A Multi-center, Open-label Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Lanadelumab (SHP643) in Chinese Subjects With Hereditary Angioedema
Phase: PHASE3
Conditions: Hereditary Angioedema (HAE)
Sponsor: Takeda

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Clinical Study Protocol Amendment 2: SHP643-304
09 Feb 2023
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION
The main purpose of this amendment 2 is to add the potential to conduct an interim analysis to 
support the supplementary New Drug Application (sNDA) submission for China pediatric 
indication. The other purposes are to emphasize the consent requirement for adolescent subjects 
(<18 years of age) that reach the age of 18 years, extend the time frame of screening from up to 
2 weeks to up to 4 weeks, and add the requirement to exclude subjects using any lanadelumab 
prior to the study to current exclusion criteria #2.
A summary of the changes incorporated into Amendment 2 is provided in the table below. Any 
minor revisions in grammar, spelling, punctuation, and format are not reflected in the summary 
of changes. 
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
2
Amendment Date
9 Feb 2023
China
Description of Each Change and Rationale 
Section(s) Affected by Change
The following information was added, an interim data analysis may be 
performed potentially to support the sNDA submission for China 
pediatric indication. The interim analysis will at least summarize the 
efficacy, safety and PK of treatment with lanadelumab in Chinese 
subjects with HAE when approximately 10 subjects complete the 
26 weeks treatment period and 4 weeks follow-up period.
Synopsis
Section 9.2 Planned Interim 
Analysis, Adaptive Design, and Data 
Monitoring Committee
To emphasize that for the adolescent subjects (<18 years of age) enrolled 
in the study that reach 18 years of age during study periods, a consent 
using the most current version of the informed consent form by subject is 
required. 
Table 1 Schedule of Study Activities
Section 8.1 Study Periods
To emphasize that both AESI and SAE should be reported to sponsor or 
CRO within 24 hours by investigator by adding AESI reporting 
requirement in administrative information and Table 1.
Administrative Information
Table 1 Schedule of Study Activities
Appendix 3.4 Safety Reporting
Extended the time frame of screening from up to 2 weeks to up to 
4 weeks for feasibility of study due to COVID-19. Accordingly, the 
maximum duration of participation was extended from 42 weeks to 
44 weeks.
Synopsis
Section 1.2 Schema
Section 4.1 Overall Design
Section 4.3 Duration of Subject 
Participation and Study Completion 
Definition
Section 8.1.1 Screening Visit and 
Washout Period
Added the requirement to exclude subjects using any lanadelumab prior 
to the study to current exclusion criteria #2.
Synopsis
Section 5.2 Exclusion Criteria
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Clinical Study Protocol Amendment 2: SHP643-304
09 Feb 2023
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
2
Amendment Date
9 Feb 2023
China
Description of Each Change and Rationale 
Section(s) Affected by Change
Updated the study progress from “ongoing” to “completed” to
two pediatric studies (Study SHP643-301 and Study SHP643-302). 
Added the summary of results of both studies that lanadelumab was 
generally well tolerated and a marked reduction in investigator-confirmed 
HAE attacks was observed in both HAE patient populations evaluated.
Added new ongoing studies: two Phase 3 studies in non-histaminergic 
angioedema subjects with normal C1 esterase inhibitor (C1-INH) 
(SHP643-303 and TAK-743-3001, and two prospective, 
non-interventional Phase 4 studies in HAE patients (Study SHP643-402 
and Study SHP643-403).
Section 2.2 Clinical Information
Remove liver toxicity (EU specific risk) as an important potential risk,
per Investigator’s Brochure Edition 10.0 Section 6.12.
Section 2.4 Benefit/Risk Assessment
AE=adverse event; AESI=adverse event of special interest; HAE=hereditary angioedema; PK=pharmacokinetic; 
SAE=serious adverse event; sNDA=supplementary New Drug Application
See Appendix 7 for protocol history, including all previous amendments.
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Clinical Study Protocol Amendment 2: SHP643-304
09 Feb 2023
ADMINISTRATIVE INFORMATION
Contacts
Certain events and study-related activities will require the investigator and/or subject to have 
appropriate contact information. The sponsor or contract research organization (CRO) will 
provide investigators with emergency medical contact information cards to be carried by each 
subject.
SAE and AESI Reporting 
If a subject experiences a serious adverse event (SAE) or an adverse event of special interest 
(AESI), the investigator must report the event to the sponsor or CRO within 24 hours, by 
completing an SAE or AE or hereditary angioedema (HAE) acute attack electronic case report 
form (eCRF) in English or report via the paper safety report form (as back-up) within 24 hours of 
becoming aware of any SAE or AESI respectively. The fax number and e-mail address are 
provided in the Form Completion Instruction.
Protocol and Safety-Related Questions or Concerns
For protocol- or safety-related questions or concerns, the investigator must contact the Takeda 
OR IQVIA medical monitor:
Takeda medical monitor
Name: 
, MD
Phone: 
E-mail: 
IQVIA medical monitor
Name: 
Phone: 
E-mail:
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Clinical Study Protocol Amendment 2: SHP643-304
09 Feb 2023
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Takeda within 1 business day. 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
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 Clinical Trial Material Compliant Form via the 
e-mail address:
ctmcomplaint@takeda.com
For instructions on reporting adverse events related to product complaints, see Appendix 3.4.
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Clinical Study Protocol Amendment 2: SHP643-304
09 Feb 2023
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE..............................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION...........................3
ADMINISTRATIVE INFORMATION.......................................................................................5
PRODUCT QUALITY COMPLAINTS......................................................................................6
TABLE OF CONTENTS ..............................................................................................................7
LIST OF IN-TEXT TABLES .....................................................................................................10
LIST OF IN-TEXT FIGURES ...................................................................................................10
LIST OF APPENDICES .............................................................................................................10
1. PROTOCOL SUMMARY ......................................................................................................11
1.1 Synopsis..............................................................................................................................11
1.2 Schema ...............................................................................................................................17
1.3 Schedule of Study Activities.............................................................................................18
2. INTRODUCTION....................................................................................................................21
2.1 Indication and Current Treatment Options in China...................................................22
2.2 Clinical Information .........................................................................................................23
2.3 Study Rationale .................................................................................................................25
2.4 Benefit/Risk Assessment...................................................................................................25
2.5 Compliance Statement......................................................................................................26
3. OBJECTIVES AND ENDPOINTS ........................................................................................27
3.1 Study Objectives................................................................................................................27
3.1.1 Primary Objective ......................................................................................................27
3.1.2 Secondary Objectives .................................................................................................27
3.2 Study Endpoints ................................................................................................................27
4. STUDY DESIGN......................................................................................................................29
4.1 Overall Design ...................................................................................................................29
4.2 Justification for Dose ........................................................................................................30
4.3 Duration of Subject Participation and Study Completion Definition..........................31
4.4 Sites and Regions...............................................................................................................31
5. STUDY POPULATION ..........................................................................................................32
5.1 Inclusion Criteria ..............................................................................................................32
5.2 Exclusion Criteria .............................................................................................................33
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5.3 Reproductive Potential .....................................................................................................34
5.3.1 Female Contraception................................................................................................34
5.3.2 Male Contraception....................................................................................................35
6. STUDY INTERVENTION......................................................................................................36
6.1 Investigational Product.....................................................................................................36
6.1.1 Identity of Investigational Product ...........................................................................36
6.1.2 Blinding the Treatment Assignment.........................................................................36
6.2 Dosing and Administration of Investigational Product.................................................36
6.2.1 Dosing and Administration........................................................................................36
6.2.2 Interactive Response Technology for Investigational Product Management.......37
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product....................37
6.3.1 Labeling.......................................................................................................................37
6.3.2 Packaging ....................................................................................................................38
6.3.3 Storage and Handling.................................................................................................38
6.4 Drug Accountability..........................................................................................................39
6.5 Subject Compliance ..........................................................................................................40
6.6 Permitted and Prohibited Treatment..............................................................................41
6.6.1 Permitted Treatment..................................................................................................41
6.6.2 Prohibited Treatment.................................................................................................41
7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .............................................................................42
7.1 Discontinuation of Study Treatment...............................................................................42
7.2 Reasons for Discontinuation ............................................................................................42
7.3 Withdrawal from the Study .............................................................................................42
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit..................................43
8. STUDY ASSESSMENTS AND PROCEDURES..................................................................44
8.1 Study Periods.....................................................................................................................44
8.1.1 Screening Visit and Washout Period ........................................................................44
8.1.2 Run-in Period..............................................................................................................45
8.1.3 Treatment Period........................................................................................................45
8.1.3.1 Visit 1 Dose 1 (Day 0)...........................................................................................45
8.1.3.2 Site Check-in (Day 7)...........................................................................................45
8.1.3.3 Visit 2 Dose 2 (Day 14); Visit 3 Dose 3 (Day 28); Visit 4 Dose 4 (Day 42); 
Visit 5 Dose 5 (Day 56); Visit 8 Dose 8 (Day 98); Visit 11 Dose 11 
(Day 140)...............................................................................................................45
8.1.3.4 Visit 6 Dose 6 (Day 70); Visit 7 Dose 7 (Day 84); Visit 9 Dose 9 (Day 112); 
Visit 10 Dose 10 (Day 126); Visit 12 Dose 12 (Day 154); Visit 13 Dose 13 
(Day 168)...............................................................................................................45
8.1.3.5 Visit 14 Dose 14 (Day 182)/Early Termination..................................................45
8.1.4 Follow-up Period and Visit 15 (Day 210) .................................................................46
8.1.5 Unscheduled Visit.......................................................................................................46
8.1.6 Additional Care of Subjects after the Study............................................................46
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8.1.7 COVID-19-related Protocol Considerations............................................................46
8.2 Study Assessments.............................................................................................................47
8.2.1 Demographic and Other Baseline Characteristics ..................................................47
8.2.1.1 Medical History and Prior and Concomitant Medications..............................47
8.2.1.2 C1-INH, C1q, and C4 Testing.............................................................................48
8.2.2 Efficacy........................................................................................................................48
8.2.3 Safety ...........................................................................................................................50
8.2.3.1 Physical Examination ..........................................................................................50
8.2.3.2 Adverse Events.....................................................................................................51
8.2.3.3 Vital Signs.............................................................................................................51
8.2.3.4 Clinical Laboratory Tests....................................................................................52
8.2.3.5 Pregnancy Test.....................................................................................................52
8.2.3.6 Electrocardiogram...............................................................................................52
8.2.4 Other Assessments......................................................................................................53
8.2.4.1 Pharmacokinetics.................................................................................................53
8.2.4.2 Pharmacodynamics..............................................................................................53
8.2.4.3 Plasma Antidrug Antibody Testing (Immunogenicity)....................................53
8.2.5 Volume of Blood to Be Drawn from Each Subject..................................................53
8.2.6 Blood Sample Collection, Storage, and Shipping ....................................................53
8.2.7 Injection Report..........................................................................................................53
8.2.8 Diary Card ..................................................................................................................54
9. STATISTICAL CONSIDERATIONS ...................................................................................55
9.1 Statistical Analysis Process...............................................................................................55
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee.........55
9.3 Sample Size and Power Considerations..........................................................................55
9.4 Statistical Analysis Set(s)..................................................................................................56
9.5 Analysis of Disposition......................................................................................................56
9.6 Medical History.................................................................................................................56
9.7 Demographics and Baseline Characteristics Analyses ..................................................56
9.8 Treatment Compliance and Extent of Exposure............................................................56
9.9 Efficacy Analyses...............................................................................................................56
9.10 Safety Analyses................................................................................................................57
9.11 Other Analyses ................................................................................................................59
9.11.1 Pharmacokinetic, Pharmacodynamic, and Immunogenicity Analyses ...............59
10. REFERENCES.......................................................................................................................60
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Clinical Study Protocol Amendment 2: SHP643-304
09 Feb 2023
1. PROTOCOL SUMMARY
1.1 Synopsis
Protocol number: SHP643-304
Drug: Lanadelumab
Title of the study: A Multi-center, Open-label Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of 
Lanadelumab (SHP643) in Chinese Subjects with Hereditary Angioedema
Short title: Lanadelumab China Study
Study phase: Phase 3
Number of subjects (total): The planned total sample size for this study is approximately 20 subjects.
Principal Investigator: Dr. 
Sites and Region: The study will be conducted in approximately 5 sites in China.
Study period (planned): 2022 to 2024
Objectives:
Primary:

To evaluate the safety of repeated subcutaneous (SC) administrations of lanadelumab in Chinese
subjects with hereditary angioedema (HAE).
Secondary:

To evaluate the pharmacokinetics (PK) of repeated SC administrations of lanadelumab in Chinese
subjects with HAE

To evaluate the pharmacodynamics (PD) of repeated SC administrations of lanadelumab in Chinese
subjects with HAE

To evaluate the efficacy of repeated SC administrations of lanadelumab in Chinese subjects with HAE

To evaluate the immunogenicity of repeated SC administration of lanadelumab and the effect on
lanadelumab PK, PD, efficacy, and safety
Rationale: The safety, PK, PD and efficacy of lanadelumab have been established by the global clinical 
development program for lanadelumab including two Phase 1 studies and one global Phase 3 pivotal study as 
well as Phase 3 extension study that are completed. 
Lanadelumab is expected to fulfill an unmet medical need in China for the prevention of angioedema attacks in 
patients with Type I or Type II HAE. As part of the approval requirements and post-approval commitment, the 
China Health authority has requested that further efficacy and safety data be collected from Chinese patients with 
Type I or Type II HAE. For that, Takeda is planning this multi-center, open-label study to evaluate the safety, 
efficacy, PK, PD, and immunogenicity of lanadelumab in the Chinese population.
Investigational product, dose, and mode of administration: The investigational product, lanadelumab, is a 
recombinant, fully human, immunoglobin G subclass 1, kappa light chain, monoclonal antibody expressed in 
Chinese hamster ovary cells. A single dose regimen of 300 mg lanadelumab will be administered to subjects 
every 2 weeks (q2wks) for 26 weeks for a total of 14 doses. Lanadelumab will be administered by SC injection in 
the upper arm, thigh, or abdominal area.
Methodology:
This open-label study will enroll Chinese subjects of 12 years of age or older with a confirmed diagnosis of HAE 
(Type I or II). 
The study includes a screening period that may require screening of 4 weeks, a washout period of 2 weeks, a 
run-in period of 4 to 8 weeks, a treatment period of 26 weeks, and a follow-up period of 4 weeks. Maximum 
study period will be 44 weeks.
 
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Screening Visit and Washout Period: 
Following informed consent, subjects will undergo screening assessments. Screened adult subjects who are on 
LTP (eg, androgens) for HAE are required to undergo a minimum 2-week washout period prior to the run-in 
period. This LTP washout period is permitted as long as the investigator determines that doing so would not place 
the subject in any undue safety risk and that the subject is at least 18 years of age (ie, LTP washout is not required 
in adolescent subjects [≥12 to <18 years of age]). Subjects who fail screening due to a single laboratory test result 
that does not meet eligibility criteria may have that laboratory test repeated at the discretion of the investigator. 
This will include a repeat of only the failed assessment rather than a repeat of all screening assessments.
Run-in Period:
Screened subjects who are not on LTP therapy for HAE or who have completed the required washout period will 
enroll and enter a run-in period of 4 to 8 weeks to determine their baseline attack rate. Only subjects meeting a 
minimum baseline attack rate of at least 1 investigator-confirmed attack per 4 weeks will be eligible for 
treatment. Subjects who experience 3 or more investigator-confirmed attacks before the end of the 4 weeks can 
exit the run-in period early and proceed to the treatment period. Subjects without at least 1 investigator-confirmed 
attack after 4 weeks will have their run-in period extended by 4 weeks, during which time they need to have at 
least 2 investigator-confirmed attacks in 8 weeks to be eligible for treatment. Subjects who do not meet the 
minimum attack rate during the run-in period, or are otherwise determined to be ineligible due to screening 
assessments, will not be allowed to enter the treatment period of the study and will be replaced with new HAE 
subjects until approximately 20 subjects have entered the treatment period. Subjects who are found to be 
ineligible during the run-in period will not be allowed to rescreen into the study.
Treatment Period:
Subjects who enter the treatment period will receive lanadelumab 300 mg q2wks for 26 weeks. Subjects who 
complete the treatment period will receive a total of 14 doses of lanadelumab from Day 0 to Day 182 (±3 days).
Follow-up Period:
After completion of the 26 weeks treatment period, subjects will be followed for an additional 4 weeks and will 
attend the follow-up visit on Day 210 (±3 days). 
In the event a monitor cannot visit the site in a timely manner due to the coronavirus disease 2019 (COVID-19) 
pandemic, alternative monitoring approaches such as remote source data verification or telephone contact may be 
used to ensure data quality and integrity and maintain subject safety. Alternative monitoring approaches should 
be used only where allowed by the local Health Authority and permitted by the institutional review board 
(IRB)/independent ethics committee (IEC).
Acute HAE attacks during the study will be managed in accordance with the investigator’s usual care of their 
subjects, including use of individualized acute therapy/rescue medications. The acute therapy/rescue medications 
include FIRAZYR, fresh frozen plasma (FFP), or other local standard of care.
Inclusion and Exclusion Criteria:
Each subject must participate in the informed consent process and provide written informed consent/assent before 
any procedures specified in the protocol are performed.
Inclusion Criteria:

Be of Chinese descent, defined as born in China and having Chinese parents and Chinese maternal and 
paternal grandparents.

The subject is male or female and ≥12 years of age at the time of informed consent.

Documented diagnosis of HAE Type I or Type II based upon all of the following:

Documented clinical history consistent with HAE (SC or mucosal, nonpruritic swelling episodes 
without accompanying urticaria).

Diagnostic testing results obtained during screening by a laboratory (approved by the sponsor) that 
confirm HAE Type I or Type II: C1 esterase inhibitor (C1-INH) functional level <40% of the 
normal level. Subjects with functional C1-INH level 40% to 50% of the normal level may be 
enrolled if they also have a C4 level below the normal range. Subjects may begin participating in the 
run-in period before these diagnostic results are available. 
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Subjects may be re-tested if results are incongruent with clinical history or believed by the 
investigator to be confounded by recent LTP use.

At least one of the following: Age at reported onset of first angioedema symptoms ≤30 years, a 
family history consistent with HAE Type I or Type II, or C1q within normal range.

Attack rate:

At the time of enrollment, subjects must experience at least 1 investigator-confirmed HAE attack per 
4 weeks during the run-in period.

The subject (or the subject’s parent/legal guardian, if applicable) has provided written informed consent 
approved by the IRB/IEC.

If the subject is an adult, be informed of the nature of the study and provide written informed 
consent before any study-specific procedures are performed.
OR

If the subject is a minor (ie, <18 years of age), have a parent/legal guardian who is informed of the 
nature of the study provide written informed consent (ie, permission) for the minor to participate in 
the study before any study-specific procedures are performed. Assent will be obtained from minor 
subjects.

Males, or non-pregnant, non-lactating females who are fertile and sexually active 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 postmenopausal for at least 
12 months.

Agree to adhere to the protocol-defined schedule of assessments and procedures.
Exclusion Criteria:
1.
Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema, 
HAE with normal C1-INH (also known as HAE Type III), idiopathic angioedema, or recurrent 
angioedema associated with urticaria.
2.
Participation in a prior lanadelumab study or use any lanadelumab prior to the study.
3.
Dosing with investigational drug or exposure to an investigational device within 4 weeks prior to 
entering to screening.
4.
Exposure to angiotensin-converting enzyme inhibitors or any estrogen-containing medications with 
systematic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks 
prior to screening. 
5.
Exposure to androgens (eg, danazol, methyltestosterone, testosterone) within 2 weeks prior to entering 
the run-in period. 
6.
Use of LTP therapy (defined as continued use) for HAE (C1-INH, attenuated androgens, or 
anti-fibrinolytics) for adult subjects within 2 weeks prior to entering the run-in period. Adolescent 
subjects (≥12 to <18 years of age) who are on LTP therapy for HAE are allowed to enter the study. 
7.
Use of short-term prophylaxis for HAE 7 days prior to entering the run-in period. Short-term 
prophylaxis is defined as FFP, C1-INH, attenuated androgens, or antifibrinolytics used to avoid 
angioedema complications from medically indicated procedures. Note: Currently, C1-INH therapies are 
not available in China.
8.
Any of the following liver function abnormalities: alanine aminotransferase (ALT) >3× upper limit of 
normal (ULN), or aspartate aminotransferase (AST) >3× ULN or bilirubin >2× ULN (unless the 
bilirubin is a result of Gilbert’s syndrome).
9.
Pregnancy or breast feeding.
10. Subject has any condition that in the opinion of the investigator or sponsor, may compromise their safety 
or compliance, preclude successful conduct of the study, or interfere with interpretation of the results 
(eg, history of substance abuse or dependence, significant pre-existing illnesses or major comorbidity the 
investigator considers may confound the interpretation of the study results).
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Maximum duration of subject participation in the study: 44 weeks.
Statistical analysis:
Analysis Sets

Full Analysis Set (FAS): All subjects who received at least 1 dose of lanadelumab (investigational 
product). All safety and efficacy analyses will be based on the FAS.

Pharmacokinetic Set (PK set): All subjects in the FAS who have at least 1 evaluable postdose PK 
concentration value. All PK analyses will be based on the PK set. 

Pharmacodynamic Set (PD set): All subjects in the FAS who have at least 1 evaluable postdose PD 
concentration value. All PD analyses will be based on the PD set.
Sample Size and Power Considerations
The planned total sample size for this study is approximately 20 subjects.
The sample size is considered adequate based on the objectives of the study and was based on clinical judgment 
and precedent studies of similar design and similar subject population and not on statistical considerations such as 
study power. With a sample size of 20 subjects exposed to lanadelumab, the probability of observing an event 
that occurs within the population at a rate of 10% is approximately 87%.
Study Endpoints
Primary:

Treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs) and adverse 
events of special interest (AESIs)

Clinical laboratory testing (hematology, clinical chemistry, coagulation, and urinalysis)

Vital signs including blood pressure (BP), heart rate (HR), body temperature, and respiratory rate

12-lead electrocardiogram (ECG)

Physical examination
Secondary:

Plasma concentrations of lanadelumab

Plasma kallikrein (pKal) activity as measured by cleaved high molecular weight kininogen (cHMWK) 
level (ie, plasma concentrations of cHMWK)

Number of investigator-confirmed HAE attacks during the efficacy evaluation periods

Number of investigator-confirmed HAE attacks requiring acute treatment during the efficacy evaluation 
periods

Number of investigator-confirmed moderate or severe HAE attacks during the efficacy evaluation 
periods

Maximum attack severity during the efficacy evaluations periods

Time to first HAE attack during the efficacy evaluation periods

Achievement of attack-free status during the efficacy evaluation periods

Number and percentage of subjects meeting the criterion of at least a 50%, 70%, 90% and 100% 
reduction in the investigator-confirmed normalized number of attacks (NNA) per 4 weeks relative to the 
run-in period NNA, and the number and percentage of subjects achieving NNA <1.0 per 4 weeks

Presence or absence of antidrug antibody (ADA) in plasma (neutralizing or non-neutralizing antibodies 
in plasma)
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09 Feb 2023

Effect on:
•
Lanadelumab plasma concentrations
•
cHMWK level
•
Number of investigator-confirmed HAE attacks during the efficacy evaluation periods
Efficacy Analyses
No statistical hypothesis testing will be performed.

Continuous efficacy endpoints will be summarized using number of subjects (n), mean, standard 
deviation (SD), median, minimum, and maximum. Whenever appropriate, raw (actual) values and 
changes from baseline will be summarized at each scheduled time point. Overall attack rates per month 
(28 days) will be estimated using summary statistics.

Categorical efficacy endpoints (eg, attack severity) will be summarized in terms of the number and 
percentage of subjects in each category of the efficacy endpoint.

Time-to-event endpoint (eg, time to the first HAE attack) will be summarized using Kaplan-Meier (KM) 
estimates. Summaries will include 25th, 50th (median) and 75% percentiles, if estimable, and the 
corresponding 95% confidence intervals. In addition, KM plots detailing each subject’s contribution to 
the analysis will be provided.
All efficacy summaries will be based on the FAS. Efficacy data, including derived data, will be presented in 
subject data listings.
Efficacy endpoints will be evaluated for the following 2 efficacy evaluation periods:

Day 0 (after study drug administration) through Day 182

Presumed steady-state period from Day 70 through Day 182
Sensitivity analysis will be performed to evaluate the robustness of the efficacy results during each efficacy 
evaluation period for the FAS population. The analysis will be repeated using all subject-reported HAE attacks 
instead of limiting the analysis to those attacks that were investigator confirmed.
Safety Analyses
No statistical hypothesis testing will be performed. 

Continuous safety endpoints (eg, change in laboratory parameter) will be summarized using number of 
subjects (n), mean, SD, median, minimum value, and maximum value. As appropriate, raw (actual) 
values and changes from baseline will be summarized overall and at each scheduled time point.

Categorical endpoints (eg, presence or absence of an outcome measure) will be summarized using 
counts and percentages. Summaries will include, but are not limited to: number and percentage of 
subjects with an outcome measure, and laboratory shift tables (categorical change from baseline). 
Baseline is defined as the last non-missing value prior to initial dosing with study drug (lanadelumab).
All safety summaries will be based on the FAS. All safety data, including derived data, will be presented in 
subject data listings.
Adverse events (AEs) will be coded using Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary. Only TEAEs will be analyzed, but all AEs including TEAEs and non-TEAEs will be provided in the 
AE subject listing. The analyses described in this section will be based on TEAEs; plainly referred to as AEs in 
this section for brevity. 

TEAE is defined as AE with onset at the time of or following initial dosing with study drug 
(lanadelumab), or medical conditions present prior to the start of study drug but increasing in severity or 
relationship at the time of or following the start of treatment, up to the last follow-up visit. For AEs with 
partial onset times, non-missing date parts will be used to determine if the AE is treatment emergent or 
not. If a determination cannot be made using the non-missing date as to when the AE occurred relative 
to study drug administration, then the AE will be classified as treatment emergent. 
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.
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For this analysis, AEs will be classified to two analysis periods:

Treatment Period AEs will include all AEs starting at or after the first exposure to study drug in this 
study to those starting before or at the subject’s last visit date during the treatment period in this study 
(AEs starting at or after treatment on Day 0 through Day 182 visit).

Follow-up Period AEs will include all AEs starting after the subject’s last visit date of the treatment 
period in this study (AEs starting after the Day 182 visit).
The number and percentage of subjects with any AE, any related AE, any SAE, any related SAE, any severe AE, 
any related severe AE, and any investigator-reported AESI, as well as the total number of events for each 
category will be summarized for each analysis period. The number of deaths due to an AE, hospitalization due to 
an AE and study discontinuation due to an AE will be summarized for each analysis period. 
The number and percentage of subjects with an AE, as well as the total number of AEs, will be summarized by 
system organ class and preferred term (PT) for each analysis period. This tabulation will be repeated for related 
AEs, SAEs, related SAEs, severe AEs, and related severe AEs. Similar summary tables for investigator-reported 
AESIs, or determined by the search tool of relevant Standardized MedDRA Queries, will also be generated.
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.
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.
Concomitant medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD). 
Usage of prior or concomitant medications (other than rescue medications) will be summarized descriptively by 
therapeutic class and PT. A separate, similar table will be provided for the subset of concomitant medications 
classified as rescue medications.
Clinical laboratory test results and vital signs, physical examination, and ECG findings will be summarized using 
descriptive statistics by visit. Clinical laboratory test results will be categorized according to reference ranges and 
the investigator’s assessment of clinical assessment and summarized as shifts from baseline. Clinically significant 
laboratory test results and changes in vital signs will be listed and summarized. Listings of physical examination 
and ECG findings will include the investigator’s assessment of clinical significance.
Pharmacokinetic, Pharmacodynamic, and Immunogenicity Analyses
Characterization of PK properties of lanadelumab in the Chinese population will be conducted via population PK 
modeling approach and reported separately.
Characterization of PK/PD properties of lanadelumab in the Chinese population will be conducted via population 
PK/PD modeling approach and reported separately.
No formal statistical hypothesis will be tested. Individual concentrations and PK parameters (not limited to 
Ctrough) of lanadelumab will be provided in subject data listing(s) and summarized using descriptive statistics 
(number of subjects, arithmetic mean, SD, coefficient of variation [CV], median, minimum, maximum, geometric 
mean, and CV of geometric mean). Figures of individual and mean (±SD) concentration-time profiles for plasma 
lanadelumab will be generated. Tabular and graphical summaries will be analyzed based on the PK set and 
PD set, as appropriate.
Immunogenicity data will be summarized using descriptive statistics.
Interim Analysis
An interim data analysis may be performed to support the supplementary New Drug Application (sNDA) 
submission for China pediatric indication. The interim analysis will at least summarize the efficacy, safety and
PK of treatment with lanadelumab in Chinese subjects with HAE. The interim analysis will be conducted when 
approximately 10 subjects complete the 26 weeks treatment period and 4 weeks follow-up period.
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1.2 Schema
Figure 1. Study Schematic Diagram
SCREENING PERIOD
Screening
(up to 4 weeks)
Informed consent, screening
Washout (if needed)
2 weeks
Run-in period
Assess attack rate
4 to 8 weeks
Enrollment
TREATMENT PERIOD
14 subcutaneous doses of lanadelumab 300 mg every 2 weeks
for 26 weeks
FOLLOW-UP PERIOD
4 weeks
 
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Table 1. Schedule of Study Activities
ADA=antidrug antibody; AE= adverse event; AESI=an adverse event of special interest; BP=blood pressure; C1-INH=C1 esterase inhibitor; Cmax=maximum plasma drug 
concentration; ECG=electrocardiogram; eCRF=electronic case report form; ET=early termination; HAE=hereditary angioedema; HbsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; HR=heart rate; LTP=long-term prophylaxis; PD=pharmacodynamic; PK=pharmacokinetic; RR=respiratory rate; 
SAE=serious adverse event; SC=subcutaneous
a Subjects will undergo a run-in period to determine their baseline HAE attack rate. Only subjects with a baseline rate of at least 1 investigator-confirmed HAE attack per 4 weeks 
will be eligible for enrollment and treatment. Subjects who experienced 3 or more investigator-confirmed attacks before the end of the 4 weeks could exit the run-in period early 
and proceed to enrollment and treatment. Subjects without at least 1 investigator-confirmed attack after 4 weeks of run-in will have their run-in period extended for another 
4 weeks, during which time they need to have at least 2 investigator-confirmed attacks in 8 weeks to proceed to enrollment and treatment. To be eligible for enrollment, subjects 
who have their run-in extended have to complete the full 8-week run-in period prior to entering the treatment period. Subjects who do not meet the minimum attack rate during 
run-in or are otherwise determined to be ineligible due to screening assessments will be considered as screen failures.
b Treatment period visits and follow-up visit will have a ±3-day window. Treatment period visits will have a maximum of 17 days or a minimum of 11 days between any 2 doses, 
starting with Dose 2, Day 14 through end of treatment.
c Subjects (and/or their parent/caregiver) are allowed to initiate self-administration under the investigator or designee supervision, after receiving the first 5 doses of lanadelumab 
at the study site administered by qualified personnel.
d Site personnel will contact the subject by phone to solicit for any attacks not already reported by the subject once between scheduled site visits or approximately 7 days after last 
contact with subject.
e In the event a subject prematurely discontinues from treatment and/or the study, ET visit procedures will be performed as soon as possible.
f For adolescent subjects (<18 years of age) enrolled in the study that reach 18 years of age during study periods, a consent using the most current version of the informed consent 
form by subject is required.
g Post run-in eligibility review must take place before Day 0 dosing.
h Adult subjects (≥18 years of age) who are on LTP therapy for HAE will be required to undergo a minimum 2-week washout period prior to the start of the run-in period. This 
LTP washout is permitted as long as the investigator determines that doing so would not place the subject at any undue safety risk and the subject is at least 18 years of age. The 
investigator will confirm that the subject had successfully completed the 2-week washout period before they can enter the run-in period. Adolescent subjects (≥12 to <18 years 
of age) who are on LTP therapy for HAE are not required to undergo LTP washout.
i An injection report will be completed by the subject (or caregiver) following each dose of lanadelumab. The injection report will collect information on the subject’s experience 
with SC injection of lanadelumab. Study personnel will document the subject’s responses in the subject’s medical record and eCRF.
j At the time of the screening visit, a diary card will be dispensed to the subject or caregiver. As soon as the subject enters the run-in period, the subject (or caregiver) should 
complete the diary card at the end of each day to record if an HAE attack happens or not. An HAE attack worksheet, part of the diary card, should be completed if the subject 
encounters any HAE attack. The investigator should check completion of diary card at each visit.
k Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment. Testing will be conducted by a central laboratory. 
l The pregnancy test is only for females of childbearing potential. Test will be conducted at the local laboratory and could be serum or urine based.
mThere will be a ±15-minute window for all vital signs. At study visits in which investigational product will be administered, vital signs including sitting or supine BP, HR, body 
temperature, and RR, are to be obtained prior to dosing and 1 hour after dosing.
n Height and weight will be collected at the screening visit only. The physical examination has to be performed prior to dosing of study drug. Physical examination findings by 
body system will be classified as normal, abnormal not clinically significant, abnormal clinically significant, or not performed by the investigator.
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Table 1. Schedule of Study Activities
o Electrocardiograms (single recordings) will be performed and assessed by the local laboratory. The ECG has to be performed prior to dosing of study drug.
p Clinical laboratory testing will be conducted at the local laboratory and will include hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count with 
differential, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, absolute platelet count), clinical chemistry (albumin, 
alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin [total and direct], blood urea nitrogen, calcium, carbon dioxide, chloride, creatinine, 
creatine phosphokinase, glucose, phosphate, magnesium, potassium, sodium, total protein, uric acid), coagulation (prothrombin time, activated partial thromboplastin time, 
international normalized ratio), and urinalysis (bilirubin, glucose, ketones, blood, nitrite, pH, protein, specific gravity, microscopy [if indicated by macroscopic findings]). Blood 
samples for clinical laboratory testing will be collected pre-dose (ie, within 2 hours prior to dosing).
q Serology testing (HBsAg, HCV, and HIV) will be conducted at the local laboratory at screening.
r Historical attack information will be collected at screening. During the study, subjects (or caregivers, in the event the subject is <18 years old or is incapacitated) are instructed 
to report details of the attack to the study site within 72 hours of the onset of the attack. 
s Site personnel will also contact the subject once a week or at approximately 7 days after last contact with the subject during the run-in period and once between study visits or 
approximately 7 days after last contact with the subject during the treatment period in order to solicit for any attack that may have occurred. In addition, during study visits, site
personnel will solicit for any new HAE attack information that was not given through prior subject contact with the site.
t Blood samples for testing PK, PD and formation of antibodies to lanadelumab will be obtained at pre-dose (ie, within 2 hours prior to dosing) except on follow-up visit, with a 
window period of ±3 days for the corresponding visit except on Day 0. Testing for PK, PD, and ADAs will be conducted at a central laboratory. 
Notes: If a subject experiences an SAE or an AESI, the investigator must report the event to the sponsor or CRO within 24 hours, by completing an SAE or AE or HAE acute 
attack eCRF in English or report via the paper safety report form (as back-up) within 24 hours of becoming aware of any SAE or AESI respectively.
Investigators are to report all SAEs to Takeda Global Patient Safety Evaluation (GPSE) Department through 30 days after the last dose of investigational product and SAEs 
considered related to investigational product >30 days after the last dose of investigational product.
Unscheduled visits may occur between the scheduled site visits as required. Assessments may be performed as clinically indicated at the discretion of the investigator.
1 Please see Section 8.1.7 for activities to be followed during an unanticipated situation like coronavirus disease 2019 outbreak.
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2. INTRODUCTION
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 
(Zuraw et al. 2013). Hereditary angioedema manifests clinically as unpredictable, intermittent 
attacks of subcutaneous (SC) or submucosal edema of the face, larynx, gastrointestinal tract, 
limbs, and/or genitalia (Zuraw 2008). 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 et al. 2009; Goring et al. 1998; Lei et al. 
2011; Nordenfelt et al. 2014; Roche et al. 2005). 
In China, HAE has been recognized and diagnosed with C1-INH antigen and C4 levels since the 
1980. However, due to the low disease awareness and shortage in C1-INH diagnosis assays, 
there are likely to be many undiagnosed patients. Currently there are only several publications 
from one clinical center that reports on Chinese HAE patients’ clinical features and their 
treatment plans. Two reports describe the clinical features of 158 and 133 Chinese HAE patients. 
In one of the most current and largest study reports in China in which retrospective data from 
158 HAE patients was analyzed, 156 patients were Type 1 (98.73%) and only 2 of were Type II 
(1.27%) and no report of Type 3 HAE patients. The number of reported cases is lower than 
expected based on the Chinese population which suggests the prevalence differs from estimates 
in other countries (ie, 1 per 50,000). However, incomplete historical clinical data and limited 
family history may not accurately depict the prevalence of HAE in China (Bork et al. 2000). 
Reported patient mean delay in diagnosis is 12.64 years, which is similar to what is reported in 
other countries. Reported patient swelling locations are extremities, face, gastrointestinal tract, 
laryngopharynx and genitalia. The face was the more commonly involved site at the first episode 
and GI was less frequent compared with the surveys from other countries. Gastrointestinal 
involvement was about 34.17% for Chinese patients which is relatively lower than reported in 
Western countries but similar to other Asian countries such as Japan and South Korea (Xu et al. 
2013). This difference may also be due to the challenges for the diagnosis of GI attacks or 
swellings.
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. 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 a pKal inhibitor is a rational 
therapeutic strategy for HAE attack prevention. The importance of pKal as a drug target in HAE 
has been described in the literature (Kaplan and Joseph 2014). 
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TAKHZYROTM (Lanadelumab-flyo, SHP643, formerly DX-2930) is a recombinant, Chinese 
hamster ovary (CHO) cell-expressed, fully human immunoglobin G subclass 1 (IgG1), kappa 
light chain, monoclonal antibody (mAb) that is a potent (Ki=125 pM) and specific inhibitor of 
the proteolytic activity of pKal. As of 24 Jul 2021, SC lanadelumab was approved for prevention 
of HAE attacks in over 50 countries, including the United States (US), European Union (EU), 
Canada, Australia, Switzerland, United Arab Emirates, Brazil, Serbia, Mexico, Israel, and China. 
As lanadelumab has a long half-life (approximately 14 days in HAE subjects), it is hypothesized 
that prophylactic treatment with lanadelumab will provide persistent suppression of pKal and 
thus prevention of angioedema attacks.
Lanadelumab is administered by SC administration and due to a prolonged half-life, has been 
studied as a twice or once monthly regimen, thus allowing infrequent SC administration.
2.1 Indication and Current Treatment Options in China
To date, there are no HAE medications commercially available in China. Lanadelumab 
(TAKHZYRO) was approved in China in December 2020 and icatibant (FIRAZYR) was approved in 
April 2021 but these drugs are not yet marketed in China. In some hospitals, patients may have 
access for the off-label use of fresh frozen plasma (FFP), due to containing Cl esterase inhibitor, 
for acute or short-term treatment. For long-term prophylaxis (LTP), oral weak androgens 
(eg, danazol 200 mg three times a day for 2 to 4 weeks, stanozolol, oxandrolone) or an 
antifibrinolytic, tranexamic acid (ε-aminocaproic acid) are used. Additionally, symptoms of an 
HAE attack, for example, severe abdominal pain, associated with vomiting, dehydration, and 
hypotension are treated only with supportive care. In cases of laryngeal attacks where laryngeal 
edema is life-threatening, more invasive measures such as intubation, cricothyrotomy or 
tracheostomy may be required.
Therapies currently available in China, however, have their respective limitations. For example, 
even though FFP has been shown to be effective, it has not been evaluated in controlled clinical 
studies and can pose potential safety risks to patients in regards to viral transmission, infusion 
reactions or allergic reactions such as urticaria (Tang et al. 2012; Zanichelli et al. 2015). 
Attenuated androgens although approved for use in some countries in Europe pose hepatoxic, 
cardiovascular and other safety risks to patients. The most recent World Allergy Organization 
guidelines recommend that weak androgens may be used as second-line therapy, with careful 
monitoring of dosage and clinical testing to mitigate safety risks. Antifibrinolytics are not 
recommended due to the lack of efficacy in LTP (Zhi et al. 2019).
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Thus, the lanadelumab clinical development plan in China was initiated to meet an unmet 
medical need for a new prophylactic treatment for patients with HAE that provides a high level 
of efficacy to prevent angioedema attacks, a positive benefit/risk profile, and convenience of 
infrequent SC administration that can be self-administered.
2.2 Clinical Information
The indication of lanadelumab for routine prophylaxis to prevent attacks of HAE in patients 
12 years and older was primarily supported by the efficacy results from a single, adequate, 
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).

Study DX-2930-01 demonstrated that lanadelumab was well tolerated by healthy subjects 
up to doses of 3.0 mg/kg without evidence of dose-limiting toxicity.

Study DX-2930-02 reported no deaths, serious adverse events (SAEs), discontinuations 
due to an adverse event (AE), or safety signals following lanadelumab treatment. In a 
prespecified efficacy analysis, a statistically significant finding of HAE attack prevention 
by lanadelumab was observed. Specifically, in comparison to placebo, attack rate was 
reduced by 100% and 88% in the 300 and 400 mg lanadelumab treatment groups, 
respectively.

Study DX-2930-03 (HELP Study™) showed that over the 26-week treatment period, all 
3 lanadelumab dose regimens, 150 mg q4wks, 300 mg q4wks, and 300 mg every 2 weeks 
(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. 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 (71% to 83%), and attacks from Day 14 through Day 182 (75% to 89%). 
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. 
Lanadelumab was generally well tolerated over the 26-week treatment period; no 
treatment-related SAEs or deaths were reported.
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
Study DX-2930-04 (HELP Study ExtensionTM) safety profile was consistent with the 
pivotal Study DX-2930-03; no treatment-related SAEs or deaths were reported. Efficacy 
was maintained and shown to be durable over the treatment period 
(132 weeks/33 months) of lanadelumab exposure across Study DX-2930-03 and 
Study DX-2930-04 for rollover subjects. 
In addition, two Phase 1 studies were completed after the initial global marketing license for 
lanadelumab. 

Study SHP643-101 evaluated the PK properties and the safety of lanadelumab 
administered as a single SC dose of 300 mg in healthy male and female adult volunteer 
subjects of Japanese descent and matched non-Hispanic, Caucasian healthy male and 
female volunteer subjects. The data indicated that the peak and systemic exposure to 
lanadelumab (Cmax, AUC0-last, and AUC0-∞) in healthy Japanese subjects was similar to 
that observed in healthy Caucasian subjects. Lanadelumab was generally safe and well 
tolerated by both ethnic groups.

Study SHP643-102 determined the bioavailability of lanadelumab administered as a 
single SC dose of 300 mg with a prefilled syringe (PFS) or autoinjector (AI) and was 
conducted in healthy adult volunteer subjects. This study showed that the total systemic 
exposure of lanadelumab (AUC0-last and AUC0-∞) following a single SC administration of 
300 mg via PFS was equivalent to that observed via AI. Overall, lanadelumab 
administered by a PFS or an AI was generally safe and well tolerated.
Two additional Phase 3 studies have been completed: a Phase 3 study in pediatric HAE subjects 
2 to <12 years (Study SHP643-301) and a Phase 3 study in Japanese HAE subjects (≥12 years; 
Study SHP643-302). The results from these studies are consistent with previous global 
registration studies that included adult and adolescent (>12 years) HAE subjects. Lanadelumab 
was generally well tolerated. No deaths, treatment-related SAEs or subject withdrawal due to 
TEAEs were reported. No new safety concerns were identified; thus, the safety profile of 
lanadelumab remains favorable and unchanged. A marked reduction in investigator-confirmed 
HAE attacks was observed in both HAE patient populations evaluated (pediatric [2 to <12 years] 
and Japanese subjects). Efficacy was observed at26-weeks of treatment (same duration as the 
pivotal DX-2930-03 study) and was maintained over the 52-week treatment period.
Ongoing Phase 3 studies include: this Phase 3 study in Chinese HAE subjects (SHP643-304) and 
Phase 3 studies in non-histaminergic angioedema subjects with normal C1 esterase inhibitor 
(C1-INH) (SHP643-303 and TAK-743-3001). Two prospective, non-interventional Phase 4 
studies in HAE patients are also ongoing (SHP643-402 and SHP643-403).
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2.3 Study Rationale
The safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of lanadelumab have 
been established by the global clinical development program for lanadelumab including 
two Phase 1 studies and one global Phase 3 pivotal study as well as Phase 3 extension study that 
are completed.
Lanadelumab is expected to fulfill an unmet medical need in China for the prevention of 
angioedema attacks in patients with Type I or Type II HAE. As part of the approval requirements 
and post-approval commitment, the China Health authority has requested that further efficacy 
and safety data be collected from Chinese patients with Type I or Type II HAE. For that, Takeda 
is planning this multi-center, open-label study to evaluate the safety, efficacy, PK, PD, and 
immunogenicity of lanadelumab in the Chinese population.
2.4 Benefit/Risk Assessment
Lanadelumab, a first-in-class mAb against active pKal, represents a therapeutic innovation that 
will address the unmet medical needs within the HAE community and thus is expected to be of 
major public health interest. It is a fully human IgG1 mAb inhibitor of active pKal with a long 
half-life, which allows for convenient, infrequent SC self-administration (eg, q2wks).
Importantly for patients, lanadelumab’s unique mechanism of action and properties allow 
reduced dosing frequency (eg, q2wks) with SC self-administration (10-60 seconds), which 
significantly reduces the burden of treatment as compared with a daily oral or twice weekly 
intravenous or SC treatment experienced by patients; therefore, lanadelumab offers a more 
effective and convenient therapy for patients suffering from HAE.
Four clinical studies supported the global marketing applications and licenses for lanadelumab 
for routine prophylaxis to prevent attacks of HAE in patients 12 years and older. The safety and 
tolerability data from these studies to date demonstrate that lanadelumab is safe and efficacious 
in HAE patients and have served as the basis of submission for global expansion.
Per the reference labeling (TAKHZYRO 2018), the most common adverse reactions are injection 
site reactions, upper respiratory infections, headache, rash, myalgia, dizziness, and diarrhea. 
Other adverse reactions that occurred at a higher incidence in TAKHZYRO-treated patients 
compared to placebo include hypersensitivity, increased aspartate aminotransferase (AST), and 
increased alanine aminotransferase (ALT).
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Hypersensitivity is an important identified risk and is discussed in the warning and precautions 
of the reference labeling. Immunogenicity is an important potential risk and monitored closely. 
Based on the review of safety data from the completed and ongoing clinical trials, the known 
cumulative exposure and continuous pharmacovigilance monitoring for the risks, the benefit-risk 
continues to be favorable.
Lanadelumab is approved in several markets including the US and the EU.
Investigators should always refer to the latest version of the SHP643 investigator’s brochure (IB) 
for the overall benefit/risk assessment and the most accurate and current information regarding 
drug metabolism, pharmacokinetics, efficacy, and safety of SHP643.
2.5 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), 
and applicable national and local regulatory requirements.
The responsibilities of the study sponsor and investigator(s) are described fully in Appendix 1.
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3. OBJECTIVES AND ENDPOINTS
3.1 Study Objectives
3.1.1 Primary Objective
The primary objective of this study is to evaluate the safety of repeated SC administrations of 
lanadelumab in Chinese subjects with HAE.
3.1.2 Secondary Objectives
The secondary objectives of this study are:

To evaluate the PK of repeated SC administrations of lanadelumab in Chinese subjects 
with HAE

To evaluate the PD of repeated SC administrations of lanadelumab in Chinese subjects 
with HAE

To evaluate the efficacy of repeated SC administrations of lanadelumab in Chinese 
subjects with HAE

To evaluate the immunogenicity of repeated SC administration of lanadelumab and the 
effect on lanadelumab PK, PD, efficacy, and safety
3.2 Study Endpoints
Table 2. Objectives and Endpoints
Objective
Endpoint(s)
Primary
•
To evaluate the safety of 
repeated SC administrations 
of lanadelumab in Chinese 
subjects with HAE.
•
Treatment-emergent adverse events (TEAEs), including serious 
adverse events (SAEs) and adverse events of special interest 
(AESIs)
•
Clinical laboratory testing (hematology, clinical chemistry, 
coagulation, and urinalysis)
•
Vital signs including blood pressure (BP), heart rate (HR), body 
temperature, and respiratory rate (RR)
•
12-lead electrocardiogram (ECG)
•
Physical examination
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Table 2. Objectives and Endpoints
Objective
Endpoint(s)
Secondary
•
To evaluate the PK of 
repeated SC administrations 
of lanadelumab in Chinese 
subjects with HAE.
•
Plasma concentrations of lanadelumab
•
To evaluate the PD of 
repeated SC administrations 
of lanadelumab in Chinese 
subjects with HAE.
•
Plasma kallikrein (pKal) activity as measured by cleaved high 
molecular weight kininogen (cHMWK) level (ie, plasma 
concentrations of cHMWK)
•
To evaluate the efficacy of 
repeated SC administrations 
of lanadelumab in Chinese 
subjects with HAE.
•
Number of investigator-confirmed HAE attacks during the efficacy 
evaluation periods
•
Number of investigator-confirmed HAE attacks requiring acute 
treatment during the efficacy evaluation periods
•
Number of investigator-confirmed moderate or severe HAE attacks 
during the efficacy evaluation periods
•
Maximum attack severity during the efficacy evaluations periods
•
Time to first HAE attack during the efficacy evaluation periods
•
Achievement of attack-free status during the efficacy evaluation 
periods
•
Number and percentage of subjects meeting the criterion of at least 
a 50%, 70%, 90% and 100% reduction in the 
investigator-confirmed normalized number of attacks (NNA) per 
4 weeks relative to the run-in period NNA, and the number and 
percentage of subjects achieving NNA <1.0 per 4 weeks
•
To evaluate the 
immunogenicity of repeated 
SC administration of 
lanadelumab and the effect 
on lanadelumab PK, PD, 
efficacy, and safety.
•
Presence or absence of antidrug antibody (ADA) in plasma 
(neutralizing or non-neutralizing antibodies in plasma)
•
Effect on:
•
Lanadelumab plasma concentrations
•
cHMWK level
•
Number of investigator-confirmed HAE attacks during the 
efficacy evaluation periods
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4. STUDY DESIGN
4.1 Overall Design
This open-label study will enroll Chinese subjects of 12 years of age or older with a confirmed 
diagnosis of HAE (Type I or II).
The study includes a screening period that may require screening of 4 weeks, a washout period 
of 2 weeks, a run-in period of 4 to 8 weeks, a treatment period of 26 weeks, and a follow-up 
period of 4 weeks.
Screening Visit and Washout Period: 
Following informed consent, subjects will undergo screening assessments. Screened adult 
subjects who are on LTP (eg, androgens) for HAE are required to undergo a minimum 2-week 
washout period prior to the run-in period. This LTP washout period is permitted as long as the 
investigator determines that doing so would not place the subject in any undue safety risk and 
that the subject is at least 18 years of age (ie, LTP washout is not required in adolescent subjects 
[≥12 to <18 years of age]). Subjects who fail screening due to a single laboratory test result that 
does not meet eligibility criteria may have that laboratory test repeated at the discretion of the 
investigator. This will include a repeat of only the failed assessment rather than a repeat of all 
screening assessments (for details see Section 8.1.1).
Run-in Period:
Screened subjects who are not on LTP therapy for HAE or who have completed the required 
washout period will enroll and enter a run-in period of 4 to 8 weeks to determine their baseline 
attack rate. Only subjects meeting a minimum baseline attack rate of at least 
1 investigator-confirmed attack per 4 weeks will be eligible for treatment. Subjects who 
experience 3 or more investigator-confirmed attacks before the end of the 4 weeks can exit the 
run-in period early and proceed to the treatment period. Subjects without at least 
1 investigator-confirmed attack after 4 weeks will have their run-in period extended by 4 weeks, 
during which time they need to have at least 2 investigator-confirmed attacks in 8 weeks to be 
eligible for treatment. Subjects who do not meet the minimum attack rate during the run-in 
period or are otherwise determined to be ineligible due to screening assessments will not be 
allowed to enter the treatment period of the study and will be replaced with new HAE subjects 
until approximately 20 subjects have entered the treatment period. Subjects who are found to be 
ineligible during the run-in period will not be allowed to rescreen into the study.
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Treatment Period:
Subjects who enter the treatment period will receive lanadelumab 300 mg every 2 weeks (q2wks) 
for 26 weeks. Subjects who complete the treatment period will receive a total of 14 doses of 
lanadelumab from Day 0 to Day 182 (±3 days).
Follow-up Period:
After completion of the 26 weeks treatment period, subjects will be followed for an additional 
4 weeks and will attend the follow-up visit on Day 210 (±3 days). 
All study procedures are detailed in the study schematic diagram (Figure 1) and schedule of 
study activities (Table 1). 
In the event a monitor cannot visit the site in a timely manner due to the coronavirus disease 
2019 (COVID-19) pandemic, alternative monitoring approaches such as remote source data 
verification or telephone contact may be used to ensure data quality and integrity and maintain 
subject safety. Alternative monitoring approaches should be used only where allowed by the 
local Health Authority and permitted by the institutional review board (IRB)/independent ethics 
committee (IEC).
Acute HAE attacks during the study will be managed in accordance with the investigator’s usual 
care of their subjects, including use of individualized acute therapy/rescue medications. The 
acute therapy/rescue medications include FIRAZYR, FFP, or other local standard of care.
4.2 Justification for Dose
The lanadelumab clinical development program in subjects with Type I and Type II HAE 
established optimal efficacy at lanadelumab 300 mg q2wks dose with steady-state trough 
concentrations around 28400 ng/mL (Cave,ss; CV=34.4). There were reductions of approximately 
50% from baseline in cleaved high molecular weight kininogen (cHMWK), the endogenous 
substrate of kallikrein as a biomarker of its activity to evaluate the pharmacodynamic bioactivity 
of lanadelumab; and the HAE attack rate remained low with low cHMWK levels at 300 mg 
q2wks. This dose regimen was well tolerated and no discernible dose-dependent or limiting 
toxicity was observed for any related TEAEs.
Population pharmacokinetic analyses using global clinical PK data showed that age, gender and 
race did not meaningfully influence the pharmacokinetics of lanadelumab after correcting for 
body weight. Body weight is the only covariate identified to affect PK of lanadelumab. However, 
HAE patients with higher body weight were responders for the lanadelumab treatment, 
suggesting sufficient exposure provided (300mg q2wks) even in the subjects with heavier body 
weight (Inhaber et al. 2019). 
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The weight range in the global populations included in the population PK analyses was between 
36.7 to 178 kg, which covers the available Chinese body weight distribution data (Zhang et al. 
2018) and is expected to show the same efficacy response. These PK properties as part of clinical 
evidences support lanadelumab is an ethnically insensitive medicine. Thus, dosage 300 mg 
q2wks is expected to be efficacious and safe in Chinese HAE population.
4.3 Duration of Subject Participation and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 44 weeks.
For the definition of study completion date, see Section 8.1.4.
4.4 Sites and Regions
The study will be conducted in approximately 5 sites in China.
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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
Each subject must meet all of the following criteria to enroll in the study:
1. Be of Chinese descent, defined as born in China and having Chinese parents and Chinese 
maternal and paternal grandparents.
2. The subject is male or female and ≥12 years of age at the time of informed consent.
3. Documented diagnosis of HAE Type I or Type II based upon all of the following:

Documented clinical history consistent with HAE (SC or mucosal, nonpruritic 
swelling episodes without accompanying urticaria).

Diagnostic testing results obtained during screening by a laboratory (approved by the 
sponsor) that confirm HAE Type I or Type II: C1-INH functional level <40% of the 
normal level. Subjects with functional C1-INH level 40% to 50% of the normal level 
may be enrolled if they also have a C4 level below the normal range. Subjects may 
begin participating in the run-in period before these diagnostic results are available. 
Subjects may be re-tested if results are incongruent with clinical history or believed 
by the investigator to be confounded by recent LTP use.

At least one of the following: Age at reported onset of first angioedema symptoms 
≤30 years, a family history consistent with HAE Type I or Type II, or C1q within 
normal range.
4. Attack rate:

At the time of enrollment, subjects must experience at least 1 investigator-confirmed 
HAE attack per 4 weeks during the run-in period.
5. The subject (or the subject’s parent/legal guardian, if applicable) has provided written 
informed consent approved by the IRB/IEC.

If the subject is an adult, be informed of the nature of the study and provide written 
informed consent before any study-specific procedures are performed.
OR

If the subject is a minor (ie, <18 years of age), have a parent/legal guardian who is 
informed of the nature of the study provide written informed consent (ie, permission) 
for the minor to participate in the study before any study-specific procedures are 
performed. Assent will be obtained from minor subjects.
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6. Males, or non-pregnant, non-lactating females who are fertile and sexually active 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 postmenopausal for at least 12 months.
7. Agree to adhere to the protocol-defined schedule of assessments and procedures.
5.2 Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study:
1. Concomitant diagnosis of another form of chronic, recurrent angioedema, such as 
acquired angioedema, HAE with normal C1-INH (also known as HAE Type III), 
idiopathic angioedema, or recurrent angioedema associated with urticaria.
2. Participation in a prior lanadelumab study or use any lanadelumab prior to the study.
3. Dosing with investigational drug or exposure to an investigational device within 4 weeks 
prior to entering to screening.
4. Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing 
medications with systematic absorption (such as oral contraceptives or hormonal 
replacement therapy) within 4 weeks prior to screening. 
5. Exposure to androgens (eg, danazol, methyltestosterone, testosterone) within 2 weeks 
prior to entering the run-in period. 
6. Use of LTP therapy (defined as continued use) for HAE (C1-INH, attenuated androgens, 
or anti-fibrinolytics) for adult subjects within 2 weeks prior to entering the run-in period. 
Adolescent subjects (≥12 to <18 years of age) who are on LTP therapy for HAE are 
allowed to enter the study.
7. Use of short-term prophylaxis for HAE 7 days prior to entering the run-in period. 
Short-term prophylaxis is defined as FFP, C1-INH, attenuated androgens, or 
anti-fibrinolytics used to avoid angioedema complications from medically indicated 
procedures. Note: Currently, C1-INH therapies are not available in China.
8. Any of the following liver function abnormalities: ALT >3× upper limit of normal 
(ULN), or AST >3× ULN or bilirubin >2× ULN (unless the bilirubin is a result of 
Gilbert’s syndrome).
9. Pregnancy or breast feeding.
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10. Subject has any condition that in the opinion of the investigator or sponsor, may 
compromise their safety or compliance, preclude successful conduct of the study, or 
interfere with interpretation of the results (eg, history of substance abuse or dependence, 
significant pre-existing illnesses or major comorbidity the investigator considers may 
confound the interpretation of the study results).
5.3 Reproductive Potential
5.3.1 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 adolescent subjects should be either:
•
Premenarchal and either Tanner stage 1, or
•
Females of childbearing potential with a negative urine and/or serum beta-human 
chorionic gonadotropin (β-hCG) pregnancy test at the screening visit. Females of 
childbearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
Female adult subjects should be either:
•
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, or
•
Of childbearing potential with a negative urine and/or serum β-hCG pregnancy test at the 
screening visit. Females of childbearing potential must agree to abstain from sexual 
activity that could result in pregnancy or agree to use acceptable methods of 
contraception.
Acceptable methods of contraception include the following:
•
Intrauterine devices plus condoms
•
Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)
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•
Non-estrogen-containing hormonal contraceptives (oral, depot, patch, injectable, or 
vaginal ring), stabilized for at least 30 days prior to the screening visit, plus condoms. 
Note: If the subject becomes sexually active during the study, she should use one of the 
other acceptable methods noted above in addition to the hormonal contraceptive until it 
has been stabilized for 30 days.
5.3.2 Male Contraception
Males, including males who are surgically sterile (post vasectomy), with female partners of 
childbearing potential must agree to be abstinent or else use a medically acceptable form of 
contraception from screening through 70 days after the final dose of investigational product.
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6. STUDY INTERVENTION
6.1 Investigational Product
6.1.1 Identity of Investigational Product
The investigational product, lanadelumab, is a recombinant, fully human, IgG1, kappa light 
chain, mAb expressed in CHO cells. It is a potent and specific inhibitor (Ki=125 pM) of the 
proteolytic activity of active pKal.
Lanadelumab drug product is a sterile preservative-free solution for SC administration and is 
provided in strength of 300 mg/2 mL (150 mg/mL).
Lanadelumab drug product is supplied in a 5 mL single-use clear Type I glass vial fitted with a 
13 mm chlorobutyl rubber stopper with FLUROTEC® on the plug and B2 coating on the top, and 
an aluminum crimp seal with a flip-off polypropylene cap. Each 300 mg vial is filled with a 
nominal volume of 2.0 mL of drug product. Each vial contains a slight overfill.
Additional information is provided in the current IB.
6.1.2 Blinding the Treatment Assignment
Not applicable, this is an open-label clinical study.
6.2 Dosing and Administration of Investigational Product
6.2.1 Dosing and Administration
A single dose regimen of 300 mg lanadelumab will be administered to subjects q2wks for 
26 weeks for a total of 14 doses.
Lanadelumab will be administered by SC injection in the upper arm, thigh, or abdominal area.
Self-administration will be permitted after a subject (and/or their parent/caregiver) has received 
appropriate training by the investigator or designee and understanding of the training must be 
confirmed by the investigator or designee. 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 treatment. Subjects (and/or their parent/caregiver) are 
allowed to initiate self-administration under the investigator or designee supervision, after 
receiving the first 5 doses of lanadelumab at the study site administered by qualified study 
personnel. Once initiated, subjects may self-administer subsequent doses of lanadelumab at the 
investigational site per schedule of study activities (Table 1).
During an unanticipated situation like COVID-19 outbreak, subjects may self-administer 
investigational product at home (see details in Section 6.4 and Section 8.1.7).
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6.2.2 Interactive Response Technology for Investigational Product Management
An interactive response technology (IRT) will be used for investigational product management 
tasks including investigational product supply management, inventory management and supply 
ordering, investigational product expiration tracking, and return of investigational product. 
Please refer to the instruction manual provided separately from this protocol that outlines the 
operating procedures regarding the IRT.
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product
The study drug will be supplied by the sponsor and prepackaged in a study kit for investigational 
studies. Each study kit will contain 1 vial of investigational product. Both the vial and carton 
(kit) will be appropriately labeled according to local regulations and bear the unique study drug 
kit number. The investigative site will provide ancillary supplies. Subjects who elect to
self-administer investigational product will be provided the following supplies as applicable:
•
1 to 2 dose(s) supply of investigational product
•
Ancillary supplies, including alcohol pads, a temperature monitoring device, and a 
container for disposal
•
Subject accountability form to record investigational product storage conditions and 
administration details
All used and unused study drug should be returned to the study kit cartons/boxes and transported 
to the site for drug accountability. Written instructions on handling and self-administration 
procedures will be provided to trained subjects (and/or their parent/caregiver) prior to initiating 
self-administration. Refer to the Pharmacy Manual for additional details on lanadelumab and its 
administration.
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, Med 
ID Number, Lot Number, Expiry Date (if applicable), Dosage Form, Directions for Use, Storage 
Conditions, Sponsor Name and Address, the statement “For clinical trial use only”, the 
statement, “Keep out of sight and reach of children”. 
Additional labels may not be added without the sponsor’s prior full agreement.
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6.3.2 Packaging
Investigational product is packaged according to applicable local and regulatory requirements for 
investigational studies.
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
All supplies of the investigational products must be stored refrigerated at 2°C to 8°C (36°F to 
46°F) in the original carton and protected from light, in a securely locked area, accessible to 
authorized persons only, until needed for dose administration. Do not freeze.
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 site 
staff, but this delegation must be documented. Investigational products are distributed by the 
pharmacy or nominated site staff.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range.
The investigator is responsible for ensuring that the temperature is monitored throughout the 
duration of the study and that records are maintained; the temperature should be monitored 
continuously by using either an in-house system, a mechanical recording device such as a 
calibrated chart recorder, or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording. The sponsor must be notified immediately upon discovery of any excursion from the 
established range. Temperature excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the investigational 
product and will provide supportive documentation as necessary. Under no circumstances should 
the product be dispensed to subjects until the impact has been determined and the product is 
deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product, eg, fumigation of a storage 
room.
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Before use, each vial of study drug should be inspected for appearance. Any vial containing 
visible particles or discoloration should not be used. Avoid shaking or vigorous agitation of the 
vial.
Any unused contents of a vial of study medication should be discarded in accordance with local 
requirements for investigational materials. Intact vials of study medication that are not used 
during the course of the clinical study should be returned to the sponsor.
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. 
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.
Home administration can only happen during an unanticipated situation like COVID-19 
outbreak. In this situation, the site may use an alternative method for dispensing. If permitted by 
local regulations and ethics committees (ECs), the investigational product can be shipped from 
the site/the local depot directly to the subject’s home address via courier. Subjects must be 
provided with instructions on how to receive, store, and ultimately return the investigational 
product.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense and administer the investigational product only to 
subjects included in this study following the procedures set out in the study protocol. Each 
subject will be given only the investigational product carrying his/her treatment assignment. All 
administered and dispensed medication will be documented in the subject’s source and/or other 
investigational product record. The investigator is responsible for ensuring the retrieval of all 
study supplies from subjects. Due to the health/safety concerns with returning the investigational 
product container, the investigator must request that subjects keep the empty investigational 
product packaging after use and return it to the site for drug accountability purposes.
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No investigational product stock or returned inventory from a 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 product must be in accordance 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
Most doses of the study drug will be administered during site visits under the direct supervision 
of the investigator or qualified site personnel designated by the investigator. However, subjects 
(and/or their parent/caregiver) are allowed to initiate self-administration under the investigator or 
designee supervision, after receiving the first 5 doses of lanadelumab at the study site 
administered by qualified study personnel.
Subjects must be instructed how to have unused investigational product and empty/used 
investigational product packaging assessed for drug accountability. 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.
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6.6 Permitted and Prohibited Treatment
6.6.1 Permitted Treatment
The following therapies are allowed during the study:
•
Therapies for co-existing conditions, including those for acute attacks of HAE (see 
Section 4.1), are permitted if not excluded in Section 6.6.2. Use of C1-INH will be 
permitted as an acute attack therapy but not as an LTP. Administration of the 
investigational product and study procedures will continue without alteration to the 
protocol-specified study schedule, even if the subject receives any treatment for an HAE 
attack.
•
The use of short-term prophylactic treatment for HAE will be permitted if medically 
indicated and will be recorded in the appropriate electronic case report form (eCRF).
•
Therapies to treat any AEs the subject experiences during the study are permitted and will 
also be recorded in the appropriate eCRF.
•
FIRAZYR, which is approved in China for treatment of HAE attacks. FIRAZYR, as a rescue 
medication, will be provided to the study site by sponsor. Detailed information about 
FIRAZYR is provided in Appendix 5. 
6.6.2 Prohibited Treatment
Use of the following treatments will not be permitted during the study:
•
LTP for HAE (eg, use of C1-INH for LTP, attenuated androgens, or antifibrinolytics)
•
ACE inhibitors
•
Estrogen-containing medications with systemic absorption (such as oral contraceptives or 
hormonal replacement therapy)
•
Androgens (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone)
•
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
If investigational product is discontinued, regardless of the reason, the evaluations listed for early 
termination will be performed as completely as possible. Whenever possible, all discontinued 
subjects should also undergo the protocol-specified evaluations at the follow-up visit. 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 and in electronic data capture (EDC).
7.2 Reasons for Discontinuation
The primary reason for discontinuation must be determined by the investigator and recorded in 
the subject’s source document. 
Reasons for discontinuation include, but are not limited to:
•
Adverse event
•
Protocol deviation
•
Withdrawal by subject (by a parent or both parents/legal guardian for pediatric subjects)
•
Lost to follow-up
•
Lack of efficacy
•
Pregnancy
•
Study termination
•
Other (if “Other” is selected, the investigator must specify in 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 (in person or by phone or video). 
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 be assessed for final safety evaluations and return any unused 
investigational product.
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8. STUDY ASSESSMENTS AND PROCEDURES
See Table 1 for the schedule of study activities. Study assessments are detailed in Section 8.2.
8.1 Study Periods
The study includes a screening period that may require screening of 4 weeks, a washout period 
of 2 weeks, a run-in period of 4 to 8 weeks, a treatment period of 26 weeks, and a follow-up 
period of 4 weeks.
For adolescent subjects (<18 years of age) enrolled in the study that reach 18 years of age during 
study periods, a consent using the most current version of the informed consent form by subject 
is required.
8.1.1 Screening Visit and Washout Period 
Informed consent, and assent when applicable, must be obtained for all subjects participating in 
the study prior to performing any study-related activities. Subjects may withdraw consent at any 
time. Participation in the study may be terminated at any time without the subject’s consent as 
determined by the investigator. The screening visit procedures, including laboratory evaluations, 
are to be completed within the screening visit. 
The investigator or qualified site personnel will confirm that all inclusion and exclusion criteria 
have been met.
Subjects who fail screening due to a single laboratory test result that does not meet eligibility 
criteria may have that laboratory test repeated at the discretion of the investigator. This will 
include a repeat of only the failed assessment rather than a repeat of all screening assessments 
(rescreening). In these cases, a new Subject Identification Code is not required. The repeat of a 
single screening assessment is allowed only once. A repeat assessment must take place within 
4 weeks of the initial screening for any subject requiring repeat of a screening assessment. Other 
screen failures may be rescreened in the future (with new informed consent and screening 
period) if their clinical course results in a change that deems them eligible for the study.
Site personnel will train subjects and caregivers on identifying symptoms of an attack, the 
requirements for reporting attacks, and the information they will be expected to provide (see 
Section 8.2.2).
Adult subjects who are on LTP therapy for HAE will be required to undergo a minimum 2-week 
washout period prior to the start of the run-in period. This LTP washout is permitted as long as 
the investigator determines that doing so would not place the subject at any undue safety risk and 
the subject was at least 18 years of age. 
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The investigator will confirm that the subject had successfully completed the 2-week washout 
period before they could enter the run-in period. Adolescent subjects (≥12 to <18 years of age) 
who are on LTP therapy for HAE are not required to undergo LTP washout.
Other assessments to be performed during screening visit are specified in Table 1.
8.1.2 Run-in Period
Subjects will undergo a run-in period to determine their baseline HAE attack rate as described in 
Section 4.1. Assessments during the run-in period include reporting of AEs, prior therapies, and 
HAE symptoms or attack data. Subjects who are found to be ineligible during the run-in period 
will not be allowed to rescreen into the study.
8.1.3 Treatment Period
There is a ±3-day window around each study visit, with a maximum of 17 days or a minimum of 
11 days between any 2 doses.
8.1.3.1 Visit 1 Dose 1 (Day 0)
Before Day 0 dosing, a post run-in eligibility review must take place. The procedures to be 
performed on Day 0 are presented in the schedule of study activities (Table 1).
8.1.3.2 Site Check-in (Day 7)
Site personnel will contact the subject by phone to solicit for any attacks not already reported by 
the subject once between scheduled site visits or approximately 7 days after last contact with 
subject. Concomitant therapies and AEs will also be collected.
8.1.3.3 Visit 2 Dose 2 (Day 14); Visit 3 Dose 3 (Day 28); Visit 4 Dose 4 (Day 42); Visit 5 
Dose 5 (Day 56); Visit 8 Dose 8 (Day 98); Visit 11 Dose 11 (Day 140)
Study treatment will be administered at the site only during these study visits and the study 
procedures to be performed are presented in the schedule of study activities (Table 1).
8.1.3.4 Visit 6 Dose 6 (Day 70); Visit 7 Dose 7 (Day 84); Visit 9 Dose 9 (Day 112); Visit 10 
Dose 10 (Day 126); Visit 12 Dose 12 (Day 154); Visit 13 Dose 13 (Day 168)
Subjects (and/or their parent/caregiver) are allowed to initiate self-administration for these doses 
at the study site as described in Section 6.2.1. The study procedures to be performed are 
presented in the schedule of study activities (Table 1).
8.1.3.5 Visit 14 Dose 14 (Day 182)/Early Termination
The final dose must be administered at the site and the study procedures must be completed as 
presented in the schedule of study activities (Table 1).
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In the event a subject prematurely discontinued from treatment and/or the study, early 
termination visit procedures will be performed as soon as possible and recorded in the 
appropriate eCRF.
8.1.4 Follow-up Period and Visit 15 (Day 210)
The follow-up period for this protocol is 4 weeks.
At the end of this period, there will be a follow-up visit to query for SAEs, AEs, and concomitant 
treatments. All AEs and SAEs that are not resolved at the time of this contact will be followed to 
closure (see Appendix 3.2). The assessments specified in Table 1 will be performed at the 
follow-up visit.
The study completion date is defined as the date on which the last subject in the study completes 
the final protocol-defined assessments. This includes the follow-up visit.
8.1.5 Unscheduled Visit
Unscheduled visits may occur between scheduled site visits as required. Assessments may be 
performed as clinically indicated at the discretion of the investigator.
8.1.6 Additional Care of Subjects after the Study
No aftercare is planned for this study.
8.1.7 COVID-19-related Protocol Considerations
On a temporary basis, in order to maintain subject safety, confidentiality, and study integrity in 
the context of healthcare delivery challenges presented by the COVID-19 pandemic, subjects 
who may be impacted should contact study sites and investigators to determine the best course of 
action. Depending on the impact, in some cases it may be possible to arrange for alternative 
solutions as permitted by local regulations. 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 monitor, while maintaining subject safety and confidentiality as the priority.
Missing data, remote visits, changes to assessment approaches, and altered visit windows during 
the COVID-19 public health emergency may affect the study results. Thus, it is important to 
identify all protocol deviations and altered data collection or assessment methods. It is crucial 
that any deviations related to COVID-19 be clearly identified as such in the eCRF.
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The following procedural changes may be considered:
•
If necessary, informed consent from a potential or current trial participant may be 
obtained via electronic informed consent capabilities, or an electronic face-to-face 
consent interview when potential participants are unable to travel to the site.
•
Subjects who discontinued from screening due to COVID-19-related factors but were 
otherwise qualified to participate in the trial may be rescreened if the medical monitor 
agrees.
•
Options for additional investigational dosing in the home setting to prevent missed doses 
at site visits. 
Note: Home administration can only happen during an unanticipated situation like 
COVID-19 outbreak. In this situation, all procedures required at that visit need to be 
completed, except vital signs, ECG, physical examination, and blood collection. In 
addition, if investigator or subject has safety concerns regarding the self-injection at 
home, please reach out to sponsor medical monitor or site for more guidance. See 
Section 6.4 for the drug supply for administration.
•
Remote checks instead of site visits (if appropriate) may be performed as a safety check 
on subject well-being.
•
Transfer to investigational sites away from risk zones to complete required visits.
8.2 Study Assessments
8.2.1 Demographic and Other Baseline Characteristics
Subject demographic information including gender, age, and race will be collected at screening. 
8.2.1.1 Medical History and Prior and Concomitant Medications
Medical and medication history will be collected and recorded in the subject’s source documents 
and in EDC.
Medical history will capture the subject’s current relevant medical status (current disease 
processes), past relevant medical status (past disease processes), history of surgery, and allergies.
At screening, subject HAE attack history will be collected. Information collected will include 
any prior history of laryngeal attacks, attack frequency, average severity, predominant attack 
location(s), average duration, acute attack therapy use, and history of LTP.
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All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment such as psychotherapy) received within 30 days prior 
to the screening visit and through the final study contact (including protocol-defined follow-up 
period) must be recorded in the subject’s source document and in EDC.
8.2.1.2 C1-INH, C1q, and C4 Testing
Samples for C1-INH, C4, and C1q assays will be obtained at screening for eligibility assessment. 
Subjects may be re-tested if results are incongruent with clinical history or believed by the 
investigator to be confounded by recent LTP use. Analysis for these assays will be conducted at 
a central laboratory.
8.2.2 Efficacy
The collection, reporting, and assessment of attacks in this study will be done in accordance with 
the HAE Attack Assessment and Reporting Procedures (HAARP) (Appendix 4.1). Site personnel 
will be trained on HAARP prior to screening subjects at their site. 
During screening, site personnel will train subjects and caregivers on identifying symptoms of an 
attack, the requirements for reporting attacks and the information they will be expected to 
provide. The subject (and caregiver) will confirm their understanding of what is required of them 
for reporting attacks to the site.
At screening, subject HAE attack history will be collected. Information collected will include 
any prior history of laryngeal attacks, attack frequency, average severity, predominant attack 
location(s), average duration, acute attack therapy use, and history of LTP.
During the study, subjects (or caregivers, in the event the subject is <18 years old) will be 
instructed to notify and report details to the study site within 72 hours of the onset of an HAE 
attack. In the event that a subject is incapacitated following an attack, this information can be 
provided to the site by a family member or other individual with detailed knowledge of the 
event. Diary card will be provided to assist in tracking any HAE attacks subjects experience. 
Weekly communication between the subjects and the site, including reports of HAE attacks, 
must be documented in the eCRF.
Subjects (or caregivers) will be asked to provide the following information when reporting an 
attack:
•
Date and time when symptoms of an attack were first experienced
•
Description of symptoms experienced, including location(s)
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•
Impact on activity and whether any assistance or medical intervention was required, 
including hospitalizations or emergency department visits
•
Any medications used to treat the attack
•
If the attack resolved, date and time the subject was no longer experiencing symptoms
Site personnel will review the information provided and solicit additional information as 
necessary to document the attack, as described in HAARP.
Subjects washing out of LTP will be contacted by the site at the end of the 2-week washout 
period. The investigator must confirm the subject has successfully completed the 2-week 
washout period before they can enter the run-in period. Confirmation of washout will be 
captured in the eCRF.
Site personnel will contact the subject or caregiver weekly, or approximately 7 days after their 
last contact with the subject, throughout the run-in period. If the subject experiences 1 or more 
investigator-confirmed HAE attacks by the end of Week 4, the subject will have fulfilled the 
run-in requirement and may proceed to the treatment period. Subjects who experience 3 or more 
investigator-confirmed attacks can exit the run-in period early and proceed to the treatment 
period. If the subject experiences no investigator-confirmed HAE attacks at the end of 4 weeks, 
the subject will remain in the run-in period for an additional 4 weeks. The maximum duration of 
the run-in period is 8 weeks. If run-in has been extended and the subject has 2 or more 
investigator-confirmed HAE attacks by the end of Week 8, the subject will have fulfilled the 
run-in requirement and may proceed to the treatment period. To be eligible for enrollment, 
subjects who have their run-in extended must complete the full 8-week run-in period prior to 
entering the treatment period. Subjects who do not meet the minimum attack rate during run-in 
will be considered as screen failures.
During the treatment period, site personnel will contact the subject or caregiver once between 
scheduled study visits or approximately 7 days after their last contact to solicit for any HAE 
attack information not already reported. 
Throughout the duration of the study, during each study visit at the investigative site, site 
personnel will solicit for any new HAE attack information that was not already provided to the 
site.
In this study HAE attacks will be captured as AEs. All AEs, regardless of seriousness, severity, 
or causal relationship to study drug, will be recorded on the AE page of the eCRF. For all SAEs 
that are reported as HAE attacks, the principal investigator or physician designee will review the 
event within 24 hours of initial notification and, in accordance with HAARP, evaluate if it 
represented a confirmed HAE attack. 
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For all non-serious AEs that are reported as HAE attacks, the principal investigator or physician 
designee will review the event within 3 days of initial notification and, in accordance with 
HAARP, evaluate if it represented a confirmed HAE attack. If necessary for the evaluation, the 
investigator or designee may contact the subject for additional information. Any subject-reported 
attack not confirmed by the investigator must have an alternate AE diagnosis recorded. All 
subject-reported and investigator-confirmed HAE attacks will be recorded in the eCRF.
Emergency department visits for HAE attacks and HAE attacks resulting in hospital admissions 
will be captured.
To be confirmed as an HAE attack, the event must have symptoms or signs consistent with an 
attack in at least one 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 clinically determine that the 
event did not represent an HAE attack if there are features that strongly refute such a diagnosis. 
For example, the reported event is accompanied by symptoms that are not consistent with an 
HAE attack (eg, urticaria), the reported event persists well beyond the typical time course of an 
HAE attack, 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 the previous attack, the new symptoms must occur 
at least 24 hours after resolution of the prior attack’s symptoms.
8.2.3 Safety
8.2.3.1 Physical Examination
A physical examination will be performed by the investigator. A physical examination will 
include the body systems listed below:
•
Height and weight (at screening visit only)
•
General appearance
•
Ears, nose, and throat
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•
Head and Neck
•
Ophthalmological
•
Respiratory
•
Cardiovascular
•
Abdomen
•
Neurological
•
Extremities
•
Dermatological
•
Lymphatic
Abnormalities identified at the screening visit and at subsequent study visits will be recorded in 
the subject’s source documents and in EDC. Physical examination findings by body system will 
be classified as normal, abnormal not clinically significant, abnormal clinically significant, or not 
performed by the investigator.
8.2.3.2 Adverse Events
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. Hypersensitivity 
reactions and events of disordered coagulation are classified as AESIs. All AEs, regardless of 
seriousness, severity, or causal relationship to study drug, will be recorded on the AE page of the 
eCRF. See Appendix 3 for definitions, assessment, collection time frame, and reporting 
procedures for AE, TEAE, SAE, AESI, unexpected AE, and suspected unexpected serious 
adverse reaction (SUSAR).
Investigators are to report all SAEs to the Takeda Global Patient Safety Evaluation (GPSE) 
Department through 30 days after the last dose of investigational product and SAEs considered 
related to investigational product >30 days after the last dose of investigational product.
8.2.3.3 Vital Signs
There will be a ±15-minute window for all vital signs. At study visits in which study drug will be 
administered, vital signs including sitting or supine BP, HR, body temperature, and RR, are to be 
obtained prior to dosing and 1 hour after dosing.
The investigator will assess whether a change from baseline in vital signs may be deemed 
clinically significant and whether the change should be considered and recorded as an AE. 
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Vital sign values should be classified according to clinical significance as determined by the 
investigator. Categorical vital signs and the clinically significant vital signs will be summarized.
8.2.3.4 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 including hematology, clinical 
chemistry, coagulation, urinalysis, and serology is provided in Appendix 2. Clinical laboratory 
tests will be conducted at a local laboratory.
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, serology), C1-INH, C4, C1q, PK, ADAs, and PD.
8.2.3.5 Pregnancy Test
A urine or serum pregnancy test will be performed on all females of childbearing potential at the 
screening visit, monthly throughout the treatment period, and at the follow-up visit according to 
the schedule of study activities (Table 1) using local laboratory. 
8.2.3.6 Electrocardiogram
A standard 12-lead ECG (single recording) will be performed and assessed by the local 
laboratory according to the schedule of study activities (Table 1).
The date and time of each ECG and its results will be documented in the source documents and 
in EDC. 
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8.2.4 Other Assessments
8.2.4.1 Pharmacokinetics
Blood samples for the measurement of plasma lanadelumab concentration will be obtained 
pre-dose (ie, within 2 hours before dosing) according to the schedule of study activities (Table 1) 
with a window period of ±3 days for the corresponding visit except on Day 0. Pharmacokinetic 
analysis will be conducted at a central laboratory. 
8.2.4.2 Pharmacodynamics 
To evaluate the PD effects of lanadelumab upon pKal activity, blood samples will be obtained at 
pre-dose (ie, within 2 hours before dosing) according to the schedule of study activities (Table 1) 
with a window period of ±3 days for the corresponding visit except on Day 0. Pharmacodynamic 
analysis will be conducted at a central laboratory.
8.2.4.3 Plasma Antidrug Antibody Testing (Immunogenicity)
Plasma samples for testing for formation of antibodies to lanadelumab will be obtained pre-dose 
(ie, within 2 hours before dosing) according to the schedule of study activities (Table 1) with a 
window period of ±3 days for the corresponding visit except on Day 0. Immunogenicity analysis 
will be conducted at a central laboratory.
8.2.5 Volume of Blood to Be Drawn from Each Subject
The amount of blood to be drawn for each assessment is provided in the operations manual. The 
amount of blood to be drawn may vary according to the instructions provided by the 
manufacturer or laboratory for an individual assessment. 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. 
8.2.6 Blood Sample Collection, Storage, and Shipping
Blood samples for laboratory assessments, PK, PD, and formation of antibodies will be collected 
at the site, according to the schedule of study activities (Table 1), by 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.
8.2.7 Injection Report
An injection report will be completed by the subject (or caregiver) following each dose of 
lanadelumab, according to the schedule of study activities (Table 1). 
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The injection report will collect information on the subject’s experience with SC injection of 
lanadelumab. Study personnel will document the subject’s responses in the subject’s medical 
record and eCRF.
8.2.8 Diary Card
A diary card will be completed by the subject (or caregiver) as soon as the subject enters the 
run-in period, according to the schedule of study activities (Table 1). The diary card will be 
dispensed to the subject (or caregiver) at the time of the screening visit. If the subject passes all 
screening assessments, the investigator or designee will inform the subject via phone call or 
video to start completing the diary card. The subject (or caregiver) should complete the diary 
card at the end of each day to record if an HAE attack happens or not. If the subject encounters 
any HAE attack, an HAE attack worksheet (part of diary card) should be completed; subjects (or 
caregivers, in the event the subject is <18 years old) should notify and report details to the study 
site within 72 hours of the onset of the HAE attack (see Section 8.2.2). The investigator should 
check completion of diary card at each visit. Study personnel will document the subject’s 
responses in the subject’s medical record and eCRF.
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9. STATISTICAL CONSIDERATIONS
9.1 Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. 
The Statistical Analysis Plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to the database lock.
All statistical analyses will be performed using SAS® Version 9.4 or higher (SAS Institute, Cary, 
NC 27513).
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
An interim data analysis may be performed to support the supplementary New Drug Application 
(sNDA) submission for China pediatric indication. The interim analysis will at least summarize 
the efficacy, safety and PK of treatment with lanadelumab in Chinese subjects with HAE. The 
interim analysis will be conducted when approximately 10 subjects complete the 26 weeks 
treatment period and 4 weeks follow-up period. 
No adaptive design, or data monitoring committee is planned for this study.
9.3 Sample Size and Power Considerations
The planned total sample size for this study is approximately 20 subjects.
The sample size is considered adequate based on the objectives of the study and was based on
clinical judgment and precedent studies of similar design and similar subject population and not 
on statistical considerations such as study power. With a sample size of 20 subjects exposed to 
lanadelumab, the probability of observing an event that occurs within the population at a rate of 
10% is approximately 87%.
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9.4 Statistical Analysis Set(s)
Analysis of study data will be based on the following analysis sets:
•
Full Analysis Set (FAS): All subjects who received at least 1 dose of lanadelumab 
(investigational product). All safety and efficacy analyses will be based on the FAS.
•
Pharmacokinetic Set (PK set): All subjects in the FAS who have at least 1 evaluable 
postdose PK concentration value. All PK analyses will be based on the PK set. 
•
Pharmacodynamic Set (PD set): All subjects in the FAS who have at least 1 evaluable 
postdose PD concentration value. All PD analyses will be based on the PD set.
9.5 Analysis of Disposition
The numbers of subjects enrolled, completing, or withdrawing, along with reasons for 
withdrawal, will be tabulated for the FAS population.
9.6 Medical History
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
and summarized by system organ class (SOC) and preferred term (PT) for the FAS population.
9.7 Demographics and Baseline Characteristics Analyses
Baseline and demographic variables will be descriptively summarized for the FAS population.
9.8 Treatment Compliance and Extent of Exposure
Treatment compliance and extent of exposure will be described by calculating the percentage of 
planned doses received by the subject and the total number of doses received by the subject and 
summarized for the FAS population.
9.9 Efficacy Analyses
The efficacy endpoints are described in Section 3.2.
No statistical hypothesis testing will be performed.
•
Continuous efficacy endpoints will be summarized using number of subjects (n), mean, 
SD, median, minimum, and maximum. Whenever appropriate, raw (actual) values and 
changes from baseline will be summarized at each scheduled time point. Overall attack 
rates per month (28 days) will be estimated using summary statistics.
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•
Categorical efficacy endpoints (eg, attack severity) will be summarized in terms of the 
number and percentage of subjects in each category of the efficacy endpoint.
•
Time-to-event endpoint (eg, time to the first HAE attack) will be summarized using 
Kaplan-Meier (KM) estimates. Summaries will include 25th, 50th (median) and 
75% percentiles, if estimable, and the corresponding 95% confidence intervals. In 
addition, KM plots detailing each subject’s contribution to the analysis will be provided.
All efficacy summaries will be based on the FAS. Efficacy data, including derived data, will be 
presented in subject data listings.
Efficacy endpoints will be evaluated for the following 2 efficacy evaluation periods:

Day 0 (after study drug administration) through Day 182

Presumed steady-state period from Day 70 through Day 182
Sensitivity analysis will be performed to evaluate the robustness of the efficacy results during 
each efficacy evaluation period for the FAS population. The analysis will be repeated using all 
subject-reported HAE attacks instead of limiting the analysis to those attacks that were 
investigator confirmed. 
9.10 Safety Analyses
The safety endpoints are described in Section 3.2.
No statistical hypothesis testing will be performed. 
•
Continuous safety endpoints (eg, change in laboratory parameter) will be summarized 
using number of subjects (n), mean, SD, median, minimum value, and maximum value. 
As appropriate, raw (actual) values and changes from baseline will be summarized 
overall and at each scheduled time point.
•
Categorical endpoints (eg, presence or absence of an outcome measure) will be 
summarized using counts and percentages. Summaries will include, but are not limited to: 
number and percentage of subjects with an outcome measure, and laboratory shift tables 
(categorical change from baseline). 
Baseline is defined as the last non-missing value prior to initial dosing with study drug 
(lanadelumab).
All safety summaries will be based on the FAS. All safety data, including derived data, will be 
presented in subject data listings.
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Adverse events will be coded using MedDRA coding dictionary. Only TEAEs will be analyzed, 
but all AEs including TEAEs and non-TEAEs will be provided in the AE subject listing. The 
analyses described in this section will be based on TEAEs; plainly referred to as AEs in this 
section for brevity. 
•
TEAE is defined as AE with onset at the time of or following initial dosing with study 
drug (lanadelumab), or medical conditions present prior to the start of study drug but 
increasing in severity or relationship at the time of or following the start of treatment, up 
to the last follow-up visit. For AEs with partial onset times, non-missing date parts will 
be used to determine if the AE is treatment emergent or not. If a determination cannot be 
made using the non-missing date as to when the AE occurred relative to study drug 
administration, then the AE will be classified as treatment emergent. 
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 two analysis periods:
•
Treatment Period AEs will include all AEs starting at or after the first exposure to study 
drug in this study to those starting before or at the subject’s last visit date during the 
treatment period in this study (AEs starting at or after treatment on Day 0 through 
Day 182 visit).
•
Follow-up Period AEs will include all AEs starting after the subject’s last visit date of the 
treatment period in this study (AEs starting after the Day 182 visit).
The number and percentage of subjects with any AE, any related AE, any SAE, any related SAE, 
any severe AE, any related severe AE, and any investigator-reported AESI, as well as the total 
number of events for each category will be summarized for each analysis period. The number of 
deaths due to an AE, hospitalization due to an AE and study discontinuation due to an AE will be 
summarized for each analysis period.
The number and percentage of subjects with an AE, as well as the total number of AEs, will be 
summarized by SOC and PT for each analysis period. This tabulation will be repeated for related 
AEs, SAEs, related SAEs, severe AEs, and related severe AEs. Similar summary tables for 
investigator-reported AESIs, or determined by the search tool of relevant Standardized MedDRA 
Queries, will also be generated.
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.
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD). Usage of prior or concomitant medications (other than rescue medications) will be 
summarized descriptively by therapeutic class and PT. A separate, similar table will be provided 
for the subset of concomitant medications classified as rescue medications.
Clinical laboratory test results and vital signs, physical examination, and ECG findings will be 
summarized using descriptive statistics by visit. Clinical laboratory test results will be 
categorized according to reference ranges and the investigator’s assessment of clinical 
assessment and summarized as shifts from baseline. Clinically significant laboratory test results 
and changes in vital signs will be listed and summarized. Listings of physical examination and 
ECG findings will include the investigator’s assessment of clinical significance.
9.11 Other Analyses
The PK, PD, and Immunogenicity endpoints are described in Section 3.2.
9.11.1 Pharmacokinetic, Pharmacodynamic, and Immunogenicity Analyses
Characterization of PK properties of lanadelumab in the Chinese population will be conducted 
via population PK modeling approach and reported separately.
Characterization of PK/PD properties of lanadelumab in the Chinese population will be 
conducted via population PK/PD modeling approach and reported separately.
No formal statistical hypothesis will be tested. Individual concentrations and PK parameters (not 
limited to Ctrough) of lanadelumab will be provided in subject data listing(s) and summarized 
using descriptive statistics (number of subjects, arithmetic mean, SD, coefficient of variation 
[CV], median, minimum, maximum, geometric mean, and CV of geometric mean). Figures of 
individual and mean (±SD) concentration-time profiles for plasma lanadelumab will be 
generated. Tabular and graphical summaries will be analyzed based on the PK set and PD set, as 
appropriate.
Immunogenicity data will be summarized using descriptive statistics.
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10. REFERENCES
Bork, K., Siedlecki, K., Bosch, S., Schopf, R. E. and Kreuz, W. 2000. Asphyxiation by laryngeal edema 
in patients with hereditary angioedema. Mayo Clin Proc, 75(4), 349-54.
Bygum, A., Andersen, K. E. and Mikkelsen, C. S. 2009. Self-administration of intravenous C1-inhibitor 
therapy for hereditary angioedema and associated quality of life benefits. Eur J Dermatol, 19(2), 
147-51.
Goring, H. D., Bork, K., Spath, P. J., Bauer, R., Ziemer, A., Hintner, H., et al. 1998. Hereditary 
angioedema in the German-speaking region. Hautarzt, 49(2), 114-22.
Inhaber, N., Zuraw, B. L., Marier, J.-F., Lu, P. and Wang, Y. 2019. Relationship Between Body Weight, 
PK/PD, and Attack Responses Following Subcutaneous Administration of Lanadelumab in 
Patients with Hereditary Angioedema. J Allergy Clin Immunol, 143(2), AB38.
Kaplan, A. P. and Joseph, K. 2014. Pathogenic mechanisms of bradykinin mediated diseases: 
dysregulation of an innate inflammatory pathway. Adv Immunol, 121, 41-89.
Lei, W. T., Shyur, S. D., Huang, L. H., Kao, Y. H. and Lo, C. Y. 2011. Type I hereditary angioedema in 
Taiwan -- clinical, biological features and genetic study. Asian Pac J Allergy Immunol, 29(4), 
327-31.
Nordenfelt, P., Dawson, S., Wahlgren, C. F., Lindfors, A., Mallbris, L. and Bjorkander, J. 2014. 
Quantifying the burden of disease and perceived health state in patients with hereditary 
angioedema in Sweden. Allergy Asthma Proc, 35(2), 185-90.
Roche, O., Blanch, A., Caballero, T., Sastre, N., Callejo, D. and Lopez-Trascasa, M. 2005. Hereditary 
angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in 
Spain. Ann Allergy Asthma Immunol, 94(4), 498-503.
Schneider, L., Lumry, W., Vegh, A., Williams, A. H. and Schmalbach, T. 2007. Critical role of kallikrein 
in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor. 
J Allergy Clin Immunol, 120(2), 416-22.
Takhzyro 2018. Package Insert. Dyax Corporation.
Tang, R., Chen, S. and Zhang, H. Y. 2012. Fresh frozen plasma for the treatment of hereditary 
angioedema acute attacks. Chin Med Sci J, 27(2), 92-5.
Tosi, M. 1998. Molecular genetics of C1 inhibitor. Immunobiology, 199(2), 358-65.
Xu, Y. Y., Jiang, Y., Zhi, Y. X., Yin, J., Wang, L. L., Wen, L. P., et al. 2013. Clinical features of 
hereditary angioedema in Chinese patients: new findings and differences from other populations. 
Eur J Dermatol, 23(4), 500-4.
Zanichelli, A., Wu, M. A., Andreoli, A., Mansi, M. and Cicardi, M. 2015. The safety of treatments for 
angioedema with hereditary C1 inhibitor deficiency. Expert Opin Drug Saf, 14(11), 1725-36.
Zhang, M., Schumann, M., Huang, T., Törmäkangas, T. and Cheng, S. 2018. Normal weight obesity and 
physical fitness in Chinese university students: an overlooked association. BMC Public Health,
18(1), 1334.
Zhi, Y. X., An, L. X., Lai, H., Liu, R. L., Sun, Y. M., Wen, L. P., et al. 2019. The expert consensus on the 
diagnosis and treatment of hereditary angioedema. Chin J Allergy Clin Immunol, 13(1), 1-4.
Zuraw, B. L. 2008. Clinical practice. Hereditary angioedema. N Engl J Med, 359(10), 1027-36.
Zuraw, B. L., Bernstein, J. A., Lang, D. M., Craig, T., Dreyfus, D., Hsieh, F., et al. 2013. A focused 
parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-
converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol, 131(6), 1491-3.
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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, 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, contract research organization [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 eCRFs 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.
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.
Appendix 1.3 Investigator’s Responsibilities
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and E6 R2 (2017), and applicable local and national 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 
multi-center 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 (multi-center study), in compliance with 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 
multi-center studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
Documentation and Retention of Records
Electronic Case Report Forms
Electronic case report forms (eCRFs) are supplied by the sponsor or 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 eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic 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 
eCRF.
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The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data. Alternative approaches may be used to ensure data quality, 
data integrity, and subject safety (eg, remote source data review via phone or video) as permitted 
by regional and local regulations. Additional details are in the monitoring plan.
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 eCRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc).
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration [FDA], European Medicines Agency [EMA], UK Medicines and 
Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
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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).
Appendix 1.4 Data Management Considerations
Data Collection
The investigators’ authorized site personnel must enter the information required by the study 
eCRF 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 eCRF data 
against the source data for completeness and accuracy. Discrepancies between source data and 
data entered on the eCRF will be addressed by qualified site personnel. When a data discrepancy 
warrants correction, the correction will be made by authorized site personnel. Data collection 
procedures will be discussed with the site at the site initiation visit and/or at the investigator’s 
meeting. 
Data Management
Data are to be entered into a clinical database as specified in the sponsor’s data management plan 
or similar. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized 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. 
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Each subject or the subject’s legally authorized representative, as applicable, is requested to sign 
and date the subject informed consent form or a certified translation if applicable, after the 
subject has received and read (or been read) the written subject information and received an 
explanation of what the study involves, including but not limited to: the objectives, potential 
benefits and risk, inconveniences, and the subject’s rights and responsibilities. A copy of the 
informed consent and assent documentation (ie, a complete set of subject information sheets and 
fully executed signature pages) must be given to the subject or the subject’s legally authorized 
representative, as applicable. This document may require translation into the local language. 
Signed consent forms must remain in each subject’s study file and must be available for 
verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form and assent 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
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.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. If required by local law, substantial amendments to the protocol must also 
be approved by the appropriate regulatory agency prior to implementation.
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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. 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
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market lanadelumab; national or local regulatory authorities; and the IRB/EC 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. 
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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 multi-center study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multi-center publication 
of the compiled and analyzed study results. If such a multi-center 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 multi-center study publication of the study results, an investigator may individually publish 
the study results from the specific site in accordance with this section. The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented.
At least sixty (60) days prior to submitting an abstract, manuscript, or other document for 
publication, a copy of the proposed publication will be provided to the sponsor by the site for 
review. Upon the sponsor’s request, the site agrees to remove any and all confidential 
information (expressly excluding study results) identified in the publication and to delay such 
submission or presentation for an additional sixty (60) day period in order to allow the sponsor 
time to file any patent application(s). All publications of the study results shall appropriately 
reference the multi-site study publication, if any, or the fact that the study results are a subset of 
data resulting from a larger multi-site study.
Takeda is committed to transparent dissemination of all scientific, technical and medical 
manuscripts generated from Takeda-supported research. Therefore, after January 1, 2018, 
Takeda will require the submission of all Takeda-supported research manuscripts to journals that 
offer public availability via Open Access (including publisher platforms/repositories and self-
archiving). Open Access refers to the free at point of entry, online availability of published 
research output with, where available, rights of re-use according to an End User License.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) Recommendation for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical journals. Participation as an investigator does not confer any rights to 
authorship of publications.
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Appendix 2 Clinical Laboratory Tests
The following clinical laboratory assessments will be performed:
Clinical Chemistry
•
Albumin
•
Alkaline phosphatase
•
Alanine aminotransferase (ALT; SGPT)
•
Aspartate aminotransferase (AST; SGOT)
•
Bilirubin (total and direct)
•
Blood urea nitrogen
•
Calcium
•
Carbon dioxide 
•
Chloride
•
Creatinine
•
Creatine phosphokinase (CPK)
•
Glucose
•
Phosphate
•
Magnesium
•
Potassium
•
Sodium
•
Total protein
•
Uric acid
Hematology
•
Hemoglobin
•
Hematocrit
•
Red blood cell count
•
White blood cell count with differential
•
Mean corpuscular volume 
•
Mean corpuscular hemoglobin
•
Mean corpuscular hemoglobin concentration
•
Absolute platelet count
Coagulation
Serology
•
Prothrombin time
•
Activated partial thromboplastin time (aPTT)
•
International Normalized Ratio (INR)
•
HBsAg
•
HCV
•
HIV
Urinalysis
•
Bilirubin
•
Glucose
•
Ketones
•
Blood
•
Nitrite
•
pH
•
Protein
•
Specific gravity
•
Microscopy (if indicated by macroscopic 
findings)
Others
•
C1-INH
•
C1q
•
C4
•
Urine and/or serum pregnancy test
•
Pharmacokinetic test
•
Pharmacodynamic test
•
Antidrug antibody test
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Appendix 3 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting
Appendix 3.1 Adverse Event Definitions
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this investigational product or medicinal product. An AE can therefore be any unfavorable 
and unintended sign (including a clinically significant laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
causality is suspected (ICH Guidance E2A 1995).
Treatment-emergent Adverse Event
A TEAE is defined as any event emerging or manifesting at or after the initiation of treatment 
with an investigational product or medicinal product or any existing event that worsens in either 
intensity or frequency following exposure to the investigational product or medicinal product.
Serious Adverse Event
A serious adverse event (SAE) is any untoward clinical manifestation of signs, symptoms or 
outcomes (whether considered related to investigational product or not) and at any dose:
•
Results in death
•
Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.
•
Requires inpatient hospitalization or prolongation of hospitalization. Note: 
Hospitalizations that are the result of elective or previously scheduled investigations 
procedures or surgery for pre-existing conditions and have not worsened after initiation 
of treatment should not be classified as SAEs. 
-
For example, an admission for a previously scheduled ventral hernia repair would not 
be classified as an SAE; however, complication(s) resulting from a hospitalization for 
an elective or previously scheduled surgery that meet(s) serious criteria must be 
reported as SAE(s).
•
Results in persistent or significant disability/incapacity
•
Results in a congenital abnormality/birth defect
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•
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 one 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.
-
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).
Adverse Events of Special Interest
Adverse events of special interest (AESIs) will be captured and monitored during this study. 
Investigators will report all AESIs 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 mAb as a class, these events are 
considered AESI for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with hypersensitivity 
reactions, regardless of causality, within 24 hours from the time of study drug 
administration. Investigators will report hypersensitivity reactions that occur after 
24 hours, only if the reactions are suspected to be related to study drug.
•
Events of Disordered Coagulation
-
Bleeding AESI 
Although aPTT prolongation due to pKal inhibition is an artifactual in vitro 
phenomenon, as a precautionary measure in evaluating the safety of lanadelumab, 
bleeding events will be reported as AESI for this study. Investigators will report all 
diagnoses, or signs and symptoms when diagnoses cannot be determined, that are 
consistent with a clinical event of bleeding. Coagulation testing (aPTT, INR, 
prothrombin time) should be performed when possible, and when temporally 
reasonable, with any reports of bleeding or for clinical conditions possibly indicative 
of bleeding.
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-
Hypercoagulable AESI
Investigators will report all diagnoses, or signs and symptoms when diagnoses cannot 
be determined, that are consistent with a thrombotic or embolic etiology.
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 from the pharmacological properties of a product.
Suspected Unexpected Serious Adverse Reaction 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (ie, including active comparators) that is both serious and 
unexpected. 
The event(s) must meet all of the following:
•
Suspected adverse reaction
•
Serious
•
Unexpected
•
Assessed as related to study treatment
Symptoms of the Disease under Study
As discussed in Section 8.2.2 of this protocol, angioedema attacks will be captured as AEs in this 
study and will be evaluated in accordance with HAARP (Appendix 4.1). 
Clinical Laboratory and Other Safety Assessment
A change in the value of a clinical laboratory parameter, vital sign measure, physical 
examination 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. 
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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.
If, at the end of the treatment period, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), vital sign, physical examination 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, physical examination or ECG 
parameter is clinically significant and represents an AE.
When laboratory abnormalities are considered to be AEs, the Division of Microbiology and 
Infectious Diseases (DMID) Adult Toxicity Table (Appendix 4.2) or DMID Pediatric Toxicity 
Tables (Appendix 4.3) will be used to assess severity. Where discrepancies in the ULN 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.
Collection of ECG parameters will be conducted and assessed by a local laboratory for all study 
subjects. 
Appendix 3.2 Collection of Adverse Events
All AEs/SAEs are collected from the time the informed consent document is signed until the 
defined follow-up period stated in Section 8.1.4. This includes events occurring during the 
screening phase of the study, regardless of whether or not investigational product is 
administered. 
All AEs/SAEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to baseline), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained.
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Appendix 3.3 Assessment of Adverse Events
Severity Categorization
If the subject experiences a change in the severity of an AE, the event should be captured once 
with the maximum severity recorded. However, 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 AEs will be assessed according to DMID Adult Toxicity Table, 
Draft, November 2007 (US National Institutes of Health: National Institute of Allergy and 
Infectious Diseases) (Appendix 4.2) and the DMID Pediatric Toxicity Table, Draft, 
November 2007 (US National Institutes of Health: National Institute of Allergy and Infectious 
Diseases) (Appendix 4.3). 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
Any treatment-emergent ECG abnormality that is considered by the investigator as clinically 
significant and requiring intervention/therapy will be assessed as a severe AE.
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”. 
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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:
Table A1. Adverse Event Relationship Categorization
Related
The temporal relationship between the event and the administration of the investigational 
product is compelling enough and/or follows a known or suspected response pattern to that 
product, and the event cannot be explained by the subject’s medical condition, other 
therapies, or accident.
Not related
The event can be readily explained by other factors such as the subject’s underlying medical 
condition, concomitant therapy, or accident and no plausible temporal or biologic 
relationship exists between the investigational product and the event.
Outcome Categorization
The outcome of AEs must be 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
Appendix 3.4 Safety Reporting
Reference Safety Information
The RSI for this study is the IB which the sponsor has provided under separate cover to all 
investigators.
Reporting Procedures
The investigator should complete a SAE electronic case report form (eCRF), an AE or a HAE 
acute attack eCRF for AESI in English and transmit to Takeda Global Patient Safety Evaluation
(GPSE) within 24 hours of becoming aware of the event. 
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If EDC fails to work, SAE/AESI will be reported via Takeda safety report form within the same 
timeframe. It is applicable to all initial and follow-up SAE/AESI reports. Of Note: HAE is the 
indication for treatment and should be considered expected as the events are considered disease 
related (progression of underlying disease) and not subject to expedited reporting. 
Appendix 3.5 Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 8.1.4 and 
must be reported to the Takeda GPSE 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 
Department within 24 hours of the reported first becoming aware of the event.
Appendix 3.6 Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms reported by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
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 8.1.4.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours of the first awareness to the Takeda GPSE using the 
paper Pregnancy Report Form. The fax number and e-mail address are provided in the Form 
Completion Instruction.
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 
post-partum.
Pregnancy complications such as abortion/miscarriage, or congenital abnormality are considered 
SAEs and must be reported using the same procedure as describing the SAE reporting.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the same procedure as describing the SAE reporting as well 
as the Takeda Pregnancy Report Form. The test date of the first positive serum/urine β-hCG test 
or ultrasound result will determine the pregnancy onset date.
Appendix 3.9 Abuse, Misuse, Overdose and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the safety reporting procedure whether or not they result in an AE/SAE as described 
in Appendix 3.4.
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
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•
Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol)
•
Overdose – Intentional or unintentional intake of a dose of investigational product higher 
than the protocol-prescribed dose
•
Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.
Appendix 3.10 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the protocol, in 
order to protect subjects participating in a clinical trial from immediate harm, these do not 
constitute de facto deviation from the protocol. Urgent safety measures may be taken by the 
sponsor or clinical investigator, and may include any of the following:
•
Immediate change in study design or study procedures
•
Temporary or permanent halt of a given clinical trial or trials
•
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. 
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The sponsor will also ensure the responsible EC(s) and relevant competent authority(s) are 
notified of the urgent safety measures taken in such cases according to local regulations.
Appendix 3.11 Regulatory Agency, Institutional Review Board, Ethics Committee and Site 
Reporting
The sponsor/CRO is responsible for reporting all SUSARs and any other applicable (serious) 
adverse drug reactions to regulatory authorities, investigators and ECs/institutions as applicable, 
in accordance with safety regulations in the countries where the study is conducted. The 
sponsor/CRO will also prepare an expedited report for other safety issues where these might 
materially alter the current benefit-risk assessment of an investigational product or that would be 
sufficient to consider changes in the investigational products administration or in the overall 
conduct of the trial.
In addition the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the lanadelumab program.
The investigator is responsible for notifying the local IRB/EC of all safety reports or significant 
safety findings that occur at his or her site as required by IRB/EC procedures and applicable 
safety regulations (see Appendix 1.5).
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Appendix 4 Scales and Assessments
The following assessments will be utilized in this study:
Full Title of Scale/Assessment
HAE ATTACK ASSESSMENT AND REPORTING PROCEDURES (HAARP)
National Institute of Allergy and Infectious Diseases, Division of Microbiology and 
Infectious Diseases (DMID) Adult Toxicity Table (Modified) (US National Institutes of 
Health; National Institute of Allergy and Infectious Diseases)
National Institute of Allergy and Infectious Diseases, Division of Microbiology and 
Infectious Diseases (DMID) Pediatric Toxicity Tables (Modified) (US National 
Institutes of Health; National Institute of Allergy and Infectious Diseases)
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 4.1 HAE ATTACK ASSESSMENT AND REPORTING PROCEDURES 
(HAARP)
1 PURPOSE
This document applies to clinical trials that involve investigator adjudication/assessment of 
angioedema attacks. The purpose of this document is to provide a definition of an HAE attack 
and to define a standardized set of procedures for the reporting and assessment of events reported 
by subjects to determine whether those events are true HAE attacks.
2 DEFINITION OF AN ATTACK
To be confirmed as an HAE attack, the event must have symptoms or signs consistent with an 
attack in at least one of the following locations:
•
Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, 
and/or genitourinary region
•
Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, 
vomiting, or diarrhea
•
Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat 
tightening, or swelling of the tongue, palate, uvula, or larynx
Despite the presence of these symptoms, the investigator may still determine clinically that the 
event did not represent an HAE attack if there are features that strongly refute such a diagnosis. 
For example, the reported event is accompanied by symptoms that are not consistent with an 
attack (eg, urticaria), the reported event persists well beyond the typical time course of an attack 
(eg, greater than 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 resolution of the prior attack's symptoms.
Attack resolution is defined as the subject no longer having symptoms of the attack. Prodromal 
symptoms by themselves are not considered an attack.
Subject report of use of acute HAE attack treatment for an attack by itself is not confirmation 
that an attack occurred.
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3 REPORTING AND ASSESSMENT OF ATTACK DATA
At screening for applicable clinical trials, subject HAE attack history will be collected by the site 
for entry into the clinical database. Information collected will include any prior history of 
laryngeal attacks, attack frequency, average severity, predominant location(s), average duration, 
acute attack therapy use, and history of LTP.
During the relevant study periods, as defined in the applicable study protocol, subjects (or 
caregivers, for subjects <18 years old) will be instructed to contact the site within 72 hours of the 
start of symptoms of an attack. In the situation that a subject is incapacitated and is unable to 
contact the site, a family member or other individual with detailed knowledge of the event can 
provide the information. Diary card will be provided to assist in tracking any HAE attacks 
subject’s experience. Any tools or devices the subject uses to track this information are not 
intended to serve as source documents for the study.
Site personnel will review the information provided by the subject or caregiver and solicit 
additional information as necessary to document the attack. Information documented by the site 
will be considered source for the study.
A designated individual at the site (the collector) will contact the subject or 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. 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 caregiver.
The investigator or designee (the assessor) will review the attack information and evaluate if the 
event represents a confirmed HAE attack. If necessary for the evaluation, the investigator or 
designee may contact the subject to receive additional information.
3.1 Subject-reported Symptoms
Subjects and caregivers can use any existing methods by which they track information about 
their attacks or diary card will be provided by the study site. However, subjects (or a caregiver) 
will need to track attacks in such a way as to be able to contact the study site as soon as possible, 
but not later than 72 hours (3 full days) after the first symptoms appear, to report the information.
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3.1.1 Attack Information
The following information should be provided by the subject (or caregiver) at the time they are 
reporting an attack to the site:
•
Date and time when symptoms of an attack were first experienced
•
Description of symptoms experienced, including location(s)
•
Impact on activity and whether any assistance or medical intervention was required, 
including hospitalizations or emergency department visits
•
Any medications used to treat the attack
•
If the attack resolved, date and time the subject was no longer experiencing symptoms
Subjects 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 should not withhold or delay any treatment they would 
normally receive to treat their attack in order 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 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 on identifying symptoms of an attack, the 
requirements for reporting attacks and the information they will be expected to provide. The 
subject will confirm their understanding of what is required of them for reporting attacks to the 
site. Sites will assess the subject’s compliance with the reporting requirements throughout the 
study and may retrain the subject if necessary in order to maintain the integrity of the data 
provided to the site.
3.1.4 Reporting Multiple Attacks
If a subject experiences symptoms they attribute to more than one unique attack they can report 
this as multiple attacks to the site. Based on the definition of an attack, it will be the 
determination of the investigator or designee as to whether events reported as being separate are 
confirmed as separate attacks or not.
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3.1.5 Caregiver Report
During screening, site personnel will train subject caregivers (if applicable) on identifying 
symptoms of an attack, the requirements for reporting attacks and the information they will be 
expected to provide. The caregiver will confirm their understanding of what is required of them 
for reporting attacks to the site. Sites will assess the caregiver’s compliance with the reporting 
requirements throughout the study and may retrain the caregiver if necessary in order to maintain 
the integrity of the data provided to the site.
3.1.6 Subject Contact with Sites
Site personnel will establish a recommended method and time window for each subject 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 is unable to reach 
someone at the site.
3.2 Site Contact with the Subject
Sites will establish a recommended day and time window for check-in calls between study visits. 
The date and time for check-ins can be modified based on when the last contact with the subject 
was made. When the site is contacted by a subject 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 misses a call from the site. 
A study schedule for each subject's on-site visits will be provided to the subject by the site.
3.2.1 Review of Subject Report of Symptoms
During contact with the subject, whether subject-initiated or a regular check-in, site personnel 
should ask the subject to provide them information about new or ongoing HAE attacks 
experienced.
The site will try to obtain all information necessary to document the attack completely. Missing 
information may impact the assessment of any attack and should be avoided whenever possible.
3.2.2 Documenting a Reported Attack
Complete and accurate documentation of each reported attack is important to making an 
investigator assessment of the attack. The site should document the following information about 
each attack reported by the subject or caregiver:
•
Date and time of contact with the subject
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•
Date and time the subject first experienced symptoms
•
Description of symptoms experienced, including location(s)
•
Impact on activity and whether any assistance was required
•
If the attack has resolved or is ongoing. If the attack has resolved, the date and time the 
subject was no longer experiencing any symptoms of the attack
•
Names of any medications used to treat the attack including HAE acute therapy or other 
non-HAE treatments
•
If hospitalization occurred
•
If a trip to the emergency department occurred
Additional probing questions about what the subject experienced to determine:
•
If the subject only experienced prodromal symptoms
•
If the subject experienced anything different than their typical attack
•
If there were any possible alternative etiologies of the symptoms. For example, a viral 
gastroenteritis outbreak in the household could explain abdominal symptoms
The overall severity of the subject’s attack will be determined by the site using the following 
definitions:
•
Mild: Transient or mild discomfort
•
Moderate: Mild to moderate limitation in activity - some assistance 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 attack.
All reported attacks will be entered by site personnel into the electronic case report form (eCRF).
3.2.3 Site Training
Site personnel responsible for collecting attack information about subject HAE attacks will need 
to pass a “Collector” training assessment covering the following:
•
definition of an HAE attack
•
requirements of subjects and caretakers for reporting attacks
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•
reporting worsening symptoms and multiple attacks
•
information to be collected from subjects and caregivers as well as the additional probing 
questions to gather context for the attack information provided
•
assessment of attack severity
•
entry of the attack data into the eCRF
•
reporting HAE attacks as adverse events
•
requirements for investigator assessment of attacks
Trainings will be conducted prior to sites screening subjects. Trainings will be documented in the 
Trial Master File. Investigators and designees will be trained on these procedures as well and 
must pass an “Assessor” training in order to officially assess attacks for this study.
All responsible persons involved in the collection of information from subjects or assessing 
attacks must be listed on FDA Form 1572 or equivalent regulatory document as applicable.
3.3 HAE Attacks as Adverse Events
At the time of each contact and scheduled study visit, site personnel will ask if the subject 
experienced any adverse events or changes to the medications they are taking.
Hereditary angioedema attacks will be captured as AEs. All AEs, regardless of seriousness, 
severity, or causal relationship to study drug, will be recorded on the AE page of the eCRF.
Any AE reported to the site meeting criteria for an SAE must be reported to sponsor (see 
Appendix 3.5). For all SAEs that are reported as HAE attacks, the principal investigator or 
physician designee will review the event within 24 hours of initial notification and, in 
accordance with HAARP, evaluate if it represented a confirmed HAE attack.
For all non-serious AEs that are reported as HAE attacks, the principal investigator or physician 
designee will review the event within 3 days of initial notification and, in accordance with 
HAARP, evaluate if it represented a confirmed HAE attack. If necessary for the evaluation, the 
investigator or designee may contact the subject for additional information. Any subject-reported 
attack not confirmed by the investigator must have an alternate AE diagnosis recorded. All 
subject-reported and investigator-confirmed HAE attacks will be recorded in the eCRF.
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4 INVESTIGATOR ATTACK ASSESSMENT
The principal investigator for a study site may identify a physician designee to assess subject 
symptom information and make attack determinations. Sites should be limited to two individuals 
responsible for assessing attacks, one of them being the principal investigator. Assessors must be 
experienced with HAE and familiar with the study subject’s disease history.
The assessor must review the information and determine whether the event is an actual attack or 
not. If needed, the assessor can contact the subject and/or caregiver to clarify information or ask 
for any additional detail. The determination will be documented along with the date and time the 
determination was made. Any event deemed not an attack must be accompanied by an 
explanation and alternative diagnosis 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, the subject’s caregiver or any 
other site personnel. Assessors may consult with one another about a particular subject’s attack 
but only one assessor makes the documented determination. It is possible for both the principal 
investigator and physician designee to assess different attacks for the same subject.
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Appendix 4.2 National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Adult Toxicity Table 
(Modified) (US National Institutes of Health; National Institute of Allergy 
and Infectious Diseases)
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
Note:  The following toxicity table is a DRAFT and designed to provide general guidance 
on parameters for monitoring safety in clinical trials.  This toxicity table is not comprehensive and 
should not be applied directly to all trials.   
When selecting a toxicity table, the following are some of the items that must be taken into 
consideration: 
•
The population being studied
o
Does the clinical trial evaluate healthy subjects, subjects with a particular disease
or condition?
•
The stage of test article development
o
Is the clinical trial a Phase I, II, III or IV?
•
The type of test article
o
Does the clinical trial evaluate a drug, device, vaccine or other biologic agent?
•
The prior human and preclinical experience with the test article
o
Are there any specific findings that require adjustment of the toxicity table?
Single site clinical trials evaluating healthy subjects should conform to the laboratory normal 
values at the single site. Multi-center clinical trials should reconcile among their laboratory normal 
values when evaluating a healthy volunteer population. 
Please confer with the DMID protocol team and DMID's Office of Clinical Research Affairs when 
selecting or developing a toxicity table for a DMID-sponsored trial. 
Takeda 
Lanadelumab 
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CONFIDENTIAL 
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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. 
Takeda 
Lanadelumab 
Clinical Study Protocol Amendment 2: SHP643-304
CONFIDENTIAL 
 
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09 Feb 2023
For non-commercial use only

DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
HEMATOLOGY 
 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hemoglobin 
 
9.5 - 10.5 gm/dL 
 
8.0  - 9.4gm/dL 
 
 6.5 - 7.9 gm/dL 
 
< 6.5 gm/dL 
 
Absolute Neutrophil Count 
 
1000-1500/mm3 
 
750-999/mm3 
 
500-749/mm3 
 
<500/mm3 
 
Platelets 
 
75,000-
99,999/mm3 
 
50,000-
74,999/mm3 
 
20,000-49,999/mm3 
 
<20,000/mm3 
WBCs  
11,000-13,000/ 
mm3 
13,000- 
15,000 /mm3 
15,000- 
30,000/mm3 
>30,000 or 
<1,000 /mm3 
% Polymorphonuclear 
Leucocytes + Band Cells 
 > 80% 
90 – 95% 
>95% 
---------- 
 
 
Abnormal 
Fibrinogen 
Low: 
100-200 mg/dL  
 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL  
 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
 
 
    ---------- 
Fibrinogen 
associated with 
gross bleeding or 
with 
disseminated 
coagulation 
 
Fibrin Split Product 
 
20-40 mcg/ml 
 
41-50 mcg/ml 
 
51-60 mcg/ml 
 
> 60 mcg/ml 
 
Prothrombin  
Time (PT) 
 
1.01 - 1.25 x ULN 
 
1.26-1.5 x ULN 
 
1.51 -3.0 x ULN 
 
>3 x ULN 
 
Activated Partial 
Thromboplastin (APPT) 
 
1.01 -1.66 x ULN 
 
1.67 - 2.33 x 
ULN 
 
2.34 - 3 x ULN 
 
> 3 x ULN 
 
Methemoglobin 
 
5.0 - 9.9 % 
 
10.0 - 14.9 % 
 
15.0 - 19.9% 
 
> 20.0 % 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
CHEMISTRIES
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hyponatremia 
130-135 mEq/L
 123-129 
mEq/L 
116-122 mEq/L
< 116 mEq/L or 
abnormal sodium 
with mental 
status changes or 
seizures 
Hypernatremia 
146-150 mEq/L
151-157 mEq/L
158-165 mEq/L
> 165 mEq/L or
abnormal sodium 
with mental 
status changes or
seizures
Hypokalemia 
3.0 - 3.4 mEq/L 
2.5 - 2.9 mEq/L 
2.0 - 2.4 mEq/L 
or intensive 
replacement 
therapy or 
hospitalization 
required 
< 2.0 mEq/L or 
abnormal 
potassium with 
 paresis, ileus or 
life-threatening 
arrhythmia 
Hyperkalemia 
5.6 - 6.0 mEq/L 
6.1 - 6.5 mEq/L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/L
or abnormal
potassium  with
life-threatening
arrhythmia
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or 
abnormal glucose 
with mental 
status changes or 
coma 
Hyperglycemia 
(nonfasting and no prior 
diabetes) 
116 - 160 mg/dL 
161- 250
mg/dL
251 - 500 mg/dL 
> 500 mg/dL or
abnormal glucose
with ketoacidosis
or seizures
Hypocalcemia 
(corrected for albumin) 
8.4 - 7.8 mg/dL 
7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL 
or abnormal 
calcium with life 
threatening 
arrhythmia or 
tetany 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
CHEMISTRIES (continued) 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Hypercalcemia 
(correct for albumin) 
 
10.6 - 11.5 mg/dL 
 
11.6 - 12.5 
mg/dL 
 
12.6 - 13.5 mg/dL 
 
> 13.5 mg/dL or 
abnormal calcium 
with life 
threatening 
arrhythmia 
 
Hypomagnesemia 
 
1.4 - 1.2 mEq/L 
 
1.1 - 0.9 mEq/L 
 
0.8 - 0.6 mEq/L 
 
< 0.6 mEq/L or 
abnormal 
magnesium with 
life-threatening 
arrhythmia 
 
Hypophosphatemia 
 
2.0 - 2.4 mg/dL 
 
1.5 -1.9 mg/dL 
or 
replacement Rx 
required 
 
1.0 -1.4 mg/dL  
intensive therapy  
or 
hospitalization 
required 
 
< 1.0 mg/dL or 
abnormal 
phosphate with 
life-threatening 
arrhythmia 
 
Hyperbilirubinemia (when 
accompanied by any increase 
in other liver function test) 
 
1.1 - <1.25 x ULN 
 
1.25 - <1.5 x 
ULN 
 
1.5 – 1.75 x ULN 
 
> 1.75 x ULN 
 
Hyperbilirubinemia (when 
other liver function are in the  
normal range) 
 
1.1 - <1.5 x ULN 
 
1.5 - <2.0 x 
ULN 
 
2.0 – 3.0 x ULN 
 
> 3.0 x ULN 
 
BUN 
 
1.25 - 2.5 x ULN 
 
2.6 - 5 x ULN 
 
5.1 - 10 x ULN 
 
> 10 x ULN 
Hyperuricemia (uric acid) 
7.5 – 10.0 mg/dL 
10.1 – 12.0 
mg/dL 
12.1 – 15.0 mg/dL 
>15.0 mg/dL 
 
 
 
Creatinine 
 
1.1 - 1.5 x ULN  
 
1.6 - 3.0 x ULN 
 
3.1 - 6 x ULN 
 
> 6 x ULN or 
dialysis required 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
ENZYMES 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
AST (SGOT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
ALT (SGPT) 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
GGT 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
Alkaline Phosphatase 
 
1.1 - <2.0 x ULN 
 
2.0 – <3.0 x ULN 
 
3.0 – 8.0 x ULN 
 
> 8 x ULN 
 
Amylase 
 
1.1 - 1.5 x ULN 
 
1.6 - 2.0 x ULN 
 
2.1 - 5.0 x ULN 
 
> 5.1 x ULN 
Lipase  
 
1.1 - 1.5 x ULN 
 
1.6 - 2.0 x ULN 
 
2.1 - 5.0 x ULN 
 
> 5.1 x ULN 
 
 
URINALYSIS 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
Proteinuria 
 
1+ 
 or  
200 mg - 1 gm 
loss/day 
 
2-3+  
or  
1- 2 gm 
loss/day 
 
4+ 
 or  
2-3.5 gm loss/day 
 
nephrotic 
syndrome  
or 
> 3.5 gm loss/day 
Hematuria 
 
microscopic only 
<10 rbc/hpf 
 
gross, no clots 
>10 rbc/hpf 
 
gross, with or 
without clots, OR 
red blood cell casts 
 
obstructive or 
required 
transfusion 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
CARDIOVASCULAR 
 
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cardiac Rhythm 
 
 
 
asymptomatic, 
transient signs, 
no 
Rx required 
 
recurrent/persistent; 
symptomatic Rx 
required 
 
unstable 
dysrythmia; 
hospitalization 
and treatment 
required 
 
Hypertension 
 
transient increase 
> 20 mm/Hg; no 
treatment 
 
recurrent, 
chronic 
increase 
 > 20mm/Hg. 
/treatment 
required 
 
acute treatment 
required; outpatient 
treatment or 
hospitalization 
possible 
 
end organ 
damage or 
hospitalization 
required 
 
Hypotension 
 
transient 
orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic 
BP, No treatment 
required 
 
symptoms due 
to orthostatic 
hypotension or 
BP decreased 
by <20 mm Hg 
systolic; 
correctable 
with oral fluid 
treatment 
 
requires IV fluids; 
no hospitalization 
required 
 
mean arterial 
pressure  
<60mm/ Hg or 
end organ 
damage or shock;   
requires 
hospitalization 
and vasopressor 
treatment 
 
Pericarditis 
 
minimal effusion 
 
mild/moderate 
asymptomatic 
effusion, no 
treatment 
 
symptomatic 
effusion; pain; 
EKG changes 
 
tamponade; 
pericardiocentesis 
or surgery 
required 
 
Hemorrhage, Blood Loss 
 
microscopic/occult 
 
mild, no 
transfusion 
 
gross blood loss; 
1-2 units transfused 
 
massive blood 
loss; > 3 units 
transfused 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
RESPIRATORY 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Cough  
 
transient- no 
treatment 
 
persistent 
cough; 
treatment 
responsive 
 
Paroxysmal cough; 
uncontrolled with 
treatment 
-------------------- 
 
Bronchospasm, Acute 
 
transient; no 
treatment; 
70% - 80% FEV1  
of peak flow 
 
requires 
treatment; 
normalizes with 
bronchodilator; 
FEV1 50% - 
70% 
(of peak flow) 
 
no normalization 
with 
bronchodilator; 
FEV1 25% - 50% 
of peak flow; or  
retractions present 
 
cyanosis: FEV1 
< 25% 
of peak flow or 
intubation 
necessary 
Dyspnea 
 
dyspnea on 
exertion 
dyspnea with 
normal activity 
dyspnea at rest 
dyspnea requiring 
Oxygen therapy 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
GASTROINTESTINAL
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
mild or transient; 
maintains 
reasonable intake 
moderate 
discomfort; 
intake 
decreased 
significantly; 
some activity 
limited 
no significant 
intake; requires IV 
fluids 
hospitalization 
required; 
Vomiting 
1 episode in 24 
hours 
2-5 episodes in
24 hours
>6 episodes in 24 
hours or needing
IV fluids
physiologic 
consequences 
requiring 
hospitalization or 
requiring 
parenteral 
nutrition 
Constipation 
requiring stool 
softener or dietary 
modification 
requiring 
laxatives 
obstipation 
requiring manual 
evacuation or 
enema 
obstruction or 
toxic megacolon 
Diarrhea 
mild or transient; 
3-4 loose
stools/day or mild 
diarrhea last < 1 
week 
moderate or 
persistent; 5-7 
loose stools/day 
or diarrhea 
lasting >1 week 
>7 loose stools/day
or bloody diarrhea;
or orthostatic
hypotension or
electrolyte
imbalance or >2L 
IV fluids required
hypotensive 
shock or 
physiologic 
consequences 
requiring 
hospitalization 
Oral Discomfort/Dysphagia 
mild discomfort; 
no difficulty 
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid 
foods 
unable to drink 
fluids; requires 
IV fluids 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT 
 
 
NEUROLOGICAL 
  
 
 
Grade 1  
 
Grade 2  
 
Grade 3  
 
Grade 4  
 
Neuro-Cerebellar 
 
slight 
incoordination 
dysdiadochokinesis 
 
intention 
tremor, 
dysmetria, 
slurred speech; 
nystagmus 
 
locomotor ataxia 
 
incapacitated 
 
Psychiatric 
 
mild anxiety or 
depression 
 
moderate 
anxiety or 
depression; 
therapy 
required; 
change in 
normal routine 
 
severe mood 
changes requiring  
therapy; or suicidal 
ideation;  or 
aggressive ideation 
 
acute psychosis 
requiring 
hospitalization;  
or suicidal 
gesture/attempt 
or hallucinations 
 
Muscle Strength 
 
subjective 
weakness 
no objective 
symptoms/ signs 
 
mild objective  
signs/symptoms 
no decrease in 
function 
 
objective weakness 
function limited 
 
paralysis 
Paresthesia (burning, tingling, 
etc.) 
mild discomfort; 
no treatment  
required 
moderate 
discomfort; 
non-narcotic 
analgesia 
required 
severe discomfort; 
or narcotic 
analgesia required 
with symptomatic 
improvement 
incapacitating; or 
not responsive to 
narcotic analgesia 
Neuro-sensory 
mild impairment in 
sensation 
(decreased 
sensation, e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area 
or symmetrical 
distribution; or 
change in taste, 
smell, vision 
and/or hearing 
moderate 
impairment 
(mod decreased 
sensation, e.g., 
vibratory, 
pinprick, 
hot/cold to 
ankles) and/or 
joint position or 
mild 
impairment that 
is not 
symmetrical 
severe impairment 
(decreased or loss 
of sensation to 
knees or wrists) or 
loss of sensation of 
at least mod degree 
in multiple 
different body 
areas (i.e., upper 
and lower 
extremities) 
sensory loss 
involves limbs 
and trunk; 
paralysis;  or 
seizures 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
MUSCULOSKELATEL 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Arthralgia 
(joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics 
and/or pain 
interfering with 
function but not 
with activities 
of daily living 
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living 
disabling pain 
Arthritis 
mild pain with 
inflammation, 
erythema or joint 
swelling – but not 
interfering with 
function 
moderate pain 
with 
inflammation, 
erythema or 
joint swelling – 
interfering with 
function, but 
not with 
activities of 
daily living 
severe pain with 
inflammation, 
erythema or joint 
swelling –and 
interfering with 
activities of daily 
living 
permanent and/or 
disabling joint 
distruction 
Myalgia 
myalgia with no 
limitation of  
activity 
muscle 
tenderness (at 
other than 
injection site) 
or with 
moderate 
impairment of 
activity 
severe muscle 
tenderness with 
marked impairment 
of activity 
frank 
myonecrosis 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) ADULT TOXICITY TABLE 
NOVEMBER 2007 
DRAFT
SKIN
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Mucocutaneous 
erythema; pruritus 
diffuse, maculo 
papular rash, 
dry 
desquamation 
vesiculation or 
moist 
desquamation or 
ulceration 
exfoliative 
dermatitis, 
mucous 
membrane 
involvement or 
erythema, 
multiforme or 
suspected 
Stevens-Johnson 
or  necrosis 
requiring surgery 
Induration 
< 15mm 
15-30 mm 
>30mm
Erythema 
< 15mm 
15-30 mm 
>30mm
Edema 
< 15mm 
15-30 mm 
>30mm
Rash at Injection Site 
< 15mm 
15-30 mm 
>30mm
Pruritus 
slight itching at 
injection site 
moderate 
itching at 
injection 
extremity 
itching over entire 
body 
SYSTEMIC
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergic Reaction 
pruritus without 
rash 
localized 
urticaria 
generalized 
urticaria; 
angioedema 
anaphylaxis 
Headache 
mild, no treatment 
required 
transient, 
moderate; 
treatment 
required 
severe; responds to 
initial narcotic 
therapy 
intractable; 
requires repeated 
narcotic therapy 
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F 
38.6 - 39.5 C or 
101.6 - 102.9 F 
39.6 - 40.5 C or 
103 - 105 F 
> 40 C or
> 105 F
Fatigue 
normal activity 
reduced < 48 hours 
 normal activity 
decreased 25- 
50% > 48 hours 
normal activity 
decreased > 50% 
can’t work 
unable to care for 
self 
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT
1
Note:  The following toxicity table is a DRAFT and designed to provide general guidance 
on parameters for monitoring safety in clinical trials.  This toxicity table is not comprehensive and should 
not be applied directly to all trials.   
When selecting a toxicity table, the following are some of the items that must be taken into consideration: 
•
The population being studied
o
Does the clinical trial evaluate healthy subjects, subjects with a particular disease or
condition?
•
The stage of test article development
o
Is the clinical trial a Phase I (is it for the fisrt time in human subjects?) , II, III or IV?
•
The type of test article
o
Does the clinical trial evaluate a drug, device, vaccine or other biologic agent?
•
The prior human and preclinical experience with the test article
o
Are there any specific findings that require adjustment of the toxicity table?
o
Has it been approved for this indication in adult population?
Single site clinical trials evaluating healthy subjects should conform to the laboratory normal values at the 
single site. Multi-center clinical trials should reconcile among their laboratory normal values when 
evaluating a healthy volunteer population. 
Please confer with the DMID protocol team and DMID's Office of Clinical Research Affairs when selecting 
or developing a toxicity table for a DMID-sponsored trial. 
Takeda 
Lanadelumab 
Clinical Study Protocol Amendment 2: SHP643-304
CONFIDENTIAL 
 
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09 Feb 2023
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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
2
 
 
ABBREVIATIONS:  Abbreviations utilized in the Table: 
ULN = Upper Limit of Normal             LLN = Lower Limit of Normal 
Rx  = Therapy                                         Req = Required 
Mod = Moderate                                     IV  = Intravenous 
ADL = Activities of Daily Living          Dec = Decreased 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
GRADE 1 
Mild  
 
Transient or mild discomfort  
 
(< 48 hours); no medical intervention/therapy required 
GRADE 2 
Moderate 
 
Mild to moderate limitation in activity - 
some assistance may be needed; no or minimal medical 
intervention/therapy required 
GRADE 3 
Severe  
 
Marked 
limitation 
in 
activity, 
some 
assistance usually required; medical intervention/therapy required, 
hospitalizations possible 
GRADE 4 
Life-threatening 
Extreme limitation in activity, significant 
assistance required; significant 
medical 
intervention/therapy 
required, hospitalization or hospice care probable 
GRADE 5                              Death 
 
SERIOUS OR LIFE-THREATENING AEs 
 
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event.  Clinical events considered to be serious or life-threatening include, 
but are not limited to:  seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, severe depression. 
 
COMMENTS REGARDING THE USE OF THESE TABLES 
 
• 
Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common 
Toxicity Criteria (CTC), and World Health Organization (WHO)) have been adapted for 
use by the Division of Microbiology and Infectious Diseases (DMID) and modified to 
better meet the needs of participants in DMID trials. 
 
•  
For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide For Estimating Severity Grade”  located above. 
 
• 
Criteria are generally grouped by body system. 
 
• 
Some protocols may have additional protocol specific grading criteria, which will 
supercede the use of these tables for specified criteria. 
Takeda 
Lanadelumab 
Clinical Study Protocol Amendment 2: SHP643-304
CONFIDENTIAL 
 
Page 103 
 
09 Feb 2023
For non-commercial use only

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DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC  TOXICITY TABLES 
NOVEMBER  2007 
DRAFT 
 
10 
cells/hpf 
cells/hpf 
 
Takeda 
Lanadelumab 
Clinical Study Protocol Amendment 2: SHP643-304
CONFIDENTIAL 
 
Page 111 
 
09 Feb 2023
 
For non-commercial use only

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