Clinical trial NCT04503603
Conditions: Healthy Volunteers
Sponsor: Takeda
Start date: 2020-08-10; Completion date: 2020-12-23
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study to evaluate the safety, tolerability and pharmacokinetics (PK) of lanadelumab administered by Intravenous (IV) infusion in healthy adult volunteers.

Detailed description:
A Randomized, Double-blind, Placebo-Controlled, Repeat-dose, Single-center Phase 1a Study to Determine the Safety, Tolerability, and Pharmacokinetics of Lanadelumab Administered Intravenously in Healthy Adult Volunteer Subjects

Arms: arm 1: Participants will receive single dose of lanadelumab 300 mg intravenous (IV) infusion on Day 1 followed by second dose on Day 4. arm 2: Participant will receive single dose of lanadelumab matching placebo (normal saline) IV infusion on Day 1 followed by second dose on Day 4.
Interventions: intervention 1: Lanadelumab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive lanadelumab 300 mg IV infusion on Day 1 followed by Day 4. intervention 2: Participants will receive placebo matching to lanadelumab IV infusion on Day 1 followed by Day 4.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
NCT Number:  
NCT04503603 
 
Study Title: 
A Randomized, Double-blind, Placebo-Controlled, Repeat-dose, Single-
center Phase 1a Study to Determine the Safety, Tolerability, and 
Pharmacokinetics of Lanadelumab Administered Intravenously in 
Healthy Adult Volunteer Subjects 
 
 
Study Number: 
TAK-743-1003 
 
Protocol Version and Date: 
Protocol Amendment 1: 16-SEP-2020 


PROTOCOL
A Randomized, Double-blind, Placebo-Controlled, Repeat-dose, Single-center Phase 1a 
Study to Determine the Safety, Tolerability, and Pharmacokinetics of Lanadelumab 
Administered Intravenously in Healthy Adult Volunteer Subjects
Study Identifier:
TAK-743-1003
Compound:
TAK-743
Date:
16 Sep 2020
Version/Amendment 
Number:
Version 2.0 / Amendment 1.0
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................2
LIST OF IN-TEXT TABLES ..........................................................................................................6
LIST OF APPENDICES..................................................................................................................6
1.0
STUDY SUMMARY...........................................................................................................7
2.0
STUDY SCHEMATIC ......................................................................................................11
3.0
SCHEDULE OF STUDY PROCEDURES .......................................................................12
4.0
INTRODUCTION .............................................................................................................16
4.1
Background..................................................................................................................16
4.2
Rationale for the Proposed Study ................................................................................16
4.3
Benefit/Risk Profile .....................................................................................................16
5.0
STUDY OBJECTIVES AND ENDPOINTS.....................................................................18
5.1
Study ObjectivesSect ...................................................................................................18
5.1.1
Study Primary Objective........................................................................................18
5.1.2
Study Exploratory Objectives................................................................................18
5.2
Endpoints .....................................................................................................................18
5.2.1
Primary Endpoint...................................................................................................18
5.2.2
Exploratory Endpoints ...........................................................................................18
6.0
STUDY DESIGN AND DESCRIPTION..........................................................................19
6.1
Study Design................................................................................................................19
6.2
Dose Escalation............................................................................................................19
6.3
Stopping Rules.............................................................................................................19
6.4
Rationale for Study Design, Dose, and Endpoints.......................................................20
6.4.1
Rationale of Study Design .....................................................................................20
6.4.2
Rationale for Dose .................................................................................................20
6.4.3
Rationale for Endpoints .........................................................................................21
6.4.4
Future Biomedical Research..................................................................................22
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters....................................................................................................................22
6.6
Study Beginning and End/Completion ........................................................................22
6.6.1
Definition of Beginning of the Study.....................................................................22
6.6.2
Definition of End of the Study...............................................................................22
6.6.3
Definition of Study Discontinuation......................................................................22
6.6.4
Criteria for Premature Termination or Suspension of the Study ...........................22
6.6.5
Criteria for Premature Termination or Suspension of a Site..................................23
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS...............24
7.1
Inclusion Criteria .........................................................................................................24
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7.2
Exclusion Criteria ........................................................................................................24
7.3
Excluded Medications, Supplements, Dietary Products..............................................25
7.4
Diet, Fluid, Activity.....................................................................................................26
7.4.1
Diet and Fluid ........................................................................................................26
7.4.2
Activity ..................................................................................................................26
7.5
Criteria for Discontinuation or Withdrawal of a Subject.............................................26
7.6
Procedures for Discontinuation or Withdrawal of a Subject .......................................27
7.7
Subject Replacement....................................................................................................27
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.......................................................28
8.1
Clinical Study Drug .....................................................................................................28
8.1.1
Clinical Study Drug Labeling................................................................................28
8.1.2
Clinical Study Drug Inventory and Storage...........................................................28
8.1.3
Clinical Study Drug Blinding ................................................................................28
8.1.4
Randomization Code Creation and Storage...........................................................28
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure ....................................28
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs.................................29
9.0
STUDY PROCEDURES ...................................................................................................30
9.1
Administrative Procedures...........................................................................................30
9.1.1
Informed Consent Procedure .................................................................................30
9.1.2
Inclusion and Exclusion.........................................................................................30
9.1.3
Medical History/Demography ...............................................................................30
9.1.4
Concomitant Medications......................................................................................30
9.2
Clinical Procedures and Assessments..........................................................................30
9.2.1
Full Physical Exam ................................................................................................31
9.2.2
Height and Weight .................................................................................................31
9.2.3
BMI........................................................................................................................31
9.2.4
Vital Signs..............................................................................................................31
9.2.5
12-Lead ECG .........................................................................................................31
9.2.6
Study Drug Administration....................................................................................32
9.2.7
AE Monitoring.......................................................................................................32
9.2.8
Drug and Alcohol Screen.......................................................................................32
9.2.9
Laboratory Procedures and Assessments...............................................................33
9.3
PK, 
 and PGx Samples.........................................................................34
9.3.1
PK Measurements ..................................................................................................35
9.3.2
......................................................................................36
9.3.3
PGx Measurements................................................................................................36
9.3.4
Confinement...........................................................................................................36
10.0
ADVERSE EVENTS.........................................................................................................37
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10.1
Definitions and Elements of AEs.................................................................................37
10.1.1 SAEs ......................................................................................................................39
10.1.2 Adverse Events of Special Interest ........................................................................40
10.2
AE Procedures .............................................................................................................40
10.2.1 Assigning Severity/Intensity of AEs......................................................................40
10.2.2 Assigning Causality of AEs...................................................................................40
10.2.3 Start Date ...............................................................................................................41
10.2.4 End Date.................................................................................................................41
10.2.5 Pattern of Adverse Event (Frequency)...................................................................41
10.2.6 Action Taken With Study Treatment.....................................................................41
10.2.7 Outcome.................................................................................................................41
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs.......................................................................................................................42
10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .....44
11.0
STATISTICAL METHODS..............................................................................................45
11.1
Statistical and Analytical Plans....................................................................................45
11.1.1 Analysis Sets..........................................................................................................45
11.1.2 Safety Analysis ......................................................................................................45
11.1.3 PK Analysis ...........................................................................................................46
11.1.4
 (Exploratory Endpoint).....................................................................46
11.2
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee..........46
11.3
Determination of Sample Size .....................................................................................46
12.0
QUALITY CONTROL AND QUALITY ASSURANCE.................................................47
12.1
Study-Site Monitoring Visits.......................................................................................47
12.2
Protocol Deviations......................................................................................................47
12.3
Quality Assurance Audits and Regulatory Agency Inspections..................................47
13.0
ETHICAL ASPECTS OF THE STUDY...........................................................................48
13.1
IRB and/or IEC Approval............................................................................................48
13.2
Subject Information, Informed Consent, and Subject Authorization ..........................49
13.3
Subject Confidentiality ................................................................................................50
13.4
Publication, Disclosure, and Clinical Study Registration Policy.................................50
13.4.1 Publication and Disclosure ....................................................................................50
13.4.2 Clinical Study Registration....................................................................................50
13.4.3 Clinical Study Results Disclosure..........................................................................51
13.5
Insurance and Compensation for Injury.......................................................................51
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION...........................................52
14.1
Administrative Information .........................................................................................52
14.1.1 Study Contact Information.....................................................................................52
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14.1.2 INVESTIGATOR AGREEMENT.........................................................................53
14.1.3 Study-Related Responsibilities..............................................................................54
14.1.4 List of Abbreviations .............................................................................................54
15.0
DATA HANDLING AND RECORDKEEPING ..............................................................56
15.1
CRFs (Electronic and Paper) .......................................................................................56
15.2
Record Retention .........................................................................................................56
16.0
REFERENCES ..................................................................................................................58
17.0
APPENDICES ...................................................................................................................59
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LIST OF IN-TEXT TABLES
Table 1
Schedule of Assessments.......................................................................................12
Table 2
Detailed Schedule of In-House Assessments (Days 1 – 11)..................................13
Table 3
Detailed Schedule of Outpatient Assessments (Study Days 14 – 112) .................15
Table 4
Predicted Clinical Exposure Margins Compared to Observed Exposure 
(NOAEL) in Cynomolgus Monkeys......................................................................21
Table 5
Excluded Medications, Supplements, and Dietary Products .................................26
Table 6
Volume of Blood to Be Drawn from Each Subject ...............................................34
Table 7
Primary Specimen Collections...............................................................................35
Table 8
Takeda Medically Significant AE List ..................................................................39
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator........................................................................59
Appendix B
Elements of the Subject Informed Consent ...........................................................61
Appendix C
Investigator Consent to the Use of Personal Information......................................64
Appendix D
Pregnancy and Contraception ................................................................................65
Appendix E
Summary of Changes from Previous Version .......................................................67
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. (TDC Americas)
95 Hayden Avenue
Lexington, MA 02421
Telephone: 
Compound:
Lanadelumab
Study Identifier: TAK-743-1003
Phase: 1a
Protocol Title: A Randomized, Double-blind, Placebo-Controlled, Repeat-dose, Single-center Phase 1a Study to 
Determine the Safety, Tolerability, and Pharmacokinetics of Lanadelumab Administered Intravenously in Healthy 
Adult Volunteer Subjects
Study Design:
This Phase 1a study is a randomized, double-blind, placebo-controlled, repeat-dose study to evaluate the safety, 
tolerability and pharmacokinetics (PK) of lanadelumab administered by IV infusion in healthy volunteers. This study 
targets to enroll 1 cohort of approximately 12 subjects, including both male and female, 19 years of age and above. 
Subjects will be randomized 3:1 (9 lanadelumab: 3 placebo subjects) to receive lanadelumab 300 mg or matching 
placebo (normal saline) via IV infusion on Day 1 and Day 4. Subjects will receive the same treatment (lanadelumab or 
placebo) for each of the two doses. Sentinel dosing will be used for the first 2 subjects (1 receiving lanadelumab and 
1 receiving placebo). A safety review team will review safety and tolerability data after the first 2 sentinel subjects 
receive both doses of study drug. If no safety findings or signals are observed, the remaining subjects (N=10) will be 
dosed. An additional cohort of 12 subjects (increasing total number of subjects to approximately 24) or dose 
modifications (e.g., reduction to a single dose) will be allowed if required based on emerging data. An interim analysis 
will be performed when all subjects have reached Day 14 or discontinued early to evaluate preliminary safety and PK. 
These data will be summarized in a preliminary report. 
The study duration will comprise a screening period (up to 21 days), a 10-day in-house treatment period, and 
7 out-patient visits. The maximal total duration of study participation for a subject is approximately 133 days if the 
maximal screening, treatment, and out-patient visit durations are included. 
Study Primary Objective:

To evaluate the safety and tolerability of two doses of lanadelumab administered 3 days apart by IV infusion 
in healthy adult volunteers 

To characterize the PK of lanadelumab after two IV doses of lanadelumab administered 3 days apart in 
healthy adult volunteers
Study Subject Population: Healthy male and female subjects aged 19 to 55 years inclusive, at screening. Body Mass 
Index (BMI) 18.0-32.0 kg/m2, inclusive, at screening
Planned Number of Subjects:
12 subjects will be enrolled
Planned Number of Sites:
1
Dose Levels:
300 mg 
Route of Administration:
Intravenous (IV)
Duration of Treatment:
One dose on Day 1 followed by a second dose on Day 
4; Single IV infusion for 60 ± 15 minutes
Planned Study Duration:
Approximately 133 days including screening period and 
follow-up.
Criteria for Inclusion:
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the study:
1.
Healthy, adult, male or female, 19-55 years of age, inclusive, at screening. 
2.
Continuous non-smoker who has not used nicotine-containing products for at least 30 days prior to the first 
dosing and throughout the study, based on subject self-reporting.
3.
Body mass index (BMI) ≥18.0 and ≤32.0 kg/m2 at screening. 
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4.
Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, 
vital signs or electrocardiograms (ECGs), per the investigator.
5.
Male, or non-pregnant, non-lactating female who agrees to comply with any applicable contraceptive 
requirements of the protocol or females of non-childbearing potential
6.
Understands the study procedures in the informed consent form (ICF) and be willing and able to comply with 
the protocol.
Criteria for Exclusion:
Subjects must not be enrolled in the study if they meet any of the following criteria:
1.
Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or 
expected during the conduct of the study.
2.
History or presence of clinically significant medical or psychiatric condition or disease per the investigator.
3.
History of any illness that might confound the results of the study or poses an additional risk to the subject by their 
participation in the study, per the investigator.
4.
History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing per the 
investigator. 
5.
History or presence of hypersensitivity or idiosyncratic reaction to the study drug(s) or related compounds.
6.
History or presence of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or psychiatric 
disease, gall bladder removal, or current or recurrent disease that could affect the action, absorption, or 
disposition of the investigational product, or clinically significant clinical or laboratory assessments per the 
investigator.
7.
Female subjects with a positive pregnancy test or lactating.
8.
Positive urine drug or alcohol results at screening.
9.
Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or 
hepatitis C virus (HCV).
10. Supine blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
11. Supine heart rate is lower than 40 beats per minute (bpm) or higher than 99 bpm at screening.
12. QTcF interval is >450 msec (males) or >470 msec (females) or ECG findings are deemed abnormal with clinical 
significance at screening per the investigator.
13. Estimated creatinine clearance <80 mL/min at screening. 
14. Unable to refrain from or anticipates the use of any drug, including prescription and non-prescription medications, 
herbal remedies, or vitamin supplements within 14 days prior to the first dosing and throughout the study. 
Medication listed as part of acceptable birth control methods will be allowed (refer to Appendix D). Thyroid 
hormone replacement medication may be permitted if the subject has been on the same stable dose for the 
immediate 3 months prior to first study drug administration. After randomization/dosing, a nonsteroidal 
anti-inflammatory drug may be administered at the discretion of the investigator. Hormone replacement 
therapy will also be allowed if the subject has been on the same stable dose for the immediate 3 months prior 
to first study drug administration.
15. Has been on a diet incompatible with the on-study diet, per the investigator, within the 30 days prior to the first 
dosing and throughout the study.
16. Donation of blood or significant blood loss within 56 days prior to the first dosing.
17. Plasma donation within 7 days prior to the first dosing.
18. Participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. The 30-day window 
or 5 half-lives will be derived from the date of the last blood collection or dosing, whichever is later, in the 
previous study to Day 1 of the current study.
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
Continuous safety endpoints (eg, change in laboratory parameter) will be summarized using number of subjects 
(n), mean, standard deviation (SD), median, minimum value, and maximum value. As appropriate, raw (actual) 
values and changes from baseline will be summarized at each scheduled time point.

Categorical endpoints (eg, presence or absence of an outcome measure) will be summarized using counts and 
percentages. Summaries will include but are not limited to: number and percentage of subjects with an outcome 
measure, and laboratory shift tables (categorical change from baseline). 

Only TEAEs will be analyzed. The number and percentage of subjects reporting any TEAEs, SAEs, AESIs, 
TEAEs related to the investigational product, TEAEs leading to withdrawal, and severe TEAEs, as well as the 
total number of events for each category, will be summarized overall and by preferred term and system organ 
class. 

Clinical laboratory tests, vital signs, and ECG results will be summarized by scheduled time point. Clinically 
significant findings will also be summarized and listed.
Statistical Methodology for Pharmacokinetic Endpoints:
Statistical analysis of PK parameters will be based on the Pharmacokinetic Set. Listing of individual PK 
concentrations and individual PK parameters of lanadelumab will be based on the PK Analysis Set. Individual 
concentrations and PK parameters of lanadelumab (estimated based on actual sample collection times) will be listed 
and summarized by treatment group with descriptive statistics (number, 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 of lanadelumab by treatment group will be generated based on nominal time 
points.
Interim Analysis, Adaptive Design, and Data Monitoring Committee
An interim analysis will be performed when all subjects have completed Day 14 visit or discontinued early to evaluate 
preliminary safety and PK. These data will be summarized in a preliminary report. No adaptive design or Data 
Monitoring Committee (DMC) are planned for this study.
Sample Size Justification:
No formal calculations were performed to determine sample size for this study. The sample size is based on feasibility 
and is similar to that of comparable studies.
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2.0
STUDY SCHEMATIC
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3.0
SCHEDULE OF STUDY PROCEDURES 
Table 1
Schedule of Assessments
Visit
Screening
In-House Treatment 
Perioda
Out-Patient Visitsb,c
Study Day
–21 to -2
-1
1 to 11
14 to 112 
(End of Study or 
Early 
Discontinuation)
Informed consent
X
Refer to Table 3
Refer to Table 4
Inclusion/exclusion criteria
X
X
Demography
X
X
Medical/Medication History
X
X
Physical examination
X
X
Vital signs (blood pressure, pulse) supine
X
X
Body temperature (oral)
X
X
Height, Weight and BMId,e
X
X
Electrocardiogram (12-lead)
X
X
Biochemistry, hematology, and urinalysis
X
X
TSH, T3, T4
X
PT, aPTT, INR (coagulation tests)
X
X
HIV, HBsAg, and HCV antibodies
X
Serum Pregnancy test (all females)
X
X
FSH (all females)
X
Urine drug screening and alcohol 
X
X
Pharmacokinetic (PK) 
 
blood sampling 
Check-in to the CRU
X
Out-patient visits
In-patient visit
X
Concomitant Medication
X
X
Adverse Event/Serious Adverse Event
X
X
aPTT=activated partial thromboplastin time; CRU=clinical research unitr; HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; INR=international normalized ratio; FSH=follicle-stimulating hormone; HIV=human 
immunodeficiency virus
PT=prothrombin time; T3=triiodothyronine; T4=thyroxine; TSH= thyroid-stimulating hormone
a Refer to Table 3 for the procedures and the timing of the procedures to be done during the in-house treatment period.
b Refer to Table 4 for the procedures and the timing of the procedures to be done during the out-patient visits.
c In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these 
assessments. End of study visit is Day 112.
d Height will only be recorded at the first visit during the screening period.
e Body mass index criteria for eligibility will be calculated at the first visit during the screening period and on Day -1.
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Table 2
Detailed Schedule of In-House Assessments (Days 1 – 11)
Study Day 
Day 1
Day 
2
Day 
3
Day 4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Hour (relative to 
dosing time)
Dose 1
Predosea
0h
1h
2h
4h
6h
12h
24h
48h
72h 
(predose)a
73h
74h
76h
78h
84h
96h
120h
144h
168h
192h
216h
240h
Dose 2
--
--
--
--
--
--
--
--
--
0h
1h
2h
4h
6h
12h
24h
48h
72h
96h
120h
144h
168h
Randomizationb
X
IP administrationc
X
X
Physical Exam
X
Vital Signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body 
Temperature 
(Oral)
X
Weight 
X
ECGe
X
X
X
X
X
X
X
X
X
X
Biochemistry, 
hematology, and 
urinalysis 
X
X
X
PT, aPTT, INR
X
Serum Pregnancy 
(all women)
X
PK
X
Xh
Xi
Xi
Xi
Xi
Xj
Xj
X
Xh
Xi
Xi
Xi
Xi
Xj
Xj
Xk
Xk
Xk
Xk
Xk
AE/SAEg
X----------------------------------------------------------------------------------------------------------------------------------------------------------------X
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Table 2
Detailed Schedule of In-House Assessments (Days 1 – 11)
Study Day 
Day 1
Day 
2
Day 
3
Day 4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Hour (relative to 
dosing time)
Dose 1
Predosea
0h
1h
2h
4h
6h
12h
24h
48h
72h 
(predose)a
73h
74h
76h
78h
84h
96h
120h
144h
168h
192h
216h
240h
Dose 2
--
--
--
--
--
--
--
--
--
0h
1h
2h
4h
6h
12h
24h
48h
72h
96h
120h
144h
168h
Concomitant 
Medicationg
X----------------------------------------------------------------------------------------------------------------------------------------------------------------X
Discharge from 
CRU
X
AE=adverse event; aPTT= activated partial thromboplastin time; CRU=clinical research unit; ECG=12- lead ECG; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; INR=international 
normalized ratio; FSH=follicle-stimulating hormone; HIV=human immunodeficiency virus; IP=investigational product; PE=physical exam; PT=prothrombin time; PK=pharmacokinetic blood sampling; 
SAE=serious adverse event; T3=triiodothyronine;T4=thyroxine ; TSH=thyroid-stimulating hormone; UDS=urine drug screen; VS=vital signs
a Assessments to be done within 2 hours prior the administration of IP. The PK sample should be collected as closely as possible to hour 0 (start of infusion/dosing) for Dose 1 and hour 72 (hour 0; start 
of infusion/dosing) for Dose 2.
b 
Randomization to be performed at the time of dosing on Day 1.
c
Investigational product administration start and stop times must be recorded in source and on the CRF. The clock time of the second infusion should be approximately the same as the first infusion. 
d
Blood pressure and heart rate measurements will be performed with subjects in a supine position. The subject should be supine and instructed to relax as much as possible for at least 5 minutes prior to 
collection. When scheduled postdose, vital signs will be performed within approximately 15 minutes of the scheduled time point. When the timing of these measurements coincides with a blood 
collection, blood pressure and heart rate should be obtained prior to the nominal time of the blood collection. 
e  ECGs will be performed with subjects rested in a supine position for at least 5 minutes prior to collecting the ECG. When scheduled postdose, ECGs will be performed within 20 minutes of scheduled 
time point. Single ECG recordings are required. ECGs will be performed in triplicate if any of the following occur: (1) the QTcF interval (calculated on line on site) is increased by >45 msec from the 
baseline; (2) an absolute QTcF value is >500 msec for any scheduled ECG; (3) if indicated per exclusion criteria #12. Subsequently, 2 additional ECGs will be collected, approximately 2-4 minutes 
apart, to confirm the original measurement. Thereafter, all subsequent ECGs will be single recordings.
f  
 
g
Adverse events/SAEs and concomitant medications will be continuously monitored throughout the study. 
h
Sample to be collected immediately after the end of the infusion within approximately 10 minutes of the scheduled time point.
i
Sample to be collected within ± 10 minutes of the scheduled timepoint. 
j
Sample to be collected within ± 15 minutes of the scheduled timepoint.
k
Sample to be collected within ± 4 hours of the scheduled timepoint.
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Table 3
Detailed Schedule of Outpatient Assessments (Study Days 14 – 112)
Study Day
Day 14
(± 1)
Day 21
(± 1)
Day 28 
(± 2)
Day 42 
(± 3)
Day 56 
(± 3)
Day 84
(± 7)
Day 112 (± 7)
(End of Study Visit / 
or Early 
Discontinuation)
Physical Exama
X
X
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
X
Body Temperature 
(Oral)
X
X
X
X
X
X
X
Weight 
X
X
X
X
X
X
X
ECGc
X
X
X
X
X
X
X
Biochemistry, 
hematology, and 
urinalysis 
X
X
X
X
X
X
X
PT, aPTT, INR
X
X
X
X
X
X
X
Serum Pregnancy 
(all women)
X
X
X
X
X
X
X
UDS & ETOH screen
X
X
X
X
X
X
X
PK
X
X
X
X
X
X
X
AE/SAEe
X
X
X
X
X
X
X
Concomitant 
Medicatione
X
X
X
X
X
X
X
AE=adverse event; aPTT= activated partial thromboplastin time; ; ECG=12- lead ECG; HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; INR=international normalized ratio; FSH=follicle-stimulating hormone; HIV=human immunodeficiency 
virus; IP=investigational product; PE=physical exam; PT=prothrombin time; PK=pharmacokinetic blood sampling; 
SAE=serious adverse event; UDS=urine drug screen; VS=vital signs
a Outpatient physical exams may be symptom driven at the discretion of the investigator. 
b Blood pressure and heart rate measurements will be performed with subjects in a supine position. The subject should be supine 
and instructed to relax as much as possible for at least 5 minutes prior to collection. When the timing of these measurements
coincides with a blood collection, blood pressure and heart rate should be obtained prior to the nominal time of the blood 
collection. 
c ECGs will be performed with subjects rested in a supine position for at least 5 minutes prior to collecting the ECG. Single ECG 
recordings are required. ECGs will be performed in triplicate if any of the following occur: (1) the QTcF interval (calculated on 
line on site) is increased by >45 msec from the baseline; (2) an absolute QTcF value is >500 msec for any scheduled ECG; (3) if 
indicated per exclusion criteria #12. Subsequently, 2 additional ECGs will be collected, approximately 2-4 minutes apart, to 
confirm the original measurement. Thereafter, all subsequent ECGs will be single recordings. 
d
e
Adverse events/SAEs and concomitant medications will be continuously monitored throughout the study.
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4.0
INTRODUCTION
4.1
Background
Lanadelumab (Takhzyro™, TAK-743, formerly SHP643 or DX-2930) is currently approved as a 
subcutaneous (SC) injection for prophylaxis to prevent attacks of hereditary angioedema (HAE) in 
patients 12 years and older. It is a recombinant, fully human, immunoglobulin G1, kappa light 
chain, monoclonal antibody and is a highly potent and a specific inhibitor of pKal. Plasma 
kallikrein is a protease that cleaves high molecular weight kininogen (HMWK) to generate cleaved 
HMWK (cHMWK) and bradykinin. Bradykinin is a potent proinflammatory and vasodilative 
nonameric peptide responsible for the characteristic symptoms of localized swelling, pain, and 
inflammation. 
For further details see the current lanadelumab Investigator’s Brochure.
4.2
Rationale for the Proposed Study
Lanadelumab is currently approved as an SC injection for prophylaxis to prevent attacks of HAE 
in patients 12 years and older. Based on the mechanism of action of lanadelumab and recent case 
studies with a competitive antagonist selective for the bradykinin B2 receptor, icatibant, there is 
strong scientific rationale to evaluate the potential for lanadelumab to treat pneumonia due to 
coronavirus disease 2019 (COVID-19). Clinical evidence supports the need for early intervention 
in patients hospitalized with COVID-19 pneumonia. Following SC administration of 300 mg 
every 2 weeks (approved dosage for the HAE indication), the time until maximum observed 
concentration (Tmax) was 4 days or longer with maximum observed concentration (Cmax) 
approximately 34 ug/mL, which may not be sufficient to meet the treatment needs (regarding the 
rate and extent of SC absorption) in patients with progressing COVID-19 disease. Intravenous 
(IV) administration of lanadelumab may be required, but IV administration has not yet been 
studied. Thus, the purpose of this study is to evaluate the safety, tolerability and pharmacokinetics 
(PK) of lanadelumab administered via the IV route in healthy adult volunteer subjects to support 
the further clinical evaluation of lanadelumab IV in COVID-19 patients.
4.3
Benefit/Risk Profile
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 submissions for global expansion.
Per the reference labeling (Takhyzro, 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 lanadelumab-treated patients compared to 
placebo include hypersensitivity, increased aspartate transaminase, and increased alanine 
transaminase.
Hypersensitivity is an important identified risk and is discussed in the warnings and precautions of 
the reference labeling. Immunogenicity is an important potential risk for lanadelumab and is 
monitored closely. The known potential risk of disordered coagulation associated with 
monoclonal antibodies has been characterized, and no unexpected signals were identified. Based 
on the review of the safety data from the completed and ongoing clinical trials, the known 
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cumulative exposure and continuous pharmacovigilance monitoring for the risks, the benefit-risk 
continues to be favorable. Always refer to the latest version of the lanadelumab Investigator’s 
Brochure for the overall benefit/risk assessment and the most accurate and current information 
regarding drug metabolism, PK, efficacy, and safety of lanadelumab. 
There will be no direct health benefit for study subjects from receipt of study drugs. An indirect 
health benefit to the healthy subjects enrolled in this study is the free medical tests received at 
screening and during the study.
The inclusion and exclusion criteria, screening, and safety monitoring practices employed by this 
protocol (ie, 12-lead electrocardiogram (ECG), vital signs, clinical laboratory tests, AE 
questioning and physical examination) are adequate to protect the subject’s safety and should 
detect all TEAEs.
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This Phase 1a study is a randomized, double-blind, placebo-controlled, repeat-dose study to 
evaluate the safety, tolerability and PK of lanadelumab administered by IV infusion in healthy 
adult volunteers. This study targets to enroll 1 cohort of approximately 12 subjects, including both 
male and female, 19 years of age and above. 
Subjects will be randomized 3:1 (9 lanadelumab: 3 placebo subjects) to receive lanadelumab 
300 mg or matching placebo (normal saline) via IV infusion on Day 1 and Day 4. Subjects will 
receive the same treatment (lanadelumab or placebo) for each of the two doses. Sentinel dosing 
will be used for the first 2 subjects (1 receiving lanadelumab and 1 receiving placebo). A safety 
review team consisting of, at a minimum, the investigator, the Sponsor’s Medical Monitor, the 
Sponsor’s Drug Safety physician and the Sponsor’s statistician will review safety (TEAEs, vital 
signs, 12-lead ECGs) and tolerability data after the first 2 sentinel subjects receive both doses of 
study drug. If no safety findings or signals are observed, the remaining subjects (N=10) will be 
dosed. An additional cohort of 12 subjects (increasing total number of subjects to approximately 
24) or dose modifications (eg, reduction to a single dose) will be allowed if required based on 
emerging data. An interim analysis will be performed when all subjects have reached Day 14 or 
discontinued early to evaluate preliminary safety and PK. These data will be summarized in a 
preliminary report. 
The study duration will comprise a screening period (up to 21 days), a 10-day in-house treatment 
period, and 7 out-patient visits. The maximal total duration of study participation for a subject is 
approximately 133 days if the maximal screening, treatment, and out-patient visit durations are 
included. 
6.2
Dose Escalation
Not applicable. 
6.3
Stopping Rules
Individual subject dosing will not continue if any of the following criteria are met:

If 2 or more subjects experience a treatment emergent adverse event (TEAE) of at least 
moderate severity (such as National Cancer Institute [NCI] Common Terminology Criteria for 
Adverse Events [CTCAE] Grade 3 or higher) in the same system organ class (SOC) considered 
related to study drug by the investigator. 

Dosing will be discontinued in an individual subject if that subject experiences a TEAE of at 
least moderate severity (CTCAE Grade 3 or higher) or laboratory abnormality that is 
considered related to study drug by the investigator. 

Individual subjects should be discontinued if any of the following laboratory findings are 
observed:
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administration has been proposed for this study to gain initial safety and tolerability and PK data 
utilizing the 300 mg dose indicated for HAE.
Exposure to lanadelumab IV administration was predicted by a simulation using a 2-compartment 
IV model with PK parameters estimated by fitting the model to mean values of lanadelumab 
concentrations in HAE clinical studies, for a single 300 mg IV infusion, and 300 mg IV infusion 
on Day 1 and Day 4 (Table 4). The exposure (predicted Cmax and area under the plasma 
time-concentration curve [AUC]) to lanadelumab is comparable to the exposure observed 
following 2 ×400 mg SC 14 days apart, and the HAE clinical exposure package; and the sufficient 
safety margins for the proposed IV dosing regimens by the nonclinical HAE package are provided 
(below) using no observed adverse effect level (NOAEL) exposure observed in both GLP and 
non-GLP monkey toxicity studies. 
Table 4
Predicted Clinical Exposure Margins Compared to Observed Exposure 
(NOAEL) in Cynomolgus Monkeys
Cynomolgus Monkey Exposure (NOAEL)
GLP Toxicity 
Repeat-Dose IV Study
(Day 22 to 29)
Non-GLP Tolerability 
Single-Dose IV Study
(Day 1 to 29)
AUClast (µg*hr/mL)
123000
137500
Cmax (µg*mL)
1640
1155
Human 300 mga
Safety Margin
AUC0-672 (µg*hr/mL)
17281
7.1
8.0
Cmax (µg*mL)
94.1
17
12
Human 2×300 mga,b
Safety Margin
AUC0-672 (µg*hr/mL)
33532
3.7
4.1
Cmax (µg*mL)
130
13
8.9
AUC0-672=area under the concentration-time curve from time 0 to 672 hours; AUClast=area under the 
concentration-time curve from time 0 to the last timepoint; Cmax=maximum observed concentration; GLP=Good 
Laboratory Practices; IV=intravenous; NOAEL=no observed adverse effect level
a
=300 mg IV infused for 60 minutes on Day 1.
b
=300 mg IV infused for 60 minutes on Day 4.
6.4.3
Rationale for Endpoints
6.4.3.1
Pharmacokinetic Endpoints
The PK endpoints are standard for this type of study.
6.4.3.2
Safety Endpoints
The key safety endpoints are typical for Phase 1 studies and will be assessed through monitoring of 
AEs, vital signs, ECGs, laboratory assessments, and physical examinations.
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6.4.4
Future Biomedical Research
Any residual plasma samples will be stored by the Sponsor or Bioanalytical facility for the 
maximal 15 years determined by the Sponsor following the last dosing. Tubes or containers will be 
identified with a barcode using an appropriate label. Samples obtained for this study may be used 
for further analyses based on emerging data. Thereafter, samples will be destroyed. 
No deoxyribonucleic acid (DNA), or ribonucleic acid (RNA) will be the focus of these analyses. 
The analyses will focus on metabolite profiling for lanadelumab or the potential use of 
lanadelumab for disease conditions based on emerging data. Samples will not be submitted to a 
public database. The Sponsor and contract research organizations involved in the clinical conduct, 
bioanalytical analyses, and PK and statistical analysis of the data will have access to the samples 
and/or the data that resulted from the analysis, if performed. 
By signing the Informed Consent Form (ICF), subjects agree to the possible future analysis of 
these samples. At any time, the subjects can contact the Clinical Research Unit (CRU) staff to 
request destruction of the residual samples once PK assessments required to meet the primary 
objective of the study are completed. 
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
An additional cohort of 12 subjects or dose modifications (eg, reduction to a single dose) will be 
allowed if required based on emerging data. If necessary, a subject may be discontinued for the 
reasons described in Section 7.5 and Section 7.6.
6.6
Study Beginning and End/Completion
6.6.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of the screening (ie, signing of the 
ICF) of the first subject.
6.6.2
Definition of End of the Study
The end of study is defined as the date of the last scheduled study procedure as outlined in the 
Schedule of Study Procedures (Section 3.0)
6.6.3
Definition of Study Discontinuation
Celerion reserves the right to terminate the study in the interest of subject welfare.
The Sponsor reserves the right to suspend or terminate the study at any time.
6.6.4
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study (refer to Stopping Rules, 
Section 6.3).
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6.6.5
Criteria for Premature Termination or Suspension of a Site
Not applicable.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study:
1. Healthy, adult, male or female, 19-55 years of age, inclusive, at screening. 
2. Continuous non-smoker who has not used nicotine-containing products for at least 30 days 
prior to the first dosing and throughout the study, based on subject self-reporting.
3. Body mass index (BMI) ≥18.0 and ≤32.0 kg/m2 at screening. 
4. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, per the investigator.
5. Male, or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential. 
6. Understands the study procedures in the ICF and be willing and able to comply with the 
protocol.
7.2
Exclusion Criteria
Subjects must not be enrolled in the study if they meet any of the following criteria:
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study.
2. History or presence of clinically significant medical or psychiatric condition or disease per 
the investigator.
3. History of any illness that might confound the results of the study or poses an additional 
risk to the subject by their participation in the study, per the investigator.
4. History or presence of alcoholism or drug abuse within the past 2 years prior to the first 
dosing per the investigator. 
5. History or presence of hypersensitivity or idiosyncratic reaction to the study drug(s) or 
related compounds.
6. History or presence of any hematological, hepatic, respiratory, cardiovascular, renal, 
neurological or psychiatric disease, gall bladder removal, or current or recurrent disease 
that could affect the action, absorption, or disposition of the investigational product, or 
clinically significant clinical or laboratory assessments per the investigator.
7. Female subjects with a positive pregnancy test or lactating.
8. Positive urine drug or alcohol results at screening.
9. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface 
antigen (HBsAg) or hepatitis C virus (HCV).
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10. Supine blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
11. Supine heart rate is lower than 40 meats per minute (bpm) or higher than 99 bpm at 
screening.
12. QTcF interval is >450 msec (males) or >470 msec (females) or ECG findings are deemed 
abnormal with clinical significance at screening per the investigator.
13. Estimated creatinine clearance <80 mL/min at screening. 
14. Unable to refrain from or anticipates the use of any drug, including prescription and 
non-prescription medications, herbal remedies, or vitamin supplements within 14 days 
prior to the first dosing and throughout the study. Medication listed as part of acceptable 
birth control methods will be allowed (refer to Appendix D). Thyroid hormone 
replacement medication may be permitted if the subject has been on the same stable dose 
for the immediate 3 months prior to first study drug administration. After 
randomization/dosing, a nonsteroidal anti-inflammatory drug may be administered at the 
discretion of the investigator. Hormone replacement therapy will also be allowed.
15. Has been on a diet incompatible with the on-study diet, per the investigator, within the 
30 days prior to the first dosing and throughout the study.
16. Donation of blood or significant blood loss within 56 days prior to the first dosing.
17. Plasma donation within 7 days prior to the first dosing.
18. Participation in another clinical study within 30 days or 5 half-lives prior to the first dosing. 
The 30-day window or 5 half-lives will be derived from the date of the last blood collection 
or dosing, whichever is later, in the previous study to Day 1 of the current study.
7.3
Excluded Medications, Supplements, Dietary Products
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 7.2. After 
each dose of study drug, a nonsteroidal anti-inflammatory drug may be administered at the 
discretion of the investigator. Thyroid hormone replacement medication may be permitted if the 
subject has been on the same stable dose for the immediate 3 months prior to the first dosing. 
Hormone replacement therapy will also be allowed if the subject has been on the same stable dose 
for the immediate 3 months prior to first study drug administration.
If deviations occur, the investigator in consultation with the Sponsor if needed will decide on a 
case by case basis whether the subject may continue participation in the study.
All medications taken by subjects during the course of the study will be recorded.
Use of excluded agents (prescription or non-prescription) or dietary products is outlined in 
Table 5. 
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Table 5
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and First Dosing (Days 
-28 to predose [Day 1])
After First Dosing (Day 1) to 
Follow-Up 
Alcohol
Prohibited from 48 hours prior to first dosing
Prohibited 48 hours prior to each 
outpatient visit during the study
Xanthine and/or caffeine
Prohibited from 24 hours prior to first dosinga
Prohibited 30 minutes prior to 
each outpatient visit during the 
studya
Medications 
See Section 7.1 and Section 7.2
See Section 7.1 and Section 7.2
Nicotine- and 
tobacco-containing and/or 
cannabis products
Prohibited for at least 30 days prior to the first 
dose 
Prohibited from first dosing until 
the follow-up visit.
(a) small amounts of caffeine derived from normal foodstuffs e.g., 250 mL/8 oz./1 cup decaffeinated coffee or other 
decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz. chocolate bar, per day, would not be 
considered a deviation to this restriction.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
When confined, standard meals and snacks will be provided at appropriate times. When confined 
in the CRU, subjects will be required to fast from all food and drink except water between meals 
and snacks provided.
7.4.2
Activity
Subjects will remain ambulatory or seated upright for the first 4 hours postdose, except when they 
are supine or semi-reclined for study procedures as noted in the protocol. 
Subjects should refrain from strenuous physical exercise 48 hours prior to admission to the CRU 
and during the in-house stays at the CRU. 
7.5
Criteria for Discontinuation or Withdrawal of a Subject
Subjects are free to withdraw from the study at any time for any reason. 
In addition, subjects may be withdrawn from the study by the investigator for the following 
reasons:

AEs.

A positive pregnancy test for females.

Positive urine drug or alcohol results.

Difficulties in blood collection.
A subject may be withdrawn by the investigator or the Sponsor if enrollment into the study is 
inappropriate, the study plan is violated, or for administrative and/or other safety reasons.
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7.6
Procedures for Discontinuation or Withdrawal of a Subject
The Investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the Investigator. In addition, efforts should be made to perform all procedures scheduled for the 
end-of-study or early termination as described in Section 3.0.
7.7
Subject Replacement
Study subjects who withdraw or discontinue early may be replaced at the discretion of the sponsor.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
Lanadelumab will be supplied by Sponsor prepackaged in a study kit. Each study kit will contain 
one (1) vial of lanadelumab 300 mg/vial liquid form. Additional information is provided in the 
current lanadelumab Investigator’s Brochure. 
The reference/comparator product is matching placebo (normal saline (NS), 0.9% sodium 
chloride) for infusion (provided by the site). Further details are provided in the Pharmacy Manual. 
8.1.1
Clinical Study Drug Labeling
Study drug containers will be affixed with a clinical label in accordance with local regulatory 
requirements.
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
subject.
8.1.2
Clinical Study Drug Inventory and Storage
The same lot number will be used throughout the study. The lot numbers and expiration dates 
(where available) of the study drugs supplied will be recorded in the final report. Study drugs will 
be stored according to the product labels provided with the product.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied.
8.1.3
Clinical Study Drug Blinding
This is a double-blind, placebo-controlled study.
8.1.4
Randomization Code Creation and Storage 
A computerized randomization scheme will be created by a Celerion statistician and it shall be 
considered blinded (as per the following). 
The randomization is available only to the unblinded CRU pharmacy staff that is preparing the 
drug who will not be involved in any other aspect of the study including administration of the drug. 
It will not be made available to the Sponsor, bioanalytical laboratory, subjects, or members of the 
staff responsible for the monitoring and evaluation of safety assessments. One set of sealed 
envelopes containing the randomization code will be supplied to the investigator at the start of the 
study.
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure
Breaking of the blind is expressly forbidden except in the event of a medical emergency where the 
identity of the drug must be known in order to properly treat the subject. An interim analysis will 
be performed when all subjects have reached Day 14 or discontinued early. Site personnel and 
subjects will remain blinded to study treatment; a Sponsor team that is separate from the clinical 
study team will review the unblinded report. Details will be reported separately in the Data 
Blinding Specification Form and Data Access Management Plan. 
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In the event of a medical emergency, it is requested that the investigator make every effort to 
contact the Study Monitor or designee prior to breaking the blind. If breaking the blind is required 
because of a medical emergency, the treatment identity would be revealed by the investigator for 
that subject only. In the event that the emergency is one that suggests that other subjects may be at 
imminent risk, the blind may be broken for all subjects dosed. The unblinding will be properly 
documented in the study file.
In all cases where the code is broken, the investigator should record the date and reason for code 
breaking.
At the end of the study, envelopes will be retained according to site procedures unless specified 
otherwise by the Sponsor.
In the absence of a medical emergency, the blinded randomization for this study will not be 
revealed until all data are entered in the database, edits checks are performed, queries closed, and 
the database is officially locked. 
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
Records will be made of the receipt and dispensing of the study drugs supplied. At the conclusion 
of the study, any unused study drugs will be retained by Celerion, returned to the Sponsor, or 
destroyed, as per Sponsor instructions. Any remaining supplies that were purchased by Celerion 
will be destroyed, if appropriate. If no supplies remain, this fact will be documented in the 
pharmacy product accountability records.
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9.0
STUDY PROCEDURES
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign, and date an 
ICF summarizing the discussion prior to screening, and will be assured that they may withdraw 
from the study at any time without jeopardizing their medical care.
Subjects will be given a copy of their signed ICF
9.1.1.1
Assignment of Screening and Randomization Numbers 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique identification number at the time of dosing, different from the screening number.
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (eg, Subject No. 101 will replace Subject No. 1).
9.1.1.2
Study Drug Assignment
All subjects will receive the treatments as detailed in Section 9.2.6. 
9.1.2
Inclusion and Exclusion 
Please refer to Section 7.1 and Section 7.2.
9.1.3
Medical History/Demography
Medical history and demographic data, including name, sex, age, race, ethnicity, and history of 
tobacco use will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited except as listed in Section 7.3. All medications taken 
by subjects during the course of the study will be recorded.
9.2
Clinical Procedures and Assessments
The Schedule of Study Procedures (Section 3.0) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the investigator and/or the Sponsor for reasons 
related to subject safety.
If required due to the COVID-19 pandemic, home visits may be substituted for on-site visits per 
the Investigator starting with the Day 28 outpatient visit. 
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9.2.1
Full Physical Exam
A full physical examination will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Symptom-driven physical examinations may be performed at out-patient visits 
times, if deemed necessary by the investigator, as noted in Table 3.
The physical examination will include a review of the following body systems: 

General appearance 

Skin

Head, eyes, ears, nose, and throat 

Spine/neck/thyroid

Musculoskeletal

Respiratory 

Cardiovascular 

Neurological 

Abdomen (including liver and kidneys)
9.2.2
Height and Weight
Body height (cm) and weight (kg) will be reported as outlined in the Schedule of Study Procedures 
(Section 3.0).
9.2.3
BMI
BMI for eligibility will be calculated at the first visit during the screening period and on Day -1. 
9.2.4
Vital Signs
Single measurements of body temperature, blood pressure and pulse will be measured as outlined 
in the Schedule of Study Procedures (Section 3.0). Additional vital signs may be taken at any other 
times, if deemed necessary.
Blood pressure and heart rate measurements will be performed with subjects in a supine position. 
The subject should be supine and instructed to relax as much as possible for at least 5 minutes prior 
to collection. The subject should remain quiet during this time and through the measurement.
Vital signs will be measured within 2 hours prior to dosing on Day 1 and Day 4. When scheduled 
postdose, vital signs will be performed within approximately 15 minutes of the scheduled time 
point. When the timing of these measurements coincides with a blood collection, blood pressure 
and heart rate should be obtained prior to the nominal time of the blood collection. 
9.2.5
12-Lead ECG
Single 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Additional ECGs may be taken at any other times, if deemed necessary by the 
investigator.
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Electrocardiograms  will be performed with subjects rested in a supine position for at least 
5 minutes prior to collecting the ECG. All ECG tracings will be reviewed by the investigator.
Electrocardiograms will be measured within 2 hours prior to dosing on Day 1 and Day 4. When 
scheduled postdose, ECGs will be performed within approximately 20 minutes of the scheduled 
time point.
9.2.6
Study Drug Administration
Lanadelumab will be provided as described in Section 8.1.
Unblinded pharmacy personnel will be responsible for providing the study drug(s) to the blinded 
study personnel for dosing as per the randomization scheme. 
The times of the beginning and the end of infusion will be recorded. Dosing interruptions will be 
recorded.
Treatments will be administered as follows:

Lanadelumab: Lanadelumab 300 mg, one dose administered via IV infusion over a period 
of 60 ±15 minutes on Day 1, followed by a second dose on Day 4

Placebo: NS administered via IV infusion over a period of 60 ±15 minutes on Day 1, 
followed by a second administration on Day 4
Complete details regarding IP preparation and administration are given in the Pharmacy Manual. 
9.2.7
AE Monitoring
Subjects will be monitored throughout the study for adverse reactions to the study drugs and/or 
procedures as described in Section 10.0.
9.2.8
Drug and Alcohol Screen 
A urine screen for drugs of abuse and alcohol will be performed at the time points described in 
Section 3.0. This screen will include marijuana. Additional drug and alcohol screens may be 
performed at the investigator’s discretion.
Urine samples are to be tested for drugs of abuse as outlined in Section 9.2.9.1 (see “Other” table).
Results of urine drug and alcohol screens will be reviewed and verified by the study monitor but 
will not be collected in the Case report form (CRF) database.
Any positive result for drugs of abuse or alcohol at screening or on Day -1 will exclude the subject 
from further participation in the study.
If any drugs of abuse or alcohol results are positive at any time point after the subject has been 
dosed, the investigator must contact the sponsor’s Medical Monitor to discuss and review the 
circumstances and to determine whether the subject may continue in the study.
Details of the discussion taken must be properly recorded in the subject’s source documents
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9.2.9
Laboratory Procedures and Assessments
All tests listed below will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). In addition, laboratory safety tests may be performed at unscheduled time points, if 
deemed necessary by the investigator.
9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Total and differential leukocyte count
Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts 
or rechecks, subjects may not have fasted for 8 hours prior to the time of sample collection.
Chemistry evaluations will consist of the following standard chemistry panel:
Amylase
Albumin
Lipase
Sodium
Blood Urea Nitrogen
Potassium
Bilirubin (total and direct)
Chloride
Alkaline phosphatase (ALP)
Glucose 
Aspartate aminotransferase (AST)
Creatinine *
Triglycerides
Low-density lipoprotein
Cholesterol
High-density lipoprotein
Alanine aminotransferase (ALT)
Magnesium
Calcium
Thyroid panel (Thyroid stimulating hormone [TSH], 
Thyroxine [T4 total], Triiodothyronine [T3])**
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula.
**At screening only 
Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red blood 
cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
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Primary specimen collection parameters are provided in Table 7.
Table 7
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma sample for PK
Plasma
Plasma sample for PK analysis
Mandatory
9.3.1
PK Measurements 
Samples from all subjects will be assayed even if the subjects do not complete the study. Samples 
for determination of plasma lanadelumab will be analyzed using validated bioanalytical methods.
Pharmacokinetic parameters of lanadelumab will be calculated from the individual 
concentration-time profiles from all evaluable subjects using compartmental or noncompartmental 
analysis methods. Actual sampling times, rather than scheduled sampling times, will be used in all 
computations involving sampling times. 
9.3.1.1
Plasma or Serum for PK Measurements
The following PK parameters will be calculated from plasma concentrations of lanadelumab, but 
not limited to, using compartmental or non-compartmental analysis (NCA) methods as 
appropriate:
AUClast:
The area under the concentration-time curve, from time 0 to the last 
quantifiable concentration, as calculated by the linear-log trapezoidal 
method.
AUC:
The area under the concentration-time curve, from time 0 extrapolated to 
infinity. AUCis calculated as AUClast plus the ratio of the last measurable 
blood concentration to the elimination rate constant.
CL:
Total plasma clearance after IV administration, calculated as Dose/AUC.
Cmax:
Maximum observed plasma drug concentration following the first IV dose 
(Cmax 1) and following the second IV dose (Cmax 2).
tmax:
Minimum observed time to reach the first Cmax 1 (Tmax 1) and to reach the 
second Cmax 2 (Tmax 2).
Vz:
Volume of distribution during the terminal disposition phase after IV 
administration.
Individual and mean plasma concentration-curves (both linear and log-linear) will be included in 
the final report.
Additional PK parameters may be estimated as appropriate.
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9.3.2
 
 
9.3.3
PGx Measurements 
Not applicable.
9.3.4
Confinement
Subjects will be housed on Day -1 and will remain in the CRU until discharge on Day 11. Subjects 
will return for study procedures as outlined in the Schedule of Study Procedures (Section 3.0) 
except if home visits are substituted for clinic visits (Section 9.2). 
At all times, a subject may be required to remain at the CRU for longer at the discretion of the 
investigator.
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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a study procedure. However, if the subject experiences a worsening or complication 
of such a concurrent medical history condition, the worsening or complication should be 
recorded appropriately as an AE (worsening or complication occurs after informed consent is 
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signed). Investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the Sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the (e)CRF, in order to capture this important safety information consistently in the 
database. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.0.

Serious adverse events (SAEs) of overdose should be reported according to the procedure 
outlined in Section 10.2.8.
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
In the event of drug overdose, the subject should be treated symptomatically.
10.1.1 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” 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 that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes, but is not limited to, any event or synonym described in the Takeda Medically 
Significant AE List (Table 8).
Table 8
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Section 10.1 and Section 10.1.1).
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10.1.2 Adverse Events of Special Interest
Adverse events of special interest (AESIs) will be captured and monitored during this study. The 
following describe the AESIs pertinent for this study and the criteria for reporting AESIs.
Hypersensitivity Reactions
As hypersensitivity reactions have been observed for monoclonal antibodies as a class, these 
events are considered AESIs for this study. Investigators will report all diagnoses, or signs and 
symptoms when diagnoses cannot be determined, that are consistent with hypersensitivity 
reactions, regardless of causality, within 24 hours from the time of study drug administration. 
Investigators will report hypersensitivity reactions that occur after 24 hours only if the reactions 
are suspected to be related to study drug.
10.2
AE Procedures
10.2.1 Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
Moderate:
An adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
10.2.2 Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, i.e., the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
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10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.4 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5 Pattern of Adverse Event (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.2.6 Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE.

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.

Drug interrupted – the dose was interrupted due to the particular AE.
10.2.7 Outcome 

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/ Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.
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
Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.8 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.8.1 Collection Period
Collection of AEs (ie, AEs, SAEs, AESIs, abnormal Liver Function Tests [LFTs]) will commence 
at the time the subject signs the informed consent. Routine collection of AEs will continue until the 
end of study visit (Day 112). For subjects who discontinue prior to the administration of study 
medication, AEs will be followed until the subject discontinues study participation. 
10.2.8.2 Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE prior to the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to Baseline or there 
is a satisfactory explanation for the change. Nonserious AEs that begin prior to the first exposure 
to investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the CRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with study drug.

Outcome of event.

Seriousness.
10.2.8.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
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A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the Sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.8.4 Reporting Special Interest AEs 
Investigators will report all AESIs to the sponsor, regardless of causality, using the same timelines 
as described for SAE reporting.
10.2.8.5 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases CRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.8.3. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.2.9 must also be 
performed. In addition, an LFT Increases CRF must be completed and transmitted with the Takeda 
SAE form (as per Section 10.2.9). 
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10.2.9 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and Institutional 
Review Boards (IRBs) or Independent Ethics Committees (IECs), as applicable, in accordance 
with national regulations in the countries where the study is conducted. Relative to the first 
awareness of the event by/or further provision to the Sponsor, SUSARs will be submitted within 
7 days for fatal and life-threatening events and 15 days for other serious events, unless otherwise 
required by national regulations. The Sponsor will also prepare an expedited report for other safety 
issues where these might materially alter the current benefit-risk assessment of an investigational 
medicinal product or that would be sufficient to consider changes in the investigational medicinal 
products administration or in the overall conduct of the study. The investigational site also will 
forward a copy of all expedited reports to his or her IRB or IEC in accordance with national 
regulations.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the CRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the Sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, and 
review of CRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the Sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the Sponsor should be notified 
immediately. The investigator guarantees access for quality assurance auditors to all study 
documents as described in Section 12.1.
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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Conference on Harminsation (ICH) Harmonised Tripartite 
Guideline for Good Clinical Practice (GCP). Each investigator will conduct the study according to 
applicable local or regional regulatory requirements and align his or her conduct in accordance 
with the “Responsibilities of the Investigator” that are listed in Appendix A. The principles of 
Helsinki are addressed through the protocol and through appendices containing requirements for 
informed consent and investigator responsibilities.
13.1
IRB and/or IEC Approval
Institutional Review Boards and IECs must be constituted according to the applicable state and 
federal/local requirements of each participating region. The Sponsor or designee will require 
documentation noting all names and titles of members who make up the respective IRB or IEC. If 
any member of the IRB or IEC has direct participation in this study, written notification regarding 
his or her abstinence from voting must also be obtained. Those American sites unwilling to provide 
names and titles of all members due to privacy and conflict of interest concerns should instead 
provide a Federal Wide Assurance Number or comparable number assigned by the Department of 
Health and Human Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the Sponsor or designee before 
commencement of the study (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The Sponsor will ship drug/notify site once the Sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the Sponsor has 
received permission from competent authority to begin the study. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
Sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and Sponsor.
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13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the Sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study, and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the Sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
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Subjects who consented and provided a PGx sample for DNA and RNA analysis can withdraw 
their consent and request disposal of a stored sample at any time prior to analysis. Notify Sponsor 
of consent withdrawal.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (Section 13.2).
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s CRF).
13.4
Publication, Disclosure, and Clinical Study Registration Policy
13.4.1 Publication and Disclosure
The investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2 Clinical Study Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
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publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for American investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the Sponsor.
Any investigator who objects to the Sponsor providing this information to callers must provide the 
Sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Study Results Disclosure 
Takeda will post the results of clinical studies on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the Sponsor or Sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the Sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the Sponsor 
or Sponsor’s designee.
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14.1.2 INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the Sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.9 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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14.1.3 Study-Related Responsibilities 
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.
14.1.4 List of Abbreviations
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC
The area under the concentration-time curve, from time 0 to infinity
AUClast
The area under the concentration-time curve, from time 0 to the last quantifiable 
concentration, as calculated by the linear-log trapezoidal method.
BMI
Body mass index
bpm
Beats per minute
CFR
Code of Federal Regulations
CL
Total clearance after IV administration
Cm
Centimeter
Cmax
Maximum observed concentration 
CRF
Case report form
CRU
Clinical Research Unit
CV
Coefficient of variance
DNA
Deoxyribonucleic acid 
ECG
Electrocardiogram
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
h
Hour(s)
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus 
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
IV
Intravenous 
kg
Kilogram
LFT
Liver function test
μg
Microgram
μmol
Micromole
MedDRA®
Medical Dictionary for Regulatory Activities®
mg
Milligram
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min
Minute
mL
Milliliter
mmHg
Millimeter of mercury
msec
Millisecond
NOAEL
No-observed-adverse-effect-level
PK
Pharmacokinetic(s)
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RNA
Ribonucleic acid
SC
Subcutaneous
SAE
Serious adverse event
SAP
Statistical analysis plan
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
Vz
Volume of distribution during the terminal disposition phase after IV administration
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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, medical history, and concurrent conditions will be coded using the MedDRA. Drugs will be 
coded using the World Health Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
Celerion standard CRFs will be supplied. CRFs are produced, stored electronically, and are 
available to the designated study team members. Each CRF is reviewed and signed by the 
Investigator. The final signed CRFs are provided to the Sponsor in the format as decided upon 
between Celerion and the Sponsor (eg, CD, flash drive, SFTP). This will be documented in the 
DMP (if applicable).
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The Principal Investigator must review the CRFs for completeness and accuracy and must sign and 
date the appropriate CRFs as indicated. Furthermore, the Investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the CRFs should be made by the Investigator or designee with use of change and modification 
records of the CRFs. The Principal Investigator must review the data change for completeness and 
accuracy, and must sign and date. 
Case report forms will be reviewed for completeness and acceptability at the study site during 
periodic visits by study monitors. The Sponsor or its designee will be permitted to review the 
subject’s medical and hospital records pertinent to the study to ensure accuracy of the CRFs. The 
completed CRFs are the sole property of the Sponsor and should not be made available in any form 
to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the Sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of CRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the Sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
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drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and Sponsor.
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.
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16.0
REFERENCES
Takhyzro 2018. Full Prescribing Information. Lexington, MA: Dyax Corp.
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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
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10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the Sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the Sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
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20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent and throughout the duration of the study or 
70 days after the last dose of study drug for discontinued subjects. Regular pregnancy tests will 
be performed throughout the study for all female subjects of childbearing potential. If a subject 
is found to be pregnant during study, study drug will be discontinued, and the investigator will 
offer the subject the choice to receive unblinded treatment information. 
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study or 70 days after the last 
dose of study drug for discontinued subjects. If the partner of the subject is found to be 
pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Pregnancy and Contraception
Pregnancy 
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period.
Any report of pregnancy for any female study or the partner of a male study participant must be 
reported within 24 hours to the Takeda Global Patient Safety Evaluation (GPSE) Group using the 
Takeda Pregnancy Report Form. A copy of the Takeda Pregnancy Report Form (and any 
applicable follow-up reports) must also be sent to the CRO/Takeda Medical Monitor using the 
details specified in the emergency contact information section of the protocol. The pregnant 
female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and condition 
of the infant. It is the responsibility of the investigator to obtain this information within 30 calendar 
days after the initial notification and approximately 30 calendar days and 1 year post-partum.
Pregnancy complications such as spontaneous abortion/miscarriage, elective abortion or 
congenital abnormality are considered SAEs and must be reported using the Takeda Safety Report 
Form.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, it 
must be reported as an SAE using the Takeda Safety Report Form as well as the Takeda Pregnancy 
Report Form. The test date of the first positive serum/urine β-HCG test or ultrasound result will 
determine the pregnancy onset date.
Contraception 
Female Contraception 
Sexually active females of childbearing potential should be using an acceptable form of 
contraception. Females of childbearing potential must be advised to use acceptable contraceptives 
throughout the study period. Female subjects who discontinue the study early must use acceptable 
contraceptives for 70 days following after the last dose of investigational product. If hormonal 
contraceptives are used, they should be administered according to the package insert. Females of 
childbearing potential who are not currently sexually active must agree to use acceptable 
contraception, as defined below, if they become sexually active during the period of the study.
Female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and follicle 
stimulating hormone (FSH) result in the laboratory post-menopausal range at screening)

Surgically sterile (having undergone one of the following surgical procedures: 
hysterectomy, bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) 
and, at least, 6 weeks post-sterilization, or

Females of childbearing potential with a negative serum beta-human chorionic 
gonadotropin (β-hCG) pregnancy test at the screening visit and Day -1. Females of 
childbearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
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CONFIDENTIAL 
Page 66
TAK-743-1003: Protocol Amendment 1
Lanadelumab
16 Sep 2020
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the first dose of investigational product, plus condoms. Note: If 
subject becomes sexually active during the study, they should use one of the other 
acceptable methods noted above in addition to the hormonal contraceptive until it has been 
stabilized for 30 days.
Male Contraception 
Male subjects must be advised to use acceptable contraceptives throughout the study period. Male 
subjects who discontinue the study early must use acceptable contraceptives for 70 days after the 
last dose. Male subjects must be advised not to donate sperm during the course of the study (or 
within 70 days of the last dose of investigational product if discontinued early). Acceptable 
methods of contraception for male subjects include:
Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam).
For non-commercial use only


For non-commercial use only

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
NCT Number:  
NCT04503603 
 
Study Title: 
A Randomized, Double-blind, Placebo-Controlled, Repeat-dose, Single-
center Phase 1a Study to Determine the Safety, Tolerability, and 
Pharmacokinetics of Lanadelumab Administered Intravenously in 
Healthy Adult Volunteer Subjects 
 
 
Study Number: 
TAK-743-1003 
 
SAP Version and Date: 
Version Final:  
21 Sep 2020 
 


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Statistical Analysis Plan Final 
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CONFIDENTIAL 
2.0 
TABLE OF CONTENTS 
1.1 
Approval Signatures.......................................................................................................2 
2.0 
TABLE OF CONTENTS .....................................................................................................3 
3.0 
LIST OF ABBREVIATIONS ..............................................................................................5 
4.0 
OBJECTIVES ......................................................................................................................6 
4.1 
Study Primary Objectives ..............................................................................................6 
4.2 
Study Exploratory Objective ..........................................................................................6 
4.3 
Study Design ..................................................................................................................6 
5.0 
ANALYSIS ENDPOINTS...................................................................................................7 
5.1 
Primary Endpoints .........................................................................................................7 
5.1.1 Safety Endpoints: .....................................................................................................7 
5.1.2 Pharmacokinetic Parameters: ...................................................................................7 
5.1.3 Exploratory Endpoints .............................................................................................7 
6.0 
DETERMINATION OF SAMPLE SIZE ............................................................................8 
7.0 
METHODS OF ANALYSIS AND PRESENTATION – CELERION GENERATED 
TFLS ....................................................................................................................................9 
7.1 
General Principles ..........................................................................................................9 
7.1.1 Study Definitions .....................................................................................................9 
7.2 
Analysis Sets ..................................................................................................................9 
7.3 
Treatment Descriptions ................................................................................................10 
7.4 
Study Information ........................................................................................................10 
7.5 
Disposition of Subjects ................................................................................................10 
7.6 
Demographic and Other Baseline Characteristics .......................................................10 
7.7 
Medical History and Concurrent Medical Conditions .................................................10 
7.8 
Medication History and Concomitant Medications .....................................................11 
7.9 
Study Drug Exposure and Compliance ........................................................................11 
7.10 
Efficacy Analysis .........................................................................................................11 
7.11 
Pharmacokinetic
............................................................11 
7.11.1 Pharmacokinetic Analysis ......................................................................................11 
7.11.2 
 .................................................................................13 
7.12 
Other Outcomes ...........................................................................................................13 
7.13 
Safety Analysis ............................................................................................................13 
7.13.1 Adverse Events ......................................................................................................14 
7.13.2 Clinical Laboratory Evaluations ............................................................................15 
7.13.3 Vital Signs ..............................................................................................................15 
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CONFIDENTIAL 
7.13.4 12-Lead ECGs ........................................................................................................17 
7.13.5 Physical Exams ......................................................................................................17 
7.13.6 Overdose ................................................................................................................17 
7.14 
Interim Analysis ...........................................................................................................17 
7.15 
Changes in the Statistical Analysis Plan ......................................................................18 
8.0 
REFERENCES ..................................................................................................................19 
 
 
 
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CONFIDENTIAL 
3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
BLQ 
below the limit of quantitation 
BMI 
body mass index 
BP 
blood pressure  
 
 
CPAP 
Clinical Pharmacology Analysis Plan 
CRF 
case report form 
CV% 
coefficient of variation  
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
IV 
Intravenous  
LLOQ 
lower limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
PK 
pharmacokinetics 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SEM 
standard error of the mean 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event  
TFL 
tables, figures, and listing 
WHO 
World Health Organization  
 
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CONFIDENTIAL 
5.0 
ANALYSIS ENDPOINTS 
5.1 
Primary Endpoints  
5.1.1 Safety Endpoints:  
• TEAEs. 
• Clinical laboratory results (hematology, serum chemistry, coagulation and urinalysis). 
• Vital signs (including blood pressure [BP], pulse, body temperature), and 12-lead ECG. 
5.1.2 Pharmacokinetic Parameters:  
• PK concentrations of lanadelumab over the study period.  
5.1.3 Exploratory Endpoints 
 
 
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Statistical Analysis Plan Final 
21 September 2020
 
CONFIDENTIAL 
6.0 
DETERMINATION OF SAMPLE SIZE 
No formal calculations were performed to determine sample size for this study. The sample size 
is based on feasibility and is similar to that of comparable studies. 
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CONFIDENTIAL 
7.3 
Treatment Descriptions 
Treatments will be described as follows in the TFLs: 
 
Treatment A: Lanadelumab 300 mg, one dose administered via IV infusion over a period 
of 60 ±15 minutes on Day 1, followed by a second dose on Day 4 
Treatment P: Placebo (normal saline) administered via IV infusion over a period of 60 ±15 
minutes on Day 1, followed by a second dose on Day 4 
7.4 
Study Information 
A study information table will be generated including the following items: date of first subject’s 
signed informed consent form, date of first dose, date of last dose, date of last subject’s last 
visit/contact, date of last subject’s last procedure for collection of data for primary endpoint, the 
version of Medical Dictionary for Regulatory Activities (MedDRA®), the version of World 
Health Organization (WHO) Dictionary, and SAS version used for creating the datasets. 
7.5 
Disposition of Subjects 
Disposition of subjects (number of subjects dosed, completed the study, discontinued from the 
study, and reason(s) for discontinuation) will be summarized by treatment and overall. Study 
completion status, including reason for discontinuation, will also be listed by subject.  
7.6 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment and 
overall. Summary statistics (number of subjects [n], mean, SD, minimum, median, and 
maximum) will be generated for continuous variables (age [recorded in the CRF], weight, height 
and body mass index [BMI]) and the number and percentage of subjects within each category 
will be presented for categorical variables (sex, race, and ethnicity). Height, weight, and BMI 
recorded at screening will be used in the baseline summaries. Demographics data will also be 
listed as recorded on the CRF, including the date of informed consent. 
7.7 
Medical History and Concurrent Medical Conditions 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing the 
informed consent form (ICF). Concurrent medical conditions are those significant ongoing 
conditions or diseases that are present at signing the ICF. Each subject’s medical history and 
concurrent medical conditions will be listed. Any medical condition started or worsening after 
taking the study drug(s) will be classified as an adverse event. All medical history will coded 
using the Medical Dictionary for Regulatory Activities (MedDRA® ), Version 23.0. The medical 
history listing will include whether the event was medical or surgical, the body system or organ 
class involved, coded term, start date (if known) and end date or whether the condition was 
ongoing, and a description of the condition or event. There will be no statistical analysis of 
medical history. 
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7.8 
Medication History and Concomitant Medications 
Medication history to be obtained includes any medication relevant to eligibility criteria and 
safety evaluation stopped at or within 28 days prior to signing the ICF. Concomitant medication 
includes any medication other than study drug taken at any time between time of signing the ICF 
through the end of the study (including follow-up visit). All medication history and concomitant 
medications recorded during the study will be coded with the WHO Dictionary, Version 01-Mar-
2020 b3, and listed. The listing will include the medication name, coded term, dosage, route of 
administration, start date and time (if known), end date and time, or whether it continued after 
study completion, and indication for use. A summary table for concomitant medication will also 
be provided.  The number and percentage of subjects receiving each WHO coded concomitant 
medication will be summarized by treatment. 
7.9 
Study Drug Exposure and Compliance 
The date, time, and dosage of each study treatment dose will be listed by subject. Using drug 
administration data, estimates of exposure to lanadelumab will be calculated as total dose and 
number of doses received over the study and summarized with descriptive statistics. 
7.10 
Efficacy Analysis 
Not applicable. 
7.11 
Pharmacokinetic
7.11.1 Pharmacokinetic Analysis 
Blood samples for the assessment of plasma lanadelumab concentrations will be collected as 
outlined in the table below. 
 
 
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CONFIDENTIAL 
Table 7:1 
Collection of Blood Samples for Pharmacokinetic Analysis 
Analyte 
Matrix 
Scheduled Time (Hours) 
Lanadelumab 
Plasma 
Predose, and 1, 2, 4, 6, 12 (Study Day 1), 24 (Study Day 2), 48 (Study Day 3), 72, 73, 
76, 78, 84 (Study Day 4), 96 (Study Day 5), 120 (Study Day 6), 144 (Study Day 7), 
168 (Study Day 8), 192 (Study Day 9), 216 (Study Day 10), 240 (Study Day 11), 312 
(Study Day 14), 480 (Study Day 21), 648 (Study Day 28), 984 (Study Day 42), 1320 
(Study Day 56), 1992 (Study Day 84), and 2664 (Study Day 112) hours postdose 
Note: The second IV infusion of 300 mg lanadelumab will be administered immediately after the 72-hour blood 
draw. Therefore, the 72-hour postdose sample on Day 1 will be the same as predose sample on Day 4. 
 
The concentration data for plasma lanadelumab will be used as reported by the respective 
bioanalytical groups without rounding for all analyses. Plasma concentration of lanadelumab 
below the limit of quantitation (BLQ) will be presented as ‘BLQ’ in the concentration table 
listings and footnoted accordingly. For the calculation of summary statistics and the generation 
of concentration plots, BLQ values will be treated as zero unless they are obvious outliers (e.g. 
BLQ value between 2 measurable values), in which case they will be treated as missing. In log-
linear plots these values would not be presented. Missing concentration values will be flagged in 
the concentration tables and footnoted as missing or not reportable (i.e., for subjects withdrawn 
or dropped from the study, subjects missing blood draws).  
The mean, median, and geometric mean (Geom Mean) for concentration values will be presented 
to 1 more level of precision than the individual concentration values. The SD of the mean will be 
presented to 2 more levels of precision than the individual concentration values. Minimum and 
maximum values will be presented to the same precision as the individual concentration values. 
Arithmetic percent coefficient of variation (CV%) and geometric percent coefficient of variation 
(Geom CV%) will be presented to 1 decimal place. 
Lanadelumab concentrations versus time will be plotted on linear (with and without SD) scale 
and semi-log scale. For summary statistics and arithmetic mean plots by sampling time, the 
nominal sampling time will be used, for individual subject plots by time, the actual sampling 
time will be used. Spaghetti plots of individual plasma lanadelumab concentrations versus time 
profiles will be plotted on linear and semi-log scales.  
 
The PK analysis will be completed by Certara, therefore, calculations of PK parameters will be 
described in a separate SAP not generated by Celerion.   
 
 
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CONFIDENTIAL 
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators. 
7.13.1 Adverse Events 
All AEs captured in the database will be listed in by-subject data listings including verbatim 
term, coded term, severity (mild, moderate, severe), relationship to study drug (related or not 
related) and action relative to the study drug as recorded in the CRF. Study procedure taken due 
to AE will also be listed. All AEs occurring during this study will be coded using the MedDRA®, 
Version 23.0. However, only TEAEs occurring after start of administration of the first dose of 
study treatment and through the end of the study (Day 112± 7) will be summarized.  
TEAEs are defined as AEs with onset at the time of or following the start of treatment with study 
medication, or medical conditions present prior to the start of treatment but increasing in severity 
or relationship at the time of or following the start of treatment. A subset of TEAEs will be 
attributed to a treatment period (Days 1-3 or Day 4-6) based on the onset date and time of the AE 
as described in Table 7:3: 
Table 7:3 
AE Treatment Period Assignment Algorithm 
Date and Time of AE With Respect to Date and Time of Dosing  
Treatment 
Period 
Day 1 Lanadelumab or Placebo Start of Dosing Date and Time ≤ Date and Time of AE < Day 4 
Lanadelumab or Placebo Start of Dosing Date and Time 
Days 1 - 3 
Day 4 Lanadelumab or Placebo Start of Dosing Date and Time ≤ Date and Time of AE< Day 4 
Lanadelumab or Placebo Start of Dosing Date and Time + 72 hours 
Day 4-6 
An overview of TEAEs summary will be provided. For each treatment, TEAEs will be coded 
using MedDRA® and tabulated by System Organ Class (SOC) and Preferred Term (PT). 
Summary tables will include number of subjects reporting the AE and as percent of safety set by 
treatment. An overview of TEAEs and TEAEs summarized by SOC and PT will be provided for 
TEAEs occurring during the treatment period of Day 1-3 and Day 4-6 as well. The most 
commonly reported non-serious TEAEs (i.e., those events reported by >5% of all subjects in 
each treatment, excluding SAEs) will also be summarized. For the list of all AE summary tables, 
see TFL Shell document. 
 
Additional TEAE summary tables will be presented by severity and relationship to study drug by 
treatment, system organ class, and preferred term. If a subject has multiple AEs with different 
severity levels within the same term, the subject will be counted in the most severe category 
only. For each relationship to study drug, if a subject has both related and unrelated AEs with the 
same term, the subject will be counted as having related TEAEs. 
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CONFIDENTIAL 
Should any SAEs (including all-cause mortalities) or AEs of Special Interest (AESIs), as 
described in the protocol, occur, they will be summarized the same way as TEAE. All AEs will 
be displayed in the data listings. AESIs, AEs leading to study withdrawal, TEAEs resulting in 
death and SAEs will also be listed. TEAEs, AESIs and SAEs will be discussed in the text of the 
study report. 
7.13.2 Clinical Laboratory Evaluations 
Serum chemistry, hematology, coagulation and urinalysis tests will be performed at screening 
and on Days -1, 11, 14 (± 1), 21 (± 1), 28 (± 2), 42 (± 3), 56 (± 3), and 84 (± 7) and at end of 
study (Day 112 ± 7) or prior to early termination from the study. Additional serum chemistry, 
hematology and urinalysis tests will also be performed on Days 2 and 5. In addition, laboratory 
safety tests may be performed at various unscheduled time points, if deemed necessary by the PI. 
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for each laboratory test by treatment and assessment time point. 
Change from baseline will be summarized in a similar manner. Baseline is defined as the last 
assessment prior to the first dosing (Day -1).  
For each laboratory test, a shift table will be developed comparing the frequency of the results at 
baseline (above normal (H), normal (N), or below normal (L)) with those postdose time points. 
For urinalysis tests, the categories are normal (N) and abnormal (A). Out-of-range values and 
corresponding recheck results will be listed.  
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. If a value fails the reference range, it will 
automatically be compared to a computer clinically significant (CS) range. If the value falls 
within the computer CS range, it will be noted as “N” for not clinical significant. If the value 
fails the computer CS range, it will be flagged with a “Y” which prompts the PI to determine 
how the out-of-range value should be followed using 4 Investigator flags: "N", not clinically 
significant, "R", requesting a recheck, "^", checking at the next scheduled visit, or "Y", clinically 
significant. All clinically significant laboratory tests, as indicated by the PI, and the 
corresponding values will be listed by subject.  All clinical laboratory data will be presented in 
by-subject data listings. 
7.13.3 Vital Signs 
Single measurements of blood pressure (systolic and diastolic), heart rate, and body temperature 
(oral) will be collected as outlined in Table 7:4. 
Table 7:4 
Vital Signs Collection Time Points  
Measurement Type 
Period 
Day 
Time Point 
Blood Pressure 
(Systolic, Diastolic), 
Heart Rate 
Screen 
 
 
1 
-1 
 
1 
Predose, Hours 1, 2, 4, 6, 12  
2, 3 
 
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CONFIDENTIAL 
Measurement Type 
Period 
Day 
Time Point 
4 
Predose, Hours 1, 2, 4, 6, 12  
5, 6, 7, 8, 9, 10, 11 
 
14 (± 1), 21 (± 1), 28 (± 2), 42 (± 
3), 56 (± 3), 84 (± 7) 
 
112 (± 7) 
End of Study or Early 
Termination    
Body Temperature 
(Oral) 
Screen 
 
 
1 
-1 
 
1 
Predose  
14 (± 1), 21 (± 1), 28 (± 2), 42 (± 
3), 56 (± 3), 84 (± 7) 
 
112 (± 7) 
End of Study or Early 
Termination    
Respiratory rate will be collected at screening only and will not be summarized.  
 
Additional unscheduled vital signs measurements may be taken at other times, if deemed 
necessary by the PI.  
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for vital 
sign results (blood pressure, heart rate and body temperature) and change from baseline by 
treatment and assessment time point. Baseline is defined as the last assessment prior to first 
dosing (Day 1 Predose).  
Vital signs will also be displayed in a data listing by subject. Abnormal vital signs will be 
identified using the reference ranges described in Table 7:5 and will be listed by subject in a 
separate listing. A categorical summary table will also be provided showing the number and 
percentage of subjects with baseline and post-baseline vital signs in each (low, normal, and high) 
category by treatment and time point. The reference ranges to be used are as follows:  
Table 7:5 
Criteria for Vital Signs Abnormal Values   
Data Type 
Parameter 
Lower Criteria 
Upper Criteria 
Actual Value 
Heart rate (bpm) 
<40 
>115 
Systolic blood pressure (mm Hg) 
<90 
≥160 
Diastolic blood pressure (mm Hg) 
<50 
≥100 
Body temperature (oC) 
 
>38.5 
Change from Baseline 
Systolic blood pressure (mm Hg) 
 
>30 (increase) 
Diastolic blood pressure (mm Hg) 
 
>30 (increase) 
* Baseline is defined as the last assessment taken prior to first dosing (Day 1 Predose). 
 
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7.13.4 12-Lead ECGs 
Standard 12-lead ECGs will be recorded as outlined in Table 7:6. 
Table 7:6 
Electrocardiograms Collection Time Points  
Measurement Type 
Period 
Day 
Time Point 
12-Lead ECG 
Screen 
 
 
1 
-1 
 
1 
Predose, Hours 1, 4 
2, 3 
 
4 
Predose  
5, 6, 7, 11 
 
14 (± 1), 21 (± 1), 28 (± 2), 42 (± 
3), 56 (± 3), 84 (± 7) 
 
112 (± 7) 
End of Study or Early 
Termination    
Per protocol, recheck ECGs may be performed in triplicates.  
 
Additional unscheduled ECGs may be recorded at other times if deemed necessary by the PI.  
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for ECG 
parameters and change from baseline by treatment and assessment time point. Baseline is defined 
as the last assessment prior to first dosing (Day 1 Predose).  
All ECG data will be displayed in a data listing by subject. Abnormal ECGs, as indicated by the 
PI (i.e., CRF Overall Interpretation: Abnormal, Not clinically significant [ANCS] or Abnormal, 
Clinically Significant [ACS]) and the corresponding ECG parameters will be listed by subject in 
a separate listing. A categorical summary table will also be provided showing the number and 
percentage of subjects with baseline and post-baseline ECG in each PI interpretation category 
(Normal, ANCS, ACS) by treatment and time point.  
7.13.5 Physical Exams 
A full physical exam will be performed at screening, on Days -1, 11, 14 (± 1), 21 (± 1), 28 (± 2), 
42 (± 3), 56 (± 3), and 84 (± 7) and at end of study (Day 112 ± 7) or prior to early termination 
from the study. Symptom-driven physical examinations may be performed at out-patient visits 
times, if deemed necessary by the investigator. Physical exam findings will be presented in a 
data listing by subject. Reproductive system findings will also be listed by subject. 
7.13.6 Overdose  
All cases of overdose will be presented in a data listing by subject. Any AEs associated with 
overdose will be documented as AEs.  
7.14 
Interim Analysis 
An interim unblinded analysis will be performed when all subjects complete Day 14 or 
discontinue prior to Day 14 to evaluate preliminary safety and PK. These data will be 
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CONFIDENTIAL 
summarized in a preliminary report. No adaptive design or Data Monitoring Committee (DMC) 
are planned for this study. A separate unblinded team will be assigned to work on the 
programming and review of the interim safety and PK TFLs.  
The following safety outputs will be provided as part of the interim analysis:  
- 
Disposition listing and table  
- 
Demographics and baseline characteristics listing and table 
- 
Dosing information and study drug exposure listing and table 
- 
Concomitant medications listing and table 
- 
All adverse events listings and tables  
- 
All clinical laboratory listings and tables  
- 
All vital signs listings and tables 
- 
All 12-lead ECG listings and tables 
The following PK outputs will be provided as part of the interim analysis:  
- 
Lanadelumab concentration listings and tables 
- 
Mean lanadelumab concentration versus time figure (linear and semi-log scales) 
Please refer to the TFL shell document for the TFL titles and shells.  
7.15 
Changes in the Statistical Analysis Plan  
There were no changes from protocol planned analysis.  
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8.0 
REFERENCES 
Not applicable.  
 
For non-commercial use only