (Day 70 to Day 182) by Treatment Group (Steady 
State Full Analysis Set) 
Table 14.2.3.5.1s 
 Poisson Regression of Investigator-Confirmed Moderate or Severe Angioedema Attacks 
during the Presumed Steady State Period (Day 70 to Day 182) by Treatment Group (modified 
Steady State Full Analysis Set) 
Table 14.2.3.5.2 
 Poisson Regression of Reported Moderate or Severe Angioedema Attacks during the 
Presumed Steady State Period (Day 70 to Day 182) by Treatment Group (Steady State Full 
Analysis Set) 
Table 14.2.3.5.3 
 Poisson Regression of Investigator-Confirmed Moderate or Severe Angioedema Attacks 
during the Presumed Steady State Period (Day 70 to Day 182) by Treatment Group (Safety 
Analysis Set) 
Table 14.2.3.7.1 
 Time to First Investigator-Confirmed Angioedema Attack After Day 0 by Treatment Group 
(Full Analysis Set) 
Table 14.2.3.7.2 
 Time to First Investigator-Confirmed Angioedema Attack After Day 70 by Treatment Group 
(Steady State Full Analysis Set) 
Table 14.2.3.8.1 
 Responder Analysis Comparing Investigator-Confirmed Normalized Number of Attacks 
(NNA) per 4 Weeks during the Treatment Period (Day 0 to Day 182) and Observation Period 
by Responder Threshold and Treatment Group (Full Analysis Set) 
Table 14.2.3.8.2 
 Responder Analysis Comparing Investigator-Confirmed Normalized Number of Attacks 
(NNA) per 4 Weeks during the Presumed Steady State Period (Day 70 to Day 182) and 
Observation Period by Responder Threshold and Treatment Group (Steady State Full 
Analysis Set) 
Table 14.2.3.9.1 
 Achievement of Normalized Number of Attacks (NNA) < 1.0 per 4 Weeks during the 
Treatment Period (Day 0 to Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.3.9.2 
 Achievement of Normalized Number of Attacks (NNA) < 1.0 per 4 Weeks during the 
Presumed Steady State Period (Day 70 to Day 182) by Treatment Group (Steady State Full 
Analysis Set) 
Table 14.2.3.10 
 Poisson Regression of High Morbidity Investigator-Confirmed Angioedema Attacks during 
the Treatment Period (Day 0 to Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.3.11.1 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks Resulting in an 
Emergency Department Visit or Admission to the Hospital during the Treatment Period (Day 
0 to Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.3.11.2 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks Resulting in an 
Emergency Department Visit during the Treatment Period (Day 0 to Day 182) by Treatment 
Group (Full Analysis Set) 
Table 14.2.3.11.3 
 Poisson Regression of Investigator-Confirmed Angioedema Attacks Resulting in Admission 
to the Hospital during the Treatment Period (Day 0 to Day 182) by Treatment Group (Full 
Analysis Set) 
Table 14.2.3.12 
 Poisson Regression of Investigator-Confirmed Laryngeal Angioedema Attacks during the 
Treatment Period (Day 0 to Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.3.13.1 
 Subject Level Characteristics of Investigator-Confirmed Angioedema Attacks during the 
Observation Period (Prior to Day 0) by Treatment Group (Full Analysis Set) 
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Table 14.2.3.13.2 
 Subject Level Characteristics of Investigator-Confirmed Angioedema Attacks during the 
Treatment Period (Day 0 to Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.3.13.3 
 Subject Level Characteristics of Investigator-Confirmed Angioedema Attacks during the 
Presumed Steady State Period (Day 70 to Day 182) by Treatment Group (Steady State Full 
Analysis Set) 
Table 14.2.3.13.4 
 Event Level Characteristics of Investigator-Confirmed Angioedema Attacks during the 
Observation Period (Prior to Day 0) by Treatment Group (Full Analysis Set) 
Table 14.2.3.13.5 
 Event Level Characteristics of Investigator-Confirmed Angioedema Attacks during the 
Treatment Period (Day 0 to Day 182) by Treatment Group (Full Analysis Set) 
Table 14.2.3.13.6 
 Event Level Characteristics of Investigator-Confirmed Angioedema Attacks during the 
Presumed Steady State Period (Day 70 to Day 182) by Treatment Group (Steady State Full 
Analysis Set) 
Table 14.2.3.14.1 
 Percentage of Angioedema Attack-free Days during the Treatment Period (Day 0 to Day 182) 
by Treatment Group (Full Analysis Set) 
Table 14.2.3.14.2 
 Percentage of Angioedema Attack-free Days during the Presumed Steady State Period (Day 
70 to Day 182) by Treatment Group (Steady State Full Analysis Set) 
Table 14.2.3.15.1 
 Achievement of Investigator-Confirmed Angioedema Attack Free Status 1 Months and 3 
Months after Day 0 during the Treatment Period (Day 0 to Day 182) by Treatment Group 
(Full Analysis Set) 
Table 14.2.3.15.2 
 Achievement of Investigator-Confirmed Angioedema Attack Free Status 1 Month and 3 
Months after Day 0 during the Presumed Steady State Period (Day 70 to Day 182) by 
Treatment Group (Steady State Full Analysis Set) 
Table 14.2.3.16 
 Summary of Investigator-Confirmed Angioedema Attacks by Treatment Group (Full 
Analysis Set) 
Table 14.2.3.17 
 Investigator-Confirmed Angioedema Attacks per Month by Study Month and  Treatment 
Group (Full Analysis Set) 
Table 14.2.3.18.1 
 Subject Listing of Efficacy Parameters - Part 1 (Full Analysis Set) 
Table 14.2.3.18.2 
 Subject Listing of Efficacy Parameters - Part 2 (Full Analysis Set) 
Table 14.2.3.18.3 
 Subject Listing of Efficacy Parameters - Part 3 (Full Analysis Set) 
Table 14.2.3.19 
 Supplementary Listing for Tipping Point Analysis: Subjects who Discontinued During the 
Treatment Period (Full Analysis Set) 
Table 14.2.4 
 Plasma Concentrations of Lanadelumab by Treatment Group and Study Visit (Full Analysis 
Set) 
Table 14.2.5.1 
 Plasma Kallikrein Activity Measured by %cHMWK by Treatment Group and Study Visit 
(Pharmacodynamic Set) 
Table 14.2.5.2 
 Plasma Kallikrein Activity Measured by pKal Concentration by Treatment Group and Study 
Visit (Pharmacodynamic Set) 
Table 14.3.1.1.1.1 
 Overall Treatment-Emergent Non-Angioedema Attack Reported Adverse Events (TEAEs) 
during the Treatment Period (Day 0 to Day 182) by Treatment Group (Safety Analysis Set) 
Table 14.3.1.1.1.2 
 Overall Treatment-Emergent Non-Angioedema Attack Reported Adverse Events (TEAEs) 
during the Treatment Period (Day 0 to Day 182) by Age Group and Treatment Group (Safety 
Analysis Set) 
Table 14.3.1.1.1.3 
 Overall Treatment-Emergent Non-Angioedema Attack Reported Adverse Events (TEAEs) 
during the Treatment Period (Day 0 to Day 182) by Sex and Treatment Group (Safety 
Analysis Set) 
Table 14.3.1.1.1.4 
 Overall Treatment-Emergent Non-Angioedema Attack Reported Adverse Events (TEAEs) 
during the Treatment Period (Day 0 to Day 182) by Race Group and Treatment Group (Safety 
Analysis Set) 
Table 14.3.1.1.1.5 
 Overall Treatment-Emergent Non-Angioedema Attack Reported Adverse Events (TEAEs) 
during the Treatment Period (Day 0 to Day 182) by Weight Group and Treatment Group 
(Safety Analysis Set) 
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Table 14.3.1.1.1.6 
 Overall Treatment-Emergent Non-Angioedema Attack Reported Adverse Events (TEAEs) 
during the Treatment Period (Day 0 to Day 182) by BMI Group and Treatment Group (Safety 
Analysis Set) 
Table 14.3.1.1.1.7 
 Overall Treatment-Emergent Non-Angioedema Attack Reported Adverse Events (TEAEs) 
during the Treatment Period (Day 0 to Day 182) by Observation Period Angioedema Attack 
Rate Group (Safety Analysis Set) 
Table 14.3.1.1.1.8 
 Overall Treatment-Emergent Non-Angioedema Attack Reported Adverse Events (TEAEs) 
during the Treatment Period (Day 0 to Day 182) by Geographical Region and Treatment 
Group (Safety Analysis Set) 
Table 14.3.1.1.1.9 
 Overall Treatment-Emergent Non-Angioedema Attack Reported Adverse Events (TEAEs) 
during the Treatment Period (Day 0 to Day 182) by Laryngeal Angioedema Attack Rate 
History and Treatment Group (Safety Analysis Set) 
Table 14.3.1.1.1.10 
 Overall Treatment-Emergent Non-Angioedema Attack Reported Adverse Events (TEAEs) 
during the Treatment Period (Day 0 to Day 182) by Normal C1-INH Subtype and Treatment 
Group (Safety Analysis Set) 
Table 14.3.1.1.2.1 
 Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class and Preferred 
Term (Safety Analysis Set) 
Table 14.3.1.1.2.2 
 Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group and Preferred Term (Safety 
Analysis Set) 
Table 14.3.1.1.2.3 
 Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Age Group, Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.2.4 
 Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Sex, Treatment Group, System Organ Class and 
Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.2.5 
 Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Race Group, Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.2.6 
 Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Weight Group, Treatment Group, System Organ 
Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.2.7 
 Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by BMI Group, Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.2.8 
 Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Observation Period Angioedema Attack Rate Group, 
Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.2.9 
 Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Geographical Region, Treatment Group, System 
Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.2.10 
 Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Laryngeal Angioedema Attack Rate History, 
Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.2.11 
 Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Normal C1-INH Subtype, Treatment Group, System 
Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.3.1 
 Related Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class and Preferred 
Term (Safety Analysis Set) 
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Table 14.3.1.1.3.2 
 Related Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group and Preferred Term (Safety 
Analysis Set) 
Table 14.3.1.1.3.3 
 Related Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Age Group, Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.3.4 
 Related Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Sex, Treatment Group, System Organ Class and 
Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.3.5 
 Related Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Race Group, Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.3.6 
 Related Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Weight Group, Treatment Group, System Organ 
Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.3.7 
 Related Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by BMI Group, Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.3.8 
 Related Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Observation Period Angioedema Attack Rate Group, 
Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.3.9 
 Related Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Geographical Region, Treatment Group, System 
Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.3.10 
 Related Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Laryngeal Angioedema Attack Rate History, 
Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.3.11 
 Related Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Normal C1-INH Subtype, Treatment Group, System 
Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.4.1 
 Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class and Preferred 
Term (Safety Analysis Set) 
Table 14.3.1.1.4.2 
 Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group and Preferred Term (Safety 
Analysis Set) 
Table 14.3.1.1.4.3 
 Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Age Group, Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.4.4 
 Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Sex, Treatment Group, System Organ Class and 
Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.4.5 
 Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Race Group, Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.4.6 
 Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Weight Group, Treatment Group, System Organ 
Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.4.7 
 Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by BMI Group, Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
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Table 14.3.1.1.4.8 
 Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Observation Period Angioedema Attack Rate Group, 
Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.4.9 
 Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Geographical Region, Treatment Group, System 
Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.4.10 
 Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Laryngeal Angioedema Attack Rate History, 
Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.4.11 
 Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Normal C1-INH Subtype, Treatment Group, System 
Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.5 
 Related Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events 
during the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.6.1 
 Serious Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class and Preferred 
Term (Safety Analysis Set) 
Table 14.3.1.1.6.2 
 Risk Difference of Serious Treatment-Emergent Non-Angioedema Attack Reported Adverse 
Events during the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ 
Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.7 
 Related Serious Treatment-Emergent Non-Angioedema Attack Reported Adverse Events 
during the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
Table 14.3.1.1.8 
 Frequently Occurring (≥5%) Treatment-Emergent Non-Angioedema Attack Reported 
Adverse Events during the Treatment Period (Day 0 to Day 182) by Treatment Group, System 
Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.2.1 
 Overall Non-Angioedema Attack Reported Adverse Events (AEs) during the Pretreatment 
Period (Prior to Day 0) by Treatment Group (Safety Analysis Set) 
Table 14.3.1.2.2 
 Non-Angioedema Attack Reported Adverse Events during the Pretreatment Period (Prior to 
Day 0) by Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.2.3 
 Severe Non-Angioedema Attack Reported Adverse Events during the Pretreatment Period 
(Prior to Day 0) by Treatment Group, System Organ Class and Preferred Term (Safety 
Analysis Set) 
Table 14.3.1.2.4 
 Serious Non-Angioedema Attack Reported Adverse Events during the Pretreatment Period 
(Prior to Day 0) by Treatment Group, System Organ Class and Preferred Term (Safety 
Analysis Set) 
Table 14.3.1.3.1 
 Overall Treatment-Emergent Non-Angioedema Attack Reported Adverse Events (TEAEs) 
during the Follow-up Period (>Day 182) by Treatment Group (Safety Analysis Set) 
Table 14.3.1.3.2 
 Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the Follow-
up Period (>Day 182) by Treatment Group, System Organ Class and Preferred Term (Safety 
Analysis Set) 
Table 14.3.1.3.3 
 Related Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Follow-up Period (>Day 182) by Treatment Group, System Organ Class and Preferred Term 
(Safety Analysis Set) 
Table 14.3.1.3.4 
 Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Follow-up Period (>Day 182) by Treatment Group, System Organ Class and Preferred Term 
(Safety Analysis Set) 
Table 14.3.1.3.5 
 Related Severe Treatment-Emergent Non-Angioedema Attack Reported Adverse Events 
during the Follow-up Period (>Day 182) by Treatment Group, System Organ Class and 
Preferred Term (Safety Analysis Set) 
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Table 14.3.1.3.6.1 
 Serious Treatment-Emergent Non-Angioedema Attack Reported Adverse Events during the 
Follow-up Period (>Day 182) by Treatment Group, System Organ Class and Preferred Term 
(Safety Analysis Set) 
Table 14.3.1.3.6.2 
 Risk Difference of Serious Treatment-Emergent Non-Angioedema Attack Reported Adverse 
Events during the Follow-up Period (>Day 182) by Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
Table 14.3.1.3.7 
 Related Serious Treatment-Emergent Non-Angioedema Attack Reported Adverse Events 
during the Follow-up Period (>Day 182) by Treatment Group, System Organ Class and 
Preferred Term (Safety Analysis Set) 
Table 14.3.1.4.1 
 Overall Treatment-Emergent Angioedema Attack Reported Adverse Events (TEAEs) during 
the Treatment Period (Day 0 to Day 182) by Treatment Group (Safety Analysis Set) 
Table 14.3.1.4.2.1 
 Treatment-Emergent Angioedema Attack Reported Adverse Events during the Treatment 
Period (Day 0 to Day 182) by Treatment Group, System Organ Class and Preferred Term 
(Safety Analysis Set) 
Table 14.3.1.4.2.2 
 Treatment-Emergent Angioedema Attack Reported Adverse Events during the Treatment 
Period (Day 0 to Day 182) by Treatment Group and Preferred Term (Safety Analysis Set) 
Table 14.3.1.4.3.1 
 Related Treatment-Emergent Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class and Preferred 
Term (Safety Analysis Set) 
Table 14.3.1.4.3.2 
 Related Treatment-Emergent Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group and Preferred Term (Safety 
Analysis Set) 
Table 14.3.1.4.4.1 
 Severe Treatment-Emergent Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class and Preferred 
Term (Safety Analysis Set) 
Table 14.3.1.4.4.2 
 Severe Treatment-Emergent Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group and Preferred Term (Safety 
Analysis Set) 
Table 14.3.1.4.5 
 Related Severe Treatment-Emergent Angioedema Attack Reported Adverse Events during 
the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class and 
Preferred Term (Safety Analysis Set) 
Table 14.3.1.4.6.1 
 Serious Treatment-Emergent Angioedema Attack Reported Adverse Events during the 
Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class and Preferred 
Term (Safety Analysis Set) 
Table 14.3.1.4.6.2 
 Risk Difference of Serious Treatment-Emergent Angioedema Attack Reported Adverse 
Events during the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ 
Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.4.7 
 Related Serious Treatment-Emergent Angioedema Attack Reported Adverse Events during 
the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ Class and 
Preferred Term (Safety Analysis Set) 
Table 14.3.1.4.8 
 Frequently Occurring (≥5%) Treatment-Emergent Angioedema Attack Reported Adverse 
Events during the Treatment Period (Day 0 to Day 182) by Treatment Group, System Organ 
Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.5.1 
 Overall Angioedema Attack Reported Adverse Events (AEs) during the Pretreatment Period 
(Prior to Day 0) by Treatment Group (Safety Analysis Set) 
Table 14.3.1.5.2 
 Angioedema Attack Reported Adverse Events during the Pretreatment Period (Prior to Day 
0) by Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.5.3 
 Severe Angioedema Attack Reported Adverse Events during the Pretreatment Period (Prior 
to Day 0) by Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.5.4 
 Serious Angioedema Attack Reported Adverse Events during the Pretreatment Period (Prior 
to Day 0) by Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.6.1 
 Overall Treatment-Emergent Angioedema Attack Reported Adverse Events (TEAEs) during 
the Follow-up Period (>Day 182) by Treatment Group (Safety Analysis Set) 
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Table 14.3.1.6.2 
 Treatment-Emergent Angioedema Attack Reported Adverse Events during the Follow-up 
Period (>Day 182) by Treatment Group, System Organ Class and Preferred Term (Safety 
Analysis Set) 
Table 14.3.1.6.3 
 Related Treatment-Emergent Angioedema Attack Reported Adverse Events during the 
Follow-up Period (>Day 182) by Treatment Group, System Organ Class and Preferred Term 
(Safety Analysis Set) 
Table 14.3.1.6.4 
 Severe Treatment-Emergent Angioedema Attack Reported Adverse Events during the 
Follow-up Period (>Day 182) by Treatment Group, System Organ Class and Preferred Term 
(Safety Analysis Set) 
Table 14.3.1.6.5 
 Related Severe Treatment-Emergent Angioedema Attack Reported Adverse Events during 
the Follow-up Period (>Day 182) by Treatment Group, System Organ Class and Preferred 
Term (Safety Analysis Set) 
Table 14.3.1.6.6.1 
 Serious Treatment-Emergent Angioedema Attack Reported Adverse Events during the 
Follow-up Period (>Day 182) by Treatment Group, System Organ Class and Preferred Term 
(Safety Analysis Set) 
Table 14.3.1.6.6.2 
 Risk Difference of Serious Treatment-Emergent Angioedema Attack Reported Adverse 
Events during the Follow-up Period (>Day 182) by Treatment Group, System Organ Class 
and Preferred Term (Safety Analysis Set) 
Table 14.3.1.6.7 
 Related Serious Treatment-Emergent Angioedema Attack Reported Adverse Events during 
the Follow-up Period (>Day 182) by Treatment Group, System Organ Class and Preferred 
Term (Safety Analysis Set) 
Table 14.3.1.7.1 
 Overall Treatment-Emergent Investigator-Reported Hypersensitivity Reaction Adverse 
Events of Special Interest (AESI) during the Treatment Period (Day 0 to Day 182) by 
Treatment Group (Safety Analysis Set) 
Table 14.3.1.7.2.1 
 Treatment-Emergent Investigator-Reported Hypersensitivity Reaction Adverse Events of 
Special Interest (AESI) during the Treatment Period (Day 0 to Day 182) by Treatment Group, 
System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.7.2.2 
 Risk Difference of Treatment-Emergent Investigator-Reported Hypersensitivity Reaction 
Adverse Events of Special Interest (AESI) during the Treatment Period (Day 0 to Day 182) by 
Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.7.3 
 Related Treatment-Emergent Investigator-Reported Hypersensitivity Reaction Adverse 
Events of Special Interest (AESI) during the Treatment Period (Day 0 to Day 182) by 
Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.8.1 
 Overall Treatment-Emergent Investigator-Reported Hypersensitivity Reaction Adverse 
Events of Special Interest (AESI) during the Pretreatment Period (Prior to Day 0) by 
Treatment Group (Safety Analysis Set) 
Table 14.3.1.8.2 
 Treatment-Emergent Investigator-Reported Hypersensitivity Reaction Adverse Events of 
Special Interest (AESI) during the Pretreatment Period (Prior to Day 0) by Treatment Group, 
System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.9.1 
 Overall Treatment-Emergent Investigator-Reported Hypersensitivity Reaction Adverse 
Events of Special Interest (AESI) during the Follow-up Period (>Day 182) by Treatment 
Group (Safety Analysis Set) 
Table 14.3.1.9.2.1 
 Treatment-Emergent Investigator-Reported Hypersensitivity Reaction Adverse Events of 
Special Interest (AESI) during the Follow-up Period (>Day 182) by Treatment Group, System 
Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.9.2.2 
 Risk Difference of Treatment-Emergent Investigator-Reported Hypersensitivity Reaction 
Adverse Events of Special Interest (AESI) during the Follow-up Period (>Day 182) by 
Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.9.3 
 Related Treatment-Emergent Investigator-Reported Hypersensitivity Reaction Adverse 
Events of Special Interest (AESI) during the Follow-up Period (>Day 182) by Treatment 
Group, System Organ Class and Preferred Term (Safety Analysis Set) 
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Table 14.3.1.10.1.1 
 Overall Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse Events of 
Special Interest (AESI) (including Injection Site Reactions) during the Treatment Period (Day 
0 to Day 182) by Treatment Group (Safety Analysis Set) 
Table 14.3.1.10.1.2 
 Overall Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse Events of 
Special Interest (AESI) (excluding Injection Site Reactions) during the Treatment Period (Day 
0 to Day 182) by Treatment Group (Safety Analysis Set) 
Table 14.3.1.10.2.1 
 Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse Events of Special 
Interest (AESI) (including Injection Site Reactions) during the Treatment Period (Day 0 to 
Day 182) by Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.10.2.2 
 Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse Events of Special 
Interest (AESI) (excluding Injection Site Reactions) during the Treatment Period (Day 0 to 
Day 182) by Treatment Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.10.3.1 
 Risk Difference of Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse 
Events of Special Interest (AESI) (including Injection Site Reactions) during the Treatment 
Period (Day 0 to Day 182) by Treatment Group, System Organ Class and Preferred Term 
(Safety Analysis Set) 
Table 14.3.1.10.3.2 
 Risk Difference of Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse 
Events of Special Interest (AESI) (excluding Injection Site Reactions) during the Treatment 
Period (Day 0 to Day 182) by Treatment Group, System Organ Class and Preferred Term 
(Safety Analysis Set) 
Table 14.3.1.10.4.1 
 Related Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse Events of 
Special Interest (AESI) (including Injection Site Reactions) during the Treatment Period (Day 
0 to Day 182) by Treatment Group, System Organ Class and Preferred Term (Safety Analysis 
Set) 
Table 14.3.1.10.4.2 
 Related Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse Events of 
Special Interest (AESI) (excluding Injection Site Reactions) during the Treatment Period (Day 
0 to Day 182) by Treatment Group, System Organ Class and Preferred Term (Safety Analysis 
Set) 
Table 14.3.1.11.1 
 Overall Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse Events of 
Special Interest (AESI) during the Pretreatment Period (Prior to Day 0) by Treatment Group 
(Safety Analysis Set) 
Table 14.3.1.11.2 
 Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse Events of Special 
Interest (AESI) during the Pretreatment Period (Prior to Day 0) by Treatment Group, System 
Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.12.1 
 Overall Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse Events of 
Special Interest (AESI) during the Follow-up Period (>Day 182) by Treatment Group (Safety 
Analysis Set) 
Table 14.3.1.12.2.1 
 Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse Events of Special 
Interest (AESI) during the Follow-up Period (>Day 182) by Treatment Group, System Organ 
Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.12.2.2 
 Risk Difference of Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse 
Events of Special Interest (AESI) during the Follow-up Period (>Day 182) by Treatment 
Group, System Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.12.3 
 Related Treatment-Emergent SMQ-Defined Hypersensitivity Reaction Adverse Events of 
Special Interest (AESI) during the Follow-up Period (>Day 182) by Treatment Group, System 
Organ Class and Preferred Term (Safety Analysis Set) 
Table 14.3.1.13.1 
 Overall Injection Site Reaction Treatment-Emergent Adverse Events during the Treatment 
Period (Day 0 to Day 182) by Treatment Group (Safety Analysis Set) 
Table 14.3.1.13.2 
 Injection Site Reaction Treatment-Emergent Adverse Events during the Treatment Period 
(Day 0 to Day 182) by Treatment Group, System Organ Class and Preferred Term (Safety 
Analysis Set) 
Table 14.3.1.13.3 
 Injection Site Reaction Treatment-Emergent Adverse Events during the Treatment Period 
(Day 0 to Day 182) by Treatment Group, System Organ Class, Preferred Term and Maximum 
Severity (Safety Analysis Set) 
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Table 14.3.1.13.4 
 Summary of Number and Duration of Injection Site Reaction Treatment-Emergent Adverse 
Events during the Treatment Period (Day 0 to Day 182) (Safety Analysis Set) 
Table 14.3.2.1.1 
 Listing of Serious Adverse Events (Safety Analysis Set) 
Table 14.3.2.1.2 
 Listing of Adverse Events Leading to Discontinuation of Study Medication (Safety Analysis 
Set) 
Table 14.3.2.1.3 
 Listing of Adverse Events Leading to Death (Safety Analysis Set) 
Table 14.3.2.1.4 
 Listing of Investigator-Reported Adverse Events of Special Interest (Safety Analysis Set) 
Table 14.3.4.1.1 
 Quantitative Clinical Laboratory Results by Treatment Group and Study Visit:  Hematology 
(Safety Analysis Set) 
Table 14.3.4.1.2 
 Clinically Significant Abnormal Clinical Laboratory Results by Treatment Group and Study 
Visit:  Hematology (Safety Analysis Set) 
Table 14.3.4.1.3 
 Listing of Clinically Significant Abnormal Clinical Laboratory Results:  Hematology (Safety 
Analysis Set) 
Table 14.3.4.2.1 
 Quantitative Clinical Laboratory Results by Treatment Group and Study Visit:  Coagulation 
(Safety Analysis Set) 
Table 14.3.4.2.2 
 Clinically Significant Abnormal Clinical Laboratory Results by Treatment Group and Study 
Visit:  Coagulation (Safety Analysis Set) 
Table 14.3.4.2.3 
 Listing of Clinically Significant Abnormal Clinical Laboratory Results:  Coagulation (Safety 
Analysis Set) 
Table 14.3.4.3.1 
 Quantitative Clinical Laboratory Results by Treatment Group and Study Visit:  Chemistry 
(Safety Analysis Set) 
Table 14.3.4.3.2 
 Clinically Significant Abnormal Clinical Laboratory Results by Treatment Group and Study 
Visit:  Chemistry (Safety Analysis Set) 
Table 14.3.4.3.3 
 Listing of Clinically Significant Abnormal Clinical Laboratory Results:  Chemistry (Safety 
Analysis Set) 
Table 14.3.3.4 
Highest Liver Function Test by Analysis Period 
(Safety Analysis Set) 
 
Table 14.3.3.3.5 
Shift Table of Highest Liver Function Test  
(Safety Analysis Set) 
Table 14.3.4.4.1 
 Quantitative Clinical Laboratory Results by Treatment Group and Study Visit:  Urinalysis 
(Safety Analysis Set) 
Table 14.3.4.4.2 
 Clinically Significant Abnormal Clinical Laboratory Results by Treatment Group and Study 
Visit:  Urinalysis (Safety Analysis Set) 
Table 14.3.4.4.3 
 Listing of Clinically Significant Abnormal Clinical Laboratory Results:  Urinalysis (Safety 
Analysis Set) 
Table 14.3.4.4.4 
 Categorical Clinical Laboratory Results by Treatment Group and Study Visit:  Urinalysis 
(Safety Analysis Set) 
Table 14.3.4.5.1 
 Actual Values and Change from Baseline in Vital Signs by Treatment Group and Study Visit 
(Safety Analysis Set) 
Table 14.3.4.5.2 
 Clinically Significant Vital Signs by Treatment Group and Study Visit (Safety Analysis Set) 
Table 14.3.4.5.3 
 Listing of Clinically Significant Vital Sign Results (Safety Analysis Set) 
Table 14.3.4.6.1 
 Actual Values and Change from Baseline in Electrocardiogram by Treatment Group and 
Study Visit (Safety Analysis Set) 
Table 14.3.4.6.2 
 Categorical Electrocardiogram Results by Treatment Group and Study Visit (Safety Analysis 
Set) 
Table 14.3.4.6.3 
 Listing of Abnormal Electrocardiogram Findings (Safety Analysis Set) 
Table 14.3.4.7 
 Biomarker Tests at Screening by Treatment Group (Safety Analysis Set) 
Table 14.3.4.8 
 Angioedema Quality of Life Item Responses by Treatment Group and Study Visit (Safety 
Analysis Set) 
Table 14.3.4.9 
 Immunogenicity by Treatment Group and Study Visit (Safety Analysis Set) 
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Figures 
Figure 14.1.1.1 
 Time to Withdrawal by Treatment Group (Full Analysis Set) 
Figure 14.2.2.1.1 
 Investigator-Confirmed Angioedema Attacks during the Treatment Period (Day 0 to Day 
182) by Treatment Group (Full Analysis Set) 
Figure 14.2.2.1.1s 
 Investigator-Confirmed Angioedema Attacks during the Treatment Period (Day 0 to Day 
182) by Treatment Group (modified Full Analysis Set) 
Figure 14.2.2.1.2 
 Reported Angioedema Attacks during the Treatment Period (Day 0 to Day 182) by Treatment 
Group (Full Analysis Set) 
Figure 14.2.2.1.3 
 Forest Plot of Rate Ratios for Investigator-Confirmed Angioedema Attacks during the 
Treatment Period (Day 0 to Day 182) by Subgroups (Full Analysis Set) 
Figure 14.2.2.1.3s 
 Forest Plot of Rate Ratios for Investigator-Confirmed Angioedema Attacks during the 
Treatment Period (Day 0 to Day 182) by Subgroups (modified Full Analysis Set) 
Figure 14.2.3.1 
 Investigator-Confirmed Moderate or Severe Angioedema Attacks during the Treatment 
Period (Day 0 to Day 182) by Treatment Group (Full Analysis Set) 
Figure 14.2.4.1 
 Investigator-Confirmed Angioedema Attacks during the Presumed Steady State Period (Day 
70 to Day 182) by Treatment Group (Steady State Full Analysis Set) 
Figure 14.2.4.1s 
 Investigator-Confirmed Angioedema Attacks during the Presumed Steady State Period (Day 
70 to Day 182) by Treatment Group (modified Steady State Full Analysis Set) 
Figure 14.2.4.2 
 Investigator-Confirmed Moderate or Severe Angioedema Attacks during the Presumed 
Steady State Period (Day 70 to Day 182) by Treatment Group (Steady State Full Analysis Set) 
Figure 14.2.4.2s 
 Investigator-Confirmed Moderate or Severe Angioedema Attacks during the Presumed 
Steady State Period (Day 70 to Day 182) by Treatment Group (modified Steady State Full 
Analysis Set) 
Figure 14.2.3.5.1 
 Time to First Angioedema Attack After Day 0 by Treatment Group (Full Analysis Set) 
Figure 14.2.3.5.2 
 Time to First Angioedema Attack After Day 70 by Treatment Group (Steady State Full 
Analysis Set) 
 
 
 
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Takeda Development Center Americas, Inc.   
                                                CONFIDENTIAL
 
Page 89 of 89 
Lanadelumab 
Statistical Analysis Plan: SHP643-303 
Final 2.0 10Nov2022 
Listings 
Listing 16.1.7 
Randomization Assignments 
Listing 16.2.1.1 
 Listing of Disposition (Screened Set) 
Listing 16.2.1.2 
Informed Consent or Assent and Reconsent (Screened Set) 
Listing 16.2.1.3 
 Listing of Analysis Populations (Screened Set) 
Listing 16.2.2.1 
 Listing of Protocol Deviations (Screened Set) 
Listing 16.2.2.1.1 
 Listing of Protocol Non-compliance (Screened Set) 
Listing 16.2.2.2 
 Listing of Inclusion and Exclusion Criteria (Screened Set) 
Listing 16.2.4.1 
 Listing of Demographics (Screened Set) 
Listing 16.2.4.2 
 Listing of Baseline Disease Characteristics - Part 1 (Screened Set) 
Listing 16.2.4.3 
 Listing of Medical History (Screened Set) 
Listing 16.2.4.4 
 Listing of Prior and Concomitant Medications (Screened Set) 
Listing 16.2.4.5 
 Listing of Prior and Concomitant Therapies (Screened Set) 
Listing 16.2.4.5 
 Listing of Prior and Concomitant Procedures (Screened Set) 
Listing 16.2.5.1 
 Listing of Study Drug Administration (Safety Analysis Set) 
Listing 16.2.5.2 
 Listing of Injection Report (Safety Analysis Set) 
Listing 16.2.5.3 
 Listing of Treatment Compliance and Exposure (Safety Analysis Set) 
Listing 16.2.5.4 
 Listing of Plasma Concentration of Lanadelumab (Pharmacokinetic Set) 
Listing 16.2.5.5 
 Listing of Kallikrein Activity (Pharmacodynamic Set) 
Listing 16.2.6 
 Listing of Angioedema Attacks (Screened Set) 
Listing 16.2.7 
 Listing of Adverse Events (Screened Set) 
Listing 16.2.8.1 
 Listing of Hematology Values (Screened Set) 
Listing 16.2.8.2 
 Listing of Coagulation Values (Screened Set) 
Listing 16.2.8.3 
 Listing of Chemistry Values (Screened Set) 
Listing 16.2.8.4 
 Listing of Urinalysis Values (Screened Set) 
Listing 16.2.8.5 
 Listing of Vital Signs (Screened Set) 
Listing 16.2.8.6 
 Listing of ECGs (Screened Set) 
Listing 16.2.8.7 
 Listing of Biomarker Tests (Screened Set) 
Listing 16.2.8.8 
 Listing of Angioedema Quality of Life Questionnaire (Full Analysis Set) 
Listing 16.2.8.9 
 Listing of Immunogenicity (Screened Set) 
 
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