An Open-Label Study to Evaluate the Long-Term Safety and Efficacy of Lanadelumab for Prevention Against Acute Attacks of Non-histaminergic Angioedema With Normal C1-Inhibitor (C1-INH)
Phase: PHASE3
Conditions: Angioedema
Sponsor: Shire

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TAK-743-3001 Clinical Study Protocol Amendment 1
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14 Sep 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
Sponsor has been revised from Shire to Takeda 
Development Center Americas (TDCA) / Takeda.
Cover Page
Protocol Signature Page
Product Quality Complaints
Section 6.4 Drug Accountability
Appendix 1.5 Ethical 
Considerations
, MD was added as contact for IQVIA 
medical monitor. 
Emergency Contact Information
Revised to include appropriate Takeda forms for reporting 
adverse events (AEs) and pregnancy. 
Shire Global drug Safety Department was revised 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
For study site regions, removed specificity to European 
Union (revised to Europe) and removed Israel. Section 4.5 
was revised to be consistent with synopsis. 
Section 1.1 Synopsis 
Section 4.5 Sites and Regions 
References to acquired angioedema (AAE) due to C1-INH 
deficiency were removed. 
Section 1.1 Synopsis 
Section 2 Introduction 
Removed exclusion criteria 4, 5, 6 and 7. 
Section 1.1 Synopsis 
Section 5.2 Exclusion Criteria 
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TAK-743-3001 Clinical Study Protocol Amendment 1
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Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected by Change
Corrected errors referring to treatment period. The treatment 
period for this study is 182 days. 
Section 1.1 Synopsis 
Section 4.4 Duration of Subject 
Participation and Study 
Completion Definition 
Pharmacokinetic and Pharmacodynamic analysis 
populations were added. 
Section 1.1 Synopsis 
Section 9.4 Statistical Analysis 
Set(s)
Section 9.7.1 Analysis of 
Pharmacokinetic Data
Section 9.7.2 Analysis of 
Pharmacodynamic Data 
“Concentration” in regards to plasma cHMWK and pKal 
levels was removed. 
Section 1.1 Synopsis 
Table 2
Exploratory biomarkers was revised to state 
“…angioedema-disease state bioactivity, including pKal 
activity.”
Section 1.1 Synopsis 
Table 2
Added legend for shaded and non-shaded columns to clarify 
on-site versus elected off-site visits. 
Table 1
Added a footnote to clarify which Visit 1 study assessments 
will not be duplicated from Study SHP643-303. 
Table 1
Provided clarification that demography data will be re-
entered at Visit 1; but for medical history, only new medical 
history will be entered. 
Table 1
Section 8.2.2.1 Study Visit 1; 
Study Day 0
Clarified that height should be measured at Visit 1 for 
subjects that are <18 years of age at the time of consent in 
Study SHP643-3001. 
Table 1
Section 8.2.2.1 Study Visit 1; 
Study Day 0
Section 8.3.5.1 Physical 
Examination 
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TAK-743-3001 Clinical Study Protocol Amendment 1
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14 Sep 2020
Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected by Change
Visits 5 and 9 were revised to subject-elected off-site visits. 
Table 1
Section 8.2 Study Periods
Section references to study assessments were added. 
Table 1
Timing of site check-in calls was added and clarified that 
additional site calls to subjects may be done as needed. 
Table 1
Provided clarification on which assessments should be 
collected pre-dose versus post-dose. 
Table 1
Added study procedure modifications due to COVID-19 
pandemic. 
Table 1
Section 8.1 Changes to Study 
Procedures Due to the COVID-19 
Pandemic 
Removed footnote regarding genotyping and other 
biomarker assay collection at Visit 1, 7, 11, and 14. 
Table 1
Section 8.3.7 Volume of Blood to 
be Drawn from Each Subject 
Revised to be more concise and include final results from 
DX-2930-04 study. 
Section 2.4.3 Clinical Studies 
with Lanadelumab 
Secondary objective regarding the subject experience with 
the prefilled syringe was revised to state “to evaluate subject 
experience of injection.”
Table 2
Combined off-site Visit 2 with all other off-site visits. 
Section 8.2 Study Periods
Added additional instructions and clarification on site 
check-in to subjects. 
Section 8.2 Study Periods
Added section on collection of angioedema attack data. 
Section 8.3.4.1 Collection of 
Angioedema Attack Data
Clarified that secondary efficacy analyses will be performed
using the Safety Population and the Reduced-Dose Safety 
Population. 
Section 9.5.2 Secondary Efficacy 
Analysis 
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Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected by Change
Revised HAE attack to angioedema attack. 
Section 9.5.2 Secondary Efficacy 
Analysis
Added a sentence to severity categorization of AEs to be 
consistent across lanadelumab studies. 
Appendix 3.3 Assessment of 
Adverse Events
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TAK-743-3001 Clinical Study Protocol Amendment 1
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14 Sep 2020
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 the 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 (eg, 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 Quality Complaint Data 
Collection Form” via the email address:
PQC@shire.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................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................9
TABLE OF CONTENTS...............................................................................................................10
LIST OF IN-TEXT TABLES ........................................................................................................15
LIST OF IN-TEXT FIGURES.......................................................................................................15
1. PROTOCOL SUMMARY.........................................................................................................16
1.1 Synopsis.............................................................................................................................16
1.2 Schema...............................................................................................................................22
1.3 Schedule of Activities........................................................................................................23
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 ...................................................................................................34
2.7 Compliance Statement .......................................................................................................37
3. OBJECTIVES AND ENDPOINTS...........................................................................................38
3.1 Study Objectives ................................................................................................................38
3.1.1 Primary Objective.....................................................................................................38
3.1.2 Secondary Objectives................................................................................................38
3.1.3 Exploratory Objectives .............................................................................................38
3.2 Study Endpoints.................................................................................................................38
4. STUDY DESIGN.......................................................................................................................40
4.1 Overall Design ...................................................................................................................40
4.2 Scientific Rationale for Study Design................................................................................41
4.3 Justification for Dose.........................................................................................................42
4.4 Duration of Subject Participation and Study Completion Definition................................43
4.5 Sites and Regions...............................................................................................................43
5. STUDY POPULATION............................................................................................................44
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5.1 Inclusion Criteria ...............................................................................................................44
5.2 Exclusion Criteria ..............................................................................................................44
5.3 Restrictions ........................................................................................................................45
5.3.1 Medical Interventions ...............................................................................................45
5.3.2 Fluid and Food Intake...............................................................................................45
5.3.3 Activity .....................................................................................................................45
5.4 Reproductive Potential.......................................................................................................45
5.4.1 Female Contraception...............................................................................................45
5.4.2 Male Contraception...................................................................................................46
6. STUDY INTERVENTION........................................................................................................47
6.1 Investigational Product ......................................................................................................47
6.1.1 Identity of Investigational Product............................................................................47
6.1.2 Blinding the Treatment Assignment.........................................................................47
6.2 Administration of Investigational Product.........................................................................47
6.2.1 Dosing.......................................................................................................................47
6.2.2 Unblinding the Treatment Assignment.....................................................................47
6.2.3 Dose Modification ....................................................................................................47
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product ..........................48
6.3.1 Labeling ....................................................................................................................48
6.3.2 Packaging..................................................................................................................48
6.3.3 Storage and Handling................................................................................................49
6.4 Drug Accountability...........................................................................................................50
6.5 Subject Compliance ...........................................................................................................51
6.6 Prior and Concomitant Therapy.........................................................................................51
6.6.1 Prior Treatment.........................................................................................................51
6.6.2 Concomitant Treatment ............................................................................................51
6.6.3 Permitted Treatment..................................................................................................52
6.6.4 Prohibited Treatment ................................................................................................52
7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL..........................................................................53
7.1 Discontinuation of Study Treatment..................................................................................53
7.2 Reasons for Discontinuation..............................................................................................53
7.3 Withdrawal from the Study................................................................................................53
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit .......................................54
7.5 Stopping Rules...................................................................................................................54
7.5.1 Study Level Stopping Rules......................................................................................54
7.5.2 Individual Stopping Rules.........................................................................................54
7.5.3 Follow-up for Subjects Meeting Stopping Criteria...................................................54
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8. STUDY ASSESSMENTS AND PROCEDURES.....................................................................55
8.1 Changes to Study Procedures Due to the COVID-19 Pandemic.......................................55
8.2 Study Periods .....................................................................................................................55
8.2.1 Screening Period.......................................................................................................55
8.2.2 Treatment Period.......................................................................................................56
8.2.2.1 Study Visit 1; Study Day 0 ..............................................................................56
8.2.2.2 Study Visits 3, 7, 11; Study Days 28, 84, 140 .................................................57
8.2.2.3 Study Visits 2, 4, 5, 6, 8, 9, 10, 12, 13; Study Days 14, 42, 56, 70, 98, 112, 
126, 154, and 168 ...................................................................................58
8.2.2.4 End of Treatment - Study Visit 14; Study Day 182.........................................58
8.2.2.5 Follow-up Period -- Study Visit 15; Study Day 196 .......................................59
8.2.3 Early Termination.....................................................................................................59
8.2.4 Additional Care of Subjects after the Study .............................................................59
8.3 Study Assessments.............................................................................................................59
8.3.1 Informed Consent......................................................................................................59
8.3.2 Eligibility Review.....................................................................................................59
8.3.3 Demographic and Other Baseline Characteristics ....................................................60
8.3.3.1 Medical and Medication History .....................................................................60
8.3.4 Efficacy.....................................................................................................................60
8.3.4.1 Collection of Angioedema Attack Data...........................................................60
8.3.4.2 Management of Acute Angioedema Attacks...................................................60
8.3.5 Safety ........................................................................................................................60
8.3.5.1 Physical Examination.......................................................................................60
8.3.5.2 Adverse Events ................................................................................................61
8.3.5.3 Adverse Events of Special Interest (AESIs)....................................................63
8.3.5.4 Vital Signs........................................................................................................63
8.3.5.5 Clinical Laboratory Tests.................................................................................64
8.3.5.6 Pregnancy Test.................................................................................................64
8.3.5.7 Electrocardiogram............................................................................................64
8.3.6 Other Study Assessments..........................................................................................64
8.3.6.1 Clinical Pharmacology.....................................................................................64
8.3.6.2 Pharmacodynamics ..........................................................................................64
8.3.6.3 Immunogenicity (Antidrug Antibody Testing)................................................64
8.3.6.4 Biomarkers.......................................................................................................65
8.3.6.5 Health-related Quality of Life (QoL)...............................................................65
8.3.6.6 Healthcare Resource Utilization ......................................................................65
8.3.6.7 Self-administration of Investigational Product................................................65
8.3.6.8 Injection Report ...............................................................................................66
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8.3.7 Volume of Blood to Be Drawn from Each Subject ..................................................66
8.3.8 Blood Sample Collection, Storage, and Shipping.....................................................67
9. STATISTICAL CONSIDERATIONS ......................................................................................68
9.1 Statistical Analysis Process................................................................................................68
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee................68
9.3 Sample Size and Power Considerations.............................................................................68
9.4 Statistical Analysis Set(s) ..................................................................................................68
9.4.1 Safety Population......................................................................................................68
9.4.2 Reduced-Dose Safety Population .............................................................................69
9.4.3 Pharmacokinetic Population .....................................................................................69
9.4.4 Pharmacodynamic Population ..................................................................................69
9.5 Efficacy Analyses ..............................................................................................................69
9.5.1 Primary Efficacy Analysis ........................................................................................69
9.5.2 Secondary Efficacy Analysis ....................................................................................69
9.5.3 Multiplicity Adjustment............................................................................................70
9.5.4 Control of Type I Error.............................................................................................70
9.5.5 Exploratory Efficacy Endpoints................................................................................70
9.6 Safety Analyses..................................................................................................................70
9.6.1 Adverse Events .........................................................................................................71
9.6.2 Laboratory Test Results............................................................................................72
9.6.3 Vital Signs.................................................................................................................72
9.6.4 Electrocardiography..................................................................................................73
9.7 Other Analyses...................................................................................................................73
9.7.1 Analysis of Pharmacokinetic Data............................................................................73
9.7.2 Analysis of Pharmacodynamic Data.........................................................................73
9.7.3 Analysis of Biomarker Data......................................................................................73
9.7.4 Analysis of Immunogenicity Data ............................................................................73
9.7.5 Health-related Quality of Life Analyses...................................................................73
9.7.6 Analysis of Experience with Study Drug Self-administration..................................74
10. REFERENCES ........................................................................................................................75
APPENDIX 1
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS.........................................................................................................79
Appendix 1.1
Regulatory and Ethical Considerations..................................................79
Appendix 1.2
Sponsor’s Responsibilities .....................................................................79
Appendix 1.3
Investigator’s Responsibilities ...............................................................80
Appendix 1.4
Data Management Considerations .........................................................83
Appendix 1.5
Ethical Considerations............................................................................83
APPENDIX 2
CLINICAL LABORATORY TESTS ....................................................87
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APPENDIX 3
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES 
FOR RECORDIANG, EVALUATING, FOLLOW-UP, AND REPORTING .................89
Appendix 3.1
Adverse Event Definitions .....................................................................89
Appendix 3.2
Collection of Adverse Events.................................................................92
Appendix 3.3
Assessment of Adverse Events ..............................................................92
Appendix 3.4
Safety Reporting.....................................................................................94
Appendix 3.5
Serious Adverse Event Collection Time Frame.....................................95
Appendix 3.6
Serious Adverse Event Onset and Resolution Dates..............................95
Appendix 3.7
Fatal Outcome ........................................................................................95
Appendix 3.8
Pregnancy...............................................................................................96
Appendix 3.9
Abuse, Misuse, Overdose and Medication Error ...................................96
Appendix 3.10
Urgent Safety Measures .........................................................................97
Appendix 3.11
Regulatory Agency, Institutional Review Board, Ethics 
Committee and Site Reporting .................................................................................98
APPENDIX 4
NON-HISTAMINERGIC BRADYKININ-MEDIATED 
ANGIOEDEMA ATTACK ASSESSMENT AND REPORTING PROCEDURES 
(BAARP), VERSION 4.0 ..................................................................................................99
APPENDIX 5
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)
100
APPENDIX 6
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS 
DISEASES, DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES 
(DMID) PEDIATRIC TOXICITY TABLES (US NATIONAL INSTITUTES OF 
HEALTH; NATIONAL INSTITUTE OF ALLERGY AND INFECTION 
DISEASES)
101
APPENDIX 7
SCALES AND ASSESSMENTS.........................................................102
APPENDIX 8
ABBREVIATIONS..............................................................................103
APPENDIX 9
PROTOCOL HISTORY ......................................................................107
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LIST OF IN-TEXT TABLES
Table 1
Schedule of Activities – Day 0 through Day 196..........................................23
Table 2
Objectives and Endpoints..............................................................................38
Table 3
Volume of Blood to Be Drawn from Each Subject.......................................67
LIST OF IN-TEXT FIGURES
Figure 1
Study Schematic Diagram .............................................................................22
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: TAK-743-3001
Drug: Lanadelumab 
Title of the study: An Open-Label Study to Evaluate the Long-Term Safety and Efficacy of Lanadelumab for 
Prevention Against Acute Attacks of Non-histaminergic Angioedema with Normal C1-Inhibitor (C1-INH)
Short title: Open-Label Study of Long-Term Safety and Efficacy of Lanadelumab for Prevention of Acute Attacks 
of Non-histaminergic Angioedema with Normal C1-Inhibitor
Study phase: Phase 3
Number of subjects (total and per treatment arm):
Approximately 75 subjects aged 12 years and older with non-histaminergic normal C1-INH angioedema who 
complete Study SHP643-303.
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 60 sites in North America, Europe, and Japan will participate.
Study period (planned):
August 2020 to January 2023
Clinical phase:
3
Objectives:
Primary: To evaluate the long-term safety of repeated subcutaneous (SC) administrations of lanadelumab in 
adolescents and adults with non-histaminergic angioedema with normal C1-INH
Secondary: 

To evaluate the long-term efficacy of lanadelumab in preventing angioedema attacks 

To characterize pharmacokinetics (PK) and pharmacodynamics (PD) following long-term SC administration of 
lanadelumab

To assess the immunogenicity of chronically administered lanadelumab

To evaluate the effect of lanadelumab on health-related quality of life (HR-QoL)

To evaluate subject experience of injection 

To evaluate the safety and efficacy of lanadelumab in subjects switched to the dosing regimen of 300 mg every 
4 weeks (q4wks) lanadelumab
Exploratory:

To evaluate exploratory biomarker(s) of angioedema disease-state bioactivity in plasma 
Rationale:
This open-label extension study will be preceded by the initiation of Study SHP643-303, 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). The rationale 
for this study is to continuously evaluate the long-term safety of repeated SC treatment with lanadelumab and the 
long-term efficacy of lanadelumab in preventing angioedema attacks for subjects with non-histaminergic 
angioedema with normal C1-INH who roll over from Study SHP643-303. 
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Investigational product, dose, and mode of administration:
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.
During the open-label extension treatment period, subjects may receive lanadelumab 300 mg every 2 weeks (q2wks) 
or may consider lanadelumab 300 mg q4wks if they have been well-controlled (eg, attack-free) for 26 consecutive 
weeks across Study SHP643-303 and Study TAK-743-3001. The dose frequency change to q4wks will be based on 
the investigator’s discretion and consultation with the sponsor’s medical monitor.
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 in the antecedent study (SHP643-303) or in this study and has 
demonstrated their understanding of self-administration.
Methodology:
Study TAK-743-3001 is an open-label, long-term safety and efficacy extension study of Study SHP643-303, to 
evaluate lanadelumab in preventing acute angioedema attacks in patients with non-histaminergic angioedema with 
normal C1-INH who roll over from Study SHP643-303.
All subjects must complete the double-blind treatment period at Day 182 of Study SHP643-303 and consent to enter 
Study TAK-743-3001. Subjects who discontinue from Study SHP643-303 after enrollment are not eligible to enroll 
in Study TAK-743-3001. 
Subjects should be asked about their interest in Study TAK-743-3001 after enrollment into SHP643-303 to 
anticipate enrollment and preparedness for Study TAK-743-3001. Willing subjects must sign informed consent for 
Study TAK-743-3001 on or after Day 168 of SHP643-303 and prior to any procedures in Study TAK-743-3001. 
Subjects who are eligible to roll over into Study TAK-743-3001, but elect not to, may not enroll in 
Study TAK-743-3001 at a later time. The first Study TAK-743-3001 visit (Day 0) will occur on the same day as the 
Study SHP643-303 Day 182 study visit. Subjects will complete all Study SHP643-303 final study assessments 
(Day 182) at which time they will be discharged from that study. No assessments conducted between the Study 
SHP643-303 Day 182 study visit and the first Study TAK-743-3001, visit (Day 0) will be duplicated. Results of the 
final SHP643-303 assessments on Day 182 will be used as the pre-dose results for Day 0 of Study TAK-743-3001.
All subjects, caregivers, investigators and study site personnel will remain blinded to the SHP643-303 treatment 
assignment until the conclusion of Study TAK-743-3001.
All subjects must adhere to the Schedule of Activities (Table 1) for the entire duration of the study. See Schedule of 
Activities (Table 1) for additional information on study visits.
Following their first open-label dose, subjects will continue to receive repeated SC administrations of open-label 
300 mg lanadelumab q2wks or may be considered to receive lanadelumab 300 mg q4wks if they have been 
well-controlled (eg, attack free) for 26 consecutive weeks across Study SHP643-303 and Study TAK-743-3001 per 
the scheduled dosing in the Study Activities Schedules. The dose frequency change to q4wks will be based on the 
investigator’s discretion and consultation with the sponsor’s medical monitor. The treatment period will last up to 
182 days from the date of the first open-label dose. The number of doses administered during this period will not 
exceed 13 doses. The Day 168 study visit is the last visit at which a dose may be administered. 
All doses should be administrated within the accepted ±4-day window around dose administration schedule (q2wks 
or q4wks in Table 1).
If a subject experiences an acute angioedema attack at any time during the study that in the opinion of the 
investigator requires medical intervention, standard of care therapy should be provided based on subject’s medical 
history and per locally approved product information. Administration of lanadelumab and study procedures will 
continue without alteration to the protocol study activities schedules, even if a subject receives treatment for a 
breakthrough angioedema attack on the day of a scheduled dose of study drug (if self-administering) or scheduled 
study visit.
All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a physical and mental 
capability of learning and willing to be trained) may be allowed to self-administer study treatment. Subjects must 
complete appropriate training in the antecedent study (SHP643-303) or in this study by the investigator or designee 
and understanding of the training must be documented by the investigator or designee. 
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Once trained, subjects may self-administer subsequent doses of lanadelumab at the investigational site (when visits 
are scheduled study site visits) or the subject’s home or other agreed upon location (when the study permits off-site 
dosing -- See Schedule of Activities [Table 1] for details). Adolescent subjects self-administering investigational 
product will be supervised by a parent/legal guardian/caregiver. Alternatively, a parent/legal guardian/caregiver, 
after completing appropriate training, will be allowed to administer lanadelumab to an adolescent without study site 
personnel supervision. Site personnel will call subjects within approximately 3 days after the planned off-site 
self-administrations to ensure the administration occurred, to collect AEs, concomitant medications, and to ensure 
all angioma attacks have been appropriately documented.
Throughout the study, study site personnel will document information in source documents (ie, the subject’s medical 
record) and electronic case report form (eCRF) regarding the subject’s experience with self-administration and 
SC administration of lanadelumab.
After completion of the treatment period, all subjects will undergo safety evaluations during a 2-week follow-up 
period.
If, at any time, a dose-related safety signal is identified either from this study or Study SHP643-303, the Sponsor 
may decide to modify the open-label lanadelumab dose and/or frequency.
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 diagnosed with non-histaminergic normal C1-INH angioedema at 
the time of enrollment into the antecedent Study SHP643-303. 
2.
Subjects must have completed the treatment period (through Day 182) of Study SHP643-303 without reporting 
a clinically significant treatment-emergent adverse event (TEAE) that would preclude subsequent exposure to 
lanadelumab.
3.
Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
4.
Males, or non-pregnant, non-lactating females who are of child-bearing potential and who agree to be abstinent 
or agree to comply with the applicable contraceptive requirements of this protocol for the duration of the study; 
or females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral 
oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months.
5.
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) at any time 
prior to study start. 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.
Discontinued from Study SHP643-303 after enrollment but before Visit 26 for any reason.
2.
Presence of important safety concerns identified in Study SHP643-303 that would preclude participation in this 
study.
3.
Dosing with an investigational product (IP, not including IP defined in antecedent Study SHP643-303) or 
exposure to an investigational device within 4 weeks prior to Day 0.
4.
Subject has a known hypersensitivity to the investigational product or its components.
5.
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).
Maximum duration of subject participation in the study:
Subjects who provide informed consent will roll over from Study SHP643-303. Eligible subjects will be enrolled 
and undergo a treatment period of up to 182 days. At the conclusion of the treatment period, subjects will be 
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followed for an additional 2 weeks.
All subjects will receive open-label lanadelumab during a treatment period of up to 182 days. 
The last dose of open-label lanadelumab administered may be given at the Day 168 study visit. 
There will be a ±4-day window around each study visit (+4 days for follow-up call at Visit 15). Subjects will be 
monitored at the study site through 1-hour post-dose for scheduled study site visits. No monitoring of vital signs will 
be performed for subjects who elect to self-administer away from the investigational site.
Statistical analysis:
Analysis Populations
The Safety Population will include all subjects who received any study drug after entering Study TAK-743-3001 
(ie, any exposure to open-label lanadelumab).
The Dose-Reduced Safety Population will include all subjects in the Safety Population who receive 300 mg q4wks 
open-label lanadelumab. 
The Pharmacokinetic population will include all subjects in the safety population who have at least 1 evaluable 
postdose PK concentration value.  
The Pharmacodynamic population will include all subjects in the safety population who have at least 1 evaluable 
postdose PD concentration value.
Criteria for Evaluation
Primary Endpoint: 
Safety measures, including:

Adverse events (AEs), including serious adverse events (SAEs) and adverse events of special interest (AESI)

Clinical laboratory testing (hematology, clinical chemistry, coagulation, and urinalysis)

Vitals signs including blood pressure, heart rate (HR), body temperature 

Weight and height (height for subjects <18 years old)

12-lead ECGs 
Secondary Endpoints:

Number of investigator-confirmed angioedema attacks during the treatment period

Number of moderate or severe angioedema attacks during the treatment period

Number of high-morbidity 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 mmHg, requires intravenous (IV) hydration, or associated with syncope or near-syncope) or laryngeal. 

Analysis of pharmacokinetics (PK) effects through measurement of plasma concentrations of lanadelumab.

Evaluation of the pharmacodynamic (PD) effects of lanadelumab through plasma cHMWK and fluorogenic 
plasma kallikrein (pKal) assay with FXIIa activation.

Presence of anti-drug antibodies (ADAs), including evaluation of neutralizing antibodies (if any confirmed 
positive anti-drug antibodies are detected)

Health-related quality of life assessments will be assessed using the AE-QoL questionnaire.

Lanadelumab Injection Report 

Safety measures, including:

AEs, including SAEs and AESIs

Clinical laboratory testing (hematology, clinical chemistry, coagulation, and urinalysis)

Vitals signs including blood pressure (BP), HR, body temperature 

Weight and height (height for subjects <18 years old)

12-lead ECGs

Efficacy measures, including:

Number of investigator-confirmed angioedema attacks during the treatment period
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
Number of moderate or severe angioedema attacks during the treatment period

Number of high-morbidity 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 mmHg, requires IV hydration, or associated with syncope or near-syncope) or 
laryngeal.
Exploratory Endpoints:

Exploratory biomarker(s) of angioedema-disease state bioactivity, including pKal activity
Safety Analyses
Adverse Events
Treatment-emergent AEs are defined as AEs with onset at the time of or following the first exposure to open-label 
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. 
In this study, angioedema attacks will be captured as AEs and will be evaluated in accordance with Non-
histaminergic Bradykinin-mediated Angioedema Attack Assessment and Reporting Procedures (BAARP).
The analyses described in this section will be based on treatment-emergent AEs; plainly referred to as AEs in this 
section for brevity. 
Related AEs are AEs classified as related to study drug by the investigator. Severe AEs are AEs classified as severe 
(Grade 3) or life threatening (Grade 4) by the investigator.
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. The number of deaths due to an AE, hospitalization due to an AE and study discontinuation due 
to an AE will be summarized. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be summarized by 
system organ class (SOC), and preferred term (PT). This tabulation will be repeated for related AEs, SAEs, related 
SAEs, severe AEs, and related severe AEs. 
Adverse event of special interest for this study are hypersensitivity reactions. Standardized Medical Dictionary for 
Regulatory Activities (MedDRA) Queries (SMQ) for AESIs will be performed using the study data. The number 
and percentage of subjects with an AESI, as well as the total number of AESIs, will be summarized by SOC and PT. 
Separate summary tables will be created for AESI and for those events with the SMQs classified as related, serious, 
related serious, severe, and related severe. A listing detailing the PT within the SMQ will be provided.
Laboratory Test Results, Vital Signs, and Electrocardiography Results
Baseline is the last non-missing value prior to first exposure to study drug in Study SHP643-303.
Actual values and change from baseline in clinical laboratory test results and vital signs will be summarized by 
study visit. 
Laboratory test results will be classified according to the reference ranges and clinical significance as determined by 
the investigator. 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 within 
each category will be summarized by study visit. 
The number and percentage of subjects with normal, abnormal not clinically significant and abnormal clinically 
significant ECG results will be summarized. 
Efficacy Analyses
Number of Investigator-confirmed Angioedema Attacks
The number of investigator-confirmed angioedema attacks during the treatment period (Day 0 through Day 182) 
expressed as a monthly angioedema attack rate, will be analyzed using each analysis population.
The treatment period investigator-confirmed monthly angioedema attack rate will be calculated for each subject as 
the number of investigator-confirmed angioedema attacks occurring during the treatment period divided by the 
number of days the subject contributed to the treatment period multiplied by 28 days. 
The baseline investigator-confirmed monthly angioedema attack rate will be calculated for each subject as the 
number of investigator-confirmed monthly angioedema attacks occurring during the baseline observation period of 
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Study SHP643-303 divided by the number of days the subject contributed to the baseline observation period 
multiplied by 28 days.
The baseline, treatment period, and treatment period change from baseline in the investigator-confirmed angioedema
attack rate will be summarized for each analysis population. The summary will include the total number of 
investigator-confirmed angioedema attacks reported during each period and subject-time in months that each subject 
contributed to each period. Figures will be created for each analysis population plotting the on-study 
investigator-confirmed angioedema attacks reported during the treatment period relative to Day 0 for each subject.
Similar summary tables will be presented for the following efficacy endpoints for each analysis population:

Number of moderate or severe investigator-confirmed angioedema attacks during the treatment period.

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 mmHg, requires IV hydration, or associated with syncope or 
near-syncope) or laryngeal.
Other Analyses
Plasma concentrations of lanadelumab and plasma kallikrein activity will be summarized by nominal PK and PD 
sampling times.
The number and percentage of subjects with positive antibodies (and whether neutralizing or non-neutralizing) and 
exploratory biomarkers will be summarized by study visit and overall.
Quality of life assessments will be summarized by study visit.
Sample Size Determination
No formal sample size calculation was performed. The sample size is not based on any statistical considerations. 
This study is designed to evaluate the safety and efficacy of open-label treatment with lanadelumab in subjects who 
completed Study SHP643-303.
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1.2 Schema
Figure 1
Study Schematic Diagram
q2wks=every 2 weeks; q4wks=every 4 weeks
*
Subjects may consider switching to lanadelumab 300 mg q4wks if they have been well-controlled (eg, attack-free) for 
26 consecutive weeks across Study SHP643-303 and Study TAK-743-3001. The dose frequency change to q4wks will be 
based on the investigator’s discretion and consultation with the sponsor’s medical monitor.
Note: Subjects with non-histaminergic angioedema with normal C1-INH may roll over from SHP643-303 study into an open-
label extension study upon completion of all assessments (in SHP643-303) scheduled on Day 182.
Subjects rolled-over 
from Study SHP643-303
(n=up to 75)
Lanadelumab 300 mg
q2wks Or q4wks*
(up to 13 doses)
Follow-up
Open-label Treatment Period 26 weeks
Two weeks
(4 weeks from the 
last dose on  Day 168)
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ADA=anti-drug antibody; ECG=Electrocardiogram; EOS=end-of-study visit; ET=early termination visit; PK=Pharmacokinetic; PD=Pharmacodynamic
a Subjects must sign informed consent for Study TAK-743-3001 on or after Day 168 of Study SHP643-303. Day 182 of Study SHP643-303 is also Day 0 of 
Study TAK-743-3001, and informed consent should be completed on this visit, if not already provided.
b These assessments will be carried over from the last study visit (Day 182) from Study SHP643-303; no study assessments will be duplicated. 
c Demography data from Study SHP643-303 will be re-entered (in clinical database) for Study TAK-743-3001. However, medical history reported in the Study 
SHP643-303 will not be re-entered into the eCRF for Study TAK-743-3001; only new medical history data will be entered.
d Height should be measured for subjects aged <18 years at time of consent for Study SHP643-3001. 
e Doses are administered within ±4 days of lanadelumab administration schedule. During the open-label extension treatment period, subjects may receive 
lanadelumab 300 mg every 2 weeks (q2wks) or may consider lanadelumab 300 mg every 4 weeks (q4wks) if they have been well-controlled (eg, attack free) 
for 26 consecutive weeks across Study SHP643-303 and Study TAK-743-3001. The dose frequency change to q4wks will be based on the investigator’s 
discretion and discussion with the sponsor’s medical monitor.
f At each on-site visit in which a dose of lanadelumab is administered, assessments will be collected prior to administration of investigational product. The 
following assessments will also be collected post-dose: vital signs, lanadelumab injection report, concomitant therapies, medications, procedures, and AE 
collection.
g Pregnancy testing may be urine- or serum-based and will be performed for females of childbearing potential.
h 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.
i 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.
j Clinical laboratory testing including hematology, serum chemistry, coagulation, and urinalysis.
k 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. 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. 
l Health-related quality of life (HRQoL) data will be obtained predose at the scheduled dosing time points.
m Site personnel will call subjects within approximately 3 days after the planned self-administration to ensure the administration occurred, to collect AEs and 
concomitant medications, and to ensure all angioma attacks have been appropriately documented. Additional site calls to the subject may be done as needed. 
n Injection reports will be collected assessing the subject’s or parent/caregiver’s experience with SC injection of investigational product.
o 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. See Section 8.1 of the protocol for additional details.
p Subjects who terminate the study early will undergo (if possible) all of the study assessments and procedures at Visit 14/ET.
q Visit 15 assessments may be collected by telephone.
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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; 
HAE=hereditary angioedema; 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: A) non-histaminergic angioedema with normal C1-INH 
and B) acquired angioedema (AAE) due to C1-INH deficiency.
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 both non-histaminergic normal C1-INH angioedema and AAE due to C1 
deficiency (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 (WK), 
which is generated by pKal concomitant with bradykinin, was also elevated in the plasma from 
patients with AAE due to C1-INH deficiency and 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). 
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The prevalence for AAE due to C1-INH deficiency or non-histaminergic normal C1-INH 
angioedema are even much lower (Busse and Buckland, 2012; Agostoni et al., 2004; 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). 
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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 
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 
Factor 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.
Source: 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 has 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 plasma 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 months 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. 
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The proposed indication of lanadelumab for routine prophylaxis to prevent attacks of HAE in 
patients 12 years and older is primarily supported by the efficacy results from a double-blind, 
placebo-controlled Phase 3 study (DX-2930-03). Supportive data, including durability of 
response and long-term safety, are provided from the open-label, Phase 3 study (DX-2930-04) 
and the proof of concept, Phase 1b, multiple ascending dose study (DX-2930-02). Prior to 
evaluating lanadelumab in subjects with HAE, a randomized, double-blind, placebo-controlled, 
Phase 1a, single ascending dose study evaluated the safety, tolerability, and PK of a single dose 
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 days 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, 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 mg 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 mg and 400 mg lanadelumab treatment groups, respectively. The 
effects on HAE attacks were associated with drug exposure.
The lanadelumab clinical development program has 2 Phase 3 clinical studies in adolescent 
(≥12 years old 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 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. The dosing regimens in this study were: 300 mg q2wks, 300 mg 
q4wks, and 150 mg q4wks.  
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 
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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%). 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. 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. 
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 has completed enrollment; the study enrolled 
212 total subjects, including 109 who rolled over from DX-2930-03 and 103 nonrollover 
subjects. The safety profile in study DX-2930-04 is consistent with the pivotal 
Study DX-2930-03. 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 over the treatment period (33 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. 
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2.4.4 Adolescent Clinical Trial Experience
The Phase 3 clinical studies for lanadelumab, pivotal Study DX-2930-03 and the open-label 
extension Study DX-2930-04, evaluated the adult and adolescent population; inclusion of 
adolescents in these studies was justified based on the similarity of the pathophysiology 
and clinical presentation of HAE in adults and adolescents, as well as by the lack of any safety 
signal identified in nonclinical and clinical studies to date. As of the data cut for the global 
marketing license or authorization application for lanadelumab, 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 years to <40 years and ≥40 years 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 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 adverse 
events of special interest (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 electrocardiograms (ECGs). 
Overall, the safety and tolerability of lanadelumab were similar in the pediatric population 
(12 years old to <18 years old) and adults (≥18 years old).
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Population PK analyses for adolescents and adults in Phase 3 studies, indicate no apparent 
influence of age on clearance 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 years to <18 years). Refer to the latest lanadelumab Investigator’s 
Brochure (IB).
2.5 Study Rationale
This open-label extension study will be preceded by the initiation of Study SHP643-303, 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-INH. The rationale for this study is to continuously evaluate the long-term safety 
of repeated subcutaneous treatment with lanadelumab and the long-term efficacy of lanadelumab 
in preventing angioedema attacks for subjects with non-histaminergic angioedema with normal 
C1-INH who roll over from Study SHP643-303. 
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 (ISR), 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 ongoing 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 
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 
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(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 
physical findings. No subject receiving treatment with lanadelumab had an abnormal, clinically 
significant 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 
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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 
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 to 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. 
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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 (Table 1).
Always refer to the latest version of the lanadelumab IB for the overall benefit/risk assessment 
and the most accurate and current information regarding drug metabolism, pharmacokinetics, 
efficacy, and safety of lanadelumab.
2.7 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, 1996; ICH E6 R2, 2016), 
Title 21 of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 
2005/28/EC), and applicable national and local regulatory requirements.
The responsibilities of the study sponsor and investigator(s) are described fully in Appendix 1.
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3. OBJECTIVES AND ENDPOINTS
3.1 Study Objectives
3.1.1 Primary Objective

To evaluate the long-term safety of repeated SC administrations of lanadelumab in 
adolescents and adults with non-histaminergic angioedema with normal C1-INH
3.1.2 Secondary Objectives

To evaluate the long-term efficacy of lanadelumab in preventing angioedema attacks 

To evaluate PK and PD following long-term SC administration of lanadelumab

To assess the immunogenicity of chronically administered lanadelumab

To evaluate the effect of lanadelumab on health-related quality of life (QoL)

To evaluate subject experience of injection 

To evaluate the safety and efficacy of lanadelumab in subjects switched to the dosing 
regimen of 300 mg q4wks lanadelumab
3.1.3 Exploratory Objectives

To evaluate exploratory biomarker(s) of angioedema disease-state bioactivity in plasma 
3.2 Study Endpoints
Table 2
Objectives and Endpoints
Objective
Endpoint(s)
Primary
•
To evaluate the long-term safety
of repeated SC administrations 
of lanadelumab in adolescents 
and adults with non-
histaminergic angioedema with 
normal C1-INH
Primary Safety Endpoints
Safety measures, including

AEs including SAEs and adverse events of special interest (AESIs)

Clinical laboratory testing (hematology, clinical chemistry, 
coagulation, and urinalysis)

Vitals signs including blood pressure (BP), heart rate (HR), body 
temperature 

Weight and height (height for subjects <18 years old) 

12-lead ECGs
Secondary
•
To evaluate the long-term 
efficacy of lanadelumab in 
preventing angioedema attacks

Number of investigator-confirmed angioedema attacks during the 
treatment period

Number of moderate or severe angioedema attacks during the 
treatment period

Number of high-morbidity 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 mmHg, 
requires IV hydration, or associated with syncope or near-syncope) or 
laryngeal. 
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Table 2
Objectives and Endpoints
Objective
Endpoint(s)
•
To characterize the PK and PD 
profile of SC administration of 
lanadelumab

Analysis of PK effects through measurement of plasma 
concentrations of lanadelumab.

Evaluation of the PD effects of lanadelumab through plasma 
cHMWK and fluorogenic pKal assay with FXIIa activation.
•
To assess the immunogenicity of 
chronically administered 
lanadelumab

Presence of ADAs, including evaluation of neutralizing antibodies (if 
any confirmed positive anti-drug antibodies are detected)
•
To evaluate the effect of 
lanadelumab on health-related 
quality of life (QoL)

Health-related QoL assessments will be assessed using the AE-QoL 
questionnaire.
•
To evaluate subject experience 
of injection

Lanadelumab Injection Report 
•
To evaluate the safety and 
efficacy of lanadelumab in 
subjects switched to the dosing 
regimen of 300 mg q4wks 
lanadelumab
Safety measures, including:

AEs, including SAEs and AESIs

Clinical laboratory testing (hematology, clinical chemistry, 
coagulation, and urinalysis)

Vitals signs including BP, HR, body temperature 

Weight and height (height for subjects <18 years old)

12-lead ECGs
Efficacy measures, including:

Number of investigator-confirmed angioedema attacks during the 
treatment period

Number of moderate or severe angioedema attacks during the 
treatment period

Number of high-morbidity 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 mmHg, 
requires IV hydration, or associated with syncope or near-syncope) or 
laryngeal.
Exploratory
•
To evaluate exploratory 
biomarker(s) of angioedema 
disease-state bioactivity in 
plasma

Exploratory biomarker(s) of angioedema-disease state bioactivity, 
including pKal activity
ADA=anti-drug antibodies; AE=adverse event; AESI=adverse event of special interest; BP=blood pressure, C1-INH=C1 
inhibitor or C1 esterase inhibitor, cHMWK=cleaved high molecular weight kininogen; FXIIa=coagulation factor XIIa; 
ECG=electrocardiogram; HR=heart rate; IV=intravenous; PD=pharmacodynamic; PK=pharmacokinetic; pKal=plasma kallikrein; 
QoL=quality of life; SAE=serious adverse event; SC=subcutaneous
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4. STUDY DESIGN
4.1 Overall Design
Study TAK-743-3001 is an open-label, long-term safety and efficacy extension study of 
Study SHP643-303 to evaluate lanadelumab in preventing acute angioedema attacks in patients 
with non-histaminergic angioedema with normal C1-INH who roll over from 
Study SHP643-303.
All subjects must complete the double-blind treatment period at Visit 26/Day 182 of 
Study SHP643-303 and consent to enter Study TAK-743-3001. Subjects who discontinue from 
Study SHP643-303 after enrollment but before Visit 26 are not eligible to enroll in 
Study TAK-743-3001. 
Subjects should be asked about their interest in Study TAK-743-3001 after enrollment into 
SHP643-303 to anticipate enrollment and preparedness for Study TAK-743-3001. Willing 
subjects must sign informed consent for Study TAK-743-3001 on or after Day 168 of 
SHP643-303 and prior to any procedures in Study TAK-743-3001. 
Subjects who are eligible to roll over into Study TAK-743-3001, but elect not to, may not enroll 
in Study TAK-743-3001 at a later time. The first Study TAK-743-3001 visit (Day 0) will occur 
on the same day as the Study SHP643-303 Day 182 study visit. Subjects will complete all 
Study SHP643-303 final study assessments (Visit 26/Day 182) at which time they will be 
discharged from that study. No assessments conducted between the Study SHP643-303 Day 182 
study visit and the first Study TAK-743-3001, visit (Day 0) will be duplicated. Results of the 
final SHP643-303 assessments on Day 182 will be used as the pre-dose results for Day 0 of 
Study TAK-743-3001.
All subjects, caregivers, investigators and study site personnel will remain blinded to the 
SHP643-303 treatment assignment until the conclusion of Study TAK-743-3001.
All subjects must adhere to the Schedule of Activities (Table 1) for the entire duration of the 
study. See Schedule of Activities (Table 1) for additional information on study visits.
Following their first open-label dose, subjects will continue to receive repeated SC 
administrations of open-label 300 mg lanadelumab q2wks or may be considered to receive 
lanadelumab 300 mg q4wks if they have been well-controlled (eg, attack free) for 26 consecutive 
weeks across Study SHP643-303 and Study TAK-743-3001 per the scheduled dosing in the 
Study Activities Schedules. The dose frequency change to q4wks will be based on the 
investigator’s discretion and consultation with the sponsor’s medical monitor. The treatment 
period will last up to 168 days from the date of the first open-label dose. The number of doses 
administered during this period will not exceed 13 doses. The Day 168 study visit is the last visit 
at which a dose may be administered. 
All doses should be administrated within the accepted ±4-day window around dose 
administration schedule (q2wks or q4wks in Table 1).
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If a subject experiences an acute angioedema attack at any time during the study that in the 
opinion of the investigator requires medical intervention, standard of care therapy should be 
provided based on subject’s medical history and per locally approved product information. 
Administration of lanadelumab and study procedures will continue without alteration to the 
protocol study activities schedules, even if a subject receives treatment for a breakthrough 
angioedema attack on the day of a scheduled dose of study drug (if self-administering) or 
scheduled study visit.
All subjects (adolescent or adult) who are considered suitable candidates (ie, those with a 
physical and mental capability of learning and willing to be trained) may be allowed to 
self-administer study treatment. Subjects must complete appropriate training in the antecedent 
study (SHP643-303) or in this study by the investigator or designee and understanding of the 
training must be documented by the investigator or designee. Once trained, subjects may 
self-administer subsequent doses of lanadelumab at the investigational site (when visits are 
scheduled study site visits) or the subject’s home or other agreed upon location (when the 
study permits off-site dosing -- See Schedule of Activities [Table 1] for details). Adolescent 
subjects self-administering investigational product will be supervised by a parent/legal 
guardian/caregiver. Alternatively, a parent/legal guardian/caregiver, after completing appropriate 
training in the antecedent study (SHP643-303) or in this study, will be allowed to administer 
lanadelumab to an adolescent without study site personnel supervision. Site personnel will call 
subjects within approximately 3 days after the planned off-site self-administrations to ensure the 
administration occurred, to collect AEs, concomitant medications, and to ensure all angioma 
attacks have been appropriately documented.
Throughout the study, study site personnel will document information in source documents (ie, 
the subject’s medical record) and electronic case report form (eCRF) regarding the subject’s 
experience with self-administration and SC administration of lanadelumab.
After completion of the treatment period, all subjects will undergo safety evaluations during a 
2-week follow-up period.
If, at any time, a dose-related safety signal is identified either from this study or 
Study SHP643-303, the Sponsor may decide to modify the open-label lanadelumab dose and/or 
frequency. 
4.2 Scientific Rationale for Study Design
This open-label extension study will be preceded by the initiation of Study SHP643-303, 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-INH and AAE due to C1-INH deficiency. The rationale for this study is to 
continuously evaluate the long-term safety of repeated subcutaneous treatment with lanadelumab 
and the long-term safety and efficacy of lanadelumab in preventing angioedema attacks for 
subjects with non-histaminergic angioedema with normal C1-INH who roll over from 
Study SHP643-303. 
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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 angioedema 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 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 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 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 includes 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 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. 
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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 q2wks dose regimen is considered to be the appropriate dose 
for the antecedent SHP643-303study and this open-label extension study in subjects with BMA 
other than Type I and Type II HAE.
4.4 Duration of Subject Participation and Study Completion Definition
Subjects who provide informed consent will roll over from Study SHP643-303. Eligible subjects 
will be enrolled and undergo a treatment period of up to 182 days. At the conclusion of the 
treatment period, subjects will be followed for an additional 2 weeks.
All subjects will receive open-label lanadelumab during a treatment period of up to 182 days. 
The last dose of open-label lanadelumab administered may be given at the Day 168 study visit. 
There will be a ±4-day window around each study visit (+4 days for follow-up call at Visit 15). 
Subjects will be monitored at the study site through 1-hour postdose for scheduled study site 
visits. No monitoring of vital signs will be performed for subjects who elect to self-administer
away from the investigational site.
The subject’s maximum duration of participation is expected to be approximately 196 days. The 
last subject last visit will be completed in approximately January 2023.
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, 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 criteria below.
1. Males and females, 12 years of age and older diagnosed with non-histaminergic normal 
C1-INH angioedema at the time of enrollment into the antecedent Study SHP643-303. 
2. Subjects must have completed the treatment period (through Visit 26/Day 182) of 
Study SHP643-303 without reporting a clinically significant TEAE that would preclude 
subsequent exposure to lanadelumab.
3. Agree to adhere to the protocol-defined schedule of treatments, assessments, and 
procedures.
4. Males, or non-pregnant, non-lactating females who are of child-bearing potential and 
who agree to be abstinent or agree to comply with the applicable contraceptive 
requirements of this protocol for the duration of the study; or females of non-childbearing 
potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, 
or bilateral tubal ligation) or post-menopausal for at least 12 months.
5. 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) at any time prior to study start. 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. Discontinued from Study SHP643-303 after enrollment but before Visit 26 for any 
reason.
2. Presence of important safety concerns identified in Study SHP643-303 that would 
preclude participation in this study.
3. Dosing with an investigational product (IP, not including IP defined in antecedent 
Study SHP643-303) or exposure to an investigational device within 4 weeks prior to 
Day 0.
4. Subject has a known hypersensitivity to the investigational product or its components.
5. 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 
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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.
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.
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•
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 activity 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).
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.
Note: Estrogen-containing medications with systemic absorption are not allowed in the study.
5.4.2 Male Contraception
Male subjects must be advised to use acceptable contraceptives throughout the study period and 
for 160 days following the dose of investigational product. Male subjects must be advised not to 
donate sperm during the course of the study and within 160 days of the dose of investigational 
product. Acceptable methods of contraception for male subjects include:

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam).
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6. STUDY INTERVENTION
6.1 Investigational Product
6.1.1 Identity of Investigational Product
The investigational 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 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.
During the open-label extension treatment period, subjects may receive lanadelumab 300 mg 
q2wks or may consider lanadelumab 300 mg q4wks if they have been well-controlled (eg, attack 
free) for 26 consecutive weeks across Study SHP643-303 and Study TAK-743-3001. The dose 
frequency change to q4wks will be based on the investigator’s discretion and consultation with 
the sponsor’s medical monitor.
Commercial icatibant will not be supplied as rescue medication for the treatment of acute 
angioedema attacks. If a subject experiences an acute angioedema attack at any time during the 
study, standard of care therapy may be provided per locally approved product information.
6.1.2 Blinding the Treatment Assignment
Not applicable.
6.2 Administration of Investigational Product
6.2.1 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 in the antecedent study 
(SHP643-303) or in this study by the investigator or designee and has demonstrated their 
understanding of self-administration.
6.2.2 Unblinding the Treatment Assignment
Not applicable.
6.2.3 Dose Modification
During the open-label extension treatment period, subjects may consider lanadelumab 300 mg 
q4wks if they have been well-controlled (eg, attack-free) for 26 consecutive weeks across 
Study SHP643-303 and Study TAK-743-3001. The dose frequency change to q4wks will be 
based on the investigator’s discretion and consultation with the sponsor’s medical monitor.
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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, 
medical identification 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.
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 (Section 8.3.6.7), will be provided the following supplies as applicable:
•
1 dose supply of investigational product
•
Ancillary supplies, and a container for sharps disposal
•
Subject accountability form to record investigational product administration details
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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°C to 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 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.
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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.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records. 
With the written agreement of the sponsor, at the end of the study all unused stock,
subject-returned investigational product, and empty/used investigational product packaging may 
be destroyed at the site or a local facility. In this case, destruction records identifying what was 
destroyed, when and how, must be obtained with copies provided to the sponsor. Destruction of 
investigational 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. 
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Investigational product being returned to the sponsor’s designated contractors must be counted 
and verified by clinical site personnel and the sponsor (or designated contract research 
organization [CRO]). For unused supplies where the 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, interactive response technology) 
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 Visit 1 (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.
6.6.1 Prior Treatment
Prior treatment will be obtained from Study SHP643-303.
Prior treatments that have a stop date in Study SHP643-303 will not be re-recorded in the 
Study TAK-743-3001 clinical database. However, any prior medication that started in 
Study SHP643-303 (or before) and are still ongoing at the time of rollover into TAK-743-3001 
will be recorded in the source documents and clinical database.
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.
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6.6.3 Permitted Treatment
The following concomitant therapies are allowed during the study:
•
Therapies for coexisting conditions, including those for acute attacks of angioedema 
attacks (see below), are permitted if not excluded during the study (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.
•
Commercial icatibant will not be supplied as rescue medication for the treatment of acute 
angioedema attacks. If a subject experiences an acute angioedema attack at any time 
during the study, standard of care therapy may be provided per locally approved product 
information. 
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 may also be rescheduled as 
long as the minimum and maximum timeframe between doses are met based on subject 
preference or physician discretion.
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) during the study.

Angiotensin-converting enzyme inhibitors or rituximab during the study.

Estrogen-containing medications with systemic absorption during the study.

Use of androgens (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) 
for non-angioedema related medical conditions or for angioedema 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 14) 
as completely as possible (Section 8.2.2.4). 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 prematurely discontinue investigational product will not be replaced.
7.2 Reasons for Discontinuation
The reason for discontinuation 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 eCRF)
7.3 Withdrawal from the Study
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution, or may be withdrawn at any 
time at the discretion of the investigator or sponsor (eg, in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the medical monitor when 
possible.
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7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject who is lost to 
follow-up at any time point prior to the last scheduled contact (office visit or 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. Subjects who prematurely discontinue investigational 
product should undergo final visit of the treatment period procedures specified for Study 
Day 182 (Visit 14) as completely as possible (Section 8.2.2.4).
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:

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
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. 

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 for the Schedule of Study Activities. Study assessments are detailed in 
Section 8.3.
8.2.1 Screening Period 
Informed consent must be obtained before any study-specific procedures are performed. Subjects 
must sign informed consent for Study TAK-743-3001 on or after Day 168 of Study SHP643-303. 
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Day 182 of Study SHP643-303 is also Day 0 of Study TAK-743-3001, and informed consent 
must be completed on this visit, if not already provided.
8.2.2 Treatment Period
8.2.2.1 Study Visit 1; Study Day 0
As indicated in Table 1, Visit 1 on Day 0 will be a scheduled on-site visit. The following 
procedures and assessments are to be performed on Day 0 prior to the first dose of 
investigational product:
•
Informed Consent 
•
Confirmation of study eligibility
•
Demographics
Note: Demography data from Study SHP643-303 will be re-entered (in clinical 
database) for Study TAK-743-3001. 
•
Documentation of height (for subjects aged <18 years at time of consent for Study 
SHP643-3001)
Subjects will undergo the following assessments on Day 0 after lanadelumab is administered as a 
SC injection:
•
Vital signs (30 minutes [±15 minutes] after completion of the injection of investigational 
product), including body temperature, HR, BP, and respiratory rate (RR)
•
Lanadelumab Injection Report
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
All subjects who take part in this protocol will have participated in Study SHP643-303. Subjects 
will enter this protocol on the same day as their last Study Visit (Day 182) in Study SHP643-303. 
The following assessments will be carried over into this study:
•
Medical History
Note: Medical history reported in the Study SHP643-303 will not be re-entered into the 
eCRF for Study TAK-743-3001; only new medical history data will be entered.
•
Complete physical examination 
•
12-lead ECG
•
Pregnancy test (for female subjects of childbearing-potential)
•
Clinical laboratory testing including hematology, serum chemistry, coagulation, and 
urinalysis
•
PK sample collection 
•
PD sample collection 
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•
Plasma ADA sample collection 
•
Biomarker sample collection
•
Health-related QoL assessment (using the AE-QoL questionnaire)
•
Prior therapies, medications, and procedures
•
Angioedema attack data
•
Adverse events collection, including SAEs and AESIs 
8.2.2.2 Study Visits 3, 7, 11; Study Days 28, 84, 140
As indicated in Table 1, Visits 3, 7, and 11 on Study Days 28, 84, and 140 respectively, will be 
scheduled on-site visits. The following procedures and assessments are to be performed on 
Days 28, 84, and 140 prior to investigational product administration:
•
Vital signs (within 60 minutes prior to the injection of investigational product), including 
body temperature, HR, BP, and RR
•
Complete physical examination (including documentation of body weight)
•
Pregnancy test (for female subjects of childbearing potential)
•
Clinical laboratory testing including hematology, serum chemistry, coagulation, and 
urinalysis
•
Concomitant therapies, medications, and procedures
•
PK sample collection (on Visits 7 and 11 only) 
•
PD sample collection (on Visits 7 and 11 only)
•
Plasma ADA sample collection (on Visits 7 and 11 only)
•
Biomarker sample collection (on Visits 7 and 11 only)
•
Health-related QoL assessment (using the AE-QoL questionnaire)
•
Angioedema attack data
•
Adverse events collection, including SAEs and AESIs 
Subjects will undergo the following assessments on Days 28, 56, 84, 112, 140 and 182 after 
lanadelumab is administered as a SC injection:
•
Vital signs (30 minutes [±15 minutes] after completion of the injection of investigational 
product), including body temperature, HR, BP, and RR
•
Lanadelumab Injection Report
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
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8.2.2.3 Study Visits 2, 4, 5, 6, 8, 9, 10, 12, 13; Study Days 14, 42, 56, 70, 98, 112, 126, 
154, and 168 
As indicated in Table 1, Visits 2, 4, 5, 6, 8, 9, 10, 12, and 13 on Study Days 14, 42, 56, 70, 98, 
112, 126, 154, and 168, respectively, will be potential subject-elected off-site activity and/or 
self-administration dosing days. The following procedures and assessments are to be performed 
prior to investigational product administration:
•
Concomitant therapies, medications, and procedures
•
Angioedema attack data
•
Adverse events collection, including SAEs and AESIs 
Subjects will undergo the following assessments after lanadelumab is administered as a SC 
injection:
•
Lanadelumab Injection Report
•
Concomitant therapies, medications, and procedures
•
Adverse events collection, including SAEs and AESIs
If a subject does not have a scheduled on-site visit on study days specified in Table 1, 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. Additional site calls to the subject may be done as needed.
8.2.2.4 End of Treatment - Study Visit 14; Study Day 182
As indicated in Table 1, Visit 14 on Day 182 will be a scheduled on-site visit. The following 
procedures and assessments are to be performed on Day 182:
•
Vital signs, including body temperature, HR, BP, and RR
•
Complete physical examination (including documentation of body weight)
•
Pregnancy test (for female subjects of childbearing-potential)
•
Clinical laboratory testing including hematology, serum chemistry, coagulation, and 
urinalysis
•
12-lead ECG
•
Concomitant therapies, medications, and procedures
•
PK sample collection 
•
PD sample collection 
•
Plasma ADA sample collection 
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•
Biomarker sample collection 
•
Health-related QoL assessment (using the AE-QoL questionnaire)
•
Angioedema attack data
•
Adverse events collection, including SAEs and AESIs 
8.2.2.5 Follow-up Period -- Study Visit 15; Study Day 196
As indicated in Table 1, the Follow-up period for this study is 14 days (2 weeks) (+4 days). The 
final end of study (EOS) visit (Day 196, Visit 15) will be by telephone call from the site. 
•
Concomitant therapies, medications, and procedures
•
Angioedema attack data
•
Adverse events collection, including SAEs and AESIs 
All AEs and SAEs that are not resolved at the time of this contact will be followed to closure 
(Appendix 3.2). Subjects will be discharged from the study after the completion of the EOS 
assessments.
8.2.3 Early Termination
All procedures and assessments scheduled for final visit of the treatment period (Day 182, 
Visit 14) will be followed for the early termination (ET) visit (Table 1).
8.2.4 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.
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).
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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
New medical and medication history will be collected and recorded in the subject’s source 
documents. 
8.3.4 Efficacy
Throughout the study (ie, from Day 0 through follow-up), angioedema attack information will be 
solicited by site personnel during scheduled study visits and site check-ins, as shown in Table 1. 
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 Non-histaminergic Bradykinin-mediated Angioedema Attack Assessment 
and Reporting Procedures (BAARP) provided in Appendix 4 of this protocol. Site personnel will 
be trained on BAARP prior to screening subjects at their site.
8.3.4.1 Collection of Angioedema Attack Data 
Angioedema attack information will be solicited by site personnel during scheduled study visits 
and site check-ins, as shown Table 1. 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 4 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
Commercial icatibant will not be supplied as rescue medication for the treatment of acute 
angioedema attacks. If a subject experiences an acute angioedema attack at any time during the 
study, standard of care therapy may be provided per locally approved product information.
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). The date and time of each 
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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
•
Dermatological
•
Lymphatic
•
Body weight for all patients 
Note: Height should be documented for subjects aged <18 years at time of consent for study 
SHP643-3001 (Visit 1 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 (ICF) 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. Up to the EOS visit, 
AEs, actions taken as a result of AEs, and follow-up results must be recorded in the 
eCRF; post-EOS visit follow-up results will be recorded in the subject's source 
documentation. Follow-up laboratory results should be filed with the subject's source 
documentation.
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•
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 14) 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 
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 nonangioedema 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 5) and the DMID Pediatric Toxicity Table (Appendix 6). 

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 4), which 
includes an assessment using BAARP criteria and an assessment using DMID criteria.
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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) 
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.
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. 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.
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8.3.5.5 Clinical Laboratory Tests
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.
A complete list of the clinical laboratory tests to be performed is provided in Appendix 2.
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; if pregnancy is suspected or on 
withdrawal (early termination visit) of the subject from the study. All 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. The date and time of each ECG and its results will be 
documented in the source documents and eCRF.
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 in Table 1. Samples should be obtained prior to dosing (ie, within 2 hours 
prior to dosing), with the exception of Day 4 and 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 in Table 1. Samples should be obtained prior to dosing (ie, within 2 hours prior 
to dosing), with the exception of Day 4 and 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 
in Table 1. 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).
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8.3.6.4 Biomarkers
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 in Table 1, 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.
8.3.6.5 Health-related Quality of Life (QoL) 
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 1.
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).
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 7.
8.3.6.6 Healthcare Resource Utilization 
Not applicable.
8.3.6.7 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.
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Self-administration will be permitted after a subject (and/or their parent/caregiver) has received 
appropriate training in the antecedent study (SHP643-303) or in this study by the investigator or 
designee in the antecedent study (SHP643-303) or in this study and has demonstrated their 
understanding of self-administration. The subject is required to return to the site for visits as 
outlined in the Study Schedule of Activities (Table 1). 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 
contact is a telephone call; however, alternate methods of contact may be considered as site 
policies permit.
8.3.6.8 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 1. 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).
Laboratory testing includes general safety parameters (hematology, serum chemistry, 
coagulation, and urinalysis), serology, pregnancy tests, PK, PD, and plasma ADA testing. All 
laboratory tests will be performed using established and validated methods.
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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), PK, ADA, and PD. Subjects will be in a seated or supine position during blood 
collection.
As shown in Table 3, during this study it is expected that approximately 109 mL of blood will be 
drawn from all subjects as specified in Table 1, 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 109 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.
Table 3
Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic
5
4
20
Pharmacodynamic
2.7
4
10.8
Antidrug antibody
5
4
20
Safety
Clinical Chemistry
5
6
30
Hematology and Coagulation
4.7
6
28.2
Total mL
22.4
24a
109
a This represents the total number of samples collected during the study. Up to 5 samples will be drawn at any given visit.
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 109 mL regardless of sex. When more than 1 blood assessment is to be 
done at the time point/period, if they require the same type of tube, the assessments may be 
combined. 
8.3.8 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. 
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, standard 
errors, and 95% confidence intervals for least squares means will be provided. Plots of the 
supporting data detailing each subject’s contribution to the analysis will be provided.
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. 
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock.
All statistical analyses will be performed using SAS® Version 9.4 or higher (SAS Institute, 
Cary, North Carolina, USA).
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
No interim analysis, adaptive design, or data monitoring committee (DMC) is planned for this 
study.
9.3 Sample Size and Power Considerations
No formal sample size calculation was performed. The sample size is not based on any statistical 
considerations. This study is designed to evaluate the safety and efficacy of open-label treatment 
with lanadelumab in subjects with normal C1-INH angioedema who participated in 
Study SHP643-303.Statistical Analysis Set(s)
9.4.1 Safety Population
The Safety Population will include all subjects who received any study drug after entering 
Study TAK-743-3001 (ie, any exposure to open-label lanadelumab). Unless otherwise specified, 
summary tabulations conducted in the Safety Population will be presented by the subject’s 
SHP643-303 treatment group (placebo or lanadelumab 300 mg q2wks) and overall.
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9.4.2 Reduced-Dose Safety Population
The Reduced-Dose Safety Population is a subset of the Safety Population and includes subjects 
who switched from lanadelumab 300 mg q2wks to a lanadelumab 300 mg q4wks dosing regimen 
during the TAK743-3001 study. The TAK-743-3001 treatment period for this analysis 
population will be partitioned by dosing regimen, such that the safety and efficacy data can be 
appropriately attributed to each dosing regimen. Unless otherwise specified, summary 
tabulations conducted on the Reduced-Dose Safety Population will be presented by dosing 
regimen (lanadelumab 300 mg q2wks and lanadelumab 300 mg q4wks). 
9.4.3 Pharmacokinetic Population
The pharmacokinetic population will include all subjects in the safety population who have at 
least 1 evaluable postdose PK concentration value. 
9.4.4 Pharmacodynamic Population
The pharmacodynamic population will include all subjects in the safety population who have at 
least 1 evaluable postdose PD concentration value.
9.5 Efficacy Analyses
9.5.1 Primary Efficacy Analysis
The primary objective for this study is safety. All efficacy endpoints are secondary.
9.5.2 Secondary Efficacy Analysis
Efficacy analyses will be performed using the Safety Population and the Reduced-Dose Safety 
Population.
Number of Investigator-confirmed Angioedema Attacks 
The number of investigator-confirmed angioedema attacks during the treatment period (Day 0 
through Day 182) expressed as a monthly angioedema attack rate will be analyzed. 
The treatment period investigator-confirmed angioedema attack rate will be calculated for each 
subject as the number of investigator-confirmed angioedema attacks occurring during the 
treatment period divided by the number of days the subject contributed to the treatment period, 
multiplied by 28 days. 
The baseline investigator-confirmed angioedema attack rate will be calculated for each subject as 
the number of investigator-confirmed angioedema attacks occurring during the baseline 
observation period during Study SHP643-303 divided by the number of days the subject 
contributed to the baseline observation period, multiplied by 28 days. 
The baseline, treatment period, and treatment period change from baseline in the 
investigator-confirmed angioedema attack rate will be summarized for each analysis population. 
The summary will include the total number of investigator-confirmed angioedema attacks 
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reported during the treatment period and subject-time in months that each subject contributed to 
the treatment period. Figures will be created for each analysis population plotting the on-study 
investigator-confirmed angioedema attacks reported during the treatment period relative to Day 0 
for each subject. 
In addition, the number of investigator-confirmed angioedema attacks per month (defined as 
28 days) will be summarized descriptively by month (per 28-day interval) for each analysis 
population. The summary will include the number, change from baseline, and percent change 
from baseline of investigator-confirmed angioedema attacks. 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 in this study will be used as the start of the first interval 
and end of the interval will be the date of first exposure to study drug in this study plus 27 days. 
Each successive interval will start the last day of the prior interval plus 1 day and end 28 days 
later. 
Similar summary tables will be presented for the following efficacy endpoints: 
•
Number of moderate or severe investigator-confirmed angioedema attacks during the 
treatment period. 
•
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 in intensity, results in hospitalization 
(except hospitalization for observation <24 hours), hemodynamically significant (systolic 
blood pressure <90, requires intravenous (IV) hydration, or associated with syncope or 
near-syncope) or laryngeal. 
9.5.3 Multiplicity Adjustment
No multiplicity adjustment will be performed for this study. Any statistical testing will be 
considered exploratory.
9.5.4 Control of Type I Error
No control of Type I error will be performed. Any statistical testing will be considered exploratory.
9.5.5 Exploratory Efficacy Endpoints
A discussion of exploratory efficacy endpoints is provided in the SAP.
9.6 Safety Analyses
All safety analyses will be performed separately on the Safety Population and Reduced-Dose 
Safety Population. If not otherwise specified, the treatment period for the Reduced-Dose Safety 
Population is defined as the time interval during which a subject receives lanadelumab 300 mg 
every 4 weeks dosing regimen.
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9.6.1 Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary. Separate summaries will be presented for each analysis population. 
Treatment-emergent AEs are defined as AEs with onset at the time of or following the first 
exposure to open-label lanadelumab in this study, or medical conditions present prior to the start 
of treatment but increasing in severity or relationship at the time of or following the start of 
treatment. For AEs with partial onset times, non-missing date parts will be used to determine if 
the AE is treatment-emergent or not. 
If a determination cannot be made using the non-missing date parts as to when the AE occurred 
relative to study drug administration, then the AE will be classified as treatment-emergent. 
The analyses described in this section will be based on TEAEs; plainly referred to as AEs in this 
section for brevity. 
Related AEs are AEs classified as related to study drug by the investigator. Severe AEs are AEs 
classified as severe (Grade 3) or life threatening (Grade 4) by the investigator. 
For this analysis, AEs will be classified to one of two analysis periods: 
•
Treatment Period: AEs will include all AEs starting at or after the first exposure to 
open-label lanadelumab in this study to those starting before or at the subject’s last visit 
date during the treatment period in this study (AEs starting at or after treatment on Day 0 
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 in this study (AEs starting after the Day 182 visit). 
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 for each analysis period. The number of 
deaths due to an AE, hospitalization due to an AE and study discontinuation due to an AE will be 
summarized for each analysis period. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by system organ class (SOC), and preferred term (PT) for each analysis period. This 
tabulation will be repeated for related AEs, SAEs, related SAEs, severe AEs, related severe AEs, 
and investigator-reported AESIs for treatment period and follow-up period. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by PT for treatment period AEs only. This tabulation will be repeated for related 
AEs and SAEs for treatment period AEs. 
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All AEs will be provided in subject listings. Listings will be presented separately for each 
analysis period. In addition, subject listings of AEs causing discontinuation of study medication, 
AEs leading to death, SAEs, related AEs, severe AEs, and AESIs will be produced. 
Adverse events of special interests s for this study are hypersensitivity reactions. Standardized 
MedDRA Queries (SMQ) for each AESI will be performed using the study data. The number 
and percentage of subjects with an AESI, as well as the total number of AESIs, will be 
summarized by SOC and PT for each analysis period. Separate summary tables will be created
for each AESI and for those events with the SMQs classified as related, serious, related serious, 
severe, and related severe. A listing detailing the PT within the SMQ will be provided. 
9.6.2 Laboratory Test Results 
Baseline is defined as the last non-missing value prior to the first exposure to lanadelumab, ie, 
baseline is the last non-missing value prior to first exposure to study drug in Study SHP643-303. 
Actual values and changes from baseline in clinical laboratory tests will be summarized by study 
visit. If more than one laboratory result is reported per study visit per parameter, the last 
non-missing result will be selected for analysis. 
Laboratory test results will be classified according to the reference ranges and clinical 
significance as determined by the investigator. The number of subjects with a non-missing result, 
and the number and percentage of subjects with a clinically significant result less than the lower 
limit of normal, non-clinically significant result less than the lower limit of normal, within the 
normal range, non-clinically significant result more than the upper limit of normal, and clinically 
significant result more than the upper limit of normal will be summarized by study visit. If more 
than one laboratory result is reported per study visit per parameter, the result yielding the most 
severe classification will be selected for analysis. 
Categorical laboratory test results (urinalysis excluding pH) will be summarized by study visit. If 
more than one laboratory result is reported per study visit per parameter, the result yielding the 
most severe classification will be selected for analysis. 
Subjects with clinically significant abnormal laboratory test results will be listed. This listing will 
include all results of the laboratory parameter that was abnormal and determined to be clinically 
significant by the investigator for a subject across study visit to identify any trends.
9.6.3 Vital Signs 
Baseline is defined as the last non-missing value prior to the first exposure to lanadelumab, ie,
baseline is the last non-missing value prior to first exposure to study drug in Study SHP643-303. 
Actual values and changes from baseline in vital signs will be summarized by study visit and 
study time point. All vital sign data will be presented in subject listings. 
Vital sign values will be classified according to clinical significance as determined by the 
investigator. The number of subjects with a non-missing result, and the number and percentage 
of subjects with a non-clinically significant result and a clinically significant result will be 
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summarized by study visit and study time point. If more than one vital sign result is reported per 
study visit and study time point per parameter, the result yielding the most severe classification 
will be selected for analysis. 
Subjects with clinically significant vital sign values will be listed. This listing will include all 
results of the vital sign parameter that was determined by the investigator to be clinically 
significant for a subject across study time points to identify any trends.
9.6.4 Electrocardiography 
The number and percentage of subjects with normal, abnormal not clinically significant, and 
abnormal clinically significant ECG results, or ECG not performed, will be summarized by study 
visit. Subjects with clinically significant ECG results will be listed. This listing will include all 
results for a subject across study time points to identify any trends.
9.7 Other Analyses
If not otherwise specified, all other analyses will be performed separately on the Safety 
Population and Reduced-Dose Safety Population. Additional analyses of PK, PD, biomarker 
data, and potential effect of ADA on PK, PD and biomarkers will be described in a separate 
PK/PD report. Additional analysis of QoL data will be described in a separate QoL report.
9.7.1 Analysis of Pharmacokinetic Data 
Pharmacokinetic analyses will be performed using the Pharmacokinetic Population. Plasma
concentration of lanadelumab will be summarized by nominal PK sampling time. 
9.7.2 Analysis of Pharmacodynamic Data 
Pharmacodynamic analyses will be performed using the Pharmacodynamic Population. Plasma 
kallikrein activity will be summarized by nominal PD sampling time. 
9.7.3 Analysis of Biomarker Data 
Additional biomarkers will be summarized by nominal sampling time. 
9.7.4 Analysis of Immunogenicity Data 
Blood samples will be collected and tested for the presence of ADA. Endpoint titers and 
assessment of in vitro neutralization will be reported for samples testing positive. The number 
and percentage of negative, positive, and/or with neutralizing antibodies antibody samples will 
be reported and will be summarized by study visit and overall.
9.7.5 Health-related Quality of Life Analyses
The HR-QoL total score and domain scores will be summarized using descriptive statistics by 
scheduled visit. A change in scores from baseline (Day 0 of Study TAK-743-3001) will be 
summarized. A change in scores from baseline on Day 0 of Study SHP-643-03 will be 
summarized. 
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9.7.6 Analysis of Experience with Study Drug Self-administration 
For the Safety Population, the responses to each item of the self-administration and subcutaneous 
injection survey will be tabulated by study visit. 
The number and percentage of subjects who performed study drug administration via study staff 
administration in-clinic, self-administration in-clinic, and self-administration at home will be 
tabulated by study visit. 
The number and percentage of subjects with >80% self-administration, with 
>80% administration by study staff in-clinic, or subjects with <80% self-administration and 
<80% administration by study staff in-clinic will be tabulated for the Safety Population. 
The number and percentage of study drug administration with a duration of 0 seconds to 
10 seconds, 11 seconds to 20 seconds, 21 seconds to 30 seconds, 31 seconds to 60 seconds, 
greater than 1 minute to less than or equal to 2 minutes, greater than 1 minute to less than or 
equal to 3 minutes, greater than 3 minutes to less than or equal to 4 minutes, greater than 
4 minutes to less than or equal to 5 minutes, and greater than 5 minutes will be summarized for 
the doses that was self-administered at home, self-administered in-clinic, administered by the 
study staff in-clinic, and overall.
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lymphoproliferative disorders: A tight relationship. Critical Reviews in Oncology / 
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in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid. 
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Hereditary angioedema in the German-speaking region. Hautarzt, 49, 114-22.
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S., Verhamme, I. M., Gruber, A., McCrae, K. & Gailani, D. 2018. A mechanism for 
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factor XII heavy chain. Blood.
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S., Verhamme, I. M., Gruber, A., McCrae, K. & Gailani, D. 2019. A mechanism for 
hereditary angioedema with normal C1 inhibitor: an inhibitory regulatory role for the 
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in Nonhuman Primates. International Journal of Toxicology, 29, 552-568.
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angioedema in Sweden. Allergy Asthma Proc, 35, 185-90.
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& Maurer, M. 2012. Development and construct validation of the angioedema quality of 
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M. 2006. Angioedema without urticaria: a large clinical survey. Cmaj, 175, 1065-70.
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panel. Allergy and asthma proceedings, 33, S145-56.
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APPENDIX 1
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS
Appendix 1.1
Regulatory and Ethical Considerations
This study is conducted in accordance with current applicable regulations including ICH E6, EU 
Directive 2001/20/EC, and all updates, as well as local ethical and legal requirements. 
Compliance with these regulations and guidelines also constitutes compliance with the ethical
principles described in the Declaration of Helsinki.
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
Appendix 1.2
Sponsor’s Responsibilities
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, current ICH GCP Guidelines, as well as all applicable national 
and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and case report forms (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 clinical research associate (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], United Kingdom [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 to the CRF, 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 CRF completion guidelines for 
the study, 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.
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 ICF or a certified translation if applicable, 
after the subject has received and read (or been read) the written subject information and 
received an explanation of what the study involves, including but not limited to: the objectives, 
potential benefits and risk, inconveniences, and the subject’s rights and responsibilities. A copy 
of the informed consent and assent documentation (ie, a complete set of subject information 
sheets and fully executed signature pages) must be given to the subject or the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
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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 Europe, 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.
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the CRO.
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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 
review 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:
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.
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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
ALT (SGPT)
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
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)
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APPENDIX 3
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDIANG, EVALUATING, FOLLOW-UP, AND REPORTING
Appendix 3.1
Adverse Event Definitions
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
investigational product or medicinal product. An AE can therefore be any unfavorable and 
unintended sign (including 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 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
An 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:

Bronchospasm associated with anaphylaxis requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in 
inpatient hospitalization; or the development of drug dependency or drug abuse.
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
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 4).
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 5) and DMID Pediatric 
Toxicity Table (Appendix 6).
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: 

activated partial thromboplastin time 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 FXII 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 8.2.2.5. 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 5) and DMID Pediatric Toxicity Table (Appendix 6). Angioedema attacks are 
also captured as AEs in this study; angioedema attacks assessed as described in BAARP 
(Appendix 4), 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 (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.
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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 8.2.2.5
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.
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 ICF, 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 (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.
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Appendix 3.8
Pregnancy 
All pregnancies are reported from the time informed consent is signed until the defined 
follow-up period stated in Section 8.2.2.5.
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)
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
Overdose – Intentional or unintentional intake of a dose of investigational product higher 
than the protocol-prescribed dose

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
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.
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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 (Appendix 1.5).
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.
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APPENDIX 4
NON-HISTAMINERGIC BRADYKININ-MEDIATED ANGIOEDEMA 
ATTACK ASSESSMENT AND REPORTING PROCEDURES (BAARP), 
VERSION 4.0 
For non-commercial use only

 
 
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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CONFIDENTIAL
 
 
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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CONFIDENTIAL
 
 
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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CONFIDENTIAL
 
 
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
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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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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. 
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4.
INVESTIGATOR ATTACK ASSESSMENT
The principal investigator for a study site may identify a physician designee to assess patient 
angioedema symptom information and make attack determinations. Sites should be limited to 2 
individuals responsible for assessing attacks, one of them being the principal investigator.
Assessors must be experienced with 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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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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APPENDIX 5
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) 
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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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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 6
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS 
DISEASES, DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC TOXICITY TABLES (US NATIONAL 
INSTITUTES OF HEALTH; NATIONAL INSTITUTE OF ALLERGY 
AND INFECTION DISEASES) 
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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 
 
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Lanadelumab
14 Sep 2020
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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 
 
 
 
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APPENDIX 7
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. 
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APPENDIX 8
ABBREVIATIONS 
Abbreviation
Definition
AAE
acquired angioedema
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)
ANGPT1
angiopoietin-1 gene 
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase (synonymous with SGOT)
AUC
area under the plasma time-concentration curve
AUC0-
area under the plasma time-concentration curve from time 0 to 
infinity
AUC0-last
area under the plasma time-concentration 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
B19V
parvovirus B19 
BP
blood pressure
BMA
bradykinin-mediated angioedema
BUN
blood urea nitrogen 
C1-INH
C1 inhibitor or C1 esterase inhibitor
CFR
Code of Federal Regulations
cHMWK
cleaved high molecular weight kininogen
Cmax
maximum observed concentration
CPK
Creatine phosphokinase 
CRF
case report form
CRA
clinical research associate
CRO
contract research organization
DMC
data monitoring committee
DMID
Division of Microbiology and Infectious Diseases
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Abbreviation
Definition
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
EOS
end of study
ePPND
enhanced pre-and post-natal development 
ET
early termination
FDA
Food and Drug Administration 
FXII
coagulation factor XII
GCP
Good Clinical Practice
HAE
hereditary angioedema
HIPAA
Health Insurance Portability and Accountability Act
HAV
hepatitis A virus
HBV
hepatitis B virus
HCV
hepatitis C virus
HEV
hepatitis E virus
HIV
human immunodeficiency virus
HMWK
high molecular weight kininogen
HR
heart rate
HR-QoL
health-related quality of life
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
IFU
Instructions for Use
IMP
investigational medicinal product
INR
international normalized ratio
IP 
investigational product
IRB
institutional review board
ISR
injection site reaction
IUD
intrauterine device
IUS
intrauterine hormone-releasing systems
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Abbreviation
Definition
KNG1
kininogen gene 
LTP
long-term prophylaxis
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
PFS
prefilled syringe
PD
Pharmacodynamic(s)
PK
pharmacokinetic(s)
pKal
plasma kallikrein
PLG
plasminogen gene
PT
preferred term
q2wks
every 2 weeks
q4wks
every 4 weeks
QoL
quality of life
RBC
red blood cell
REB
research ethics board
RR
respiratory rate
RSI
reference safety information
SAE
serious adverse event 
SAP
statistical analysis plan
SC
subcutaneous(ly)
SD
standard deviation
SMQ
Standard MedDRA Queries
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction 
TEAE
treatment-emergent adverse event
tmax
time to maximum concentration
ULN
upper limit of normal
UK
United Kingdom
US
United States
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Abbreviation
Definition
WBC
white blood cell
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